04625nas a2201141 4500008004100000022001400041245011000055210006900165260000900234300001200243490000700255520126600262653002401528653001301552653002301565653001101588653001501599653002001614100001901634700002301653700002201676700002101698700002001719700002301739700002101762700002601783700001901809700002001828700001901848700002201867700002301889700002401912700001701936700002101953700001701974700001601991700002402007700002502031700002502056700002302081700002302104700002702127700002402154700001602178700002102194700002602215700002502241700002102266700002102287700001902308700003202327700002102359700002202380700002002402700001902422700002602441700001802467700001802485700002302503700002102526700001902547700001902566700002202585700001802607700001902625700001802644700002302662700001802685700002002703700001902723700003302742700002602775700002702801700002502828700002302853700001802876700002302894700001702917700002402934700001802958700002202976700002502998700002003023700002303043700002003066700002603086700002003112700001903132700002203151700002203173700002003195700002303215700002103238700001803259700002403277710003503301856014703336 2024 eng d a1664-322400aDrug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.0 aDrugtarget identification in COVID19 disease mechanisms using co c2023 a12828590 v143 a
INTRODUCTION: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing.
METHODS: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.
RESULTS: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19.
DISCUSSION: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.
10aComputer Simulation10aCOVID-1910adrug repositioning10aHumans10aSARS-CoV-210aSystems biology1 aNiarakis, Anna1 aOstaszewski, Marek1 aMazein, Alexander1 aKuperstein, Inna1 aKutmon, Martina1 aGillespie, Marc, E1 aFunahashi, Akira1 aAcencio, Marcio, Luis1 aHemedan, Ahmed1 aAichem, Michael1 aKlein, Karsten1 aCzauderna, Tobias1 aBurtscher, Felicia1 aYamada, Takahiro, G1 aHiki, Yusuke1 aHiroi, Noriko, F1 aHu, Finterly1 aPham, Nhung1 aEhrhart, Friederike1 aWillighagen, Egon, L1 aValdeolivas, Alberto1 aDugourd, Aurélien1 aMessina, Francesco1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aSoliman, Sylvain1 aAghamiri, Sara, Sadat1 aPuniya, Bhanwar, Lal1 aNaldi, Aurélien1 aHelikar, Tomáš1 aSingh, Vidisha1 aFernández, Marco, Fariñas1 aBermudez, Viviam1 aTsirvouli, Eirini1 aMontagud, Arnau1 aNoël, Vincent1 aPonce-de-Leon, Miguel1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aLuna, Augustin1 aPiñero, Janet1 aFurlong, Laura, I1 aBalaur, Irina1 aRougny, Adrien1 aJarosz, Yohan1 aOverall, Rupert, W1 aPhair, Robert1 aPerfetto, Livia1 aMatthews, Lisa1 aRex, Devasahayam, Arokia Bal1 aOrlic-Milacic, Marija1 aGomez, Luis, Cristobal1 aDe Meulder, Bertrand1 aRavel, Jean, Marie1 aJassal, Bijay1 aSatagopam, Venkata1 aWu, Guanming1 aGolebiewski, Martin1 aGawron, Piotr1 aCalzone, Laurence1 aBeckmann, Jacques, S1 aEvelo, Chris, T1 aD'Eustachio, Peter1 aSchreiber, Falk1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aKuiper, Martin1 aValencia, Alfonso1 aWolkenhauer, Olaf1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community uhttps://www.clinbioinfosspa.es/content/drug-target-identification-covid-19-disease-mechanisms-using-computational-systems-biology-approaches-002373nas a2200337 4500008004100000022001400041245017900055210006900234260001600303490000700319520115700326100002601483700003301509700002201542700002901564700001901593700001701612700002101629700003401650700002801684700002301712700002601735700002301761700002001784700001701804700002001821700002201841700002001863700001801883856013401901 2023 eng d a1422-006700aDetection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia.0 aDetection of High Level of CoInfection and the Emergence of Nove c2023 Jan 260 v243 aRecombination is an evolutionary strategy to quickly acquire new viral properties inherited from the parental lineages. The systematic survey of the SARS-CoV-2 genome sequences of the Andalusian genomic surveillance strategy has allowed the detection of an unexpectedly high number of co-infections, which constitute the ideal scenario for the emergence of new recombinants. Whole genome sequence of SARS-CoV-2 has been carried out as part of the genomic surveillance programme. Sample sources included the main hospitals in the Andalusia region. In addition to the increase of co-infections and known recombinants, three novel SARS-CoV-2 delta-omicron and omicron-omicron recombinant variants with two break points have been detected. Our observations document an epidemiological scenario in which co-infection and recombination are detected more frequently. Finally, we describe a family case in which co-infection is followed by the detection of a recombinant made from the two co-infecting variants. This increased number of recombinants raises the risk of emergence of recombinant variants with increased transmissibility and pathogenicity.
1 aPerez-Florido, Javier1 aCasimiro-Soriguer, Carlos, S1 aOrtuno, Francisco1 aFernandez-Rueda, Jose, L1 aAguado, Andrea1 aLara, María1 aRiazzo, Cristina1 aRodriguez-Iglesias, Manuel, A1 aCamacho-Martinez, Pedro1 aMerino-Diaz, Laura1 aPupo-Ledo, Inmaculada1 ade Salazar, Adolfo1 aViñuela, Laura1 aFuentes, Ana1 aChueca, Natalia1 aGarcía, Federico1 aDopazo, Joaquin1 aLepe, Jose, A uhttps://www.clinbioinfosspa.es/content/detection-high-level-co-infection-and-emergence-novel-sars-cov-2-delta-omicron-and-omicron02629nas a2200205 4500008004100000022001400041245020600055210006900261260001600330520167600346100002002022700002102042700002302063700003102086700002102117700003202138700002002170700002002190856021302210 2023 eng d a1578-898900aEvidence of the association between increased use of direct oral anticoagulants and a reduction in the rate of atrial fibrillation-related stroke and major bleeding at the population level (2012-2019).0 aEvidence of the association between increased use of direct oral c2023 Nov 203 aBACKGROUND: The introduction of direct-acting oral anticoagulants (DOACs) has shown to decrease atrial fibrillation (AF)-related stroke and bleeding rates in clinical studies, but there is no certain evidence about their effects at the population level. Our aim was to assess changes in AF-related stroke and major bleeding rates between 2012 and 2019 in Andalusia (Spain), and the association between DOACs use and events rates at the population level.
METHODS: All patients with an AF diagnosis from 2012 to 2019 were identified using the Andalusian Health Population Base, that provides clinical information on all Andalusian people. Annual ischemic and hemorrhagic stroke, major bleeding rates, and used antithrombotic treatments were determined. Marginal hazard ratios (HR) were calculated for each treatment.
RESULTS: A total of 95,085 patients with an AF diagnosis were identified. Mean age was 76.1±10.2 years (49.7% women). An increase in the use of DOACs was observed throughout the study period in both males and females (p<0.001). The annual rate of ischemic stroke decreased by one third, while that of hemorrhagic stroke and major bleeding decreased 2-3-fold from 2012 to 2019. Marginal HR was lower than 0.50 for DOACs compared to VKA for all ischemic or hemorrhagic events.
CONCLUSIONS: In this contemporary population-based study using clinical and administrative databases in Andalusia, a significant reduction in the incidence of AF-related ischemic and hemorrhagic stroke and major bleeding was observed between 2012 and 2019. The increased use of DOACs seems to be associated with this reduction.
1 aLoucera, Carlos1 aCarmona, Rosario1 aBostelmann, Gerrit1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aGonzalez-Manzanares, Rafael1 aDopazo, Joaquin1 aAnguita, Manuel uhttps://www.clinbioinfosspa.es/content/evidence-association-between-increased-use-direct-oral-anticoagulants-and-reduction-rate-atrial-fibrillation-related-stroke-and-major-bleeding-population-level-2012-201902653nas a2200409 4500008004100000022001400041245014400055210006900199260001600268300000800284490000600292520117700298100002801475700003601503700002001539700001801559700003301577700002901610700003801639700003601677700002601713700003401739700003701773700002701810700002901837700001701866700001901883700002601902700002501928700002001953700001901973700002401992700002902016700003002045700003202075856013602107 2023 eng d a2399-364200aMetabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.0 aMetabolic reprogramming by Acly inhibition using SB204990 alters c2023 Mar 08 a2500 v63 aATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.
1 aSola-García, Alejandro1 aCáliz-Molina, María, Ángeles1 aEspadas, Isabel1 aPetr, Michael1 aPanadero-Morón, Concepción1 aGonzález-Morán, Daniel1 aMartín-Vázquez, María, Eugenia1 aNarbona-Pérez, Álvaro, Jesús1 aLópez-Noriega, Livia1 aMartínez-Corrales, Guillermo1 aLópez-Fernández-Sobrino, Raúl1 aCarmona-Marin, Lina, M1 aMartínez-Force, Enrique1 aYanes, Oscar1 aVinaixa, Maria1 aLópez-López, Daniel1 aReyes, José, Carlos1 aDopazo, Joaquin1 aMartín, Franz1 aGauthier, Benoit, R1 aScheibye-Knudsen, Morten1 aCapilla-González, Vivian1 aMartín-Montalvo, Alejandro uhttps://www.clinbioinfosspa.es/content/metabolic-reprogramming-acly-inhibition-using-sb-204990-alters-glucoregulation-and-modulates02401nas a2200301 4500008004100000022001400041245012200055210006900177260001600246300001100262520135200273100002301625700002701648700002601675700001801701700002701719700001801746700002101764700002301785700002401808700003201832700002401864700002201888700002001910700001601930700002301946856013001969 2023 eng d a1474-972600amicroRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.0 amicroRNAsmediated regulation of insulin signaling in white adipo c2023 Jul 04 ae139193 aCaloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.
1 aCorrales, Patricia1 aMartin-Taboada, Marina1 aVivas-García, Yurena1 aTorres, Lucia1 aRamirez-Jimenez, Laura1 aLopez, Yamila1 aHorrillo, Daniel1 aVila-Bedmar, Rocio1 aBarber-Cano, Eloisa1 aIzquierdo-Lahuerta, Adriana1 aPeña-Chilet, Maria1 aMartínez, Carmen1 aDopazo, Joaquin1 aRos, Manuel1 aMedina-Gomez, Gema uhttps://www.clinbioinfosspa.es/content/micrornas-mediated-regulation-insulin-signaling-white-adipose-tissue-during-aging-role03356nas a2200265 4500008004100000022001400041245012500055210006900180260001600249300000800265490000600273520241900279100001802698700001902716700003602735700002902771700002702800700002002827700001802847700002002865700002002885700003102905700001902936856013502955 2023 eng d a2058-771600aRapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.0 aRapid degeneration of iPSCderived motor neurons lacking Gdap1 en c2023 Jul 01 a2170 v93 aCharcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1 motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1 iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.
1 aLeón, Marian1 aPrieto, Javier1 aMolina-Navarro, María, Micaela1 aGarcia-Garcia, Francisco1 aBarneo-Muñoz, Manuela1 aPonsoda, Xavier1 aSáez, Rosana1 aPalau, Francesc1 aDopazo, Joaquin1 aBelmonte, Juan, Carlos Izp1 aTorres, Josema uhttps://www.clinbioinfosspa.es/content/rapid-degeneration-ipsc-derived-motor-neurons-lacking-gdap1-engages-mitochondrial-sustained02339nas a2200229 4500008004100000022001400041245013100055210006900186260001600255300000800271490000700279520147800286100002001764700002101784700002701805700002301832700003101855700002101886700002401907700002001931856015801951 2023 eng d a1743-422X00aReal-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments.0 aRealworld evidence with a retrospective cohort of 15968 COVID19 c2023 Oct 06 a2260 v203 aPURPOSE: Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19.
METHODS: Using data from a central registry of electronic health records (the Andalusian Population Health Database), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient outcomes, including survival and lymphocyte progression, was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020.
RESULTS: Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality.
CONCLUSIONS: In this study we have taken advantage of the availability of a regional clinical database to study the effect of drugs, which patients were taking for other indications, on their survival. The large size of the database allowed us to control covariates effectively.
1 aLoucera, Carlos1 aCarmona, Rosario1 aEsteban-Medina, Marina1 aBostelmann, Gerrit1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/real-world-evidence-retrospective-cohort-15968-covid-19-hospitalized-patients-suggests-21-new-effective-treatments02575nas a2200457 4500008004100000022001400041245008300055210006900138260001600207490000700223520116500230653001301395653001801408653001101426653001301437653001401450653001401464653001501478100002001493700002601513700003301539700002501572700002101597700002301618700003201641700003101673700002101704700002901725700002601754700002001780700002501800700002701825700002801852700002301880700002301903700002001926700001801946700002201964700002001986856011102006 2022 eng d a1999-491500aAssessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.0 aAssessing the Impact of SARSCoV2 Lineages and Mutations on Patie c2022 Aug 270 v143 aOBJECTIVES: More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain.
METHODS: A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis.
RESULTS: A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins.
CONCLUSIONS: This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.
10aCOVID-1910aGenome, Viral10aHumans10amutation10aPandemics10aPhylogeny10aSARS-CoV-21 aLoucera, Carlos1 aPerez-Florido, Javier1 aCasimiro-Soriguer, Carlos, S1 aOrtuno, Francisco, M1 aCarmona, Rosario1 aBostelmann, Gerrit1 aMartínez-González, Javier1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aRodríguez-Baño, Jesús1 aRomero-Gómez, Manuel1 aLorusso, Nicola1 aGarcia-León, Javier1 aNavarro-Marí, Jose, M1 aCamacho-Martinez, Pedro1 aMerino-Diaz, Laura1 ade Salazar, Adolfo1 aViñuela, Laura1 aLepe, Jose, A1 aGarcía, Federico1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/assessing-impact-sars-cov-2-lineages-and-mutations-patient-survival02679nas a2200337 4500008004100000022001400041245011500055210006900170260001600239520155800255100001601813700001901829700002001848700001901868700003101887700002201918700002501940700001701965700001701982700001901999700002102018700002702039700002002066700002202086700002202108700001902130700002002149700002102169710002002190856013102210 2022 eng d a1399-000400aCIBERER: Spanish National Network for Research on Rare Diseases: a highly productive collaborative initiative.0 aCIBERER Spanish National Network for Research on Rare Diseases a c2022 Jan 203 aCIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on Rare Diseases currently consists of 75 research groups belonging to universities, research centers and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical and cellular research of rare diseases. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this paper, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions towards the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to rare disease research. This article is protected by copyright. All rights reserved.
1 aLuque, Juan1 aMendes, Ingrid1 aGómez, Beatriz1 aMorte, Beatriz1 ade Heredia, Miguel, López1 aHerreras, Enrique1 aCorrochano, Virginia1 aBueren, Juan1 aGallano, Pia1 aArtuch, Rafael1 aFillat, Cristina1 aPérez-Jurado, Luis, A1 aMontoliu, Lluis1 aCarracedo, Ángel1 aMillán, José, M1 aWebb, Susan, M1 aPalau, Francesc1 aLapunzina, Pablo1 aCIBERER Network uhttps://www.clinbioinfosspa.es/content/ciberer-spanish-national-network-research-rare-diseases-highly-productive-collaborative03523nas a2200553 4500008004100000022001400041245007400055210006900129260001300198300001000211490000700221520170300228100002701931700002001958700003101978700002802009700003002037700002502067700001702092700002702109700003202136700002602168700002602194700003502220700003102255700001702286700003102303700003002334700003302364700003302397700003502430700003302465700002502498700003102523700002602554700002502580700002002605700002302625700002302648700002102671700002902692700003102721700002002752700002002772700002102792700002702813710002202840856010702862 2022 eng d a1579-212900aIncidence and Prevalence of Children's Diffuse Lung Disease in Spain.0 aIncidence and Prevalence of Childrens Diffuse Lung Disease in Sp c2022 Jan a22-290 v583 aBACKGROUND: Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain.
METHODS: Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019.
RESULTS: A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47).
CONCLUSIONS: We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.
1 aTorrent-Vernetta, Alba1 aGaboli, Mirella1 aCastillo-Corullón, Silvia1 aMondéjar-López, Pedro1 aSantiago, Verónica, Sanz1 aCosta-Colomer, Jordi1 aOsona, Borja1 aTorres-Borrego, Javier1 ade la Serna-Blázquez, Olga1 aAlonso, Sara, Bellón1 aAguilera, Pilar, Caro1 ade Atauri, Álvaro, Gimeno-Dí1 aSoria, Alfredo, Valenzuela1 aAyats, Roser1 ade Vicente, Carlos, Martin1 aGonzález, Valle, Velasco1 aGonzález, José, Domingo Mo1 aCalderín, Elisa, María Can1 aPastor-Vivero, María, Dolores1 aÁlvarez, María, Ángeles V1 aRovira-Amigo, Sandra1 aSerrano, Ignacio, Iglesias1 aIzquierdo, Ana, Díez1 aMessa, Inés, de Mir1 aGartner, Silvia1 aNavarro, Alexandra1 aBaz-Redón, Noelia1 aCarmona, Rosario1 aCamats-Tarruella, Núria1 aFernández-Cancio, Mónica1 aRapp, Christina1 aDopazo, Joaquin1 aGriese, Matthias1 aMoreno-Galdó, Antonio1 aChILD-Spain Group uhttps://www.clinbioinfosspa.es/content/incidence-and-prevalence-childrens-diffuse-lung-disease-spain-008213nas a2202125 4500008004100000022001400041245005800055210005600113260001600169520175300185100001701938700002901955700002801984700002002012700002702032700002002059700003002079700003402109700002902143700002702172700003102199700002002230700002502250700002002275700002802295700002302323700002102346700001902367700002902386700002302415700001802438700002202456700002402478700002902502700002902531700002902560700002102589700002502610700002302635700001802658700002002676700002002696700002602716700002402742700001802766700002202784700002402806700003102830700002802861700001802889700002102907700003202928700002502960700003102985700003003016700002403046700001903070700003303089700002903122700002903151700003403180700002803214700002503242700002503267700003303292700003203325700002903357700003303386700002703419700003003446700002903476700002803505700002503533700002903558700002003587700002803607700002103635700002603656700002603682700003303708700002703741700002303768700003103791700001903822700002703841700002403868700002603892700002203918700002003940700002203960700002103982700002804003700002004031700002504051700002004076700002904096700002604125700003004151700001804181700002604199700002104225700002704246700002804273700003304301700003104334700002804365700002704393700001604420700002504436700002404461700002004485700002704505700003704532700002104569700002504590700002004615700002504635700002104660700001704681700002204698700002004720700002304740700003004763700002404793700001804817700002204835700001904857700002204876700002804898700001904926700001904945700001704964700002004981700002605001700001905027700002005046700002205066700001905088700003105107700002205138700002205160700002105182700001805203700002105221700002605242700002605268700003005294700002105324700002305345700002405368700002005392700002305412700001605435700002005451700003205471700002005503700001805523700002005541700001805561700001705579700002005596700001805616700001805634700001805652700001905670700002205689700002305711700003005734700001805764700002605782700002205808700002805830700001905858700002105877700002205898710002505920710002505945710002405970856009305994 2022 eng d a1460-208300aNovel genes and sex differences in COVID-19 severity.0 aNovel genes and sex differences in COVID19 severity c2022 Jun 163 aHere we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
1 aCruz, Raquel1 ade Almeida, Silvia, Diz-1 aHeredia, Miguel, López1 aQuintela, Inés1 aCeballos, Francisco, C1 aPita, Guillermo1 aLorenzo-Salazar, José, M1 aGonzález-Montelongo, Rafaela1 aGago-Domínguez, Manuela1 aPorras, Marta, Sevilla1 aCastaño, Jair, Antonio Te1 aNevado, Julián1 aAguado, Jose, María1 aAguilar, Carlos1 aAguilera-Albesa, Sergio1 aAlmadana, Virginia1 aAlmoguera, Berta1 aAlvarez, Nuria1 aAndreu-Bernabeu, Álvaro1 aArana-Arri, Eunate1 aArango, Celso1 aArranz, María, J1 aArtiga, Maria-Jesus1 aBaptista-Rosas, Raúl, C1 aBarreda-Sánchez, María1 aBelhassen-Garcia, Moncef1 aBezerra, Joao, F1 aBezerra, Marcos, A C1 aBoix-Palop, Lucía1 aBrión, Maria1 aBrugada, Ramón1 aBustos, Matilde1 aCalderón, Enrique, J1 aCarbonell, Cristina1 aCastano, Luis1 aCastelao, Jose, E1 aConde-Vicente, Rosa1 aCordero-Lorenzana, Lourdes1 aCortes-Sanchez, Jose, L1 aCorton, Marta1 aDarnaude, Teresa1 aDe Martino-Rodríguez, Alba1 aCampo-Pérez, Victor1 aBustamante, Aranzazu, Diaz1 aDomínguez-Garrido, Elena1 aLuchessi, André, D1 aEirós, Rocío1 aSanabria, Gladys, Mercedes E1 aFariñas, María, Carmen1 aFernández-Robelo, Uxía1 aFernández-Rodríguez, Amanda1 aFernández-Villa, Tania1 aGil-Fournier, Belén1 aGómez-Arrue, Javier1 aÁlvarez, Beatriz, González1 aQuirós, Fernan, Gonzalez B1 aGonzález-Peñas, Javier1 aGutiérrez-Bautista, Juan, F1 aHerrero, María, José1 aHerrero-Gonzalez, Antonio1 aJimenez-Sousa, María, A1 aLattig, María, Claudia1 aBorja, Anabel, Liger1 aLopez-Rodriguez, Rosario1 aMancebo, Esther1 aMartín-López, Caridad1 aMartín, Vicente1 aMartinez-Nieto, Oscar1 aMartinez-Lopez, Iciar1 aMartinez-Resendez, Michel, F1 aMartinez-Perez, Ángel1 aMazzeu, Juliana, A1 aMacías, Eleuterio, Merayo1 aMinguez, Pablo1 aCuerda, Victor, Moreno1 aSilbiger, Vivian, N1 aOliveira, Silviene, F1 aOrtega-Paino, Eva1 aParellada, Mara1 aPaz-Artal, Estela1 aSantos, Ney, P C1 aPérez-Matute, Patricia1 aPerez, Patricia1 aPérez-Tomás, Elena1 aPerucho, Teresa1 aPinsach-Abuin, Mel, Lina1 aPompa-Mera, Ericka, N1 aPorras-Hurtado, Gloria, L1 aPujol, Aurora1 aLeón, Soraya, Ramiro1 aResino, Salvador1 aFernandes, Marianne, R1 aRodríguez-Ruiz, Emilio1 aRodriguez-Artalejo, Fernando1 aRodriguez-Garcia, José, A1 aRuiz-Cabello, Francisco1 aRuiz-Hornillos, Javier1 aRyan, Pablo1 aSoria, José, Manuel1 aSouto, Juan, Carlos1 aTamayo, Eduardo1 aTamayo-Velasco, Alvaro1 aTaracido-Fernandez, Juan, Carlos1 aTeper, Alejandro1 aTorres-Tobar, Lilian1 aUrioste, Miguel1 aValencia-Ramos, Juan1 aYáñez, Zuleima1 aZarate, Ruth1 aNakanishi, Tomoko1 aPigazzini, Sara1 aDegenhardt, Frauke1 aButler-Laporte, Guillaume1 aMaya-Miles, Douglas1 aBujanda, Luis1 aBouysran, Youssef1 aPalom, Adriana1 aEllinghaus, David1 aMartínez-Bueno, Manuel1 aRolker, Selina1 aAmitrano, Sara1 aRoade, Luisa1 aFava, Francesca1 aSpinner, Christoph, D1 aPrati, Daniele1 aBernardo, David1 aGarcía, Federico1 aDarcis, Gilles1 aFernández-Cadenas, Israel1 aHolter, Jan, Cato1 aBanales, Jesus, M1 aFrithiof, Robert1 aDuga, Stefano1 aAsselta, Rosanna1 aPereira, Alexandre, C1 aRomero-Gómez, Manuel1 aNafría-Jiménez, Beatriz1 aHov, Johannes, R1 aMigeotte, Isabelle1 aRenieri, Alessandra1 aPlanas, Anna, M1 aLudwig, Kerstin, U1 aButi, Maria1 aRahmouni, Souad1 aAlarcón-Riquelme, Marta, E1 aSchulte, Eva, C1 aFranke, Andre1 aKarlsen, Tom, H1 aValenti, Luca1 aZeberg, Hugo1 aRichards, Brent1 aGanna, Andrea1 aBoada, Mercè1 aRojas, Itziar1 aRuiz, Agustín1 aSánchez, Pascual1 aReal, Luis, Miguel1 aGuillén-Navarro, Encarna1 aAyuso, Carmen1 aGonzález-Neira, Anna1 aRiancho, José, A1 aRojas-Martinez, Augusto1 aFlores, Carlos1 aLapunzina, Pablo1 aCarracedo, Ángel1 aSCOURGE Cohort Group1 aHOSTAGE Cohort Group1 aGRA@CE Cohort Group uhttps://www.clinbioinfosspa.es/content/novel-genes-and-sex-differences-covid-19-severity03091nas a2200241 4500008004100000022001400041245013700055210006900192260001600261300001000277490000700287520215900294100002402453700003202477700003202509700002102541700002102562700002602583700004102609700002002650700004302670856013602713 2022 eng d a2045-232200aProtein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus.0 aProtein and functional isoform levels and genetic variants of th c2022 Jul 02 a112190 v123 aSystemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case-control study includes a cohort (women, 18-60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal-Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r = 0.67, p ≤ 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.
1 aOrtiz-Aljaro, Pilar1 aMontes-Cano, Marco, Antonio1 aGarcía-Lozano, José-Raúl1 aAquino, Virginia1 aCarmona, Rosario1 aPerez-Florido, Javier1 aGarcía-Hernández, Francisco, José1 aDopazo, Joaquin1 aGonzález-Escribano, María, Francisca uhttps://www.clinbioinfosspa.es/content/protein-and-functional-isoform-levels-and-genetic-variants-baff-and-april-pathway-components02443nas a2200241 4500008004100000022001400041245012800055210006900183260001600252490000700268520156100275100003101836700002001867700001901887700002701906700001901933700002001952700002901972700002402001700002402025700002002049856013202069 2022 eng d a2076-392100aAn SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in Mice.0 aSPMEnriched Marine Oil Supplement Shifted Microglia Polarization c2022 Dec 300 v123 aRetinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.
1 aOlivares-González, Lorena1 aVelasco, Sheyla1 aGallego, Idoia1 aEsteban-Medina, Marina1 aPuras, Gustavo1 aLoucera, Carlos1 aMartínez-Romero, Alicia1 aPeña-Chilet, Maria1 aPedraz, José, Luis1 aRodrigo, Regina uhttps://www.clinbioinfosspa.es/content/spm-enriched-marine-oil-supplement-shifted-microglia-polarization-toward-m2-ameliorating02338nas a2200373 4500008004100000022001400041245009100055210006900146260001600215300000800231490000700239520108200246653002401328653002601352653002301378653001101401100003001412700002901442700002801471700002801499700003701527700002401564700003101588700001801619700002701637700002501664700003101689700002401720700002001744700002601764700003201790700002501822856011701847 2021 eng d a1471-210500aA comprehensive database for integrated analysis of omics data in autoimmune diseases.0 acomprehensive database for integrated analysis of omics data in c2021 Jun 24 a3430 v223 aBACKGROUND: Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified resource is imperative to assist researchers in this field.
RESULTS: Here, we present Autoimmune Diseases Explorer ( https://adex.genyo.es ), a database that integrates 82 curated transcriptomics and methylation studies covering 5609 samples for some of the most common autoimmune diseases. The database provides, in an easy-to-use environment, advanced data analysis and statistical methods for exploring omics datasets, including meta-analysis, differential expression or pathway analysis.
CONCLUSIONS: This is the first omics database focused on autoimmune diseases. This resource incorporates homogeneously processed data to facilitate integrative analyses among studies.
10aAutoimmune Diseases10aComputational Biology10aDatabases, Factual10aHumans1 aMartorell-Marugán, Jordi1 aLópez-Domínguez, Raúl1 aGarcía-Moreno, Adrián1 aToro-Domínguez, Daniel1 aVillatoro-García, Juan, Antonio1 aBarturen, Guillermo1 aMartín-Gómez, Adoración1 aTroule, Kevin1 aGómez-López, Gonzalo1 aAl-Shahrour, Fátima1 aGonzález-Rumayor, Víctor1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aSaez-Rodriguez, Julio1 aAlarcón-Riquelme, Marta, E1 aCarmona-Sáez, Pedro uhttps://www.clinbioinfosspa.es/content/comprehensive-database-integrated-analysis-omics-data-autoimmune-diseases07193nas a2202077 4500008004100000022001400041245010000055210006900155260001200224300001100236490000700247520130900254653002101563653002601584653002201610653001301632653001401645653001601659653002301675653003101698653003201729653001101761653002301772653002201795653002101817653001601838653003601854653001801890653003201908653001501940653002401955653001301979653002601992653001902018100002302037700001902060700002202079700002102101700001802122700002702140700001902167700002602186700002602212700001802238700001902256700001702275700002202292700002102314700001902335700002902354700001802383700001602401700002902417700001802446700002302464700002202487700002002509700002002529700002702549700002102576700001702597700001802614700002402632700002102656700001602677700002102693700001902714700002302733700002302756700002002779700001702799700001902816700002402835700002102859700002402880700001702904700002302921700002402944700001902968700002002987700001903007700001903026700002903045700002303074700002003097700001703117700001803134700002403152700003303176700002003209700002003229700001603249700001503265700001803280700001903298700002603317700002703343700002003370700002403390700001803414700002403432700002203456700002203478700001903500700002003519700002103539700001803560700001503578700002203593700002303615700001703638700001903655700002403674700001703698700001803715700001703733700002303750700001803773700001803791700002303809700002103832700001703853700002203870700002003892700001803912700001803930700002303948700002103971700002503992700001804017700002004035700001704055700001904072700001704091700002104108700002504129700002704154700002404181700001604205700002104221700002504242700001704267700002004284700001804304700002504322700002404347700002304371700002104394700001904415700002204434700001804456700001604474700002204490700002004512700001804532700002504550700001904575700002204594700002404616700002304640700002004663700002304683700002204706700002304728700002304751700002604774700002004800700002204820700002004842700002304862700002104885700001804906700002404924710003504948856013204983 2021 eng d a1744-429200aCOVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.0 aCOVID19 Disease Map a computational knowledge repository of viru c2021 10 ae103870 v173 aWe need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.
10aAntiviral Agents10aComputational Biology10aComputer Graphics10aCOVID-1910aCytokines10aData Mining10aDatabases, Factual10aGene Expression Regulation10aHost Microbial Interactions10aHumans10aImmunity, Cellular10aImmunity, Humoral10aImmunity, Innate10aLymphocytes10aMetabolic Networks and Pathways10aMyeloid Cells10aProtein Interaction Mapping10aSARS-CoV-210aSignal Transduction10aSoftware10aTranscription Factors10aViral Proteins1 aOstaszewski, Marek1 aNiarakis, Anna1 aMazein, Alexander1 aKuperstein, Inna1 aPhair, Robert1 aOrta-Resendiz, Aurelio1 aSingh, Vidisha1 aAghamiri, Sara, Sadat1 aAcencio, Marcio, Luis1 aGlaab, Enrico1 aRuepp, Andreas1 aFobo, Gisela1 aMontrone, Corinna1 aBrauner, Barbara1 aFrishman, Goar1 aGómez, Luis, Cristóbal1 aSomers, Julia1 aHoch, Matti1 aGupta, Shailendra, Kumar1 aScheel, Julia1 aBorlinghaus, Hanna1 aCzauderna, Tobias1 aSchreiber, Falk1 aMontagud, Arnau1 ade Leon, Miguel, Ponce1 aFunahashi, Akira1 aHiki, Yusuke1 aHiroi, Noriko1 aYamada, Takahiro, G1 aDräger, Andreas1 aRenz, Alina1 aNaveez, Muhammad1 aBocskei, Zsolt1 aMessina, Francesco1 aBörnigen, Daniela1 aFergusson, Liam1 aConti, Marta1 aRameil, Marius1 aNakonecnij, Vanessa1 aVanhoefer, Jakob1 aSchmiester, Leonard1 aWang, Muying1 aAckerman, Emily, E1 aShoemaker, Jason, E1 aZucker, Jeremy1 aOxford, Kristie1 aTeuton, Jeremy1 aKocakaya, Ebru1 aSummak, Gökçe, Yağmur1 aHanspers, Kristina1 aKutmon, Martina1 aCoort, Susan1 aEijssen, Lars1 aEhrhart, Friederike1 aRex, Devasahayam, Arokia Bal1 aSlenter, Denise1 aMartens, Marvin1 aPham, Nhung1 aHaw, Robin1 aJassal, Bijay1 aMatthews, Lisa1 aOrlic-Milacic, Marija1 aRibeiro, Andrea, Senff1 aRothfels, Karen1 aShamovsky, Veronica1 aStephan, Ralf1 aSevilla, Cristoffer1 aVarusai, Thawfeek1 aRavel, Jean-Marie1 aFraser, Rupsha1 aOrtseifen, Vera1 aMarchesi, Silvia1 aGawron, Piotr1 aSmula, Ewa1 aHeirendt, Laurent1 aSatagopam, Venkata1 aWu, Guanming1 aRiutta, Anders1 aGolebiewski, Martin1 aOwen, Stuart1 aGoble, Carole1 aHu, Xiaoming1 aOverall, Rupert, W1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aVega, Carlos1 aGrouès, Valentin1 aVazquez, Miguel1 aPorras, Pablo1 aLicata, Luana1 aIannuccelli, Marta1 aSacco, Francesca1 aNesterova, Anastasia1 aYuryev, Anton1 ade Waard, Anita1 aTurei, Denes1 aLuna, Augustin1 aBabur, Ozgun1 aSoliman, Sylvain1 aValdeolivas, Alberto1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aHelikar, Tomáš1 aPuniya, Bhanwar, Lal1 aModos, Dezso1 aTreveil, Agatha1 aOlbei, Marton1 aDe Meulder, Bertrand1 aBallereau, Stephane1 aDugourd, Aurélien1 aNaldi, Aurélien1 aNoël, Vincent1 aCalzone, Laurence1 aSander, Chris1 aDemir, Emek1 aKorcsmaros, Tamas1 aFreeman, Tom, C1 aAugé, Franck1 aBeckmann, Jacques, S1 aHasenauer, Jan1 aWolkenhauer, Olaf1 aWilighagen, Egon, L1 aPico, Alexander, R1 aEvelo, Chris, T1 aGillespie, Marc, E1 aStein, Lincoln, D1 aHermjakob, Henning1 aD'Eustachio, Peter1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aValencia, Alfonso1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community uhttps://www.clinbioinfosspa.es/content/covid19-disease-map-computational-knowledge-repository-virus-host-interaction-mechanisms03508nas a2200709 4500008004100000022001400041245008200055210006900137260001500206300001600221490000700237520139500244653001201639653002301651653001801674653002301692653001001715653001901725653002201744653002501766653001801791653001301809653001101822653001301833653002301846653001301869653001001882100002401892700001801916700002601934700002501960700002101985700002102006700002602027700002002053700002902073700002302102700002902125700002602154700002002180700002702200700002702227700001802254700001902272700003002291700001802321700003402339700001902373700002902392700002702421700001902448700002502467700001702492700002802509700002802537700001902565700002202584700001902606700002002625710004302645856011002688 2021 eng d a1362-496200aCSVS, a crowdsourcing database of the Spanish population genetic variability.0 aCSVS a crowdsourcing database of the Spanish population genetic c2021 01 08 aD1130-D11370 v493 aThe knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.
10aAlleles10aChromosome Mapping10aCrowdsourcing10aDatabases, Genetic10aExome10aGene Frequency10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aInternet10aPrecision Medicine10aSoftware10aSpain1 aPeña-Chilet, Maria1 aRoldán, Gema1 aPerez-Florido, Javier1 aOrtuno, Francisco, M1 aCarmona, Rosario1 aAquino, Virginia1 aLópez-López, Daniel1 aLoucera, Carlos1 aFernandez-Rueda, Jose, L1 aGallego, Asunción1 aGarcia-Garcia, Francisco1 aGonzález-Neira, Anna1 aPita, Guillermo1 aNúñez-Torres, Rocío1 aSantoyo-López, Javier1 aAyuso, Carmen1 aMinguez, Pablo1 aAvila-Fernandez, Almudena1 aCorton, Marta1 aMoreno-Pelayo, Miguel, Ángel1 aMorin, Matías1 aGallego-Martinez, Alvaro1 aLopez-Escamez, Jose, A1 aBorrego, Salud1 aAntiňolo, Guillermo1 aAmigo, Jorge1 aSalgado-Garrido, Josefa1 aPasalodos-Sanchez, Sara1 aMorte, Beatriz1 aCarracedo, Ángel1 aAlonso, Ángel1 aDopazo, Joaquin1 aSpanish Exome Crowdsourcing Consortium uhttps://www.clinbioinfosspa.es/content/csvs-crowdsourcing-database-spanish-population-genetic-variability03233nas a2200613 4500008004100000022001400041245014900055210006900204260001200273300001200285490000800297520129600305653002101601653002601622653001301648653001001661653003101671653003201702653001101734653000901745653003301754653002101787653001901808653002201827653001301849653002601862653003401888653002701922100003001949700002701979700002802006700001702034700001902051700001902070700002102089700002902110700002202139700001902161700002402180700002202204700002102226700001902247700002102266700002202287700001702309700001902326700002002345700002602365700003002391700001902421700002602440700001902466856013402485 2021 eng d a1552-483300aDe novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.0 aDe novo small deletion affecting transcription start site of sho c2021 03 a877-8830 v1853 aDisruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.
10aChild, Preschool10aCytoskeletal Proteins10aDwarfism10aExons10aGene Expression Regulation10aGenetic Association Studies10aHumans10aMale10aNeurodevelopmental Disorders10aProtein Isoforms10aRNA, Messenger10aSequence Deletion10aSyndrome10aTranscription Factors10aTranscription Initiation Site10aTranscription, Genetic1 aMartinez-Delgado, Beatriz1 aLopez-Martin, Estrella1 aLara-Herguedas, Julián1 aMonzon, Sara1 aCuesta, Isabel1 aJuliá, Miguel1 aAquino, Virginia1 aRodriguez-Martin, Carlos1 aDamian, Alejandra1 aGonzalo, Irene1 aGomez-Mariano, Gema1 aBaladron, Beatriz1 aCazorla, Rosario1 aIglesias, Gema1 aRoman, Enriqueta1 aRos, Purificacion1 aTutor, Pablo1 aMellor, Susana1 aJimenez, Carlos1 aCabrejas, Maria, Jose1 aGonzalez-Vioque, Emiliano1 aAlonso, Javier1 aBermejo-Sánchez, Eva1 aPosada, Manuel uhttps://www.clinbioinfosspa.es/content/de-novo-small-deletion-affecting-transcription-start-site-short-isoform-auts2-gene-patient03083nas a2200493 4500008004100000022001400041245014600055210006900201260001200270300001400282490000700296520140800303100002001711700002401731700002901755700002801784700002501812700002501837700001801862700002401880700002901904700003101933700003501964700002101999700003102020700002102051700001902072700002802091700001802119700003102137700002802168700001702196700003902213700001702252700002502269700002202294700002002316700002302336700001802359700002202377700002902399700002502428856013602453 2021 eng d a1878-026100aA DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.0 aDNA damage repair geneassociated signature predicts responses of c2021 12 a3691-37050 v153 aPredictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.
1 aMoura, David, S1 aPeña-Chilet, Maria1 aVarela, Juan, Antonio Co1 aAlvarez-Alegret, Ramiro1 aAgra-Pujol, Carolina1 aIzquierdo, Francisco1 aRamos, Rafael1 aOrtega-Medina, Luis1 aMartin-Davila, Francisco1 aCastilla-Ramirez, Carolina1 aHernandez-Leon, Carmen, Nieves1 aRomagosa, Cleofe1 aSalgado, Maria, Angeles Va1 aLavernia, Javier1 aBagué, Silvia1 aMayodormo-Aranda, Empar1 aVicioso, Luis1 aBarceló, Jose, Emilio Her1 aRubio-Casadevall, Jordi1 ade Juan, Ana1 aFiaño-Valverde, Maria, Concepcion1 aHindi, Nadia1 aLopez-Alvarez, Maria1 aLacerenza, Serena1 aDopazo, Joaquin1 aGutierrez, Antonio1 aAlvarez, Rosa1 aValverde, Claudia1 aMartinez-Trufero, Javier1 aMartin-Broto, Javier uhttps://www.clinbioinfosspa.es/content/dna-damage-repair-gene-associated-signature-predicts-responses-patients-advanced-soft-tissue00926nas a2200229 4500008004100000022001400041245021100055210006900266260001600335490000700351100002900358700002600387700002000413700003400433700002300467700003100490700003300521700002500554700002000579700001900599856007800618 2021 eng d a1868-707500aGenome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system developmentAbstractBackgroundResultsConclusionsGraphic abstract0 aGenomewide analysis of DNA methylation in Hirschsprung enteric p cJan-12-20210 v131 aVillalba-Benito, Leticia1 aLópez-López, Daniel1 aTorroglosa, Ana1 aCasimiro-Soriguer, Carlos, S.1 aLuzón-Toro, Berta1 aFernández, Raquel, María1 aMoya-Jiménez, María, José1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://link.springer.com/article/10.1186/s13148-021-01040-6/fulltext.html02553nas a2200301 4500008004100000022001400041245009700055210006900152260001500221490000700236520154600243653001801789653001401807653001501821653002801836100002501864700002001889700003301909700001801942700002901960700002401989700002302013700002002036700002202056700002602078700002002104856012702124 2021 eng d a2047-217X00aHighly accurate whole-genome imputation of SARS-CoV-2 from partial or low-quality sequences.0 aHighly accurate wholegenome imputation of SARSCoV2 from partial c2021 12 020 v103 aBACKGROUND: The current SARS-CoV-2 pandemic has emphasized the utility of viral whole-genome sequencing in the surveillance and control of the pathogen. An unprecedented ongoing global initiative is producing hundreds of thousands of sequences worldwide. However, the complex circumstances in which viruses are sequenced, along with the demand of urgent results, causes a high rate of incomplete and, therefore, useless sequences. Viral sequences evolve in the context of a complex phylogeny and different positions along the genome are in linkage disequilibrium. Therefore, an imputation method would be able to predict missing positions from the available sequencing data.
RESULTS: We have developed the impuSARS application, which takes advantage of the enormous number of SARS-CoV-2 genomes available, using a reference panel containing 239,301 sequences, to produce missing data imputation in viral genomes. ImpuSARS was tested in a wide range of conditions (continuous fragments, amplicons or sparse individual positions missing), showing great fidelity when reconstructing the original sequences, recovering the lineage with a 100% precision for almost all the lineages, even in very poorly covered genomes (<20%).
CONCLUSIONS: Imputation can improve the pace of SARS-CoV-2 sequencing production by recovering many incomplete or low-quality sequences that would be otherwise discarded. ImpuSARS can be incorporated in any primary data processing pipeline for SARS-CoV-2 whole-genome sequencing.
10aGenome, Viral10aPhylogeny10aSARS-CoV-210aWhole Genome Sequencing1 aOrtuno, Francisco, M1 aLoucera, Carlos1 aCasimiro-Soriguer, Carlos, S1 aLepe, Jose, A1 aMartinez, Pedro, Camacho1 aDiaz, Laura, Merino1 ade Salazar, Adolfo1 aChueca, Natalia1 aGarcía, Federico1 aPerez-Florido, Javier1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/highly-accurate-whole-genome-imputation-sars-cov-2-partial-or-low-quality-sequences02201nas a2200325 4500008004100000022001400041245010300055210006900158260001300227300001400240490000700254520111400261653001201375653002201387653003501409653002801444653001301472653001101485653001801496653001801514653001901532100003501551700002501586700002901611700002301640700002901663700002401692700002601716856013301742 2021 eng d a1432-085100aImmunotherapy in nonsmall-cell lung cancer: current status and future prospects for liquid biopsy.0 aImmunotherapy in nonsmallcell lung cancer current status and fut c2021 May a1177-11880 v703 aImmunotherapy has been one of the great advances in the recent years for the treatment of advanced tumors, with nonsmall-cell lung cancer (NSCLC) being one of the cancers that has benefited most from this approach. Currently, the only validated companion diagnostic test for first-line immunotherapy in metastatic NSCLC patients is testing for programmed death ligand 1 (PD-L1) expression in tumor tissues. However, not all patients experience an effective response with the established selection criteria and immune checkpoint inhibitors (ICIs). Liquid biopsy offers a noninvasive opportunity to monitor disease in patients with cancer and identify those who would benefit the most from immunotherapy. This review focuses on the use of liquid biopsy in immunotherapy treatment of NSCLC patients. Circulating tumor cells (CTCs), cell-free DNA (cfDNA) and exosomes are promising tools for developing new biomarkers. We discuss the current application and future implementation of these parameters to improve therapeutic decision-making and identify the patients who will benefit most from immunotherapy.
10aAnimals10aBiomarkers, Tumor10aCarcinoma, Non-Small-Cell Lung10aCell-Free Nucleic Acids10aExosomes10aHumans10aImmunotherapy10aLiquid Biopsy10aLung Neoplasms1 aBrozos-Vázquez, Elena, María1 aDíaz-Peña, Roberto1 aGarcía-González, Jorge1 aLeón-Mateos, Luis1 aMondelo-Macía, Patricia1 aPeña-Chilet, Maria1 aLópez-López, Rafael uhttps://www.clinbioinfosspa.es/content/immunotherapy-nonsmall-cell-lung-cancer-current-status-and-future-prospects-liquid-biopsy02746nas a2200253 4500008004100000022001400041245011600055210006900171260001600240490000700256520183900263100002002102700002402122700002202146700002002168700002802188700002702216700002602243700002902269700002002298700001802318700002602336856013002362 2021 eng d a2075-442600aImplementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System.0 aImplementing Personalized Medicine in COVID19 in Andalusia An Op c2021 May 260 v113 aThe COVID-19 pandemic represents an unprecedented opportunity to exploit the advantages of personalized medicine for the prevention, diagnosis, treatment, surveillance and management of a new challenge in public health. COVID-19 infection is highly variable, ranging from asymptomatic infections to severe, life-threatening manifestations. Personalized medicine can play a key role in elucidating individual susceptibility to the infection as well as inter-individual variability in clinical course, prognosis and response to treatment. Integrating personalized medicine into clinical practice can also transform health care by enabling the design of preventive and therapeutic strategies tailored to individual profiles, improving the detection of outbreaks or defining transmission patterns at an increasingly local level. SARS-CoV2 genome sequencing, together with the assessment of specific patient genetic variants, will support clinical decision-makers and ultimately better ways to fight this disease. Additionally, it would facilitate a better stratification and selection of patients for clinical trials, thus increasing the likelihood of obtaining positive results. Lastly, defining a national strategy to implement in clinical practice all available tools of personalized medicine in COVID-19 could be challenging but linked to a positive transformation of the health care system. In this review, we provide an update of the achievements, promises, and challenges of personalized medicine in the fight against COVID-19 from susceptibility to natural history and response to therapy, as well as from surveillance to control measures and vaccination. We also discuss strategies to facilitate the adoption of this new paradigm for medical and public health measures during and after the pandemic in health care systems.
1 aDopazo, Joaquin1 aMaya-Miles, Douglas1 aGarcía, Federico1 aLorusso, Nicola1 aCalleja, Miguel, Ángel1 aPareja, María, Jesús1 aLópez-Miranda, José1 aRodríguez-Baño, Jesús1 aPadillo, Javier1 aTúnez, Isaac1 aRomero-Gómez, Manuel uhttps://www.clinbioinfosspa.es/content/implementing-personalized-medicine-covid-19-andalusia-opportunity-transform-healthcare01938nas a2200277 4500008004100000022001400041245011400055210006900169260001600238490000700254520095600261100002701217700002401244700002601268700003001294700001901324700001901343700003401362700003601396700002001432700002001452700001801472700001701490700002001507856013301527 2021 eng d a2072-669400aMutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development.0 aMutational Characterization of Cutaneous Melanoma Supports Diver c2021 Oct 180 v133 aAccording to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being . The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included , , , and . We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.
1 aMillán-Esteban, David1 aPeña-Chilet, Maria1 aGarcía-Casado, Zaida1 aManrique-Silva, Esperanza1 aRequena, Celia1 aBañuls, José1 aLopez-Guerrero, Jose, Antonio1 aRodríguez-Hernández, Aranzazu1 aTraves, Víctor1 aDopazo, Joaquin1 aVirós, Amaya1 aKumar, Rajiv1 aNagore, Eduardo uhttps://www.clinbioinfosspa.es/content/mutational-characterization-cutaneous-melanoma-supports-divergent-pathways-model-melanoma03248nas a2201189 4500008004100000022001400041245003300055210002900088260001600117100002300133700002200156700001900178700001500197700002500212700001700237700001900254700001700273700002900290700001800319700001600337700002200353700001300375700001700388700002000405700001800425700002500443700002500468700002800493700001800521700001900539700001900558700002300577700002600600700002400626700002500650700002600675700001700701700001400718700002400732700001600756700002100772700002100793700001500814700001900829700002100848700002100869700002400890700001700914700002600931700001900957700001700976700002100993700002501014700002301039700001601062700002301078700001901101700002101120700001901141700002401160700002701184700002001211700002101231700002101252700002201273700002001295700002101315700002001336700001901356700001801375700001901393700002501412700002201437700002401459700001901483700002101502700001901523700001901542700001701561700002601578700002401604700001601628700001801644700002201662700001701684700001801701700001401719700002501733700001701758700002301775700001701798700001801815700002401833700002801857700001801885700001801903700001901921700001701940700002201957700002501979856005402004 2021 eng d a1061-403600aThe NCI Genomic Data Commons0 aNCI Genomic Data Commons cOct-02-20221 aHeath, Allison, P.1 aFerretti, Vincent1 aAgrawal, Stuti1 aAn, Maksim1 aAngelakos, James, C.1 aArya, Renuka1 aBajari, Rosita1 aBaqar, Bilal1 aBarnowski, Justin, H. B.1 aBurt, Jeffrey1 aCatton, Ann1 aChan, Brandon, F.1 aChu, Fay1 aCullion, Kim1 aDavidsen, Tanja1 aDo, Phuong-My1 aDompierre, Christian1 aFerguson, Martin, L.1 aFitzsimons, Michael, S.1 aFord, Michael1 aFukuma, Miyuki1 aGaheen, Sharon1 aGanji, Gajanan, L.1 aGarcia, Tzintzuni, I.1 aGeorge, Sameera, S.1 aGerhard, Daniela, S.1 aGerthoffert, Francois1 aGomez, Fauzi1 aHan, Kang1 aHernandez, Kyle, M.1 aIssac, Biju1 aJackson, Richard1 aJensen, Mark, A.1 aJoshi, Sid1 aKadam, Ajinkya1 aKhurana, Aishmit1 aKim, Kyle, M. J.1 aKraft, Victoria, E.1 aLi, Shenglai1 aLichtenberg, Tara, M.1 aLodato, Janice1 aLolla, Laxmi1 aMartinov, Plamen1 aMazzone, Jeffrey, A.1 aMiller, Daniel, P.1 aMiller, Ian1 aMiller, Joshua, S.1 aMiyauchi, Koji1 aMurphy, Mark, W.1 aNullet, Thomas1 aOgwara, Rowland, O.1 aOrtuño, Francisco, M.1 aPedrosa, Jesús1 aPham, Phuong, L.1 aPopov, Maxim, Y.1 aPorter, James, J.1 aPowell, Raymond1 aRademacher, Karl1 aReid, Colin, P.1 aRich, Samantha1 aRogel, Bessie1 aSahni, Himanso1 aSavage, Jeremiah, H.1 aSchmitt, Kyle, A.1 aSimmons, Trevar, J.1 aSislow, Joseph1 aSpring, Jonathan1 aStein, Lincoln1 aSullivan, Sean1 aTang, Yajing1 aThiagarajan, Mathangi1 aTroyer, Heather, D.1 aWang, Chang1 aWang, Zhining1 aWest, Bedford, L.1 aWilmer, Alex1 aWilson, Shane1 aWu, Kaman1 aWysocki, William, P.1 aXiang, Linda1 aYamada, Joseph, T.1 aYang, Liming1 aYu, Christine1 aYung, Christina, K.1 aZenklusen, Jean, Claude1 aZhang, Junjun1 aZhang, Zhenyu1 aZhao, Yuanheng1 aZubair, Ariz1 aStaudt, Louis, M.1 aGrossman, Robert, L. uhttp://www.nature.com/articles/s41588-021-00791-502217nas a2200349 4500008004100000022001400041245009500055210006900150260001500219300000900234490000700243520109300250100002301343700001801366700001901384700002201403700002301425700001601448700002701464700001901491700001501510700001601525700001801541700001901559700001301578700001501591700001801606700001701624700002601641710007101667856012901738 2021 eng d a2041-172300aOrchestrating and sharing large multimodal data for transparent and reproducible research.0 aOrchestrating and sharing large multimodal data for transparent c2021 10 04 a57970 v123 aReproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA ( orcestra.ca ), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.
1 aMammoliti, Anthony1 aSmirnov, Petr1 aNakano, Minoru1 aSafikhani, Zhaleh1 aEeles, Christopher1 aSeo, Heewon1 aNair, Sisira, Kadambat1 aMer, Arvind, S1 aSmith, Ian1 aHo, Chantal1 aBeri, Gangesh1 aKusko, Rebecca1 aLin, Eva1 aYu, Yihong1 aMartin, Scott1 aHafner, Marc1 aHaibe-Kains, Benjamin1 aMassive Analysis Quality Control (MAQC) Society Board of Directors uhttps://www.clinbioinfosspa.es/content/orchestrating-and-sharing-large-multimodal-data-transparent-and-reproducible-research00782nas a2200229 4500008004100000245009000041210006900131260001600200300000800216490000700224100003400231700002600265700003000291700002600321700002700347700002000374700003600394700002800430700002000458700002900478856004500507 2021 eng d00aPhylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain)0 aPhylogenetic Analysis of the 2020 West Nile Virus WNV Outbreak i cJan-05-2021 a8360 v131 aCasimiro-Soriguer, Carlos, S.1 aPerez-Florido, Javier1 aFernandez-Rueda, Jose, L.1 aPedrosa-Corral, Irene1 aGuillot-Sulay, Vicente1 aLorusso, Nicola1 aMartinez-Gonzalez, Luis, Javier1 aNavarro-Marí, Jose, M.1 aDopazo, Joaquin1 aSanbonmatsu-Gámez, Sara uhttps://www.mdpi.com/1999-4915/13/5/836 02569nas a2200253 4500008004100000022001400041245008300055210006900138260000900207300001100216490000700227520173400234100003601968700002502004700002902029700001802058700002102076700001902097700002602116700002202142700002002164710002002184856011102204 2021 eng d a1662-509900aPresenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome.0 aPresenilin1 Mutations Are a Cause of Primary Lateral SclerosisLi c2021 a7210470 v143 aBackground and Purpose: Primary lateral sclerosis (PLS) is a progressive upper motor neuron (UMN) disorder. It is debated whether PLS is part of the amyotrophic lateral sclerosis (ALS) spectrum, or a syndrome encompassing different neurodegenerative diseases. Recently, new diagnostic criteria for PLS have been proposed. We describe four patients of two pedigrees, meeting definite PLS criteria and harboring two different mutations in presenilin 1 ().
Methods: Patients underwent neurological and neuropsychological examination, MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid-related biomarkers, and next-generation sequencing (NGS) testing.
Results: Four patients, aged 25-45 years old, presented with a progressive UMN syndrome meeting clinical criteria of definite PLS. Cognitive symptoms and signs were mild or absent during the first year of the disease but appeared or progressed later in the disease course. Brain MRI showed microbleeds in two siblings, but iron-related hypointensities in the motor cortex were absent. Brain FDG-PET showed variable areas of hypometabolism, including the motor cortex and frontotemporal lobes. Amyloid deposition was confirmed with either cerebrospinal fluid (CSF) or imaging biomarkers. Two heterozygous likely pathogenic mutations in (p.Pro88Leu and p.Leu166Pro) were found in the NGS testing.
Conclusion: Clinically defined PLS is a syndrome encompassing different neurodegenerative diseases. The NGS testing should be part of the diagnostic workup in patients with PLS, at least in those with red flags, such as early-onset, cognitive impairment, and/or family history of neurodegenerative diseases.
1 aVázquez-Costa, Juan, Francisco1 aPayá-Montes, María1 aMartínez-Molina, Marina1 aJaijo, Teresa1 aSzymanski, Jazek1 aMazón, Miguel1 aSopena-Novales, Pablo1 aPérez-Tur, Jordi1 aSevilla, Teresa1 aENoD Consortium uhttps://www.clinbioinfosspa.es/content/presenilin-1-mutations-are-cause-primary-lateral-sclerosis-syndrome02761nas a2200385 4500008004100000022001400041245015900055210006900214260001500283300001000298490000700308520150900315653001601824653001301840653001101853653001101864653002601875653000901901653002601910653001001936653002201946653001401968100002001982700002402002700002702026700003102053700002102084700002602105700002902131700001802160700002002178700002002198700002802218856012902246 2021 eng d a2045-232200aReal world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients.0 aReal world evidence of calcifediol or vitamin D prescription and c2021 12 03 a233800 v113 aCOVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.
10aCalcifediol10aCOVID-1910aFemale10aHumans10aKaplan-Meier Estimate10aMale10aRetrospective Studies10aSpain10aSurvival Analysis10aVitamin D1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aLópez-Miranda, José1 aRodríguez-Baño, Jesús1 aTúnez, Isaac1 aBouillon, Roger1 aDopazo, Joaquin1 aGomez, Jose, Manuel Que uhttps://www.clinbioinfosspa.es/content/real-world-evidence-calcifediol-or-vitamin-d-prescription-and-mortality-rate-covid-1905409nas a2201477 4500008004100000022001400041245007800055210006900133260001200202300001400214490000700228520122900235653002601464653001401490653001101504653001501515653003501530653002001565653003801585100001901623700001901642700001801661700002301679700002401702700002301726700002101749700002801770700001801798700002501816700002401841700002701865700001801892700002301910700002001933700001501953700002201968700002001990700002702010700002102037700002202058700001802080700001902098700002702117700002002144700001902164700002002183700002102203700001702224700002102241700002302262700002002285700002202305700002002327700001802347700002302365700001802388700002102406700002602427700001902453700001702472700001802489700002402507700001902531700001602550700001702566700001602583700002102599700002102620700002102641700002102662700002202683700002202705700002102727700001602748700001702764700001502781700002102796700001702817700002402834700002202858700002002880700002402900700001802924700001602942700002302958700002102981700002403002700001703026700002603043700002403069700002503093700002403118700002203142700002103164700001703185700001903202700001803221700001803239700001303257700001703270700001603287700001903303700002703322700002003349700001703369700002203386700001903408700001903427700002603446700001903472700002903491700002103520700001603541700002203557700001603579700002003595700002403615700001903639700002403658700002203682700002003704700001803724710003303742710004903775856010703824 2021 eng d a1546-170X00aReporting guidelines for human microbiome research: the STORMS checklist.0 aReporting guidelines for human microbiome research the STORMS ch c2021 11 a1885-18920 v273 aThe particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.
10aComputational Biology10aDysbiosis10aHumans10aMicrobiota10aObservational Studies as Topic10aResearch Design10aTranslational Science, Biomedical1 aMirzayi, Chloe1 aRenson, Audrey1 aZohra, Fatima1 aElsafoury, Shaimaa1 aGeistlinger, Ludwig1 aKasselman, Lora, J1 aEckenrode, Kelly1 avan de Wijgert, Janneke1 aLoughman, Amy1 aMarques, Francine, Z1 aMacIntyre, David, A1 aArumugam, Manimozhiyan1 aAzhar, Rimsha1 aBeghini, Francesco1 aBergstrom, Kirk1 aBhatt, Ami1 aBisanz, Jordan, E1 aBraun, Jonathan1 aBravo, Hector, Corrada1 aBuck, Gregory, A1 aBushman, Frederic1 aCasero, David1 aClarke, Gerard1 aCollado, Maria, Carmen1 aCotter, Paul, D1 aCryan, John, F1 aDemmer, Ryan, T1 aDevkota, Suzanne1 aElinav, Eran1 aEscobar, Juan, S1 aFettweis, Jennifer1 aFinn, Robert, D1 aFodor, Anthony, A1 aForslund, Sofia1 aFranke, Andre1 aFurlanello, Cesare1 aGilbert, Jack1 aGrice, Elizabeth1 aHaibe-Kains, Benjamin1 aHandley, Scott1 aHerd, Pamela1 aHolmes, Susan1 aJacobs, Jonathan, P1 aKarstens, Lisa1 aKnight, Rob1 aKnights, Dan1 aKoren, Omry1 aKwon, Douglas, S1 aLangille, Morgan1 aLindsay, Brianna1 aMcGovern, Dermot1 aMcHardy, Alice, C1 aMcWeeney, Shannon1 aMueller, Noel, T1 aNezi, Luigi1 aOlm, Matthew1 aPalm, Noah1 aPasolli, Edoardo1 aRaes, Jeroen1 aRedinbo, Matthew, R1 aRühlemann, Malte1 aSartor, Balfour1 aSchloss, Patrick, D1 aSchriml, Lynn1 aSegal, Eran1 aShardell, Michelle1 aSharpton, Thomas1 aSmirnova, Ekaterina1 aSokol, Harry1 aSonnenburg, Justin, L1 aSrinivasan, Sujatha1 aThingholm, Louise, B1 aTurnbaugh, Peter, J1 aUpadhyay, Vaibhav1 aWalls, Ramona, L1 aWilmes, Paul1 aYamada, Takuji1 aZeller, Georg1 aZhang, Mingyu1 aZhao, Ni1 aZhao, Liping1 aBao, Wenjun1 aCulhane, Aedin1 aDevanarayan, Viswanath1 aDopazo, Joaquin1 aFan, Xiaohui1 aFischer, Matthias1 aJones, Wendell1 aKusko, Rebecca1 aMason, Christopher, E1 aMercer, Tim, R1 aSansone, Susanna-Assunta1 aScherer, Andreas1 aShi, Leming1 aThakkar, Shraddha1 aTong, Weida1 aWolfinger, Russ1 aHunter, Christopher1 aSegata, Nicola1 aHuttenhower, Curtis1 aDowd, Jennifer, B1 aJones, Heidi, E1 aWaldron, Levi1 aGenomic Standards Consortium1 aMassive Analysis and Quality Control Society uhttps://www.clinbioinfosspa.es/content/reporting-guidelines-human-microbiome-research-storms-checklist01585nas a2200505 4500008004100000245010600041210007100147260001600218300000800234490000700242100002700249700001900276700002000295700002800315700002900343700002700372700002800399700002500427700002000452700001700472700001900489700001900508700002000527700002100547700002900568700002600597700002700623700002200650700002700672700001800699700002200717700001500739700001800754700002100772700001900793700002100812700001800833700001800851700002400869700002200893700002100915710003200936710002400968856008700992 2021 eng d00aSchuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review0 aSchuurs–Hoeijmakers Syndrome PACS1 Neurodevelopmental Disorder S cJan-05-2021 a7380 v121 aTenorio-Castaño, Jair1 aMorte, Beatriz1 aNevado, Julián1 aMartínez-Glez, Víctor1 aSantos-Simarro, Fernando1 aGarcía-Miñaur, Sixto1 aPalomares-Bralo, María1 aPacio-Míguez, Marta1 aGómez, Beatriz1 aArias, Pedro1 aAlcochea, Alba1 aCarrión, Juan1 aArias, Patricia1 aAlmoguera, Berta1 aLópez-Grondona, Fermina1 aLorda-Sanchez, Isabel1 aGalán-Gómez, Enrique1 aValenzuela, Irene1 aPerez, María, Méndez1 aCuscó, Ivón1 aBarros, Francisco1 aPié, Juan1 aRamos, Sergio1 aRamos, Feliciano1 aKuechler, Alma1 aTizzano, Eduardo1 aAyuso, Carmen1 aKaiser, Frank1 aPérez-Jurado, Luis1 aCarracedo, Ángel1 aLapunzina, Pablo1 aThe ENoD-CIBERER Consortium1 aThe SIDE Consortium uhttps://www.mdpi.com/2073-4425/12/5/738https://www.mdpi.com/2073-4425/12/5/738/pdf03601nas a2200505 4500008004100000022001400041245013900055210006900194260001500263300000700278490000700285520188200292653001702174653002602191653001402217653003202231653000902263653001102272653001502283653001702298653003202315653002902347653001402376100003502390700003102425700003302456700002002489700001802509700002802527700003202555700002902587700003002616700002602646700001902672700003602691700002202727700002902749700002802778700003102806700002602837700002602863700003302889700004002922856013302962 2021 eng d a1528-365800aTaxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.0 aTaxonomic variations in the gut microbiome of gout patients with c2021 05 24 a500 v273 aOBJECTIVE: To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism.
METHODS: Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways.
RESULTS: We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination.
CONCLUSION: Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.
10aBiodiversity10aComputational Biology10aDysbiosis10aGastrointestinal Microbiome10aGout10aHumans10aMetagenome10ametagenomics10aProtein Interaction Mapping10aProtein Interaction Maps10aUric Acid1 aMéndez-Salazar, Eder, Orlando1 aVázquez-Mellado, Janitzia1 aCasimiro-Soriguer, Carlos, S1 aDopazo, Joaquin1 aCubuk, Cankut1 aZamudio-Cuevas, Yessica1 aFrancisco-Balderas, Adriana1 aMartínez-Flores, Karina1 aFernández-Torres, Javier1 aLozada-Pérez, Carlos1 aPineda, Carlos1 aSánchez-González, Austreberto1 aSilveira, Luis, H1 aBurguete-García, Ana, I1 aOrbe-Orihuela, Citlalli1 aLagunas-Martínez, Alfredo1 aVazquez-Gomez, Alonso1 aLópez-Reyes, Alberto1 aPalacios-González, Berenice1 aMartínez-Nava, Gabriela, Angélica uhttps://www.clinbioinfosspa.es/content/taxonomic-variations-gut-microbiome-gout-patients-and-without-tophi-might-have-functional00678nas a2200217 4500008004100000245007400041210006900115260001600184490000700200100001800207700002000225700002100245700001700266700001600283700001900299700002200318700002200340700001900362700002500381856005400406 2021 eng d00aUniform genomic data analysis in the NCI Genomic Data CommonsAbstract0 aUniform genomic data analysis in the NCI Genomic Data CommonsAbs cJan-12-20210 v121 aZhang, Zhenyu1 aHernandez, Kyle1 aSavage, Jeremiah1 aLi, Shenglai1 aMiller, Dan1 aAgrawal, Stuti1 aOrtuno, Francisco1 aStaudt, Louis, M.1 aHeath, Allison1 aGrossman, Robert, L. uhttp://www.nature.com/articles/s41467-021-21254-902120nas a2200409 4500008004100000022001400041245012500055210006900180260001200249300001300261490000700274520080500281653001501086653002101101653002601122653002301148653003001171653001301201653004201214653001101256653002401267653001301291653001201304653002401316653001301340653001801353653002701371653001301398100003101411700002601442700002501468700002401493700002001517700002201537700002001559856013101579 2021 eng d a1553-735800aA versatile workflow to integrate RNA-seq genomic and transcriptomic data into mechanistic models of signaling pathways.0 aversatile workflow to integrate RNAseq genomic and transcriptomi c2021 02 ae10087480 v173 aMIGNON is a workflow for the analysis of RNA-Seq experiments, which not only efficiently manages the estimation of gene expression levels from raw sequencing reads, but also calls genomic variants present in the transcripts analyzed. Moreover, this is the first workflow that provides a framework for the integration of transcriptomic and genomic data based on a mechanistic model of signaling pathway activities that allows a detailed biological interpretation of the results, including a comprehensive functional profiling of cell activity. MIGNON covers the whole process, from reads to signaling circuit activity estimations, using state-of-the-art tools, it is easy to use and it is deployable in different computational environments, allowing an optimized use of the resources available.
10aAlgorithms10aCell Line, Tumor10aComputational Biology10aDatabases, Factual10aGene Expression Profiling10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aModels, Theoretical10amutation10aRNA-seq10aSignal Transduction10aSoftware10aTranscriptome10awhole exome sequencing10aWorkflow1 aGarrido-Rodriguez, Martín1 aLópez-López, Daniel1 aOrtuno, Francisco, M1 aPeña-Chilet, Maria1 aMuñoz, Eduardo1 aCalzado, Marco, A1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/versatile-workflow-integrate-rna-seq-genomic-and-transcriptomic-data-mechanistic-models02937nas a2200613 4500008004100000022001400041245012600055210006900181260001500250300001500265490000700280520120500287653001801492653001101510653001301521653001101534653002101545653000901566653001401575653002001589653001301609653001501622653001801637100001301655700002401668700001201692700001701704700001601721700001701737700001601754700001601770700001201786700001401798700001601812700001501828700002101843700002101864700002201885700001501907700002301922700002101945700002101966700001601987700001602003700002102019700002502040700001902065700001702084700001402101700001802115700002602133710003102159856013302190 2020 eng d a2405-472000aCommunity Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics.0 aCommunity Assessment of the Predictability of Cancer Protein and c2020 08 26 a186-195.e90 v113 aCancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper's transparent peer review process is included in the Supplemental Information.
10aCrowdsourcing10aFemale10aGenomics10aHumans10aMachine Learning10aMale10aNeoplasms10aPhosphoproteins10aProteins10aProteomics10aTranscriptome1 aYang, Mi1 aPetralia, Francesca1 aLi, Zhi1 aLi, Hongyang1 aMa, Weiping1 aSong, Xiaoyu1 aKim, Sunkyu1 aLee, Heewon1 aYu, Han1 aLee, Bora1 aBae, Seohui1 aHeo, Eunji1 aKaczmarczyk, Jan1 aStępniak, Piotr1 aWarchoł, Michał1 aYu, Thomas1 aCalinawan, Anna, P1 aBoutros, Paul, C1 aPayne, Samuel, H1 aReva, Boris1 aBoja, Emily1 aRodriguez, Henry1 aStolovitzky, Gustavo1 aGuan, Yuanfang1 aKang, Jaewoo1 aWang, Pei1 aFenyö, David1 aSaez-Rodriguez, Julio1 aNCI-CPTAC-DREAM Consortium uhttps://www.clinbioinfosspa.es/content/community-assessment-predictability-cancer-protein-and-phosphoprotein-levels-genomics-and01798nas a2200577 4500008004100000022001400041245011100055210006900166260001500235300000800250490000600258653002000264653002600284653002700310653001300337653002300350653003200373653003100405653001100436653003000447653002300477653001400500653002100514653001500535100002300550700002200573700002300595700002100618700001900639700002300658700002300681700002500704700002000729700001900749700002000768700002100788700001600809700002200825700002200847700002300869700002000892700002700912700002300939700002200962700002100984700002001005700002101025700001801046700002401064856013201088 2020 eng d a2052-446300aCOVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms.0 aCOVID19 Disease Map building a computational repository of SARSC c2020 05 05 a1360 v710aBetacoronavirus10aComputational Biology10aCoronavirus Infections10aCOVID-1910aDatabases, Factual10aHost Microbial Interactions10aHost-Pathogen Interactions10aHumans10aInternational Cooperation10aModels, Biological10aPandemics10aPneumonia, Viral10aSARS-CoV-21 aOstaszewski, Marek1 aMazein, Alexander1 aGillespie, Marc, E1 aKuperstein, Inna1 aNiarakis, Anna1 aHermjakob, Henning1 aPico, Alexander, R1 aWillighagen, Egon, L1 aEvelo, Chris, T1 aHasenauer, Jan1 aSchreiber, Falk1 aDräger, Andreas1 aDemir, Emek1 aWolkenhauer, Olaf1 aFurlong, Laura, I1 aBarillot, Emmanuel1 aDopazo, Joaquin1 aOrta-Resendiz, Aurelio1 aMessina, Francesco1 aValencia, Alfonso1 aFunahashi, Akira1 aKitano, Hiroaki1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard uhttps://www.clinbioinfosspa.es/content/covid-19-disease-map-building-computational-repository-sars-cov-2-virus-host-interaction03125nas a2200673 4500008004100000022001400041245010800055210006900163260000900232490000600241520108900247653002601336653003101362653004201393653001101435100001901446700002101465700002001486700001901506700003301525700002701558700003501585700002001620700002201640700001201662700001801674700002201692700001301714700002101727700002001748700002101768700001801789700001801807700002601825700001801851700001601869700002401885700001801909700002101927700001701948700002701965700001801992700002302010700001902033700002702052700001402079700002302093700001702116700001902133700001502152700002202167700002102189700002202210700001702232700003202249700001802281700002402299856012802323 2020 eng d a2046-140200aThe ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research.0 aELIXIR Human Copy Number Variations Community building bioinform c20200 v93 aCopy number variations (CNVs) are major causative contributors both in the genesis of genetic diseases and human neoplasias. While "High-Throughput" sequencing technologies are increasingly becoming the primary choice for genomic screening analysis, their ability to efficiently detect CNVs is still heterogeneous and remains to be developed. The aim of this white paper is to provide a guiding framework for the future contributions of ELIXIR's recently established with implications beyond human disease diagnostics and population genomics. This white paper is the direct result of a strategy meeting that took place in September 2018 in Hinxton (UK) and involved representatives of 11 ELIXIR Nodes. The meeting led to the definition of priority objectives and tasks, to address a wide range of CNV-related challenges ranging from detection and interpretation to sharing and training. Here, we provide suggestions on how to align these tasks within the ELIXIR Platforms strategy, and on how to frame the activities of this new ELIXIR Community in the international context.
10aComputational Biology10aDNA Copy Number Variations10aHigh-Throughput Nucleotide Sequencing10aHumans1 aSalgado, David1 aArmean, Irina, M1 aBaudis, Michael1 aBeltran, Sergi1 aCapella-Gutíerrez, Salvador1 aCarvalho-Silva, Denise1 aDel Angel, Victoria, Dominguez1 aDopazo, Joaquin1 aFurlong, Laura, I1 aGao, Bo1 aGarcia, Leyla1 aGerloff, Dietlind1 aGut, Ivo1 aGyenesei, Attila1 aHabermann, Nina1 aHancock, John, M1 aHanauer, Marc1 aHovig, Eivind1 aJohansson, Lennart, F1 aKeane, Thomas1 aKorbel, Jan1 aLauer, Katharina, B1 aLaurie, Steve1 aLeskošek, Brane1 aLloyd, David1 aMarqués-Bonet, Tomás1 aMei, Hailiang1 aMonostory, Katalin1 aPiñero, Janet1 aPoterlowicz, Krzysztof1 aRath, Ana1 aSamarakoon, Pubudu1 aSanz, Ferran1 aSaunders, Gary1 aSie, Daoud1 aSwertz, Morris, A1 aTsukanov, Kirill1 aValencia, Alfonso1 aVidak, Marko1 aGonzález, Cristina, Yenyxe1 aYlstra, Bauke1 aBéroud, Christophe uhttps://www.clinbioinfosspa.es/content/elixir-human-copy-number-variations-community-building-bioinformatics-infrastructure02422nas a2200481 4500008004100000022001400041245004700055210004600102260001600148300001100164490000700175520106100182100001901243700002701262700001901289700002001308700002201328700002101350700002001371700001901391700002401410700001501434700002501449700002301474700002401497700002001521700002701541700002401568700002001592700002101612700002201633700002201655700002901677700001801706700001301724700001701737700001601754700002001770700002501790700001901815700002601834856008001860 2020 eng d a2589-004200aImmune Cell Associations with Cancer Risk.0 aImmune Cell Associations with Cancer Risk c2020 Jul 24 a1012960 v233 aProper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations with immune features. Polygenic risk scores also reveal associations with immune and/or stromal cell contents, and breast cancer scores show consistent results in normal and tumor tissue. SH2B3 links peripheral alterations of several immune cell types to the risk of this malignancy. Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers. A retrospective case-cohort study indicates a positive association between blood counts of basophils, leukocytes, and monocytes and age at breast cancer diagnosis. These findings broaden our knowledge of the role of the immune system in cancer and highlight promising prevention strategies for individuals at high risk.
1 aPalomero, Luis1 aGalván-Femenía, Ivan1 ade Cid, Rafael1 aEspín, Roderic1 aBarnes, Daniel, R1 aBlommaert, Eline1 aGil-Gil, Miguel1 aFalo, Catalina1 aStradella, Agostina1 aOuchi, Dan1 aRoso-Llorach, Albert1 aViolan, Concepció1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aExtremera, Ana, Isabel1 aGarcía-Valero, Mar1 aHerranz, Carmen1 aMateo, Francesca1 aMereu, Elisabetta1 aBeesley, Jonathan1 aChenevix-Trench, Georgia1 aRoux, Cecilia1 aMak, Tak1 aBrunet, Joan1 aHakem, Razq1 aGorrini, Chiara1 aAntoniou, Antonis, C1 aLázaro, Conxi1 aPujana, Miquel, Angel uhttps://www.clinbioinfosspa.es/content/immune-cell-associations-cancer-risk01460nas a2200217 4500008004100000022001400041245006500055210006200120260001900182300001200201490000700213520073900220653002200959653001100981100003700992700002901029700003801058700003101096700002001127856009501147 2020 spa d a1578-128300a[Impact assessment on data protection in research projects].0 aImpact assessment on data protection in research projects c2020 Sep - Oct a521-5230 v343 aRecent changes in European regulations for personal data protection still allow the use of health data for research purposes, but they have set the Impact Assessment on Data Protection as an instrument for reflection and risk analysis in the process of data processing. The publication of a guide for facilitates this impact assessment, although it is not directly applicable to research projects. Experience in a specific project is detailed, showing how the context of the treatment becomes relevant with respect to the data characteristics. Carrying out an impact assessment is an opportunity to ensure compliance with the principles of data protection in an increasingly complex environment with greater ethical challenges.
10aComputer Security10aHumans1 aGarcía-León, Francisco, Javier1 aVillegas-Portero, Román1 aGoicoechea-Salazar, Juan, Antonio1 aMuñoyerro-Muñiz, Dolores1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/impact-assessment-data-protection-research-projects03275nas a2200493 4500008004100000022001400041245012000055210006900175260001200244490000600256520175600262653001002018653000902028653004102037653001102078653001102089653000902100653001602109653001402125653001202139653001402151653001602165100002502181700001702206700002302223700002902246700002002275700002202295700002402317700002502341700002402366700002302390700002502413700002802438700002202466700001902488700002402507700002002531700002702551700002502578700002002603700002602623856013202649 2020 eng d a2051-142600aNivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.0 aNivolumab and sunitinib combination in advanced soft tissue sarc c2020 110 v83 aBACKGROUND: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).
METHODS: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).
RESULTS: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).
CONCLUSIONS: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.
10aAdult10aAged10aAntineoplastic Agents, Immunological10aFemale10aHumans10aMale10aMiddle Aged10aNivolumab10aSarcoma10aSunitinib10aYoung Adult1 aMartin-Broto, Javier1 aHindi, Nadia1 aGrignani, Giovanni1 aMartinez-Trufero, Javier1 aRedondo, Andres1 aValverde, Claudia1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aD'Ambrosio, Lorenzo1 aGutierrez, Antonio1 aPerez-Vega, Herminia1 aEncinas-Tobajas, Victor1 ade Alava, Enrique1 aCollini, Paola1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aCarrasco-Garcia, Irene1 aLopez-Alvarez, Maria1 aMoura, David, S1 aLopez-Martin, Jose, A uhttps://www.clinbioinfosspa.es/content/nivolumab-and-sunitinib-combination-advanced-soft-tissue-sarcomas-multicenter-single-arm05180nas a2201117 4500008004100000022001400041245011300055210006900168260001200237300001200249490000700261520174900268653001402017653003102031653001502062653002502077653001902102653005102121653001102172653002902183653003802212653001102250653000902261653002302270653003602293653002702329100002202356700001702378700002402395700002802419700003302447700002702480700001502507700002402522700002902546700002602575700002802601700001702629700002002646700002102666700001902687700002702706700001902733700002002752700002402772700003002796700001902826700002602845700002902871700001802900700002102918700002202939700003202961700002002993700002603013700002903039700002103068700002203089700002103111700001903132700002703151700002403178700002903202700003203231700002003263700001803283700003103301700002803332700001603360700002503376700003103401700003303432700002903465700002203494700002103516700002403537700001903561700002503580700001703605700001703622700001803639700002303657700002003680700001603700700002203716700002503738700001803763700002303781700002003804700002003824700002103844700003303865700001703898700002103915856012603936 2020 eng d a1468-624400aOptimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.0 aOptimised molecular genetic diagnostics of Fanconi anaemia by wh c2020 04 a258-2680 v573 aPURPOSE: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.
METHODS: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.
RESULTS: We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.
10aCell Line10aDNA Copy Number Variations10aDNA Repair10aDNA-Binding Proteins10aFanconi Anemia10aFanconi Anemia Complementation Group A Protein10aFemale10aGene Knockout Techniques10aGenetic Predisposition to Disease10aHumans10aMale10aMutation, Missense10aPolymorphism, Single Nucleotide10awhole exome sequencing1 aBogliolo, Massimo1 aPujol, Roser1 aAza-Carmona, Miriam1 aMuñoz-Subirana, Núria1 aRodriguez-Santiago, Benjamin1 aCasado, José, Antonio1 aRio, Paula1 aBauser, Christopher1 aReina-Castillón, Judith1 aLopez-Sanchez, Marcos1 aGonzalez-Quereda, Lidia1 aGallano, Pia1 aCatalá, Albert1 aRuiz-Llobet, Ana1 aBadell, Isabel1 aDiaz-Heredia, Cristina1 aHladun, Raquel1 aSenent, Leonort1 aArgiles, Bienvenida1 aBurgues, Juan, Miguel Ber1 aBañez, Fatima1 aArrizabalaga, Beatriz1 aAlmaraz, Ricardo, López1 aLopez, Monica1 aFiguera, Ángela1 aMolinés, Antonio1 ade Soto, Inmaculada, Pérez1 aHernando, Inés1 aMuñoz, Juan, Antonio1 aMarin, Maria, Del Rosari1 aBalmaña, Judith1 aStjepanovic, Neda1 aCarrasco, Estela1 aCuesta, Isabel1 aCosuelo, José, Miguel1 aRegueiro, Alexandra1 aJimenez, José, Moraleda1 aGalera-Miñarro, Ana, Maria1 aRosiñol, Laura1 aCarrió, Anna1 aBeléndez-Bieler, Cristina1 aSoto, Antonio, Escudero1 aCela, Elena1 ade la Mata, Gregorio1 aFernández-Delgado, Rafael1 aGarcia-Pardos, Maria, Carmen1 aSáez-Villaverde, Raquel1 aBarragaño, Marta1 aPortugal, Raquel1 aLendinez, Francisco1 aHernadez, Ines1 aVagace, José, Manue1 aTapia, Maria1 aNieto, José1 aGarcia, Marta1 aGonzalez, Macarena1 aVicho, Cristina1 aGalvez, Eva1 aValiente, Alberto1 aAntelo, Maria, Luisa1 aAncliff, Phil1 aGarcía, Francisco1 aDopazo, Joaquin1 aSevilla, Julian1 aPaprotka, Tobias1 aPérez-Jurado, Luis, Alberto1 aBueren, Juan1 aSurralles, Jordi uhttps://www.clinbioinfosspa.es/content/optimised-molecular-genetic-diagnostics-fanconi-anaemia-whole-exome-sequencing-and04661nas a2200625 4500008004100000022001400041245010700055210006900162260001200231300001200243490000700255520277400262653000903036653001103045653002203056653001103078653001403089653000903103653001603112653002403128653001403152653002403166653003003190653001603220653004903236653002803285653001703313653001803330100002503348700001903373700001903392700001903411700001703430700001603447700002003463700002103483700002203504700003403526700002003560700002403580700002303604700001903627700002003646700002003666700002503686700002303711700002203734700002003756700002903776700003203805700002103837700002003858700002403878856013303902 2020 eng d a1474-548800aPazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of typical solitary fibrous tumours a mu c2020 03 a456-4660 v213 aBACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.
METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.
FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).
INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.
FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
10aAged10aFemale10aFollow-Up Studies10aHumans10aIndazoles10aMale10aMiddle Aged10aNeoplasm Metastasis10aPrognosis10aProspective Studies10aProtein Kinase Inhibitors10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Rate1 aMartin-Broto, Javier1 aCruz, Josefina1 aPenel, Nicolas1 aLe Cesne, Axel1 aHindi, Nadia1 aLuna, Pablo1 aMoura, David, S1 aBernabeu, Daniel1 ade Alava, Enrique1 aLopez-Guerrero, Jose, Antonio1 aDopazo, Joaquin1 aPeña-Chilet, Maria1 aGutierrez, Antonio1 aCollini, Paola1 aKaranian, Marie1 aRedondo, Andres1 aLopez-Pousa, Antonio1 aGrignani, Giovanni1 aDiaz-Martin, Juan1 aMarcilla, David1 aFernandez-Serra, Antonio1 aGonzalez-Aguilera, Cristina1 aCasali, Paolo, G1 aBlay, Jean-Yves1 aStacchiotti, Silvia uhttps://www.clinbioinfosspa.es/content/pazopanib-treatment-typical-solitary-fibrous-tumours-multicentre-single-arm-phase-2-trial02758nas a2200373 4500008004100000022001400041245009300055210006900148260001500217300001400232490000700246520158800253653002801841653001101869653003501880653002401915653001801939653001301957653001701970653001801987653002202005100001702027700002102044700002102065700002002086700002902106700002002135700002202155700002002177700001902197700001702216700002302233856012802256 2020 eng d a1549-491800aPlatform to study intracellular polystyrene nanoplastic pollution and clinical outcomes.0 aPlatform to study intracellular polystyrene nanoplastic pollutio c2020 10 01 a1321-13250 v383 aIncreased pollution by plastics has become a serious global environmental problem, but the concerns for human health have been raised after reported presence of microplastics (MPs) and nanoplastics (NPs) in food and beverages. Unfortunately, few studies have investigate the potentially harmful effects of MPs/NPs on early human development and human health. Therefore, we used a new platform to study possible effects of polystyrene NPs (PSNPs) on the transcription profile of preimplantation human embryos and human induced pluripotent stem cells (hiPSCs). Two pluripotency genes, LEFTY1 and LEFTY2, which encode secreted ligands of the transforming growth factor-beta, were downregulated, while CA4 and OCLM, which are related to eye development, were upregulated in both samples. The gene set enrichment analysis showed that the development of atrioventricular heart valves and the dysfunction of cellular components, including extracellular matrix, were significantly affected after exposure of hiPSCs to PSNPs. Finally, using the HiPathia method, which uncovers disease mechanisms and predicts clinical outcomes, we determined the APOC3 circuit, which is responsible for increased risk for ischemic cardiovascular disease. These results clearly demonstrate that better understanding of NPs bioactivities and its implications for human health is of extreme importance. Thus, the presented platform opens further aspects to study interactions between different environmental and intracellular pollutions with the aim to decipher the mechanism and origin of human diseases.
10aEnvironmental Pollution10aHumans10aInduced Pluripotent Stem Cells10aIntracellular Space10aNanoparticles10aPlastics10aPolystyrenes10aTranscriptome10aTreatment Outcome1 aBojic, Sanja1 aFalco, Matias, M1 aStojkovic, Petra1 aLjujic, Biljana1 aJankovic, Marina, Gazdic1 aArmstrong, Lyle1 aMarkovic, Nebojsa1 aDopazo, Joaquin1 aLako, Majlinda1 aBauer, Roman1 aStojkovic, Miodrag uhttps://www.clinbioinfosspa.es/content/platform-study-intracellular-polystyrene-nanoplastic-pollution-and-clinical-outcomes02128nas a2200325 4500008004100000022001400041245008900055210006900144260001200213300001400225490000700239520106200246653001801308653003101326653004201357653001101399653003101410653001301441653003901454100002601493700002001519700002101539700002101560700002001581700002001601700002001621700001901641700002001660856012201680 2020 eng d a1098-100400aSMN1 copy-number and sequence variant analysis from next-generation sequencing data.0 aSMN1 copynumber and sequence variant analysis from nextgeneratio c2020 12 a2073-20770 v413 aSpinal muscular atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next-generation sequencing (NGS) very difficult. Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes Project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available at https://www.github.com/babelomics/SMAca.
10aBase Sequence10aDNA Copy Number Variations10aHigh-Throughput Nucleotide Sequencing10aHumans10aReproducibility of Results10aSoftware10aSurvival of Motor Neuron 1 Protein1 aLópez-López, Daniel1 aLoucera, Carlos1 aCarmona, Rosario1 aAquino, Virginia1 aSalgado, Josefa1 aPasalodos, Sara1 aMiranda, María1 aAlonso, Ángel1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/smn1-copy-number-and-sequence-variant-analysis-next-generation-sequencing-data03115nas a2200493 4500008004100000022001400041245014400055210006900199260001500268490000700283520148700290653001201777653003601789653003001825653003101855653001801886653001101904653003601915653000901951653001501960653002401975653003401999653003302033653002402066653000902090653002502099653001502124653001702139653002302156653001802179653003402197653001802231100001802249700002902267700001702296700002402313700002102337700003102358700002002389700002102409700002602430700003402456856013102490 2020 eng d a2073-442500aTranscriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.0 aTranscriptomic Analysis of a Diabetic SkinHumanized Mouse Model c2020 12 310 v123 aDefective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.
10aAnimals10aDiabetes Mellitus, Experimental10aGene Expression Profiling10aGene Expression Regulation10aGene ontology10aHumans10aMetabolic Networks and Pathways10aMice10aMice, Nude10aMicroarray Analysis10aMolecular Sequence Annotation10aPrincipal Component Analysis10aSignal Transduction10aSkin10aSkin Transplantation10aSkin Ulcer10aStreptozocin10aTissue Engineering10aTranscriptome10aTransplantation, Heterologous10aWound Healing1 aLeón, Carlos1 aGarcia-Garcia, Francisco1 aLlames, Sara1 aGarcía-Pérez, Eva1 aCarretero, Marta1 aArriba, María, Del Carmen1 aDopazo, Joaquin1 aDel Rio, Marcela1 aEscamez, Maria, José1 aMartínez-Santamaría, Lucía uhttps://www.clinbioinfosspa.es/content/transcriptomic-analysis-diabetic-skin-humanized-mouse-model-dissects-molecular-pathways01363nas a2200433 4500008004100000022001400041245006500055210006400120260001200184300001200196490000800208653001500216653002800231653003100259100002600290700002800316700001700344700002600361700001800387700001300405700002000418700002100438700002000459700002100479700002200500700002400522700002100546700002200567700002000589700001800609700001900627700002300646700001900669700002500688700002200713700002300735710007100758856010000829 2020 eng d a1476-468700aTransparency and reproducibility in artificial intelligence.0 aTransparency and reproducibility in artificial intelligence c2020 10 aE14-E160 v58610aAlgorithms10aArtificial Intelligence10aReproducibility of Results1 aHaibe-Kains, Benjamin1 aAdam, George, Alexandru1 aHosny, Ahmed1 aKhodakarami, Farnoosh1 aWaldron, Levi1 aWang, Bo1 aMcIntosh, Chris1 aGoldenberg, Anna1 aKundaje, Anshul1 aGreene, Casey, S1 aBroderick, Tamara1 aHoffman, Michael, M1 aLeek, Jeffrey, T1 aKorthauer, Keegan1 aHuber, Wolfgang1 aBrazma, Alvis1 aPineau, Joelle1 aTibshirani, Robert1 aHastie, Trevor1 aIoannidis, John, P A1 aQuackenbush, John1 aAerts, Hugo, J W L1 aMassive Analysis Quality Control (MAQC) Society Board of Directors uhttps://www.clinbioinfosspa.es/content/transparency-and-reproducibility-artificial-intelligence02335nas a2200289 4500008004100000022001400041245008800055210006900143260001500212300001400227490000700241520142800248653001201676653002701688653002601715653001101741653002401752653001301776100002801789700001701817700002501834700001701859700001501876700002401891700001501915856011501930 2020 eng d a1367-481100aUsing AnABlast for intergenic sORF prediction in the Caenorhabditis elegans genome.0 aUsing AnABlast for intergenic sORF prediction in the Caenorhabdi c2020 12 08 a4827-48320 v363 aMOTIVATION: Short bioactive peptides encoded by small open reading frames (sORFs) play important roles in eukaryotes. Bioinformatics prediction of ORFs is an early step in a genome sequence analysis, but sORFs encoding short peptides, often using non-AUG initiation codons, are not easily discriminated from false ORFs occurring by chance.
RESULTS: AnABlast is a computational tool designed to highlight putative protein-coding regions in genomic DNA sequences. This protein-coding finder is independent of ORF length and reading frame shifts, thus making of AnABlast a potentially useful tool to predict sORFs. Using this algorithm, here, we report the identification of 82 putative new intergenic sORFs in the Caenorhabditis elegans genome. Sequence similarity, motif presence, expression data and RNA interference experiments support that the underlined sORFs likely encode functional peptides, encouraging the use of AnABlast as a new approach for the accurate prediction of intergenic sORFs in annotated eukaryotic genomes.
AVAILABILITY AND IMPLEMENTATION: AnABlast is freely available at http://www.bioinfocabd.upo.es/ab/. The C.elegans genome browser with AnABlast results, annotated genes and all data used in this study is available at http://www.bioinfocabd.upo.es/celegans.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
10aAnimals10aCaenorhabditis elegans10aComputational Biology10aGenome10aOpen Reading Frames10aSoftware1 aCasimiro-Soriguer, C, S1 aRigual, M, M1 aBrokate-Llanos, A, M1 aMuñoz, M, J1 aGarzón, A1 aPérez-Pulido, A, J1 aJimenez, J uhttps://www.clinbioinfosspa.es/content/using-anablast-intergenic-sorf-prediction-caenorhabditis-elegans-genome03269nas a2200685 4500008004100000022001400041245011800055210006900173260001500242300000900257490000700266520115400273653001901427653005101446653001701497653002201514653002101536653002601557653002201583653002001605653003001625653001901655653001301674653001101687653003101698653001301729653001401742653002101756653003501777653004101812653002201853100002301875700001701898700001901915700001801934700002301952700001901975700001501994700001702009700001602026700002002042700001602062700002402078700001902102700001802121700002402139700001802163700002502181700001702206700001902223700002302242700002702265700002002292700002502312700002002337700002102357700002602378710005702404856012202461 2019 eng d a2041-172300aCommunity assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen.0 aCommunity assessment to advance computational prediction of canc c2019 06 17 a26740 v103 aThe effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
10aADAM17 Protein10aAntineoplastic Combined Chemotherapy Protocols10aBenchmarking10aBiomarkers, Tumor10aCell Line, Tumor10aComputational Biology10aDatasets as Topic10aDrug Antagonism10aDrug Resistance, Neoplasm10aDrug Synergism10aGenomics10aHumans10aMolecular Targeted Therapy10amutation10aNeoplasms10apharmacogenetics10aPhosphatidylinositol 3-Kinases10aPhosphoinositide-3 Kinase Inhibitors10aTreatment Outcome1 aMenden, Michael, P1 aWang, Dennis1 aMason, Mike, J1 aSzalai, Bence1 aBulusu, Krishna, C1 aGuan, Yuanfang1 aYu, Thomas1 aKang, Jaewoo1 aJeon, Minji1 aWolfinger, Russ1 aNguyen, Tin1 aZaslavskiy, Mikhail1 aJang, In, Sock1 aGhazoui, Zara1 aAhsen, Mehmet, Eren1 aVogel, Robert1 aNeto, Elias, Chaibub1 aNorman, Thea1 aK Y Tang, Eric1 aGarnett, Mathew, J1 aDi Veroli, Giovanni, Y1 aFawell, Stephen1 aStolovitzky, Gustavo1 aGuinney, Justin1 aDry, Jonathan, R1 aSaez-Rodriguez, Julio1 aAstraZeneca-Sanger Drug Combination DREAM Consortium uhttps://www.clinbioinfosspa.es/content/community-assessment-advance-computational-prediction-cancer-drug-combinations02824nas a2200397 4500008004100000022001400041245011600055210006900171260000900240300000600249490000600255520157600261653002601837653002401863653001901887653002901906653001101935653001301946653003601959653002301995653001402018653001402032653001302046653001802059100001802077700002202095700001902117700001602136700002402152700002202176700002102198700002002219700003102239700002002270856013602290 2019 eng d a2056-718900aDifferential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models.0 aDifferential metabolic activity and discovery of therapeutic tar c2019 a70 v53 aIn spite of the increasing availability of genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene expression and the understanding of their contribution to the molecular mechanisms that ultimately account for the phenotype studied. Alterations in the metabolism are behind the initiation and progression of many diseases, including cancer. The wealth of available knowledge on metabolic processes can therefore be used to derive mechanistic models that link gene expression perturbations to changes in metabolic activity that provide relevant clues on molecular mechanisms of disease and drug modes of action (MoA). In particular, pathway modules, which recapitulate the main aspects of metabolism, are especially suitable for this type of modeling. We present Metabolizer, a web-based application that offers an intuitive, easy-to-use interactive interface to analyze differences in pathway metabolic module activities that can also be used for class prediction and in silico prediction of knock-out (KO) effects. Moreover, Metabolizer can automatically predict the optimal KO intervention for restoring a diseased phenotype. We provide different types of validations of some of the predictions made by Metabolizer. Metabolizer is a web tool that allows understanding molecular mechanisms of disease or the MoA of drugs within the context of the metabolism by using gene expression measurements. In addition, this tool automatically suggests potential therapeutic targets for individualized therapeutic interventions.
10aComputational Biology10aComputer Simulation10aDrug discovery10aGene Regulatory Networks10aHumans10aInternet10aMetabolic Networks and Pathways10aModels, Biological10aNeoplasms10aPhenotype10aSoftware10aTranscriptome1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aRian, Kinza1 aSalavert, Francisco1 aPujana, Miguel, A1 aMateo, Francesca1 aHerranz, Carmen1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/differential-metabolic-activity-and-discovery-therapeutic-targets-using-summarized-metabolic05146nas a2200745 4500008004100000022001400041245013000055210006900185260001200254300001200266490000800278520304400286653001503330653001003345653001103355653001203366653002503378653002003403653001003423653002103433653002603454653003803480653002503518653003403543653001103577653001603588653001303604653003103617653002303648653001103671653001103682653002003693653000903713653001603722653001303738653002503751653003103776653002503807653001203832653000903844653002603853653001603879100002203895700001303917700001303930700002303943700001503966700001903981700002404000700001604024700001604040700002904056700001404085700001504099700002704114700002404141700001404165700001204179700001604191700001504207700001504222700001404237700001504251856013404266 2019 eng d a1365-213300aFibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.0 aFibroblast activation and abnormal extracellular matrix remodell c2019 09 a512-5220 v1813 aBACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.
OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.
METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.
RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.
CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.
10aAdolescent10aAdult10aBiopsy10aBlister10aCase-Control Studies10aCells, Cultured10aChild10aChild, Preschool10aEpidermolysis Bullosa10aEpidermolysis Bullosa Dystrophica10aExtracellular Matrix10aExtracellular Matrix Proteins10aFemale10aFibroblasts10aFibrosis10aGene Expression Regulation10aHealthy Volunteers10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10amutation10aPeriodontal Diseases10aPhotosensitivity Disorders10aPrimary Cell Culture10aRNA-seq10aSkin10aXeroderma Pigmentosum10aYoung Adult1 aChacón-Solano, E1 aLeón, C1 aDíaz, F1 aGarcía-García, F1 aGarcía, M1 aEscámez, M, J1 aGuerrero-Aspizua, S1 aConti, C, J1 aMencía, Á1 aMartínez-Santamaría, L1 aLlames, S1 aPévida, M1 aCarbonell-Caballero, J1 aPuig-Butillé, J, A1 aMaseda, R1 aPuig, S1 ade Lucas, R1 aBaselga, E1 aLarcher, F1 aDopazo, J1 aDel Rio, M uhttps://www.clinbioinfosspa.es/content/fibroblast-activation-and-abnormal-extracellular-matrix-remodelling-common-hallmarks-three05186nas a2200661 4500008004100000022001400041245013800055210006900193260001200262300001200274490000700286520316900293653001003462653000903472653002803481653002603509653001103535653001103546653001403557653000903571653001603580653002603596653001603622653004903638653002603687653002803713653001703741653002203758100002503780700002403805700002503829700002003854700002103874700002203895700002103917700002203938700002303960700002003983700002404003700002204027700002204049700001804071700001904089700003004108700002904138700002304167700001804190700002904208700002404237700001704261700001504278700002004293700002704313700001804340700002004358700001904378856012704397 2019 eng d a1474-548800aPazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of advanced malignant and dedifferentiat c2019 01 a134-1440 v203 aBACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.
METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.
FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).
INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.
FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
10aAdult10aAged10aAngiogenesis Inhibitors10aAntineoplastic Agents10aFemale10aHumans10aIndazoles10aMale10aMiddle Aged10aMultivariate Analysis10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSoft Tissue Neoplasms10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Analysis1 aMartin-Broto, Javier1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aRedondo, Andres1 aBernabeu, Daniel1 ade Alava, Enrique1 aCasali, Paolo, G1 aItaliano, Antoine1 aGutierrez, Antonio1 aMoura, David, S1 aPeña-Chilet, Maria1 aDiaz-Martin, Juan1 aBiscuola, Michele1 aTaron, Miguel1 aCollini, Paola1 aRanchere-Vince, Dominique1 aDel Muro, Xavier, Garcia1 aGrignani, Giovanni1 aDumont, Sarah1 aMartinez-Trufero, Javier1 aPalmerini, Emanuela1 aHindi, Nadia1 aSebio, Ana1 aDopazo, Joaquin1 aTos, Angelo, Paolo Dei1 aLeCesne, Axel1 aBlay, Jean-Yves1 aCruz, Josefina uhttps://www.clinbioinfosspa.es/content/pazopanib-treatment-advanced-malignant-and-dedifferentiated-solitary-fibrous-tumour02570nas a2200253 4500008004100000022001400041245011000055210006900165260001600234300000800250490000700258520169900265653002601964653002301990653001302013653002802026100002202054700002402076700002002100700002402120700002002144700002002164856013202184 2019 eng d a1471-210500aPyCellBase, an efficient python package for easy retrieval of biological data from heterogeneous sources.0 aPyCellBase an efficient python package for easy retrieval of bio c2019 Mar 28 a1590 v203 aBACKGROUND: Biological databases and repositories are incrementing in diversity and complexity over the years. This rapid expansion of current and new sources of biological knowledge raises serious problems of data accessibility and integration. To handle the growing necessity of unification, CellBase was created as an integrative solution. CellBase provides a centralized NoSQL database containing biological information from different and heterogeneous sources. Access to this information is done through a RESTful web service API, which provides an efficient interface to the data.
RESULTS: In this work we present PyCellBase, a Python package that provides programmatic access to the rich RESTful web service API offered by CellBase. This package offers a fast and user-friendly access to biological information without the need of installing any local database. In addition, a series of command-line tools are provided to perform common bioinformatic tasks, such as variant annotation. CellBase data is always available by a high-availability cluster and queries have been tuned to ensure a real-time performance.
CONCLUSION: PyCellBase is an open-source Python package that provides an efficient access to heterogeneous biological information. It allows to perform tasks that require a comprehensive set of knowledge resources, as for example variant annotation. Queries can be easily fine-tuned to retrieve the desired information of particular biological features. PyCellBase offers the convenience of an object-oriented scripting language and provides the ability to integrate the obtained results into other Python applications and pipelines.
10aComputational Biology10aDatabases, Factual10aSoftware10aUser-Computer Interface1 aPerez-Gil, Daniel1 aLopez, Francisco, J1 aDopazo, Joaquin1 aMarin-Garcia, Pablo1 aRendon, Augusto1 aMedina, Ignacio uhttps://www.clinbioinfosspa.es/content/pycellbase-efficient-python-package-easy-retrieval-biological-data-heterogeneous-sources01484nas a2200421 4500008004100000245011900041210006900160260001600229490000600245110005300251700001800304700001800322700002300340700002500363700001600388700001900404700001500423700001800438700001900456700002400475700001900499700002200518700001600540700003100556700001800587700001800605700001800623700001900641700002200660700002300682700002700705700002700732700001900759700002400778700002500802700002600827856020900853 2018 eng d00aA crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection0 acrowdsourced analysis to identify ab initio molecular signatures cJan-12-20180 v91 aThe Respiratory Viral DREAM Challenge Consortium1 aFourati, Slim1 aTalla, Aarthi1 aMahmoudian, Mehrad1 aBurkhart, Joshua, G.1 aKlén, Riku1 aHenao, Ricardo1 aYu, Thomas1 aAydın, Zafer1 aYeung, Ka, Yee1 aAhsen, Mehmet, Eren1 aAlmugbel, Reem1 aJahandideh, Samad1 aLiang, Xiao1 aNordling, Torbjörn, E. M.1 aShiga, Motoki1 aStanescu, Ana1 aVogel, Robert1 aPandey, Gaurav1 aChiu, Christopher1 aMcClain, Micah, T.1 aWoods, Christopher, W.1 aGinsburg, Geoffrey, S.1 aElo, Laura, L.1 aTsalik, Ephraim, L.1 aMangravite, Lara, M.1 aSieberts, Solveig, K. uhttp://www.nature.com/articles/s41467-018-06735-8http://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-802577nas a2200529 4500008004100000022001400041245008700055210006900142260001500211300000800226490000600234520103000240653001001270653001801280653001001298653001101308653002001319653001101339653002301350653002301373653001901396653002501415653001801440100002301458700002701481700002101508700002501529700001601554700001901570700001701589700002201606700002401628700003101652700002101683700002401704700001901728700002401747700001801771700001801789700002101807700002001828700002001848700002101868700002301889700002001912856011501932 2018 eng d a2041-172300aThe effects of death and post-mortem cold ischemia on human tissue transcriptomes.0 aeffects of death and postmortem cold ischemia on human tissue tr c2018 02 13 a4900 v93 aPost-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues.
10aBlood10aCold Ischemia10aDeath10aFemale10agene expression10aHumans10aModels, Biological10aPostmortem Changes10aRNA, Messenger10aStochastic Processes10aTranscriptome1 aFerreira, Pedro, G1 aMuñoz-Aguirre, Manuel1 aReverter, Ferran1 aGodinho, Caio, P Sá1 aSousa, Abel1 aAmadoz, Alicia1 aSodaei, Reza1 aHidalgo, Marta, R1 aPervouchine, Dmitri1 aCarbonell-Caballero, José1 aNurtdinov, Ramil1 aBreschi, Alessandra1 aAmador, Raziel1 aOliveira, Patrícia1 aCubuk, Cankut1 aCurado, João1 aAguet, François1 aOliveira, Carla1 aDopazo, Joaquin1 aSammeth, Michael1 aArdlie, Kristin, G1 aGuigó, Roderic uhttps://www.clinbioinfosspa.es/content/effects-death-and-post-mortem-cold-ischemia-human-tissue-transcriptomes02677nas a2200373 4500008004100000022001400041245014700055210006900202260001500271300000900286490000600295520150800301653002801809653002901837653001901866653002001885653001101905653001301916653001901929653002601948100001401974700001301988700001802001700001402019700002602033700001502059700002502074700002702099700001202126700001502138700001102153700001302164856012602177 2018 eng d a2045-232200aEvolution of the Quorum network and the mobilome (plasmids and bacteriophages) in clinical strains of Acinetobacter baumannii during a decade.0 aEvolution of the Quorum network and the mobilome plasmids and ba c2018 02 06 a25230 v83 aIn this study, we compared eighteen clinical strains of A. baumannii belonging to the ST-2 clone and isolated from patients in the same intensive care unit (ICU) in 2000 (9 strains referred to collectively as Ab_GEIH-2000) and 2010 (9 strains referred to collectively as Ab_GEIH-2010), during the GEIH-REIPI project (Umbrella BioProject PRJNA422585). We observed two main molecular differences between the Ab_GEIH-2010 and the Ab_GEIH-2000 collections, acquired over the course of the decade long sampling interval and involving the mobilome: i) a plasmid harbouring genes for bla ß-lactamase and abKA/abkB proteins of a toxin-antitoxin system; and ii) two temperate bacteriophages, Ab105-1ϕ (63 proteins) and Ab105-2ϕ (93 proteins), containing important viral defence proteins. Moreover, all Ab_GEIH-2010 strains contained a Quorum functional network of Quorum Sensing (QS) and Quorum Quenching (QQ) mechanisms, including a new QQ enzyme, AidA, which acts as a bacterial defence mechanism against the exogenous 3-oxo-C12-HSL. Interestingly, the infective capacity of the bacteriophages isolated in this study (Ab105-1ϕ and Ab105-2ϕ) was higher in the Ab_GEIH-2010 strains (carrying a functional Quorum network) than in the Ab_GEIH-2000 strains (carrying a deficient Quorum network), in which the bacteriophages showed little or no infectivity. This is the first study about the evolution of the Quorum network and the mobilome in clinical strains of Acinetobacter baumannii during a decade.
10aAcinetobacter baumannii10aAcinetobacter Infections10aBacteriophages10aCross Infection10aHumans10aPlasmids10aQuorum Sensing10aRetrospective Studies1 aLópez, M1 aRueda, A1 aFlorido, J, P1 aBlasco, L1 aFernández-García, L1 aTrastoy, R1 aFernández-Cuenca, F1 aMartínez-Martínez, L1 aVila, J1 aPascual, A1 aBou, G1 aTomas, M uhttps://www.clinbioinfosspa.es/content/evolution-quorum-network-and-mobilome-plasmids-and-bacteriophages-clinical-strains02787nas a2200349 4500008004100000022001400041245008700055210006900142260001200211490000600223520171300229653001201942653003001954653001101984653002201995653001302017653001102030653000902041653001002050653002702060100003302087700002902120700002002149700003002169700002102199700001902220700002002239700001902259700001902278700002202297856011802319 2018 eng d a2057-585800aThe first complete genomic structure of Butyrivibrio fibrisolvens and its chromid.0 afirst complete genomic structure of Butyrivibrio fibrisolvens an c2018 100 v43 aButyrivibrio fibrisolvens forms part of the gastrointestinal microbiome of ruminants and other mammals, including humans. Indeed, it is one of the most common bacteria found in the rumen and plays an important role in ruminal fermentation of polysaccharides, yet, to date, there is no closed reference genome published for this species in any ruminant animal. We successfully assembled the nearly complete genome sequence of B. fibrisolvens strain INBov1 isolated from cow rumen using Illumina paired-end reads, 454 Roche single-end and mate pair sequencing technology. Additionally, we constructed an optical restriction map of this strain to aid in scaffold ordering and positioning, and completed the first genomic structure of this species. Moreover, we identified and assembled the first chromid of this species (pINBov266). The INBov1 genome encodes a large set of genes involved in the cellulolytic process but lacks key genes. This seems to indicate that B. fibrisolvens plays an important role in ruminal cellulolytic processes, but does not have autonomous cellulolytic capacity. When searching for genes involved in the biohydrogenation of unsaturated fatty acids, no linoleate isomerase gene was found in this strain. INBov1 does encode oleate hydratase genes known to participate in the hydrogenation of oleic acids. Furthermore, INBov1 contains an enolase gene, which has been recently determined to participate in the synthesis of conjugated linoleic acids. This work confirms the presence of a novel chromid in B. fibrisolvens and provides a new potential reference genome sequence for this species, providing new insight into its role in biohydrogenation and carbohydrate degradation.
10aAnimals10aButyrivibrio fibrisolvens10aCattle10aGenome, Bacterial10aGenomics10aHumans10aMilk10aRumen10aSequence Analysis, DNA1 aHernáez, Javier, Rodríguez1 aCucchi, Maria, Esperanza1 aCravero, Silvio1 aMartinez, Maria, Carolina1 aGonzalez, Sergio1 aPuebla, Andrea1 aDopazo, Joaquin1 aFarber, Marisa1 aPaniego, Norma1 aRivarola, Máximo uhttps://www.clinbioinfosspa.es/content/first-complete-genomic-structure-butyrivibrio-fibrisolvens-and-its-chromid02950nas a2200445 4500008004100000022001400041245009500055210006900150260001500219300001400234490000700248520156700255653002101822653002101843653002401864653003001888653004301918653002901961653001101990653002602001653001502027653001302042653001402055653001402069653001402083653001402097653002702111653002702138653001802165653002202183100001802205700002202223700001902245700002202264700002102286700002002307700003102327700002002358856012602378 2018 eng d a1538-744500aGene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape.0 aGene Expression Integration into Pathway Modules Reveals a PanCa c2018 11 01 a6059-60720 v783 aMetabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies. Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. .
10aCell Line, Tumor10aCluster Analysis10aDisease Progression10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aGene Regulatory Networks10aHumans10aKaplan-Meier Estimate10aMetabolome10amutation10aNeoplasms10aOncogenes10aPhenotype10aPrognosis10aRNA, Small Interfering10aSequence Analysis, RNA10aTranscriptome10aTreatment Outcome1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aPujana, Miguel, A1 aMateo, Francesca1 aHerranz, Carmen1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/gene-expression-integration-pathway-modules-reveals-pan-cancer-metabolic-landscape03417nas a2200793 4500008004100000022001400041245009300055210006900148260001500217300000900232490000600241520096600247653001201213653001401225653002301239653001801262653003601280653003001316653001101346653003101357653001101388653002401399653002101423653001201444653002801456653002501484653004101509653001601550653000901566653000901575653002301584653001501607653003901622653001701661653003001678653003401708100002801742700002201770700003201792700002901824700002601853700002601879700003101905700003301936700002201969700003101991700001902022700002002041700002002061700002202081700002002103700002302123700001602146700002302162700002302185700002302208700001902231700002502250700002902275700002102304700002502325700003202350700001602382700001802398700003802416700001702454700002402471856012802495 2018 eng d a2041-172300aLRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.0 aLRH1 agonism favours an immuneislet dialogue which protects agai c2018 04 16 a14880 v93 aType 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.
10aAnimals10aApoptosis10aCell Communication10aCell Survival10aDiabetes Mellitus, Experimental10aDiabetes Mellitus, Type 210aFemale10aGene Expression Regulation10aHumans10aHypoglycemic Agents10aImmunity, Innate10ainsulin10aInsulin-Secreting Cells10aIslets of Langerhans10aIslets of Langerhans Transplantation10aMacrophages10aMale10aMice10aMice, Inbred C57BL10aPhenalenes10aReceptors, Cytoplasmic and Nuclear10aStreptozocin10aT-Lymphocytes, Regulatory10aTransplantation, Heterologous1 aCobo-Vuilleumier, Nadia1 aLorenzo, Petra, I1 aRodríguez, Noelia, García1 aGómez, Irene, de Gracia1 aFuente-Martin, Esther1 aLópez-Noriega, Livia1 aMellado-Gil, José, Manuel1 aRomero-Zerbo, Silvana-Yanina1 aBaquié, Mathurin1 aLachaud, Christian, Claude1 aStifter, Katja1 aPerdomo, German1 aBugliani, Marco1 aDe Tata, Vincenzo1 aBosco, Domenico1 aParnaud, Geraldine1 aPozo, David1 aHmadcha, Abdelkrim1 aFlorido, Javier, P1 aToscano, Miguel, G1 ade Haan, Peter1 aSchoonjans, Kristina1 aPalazón, Luis, Sánchez1 aMarchetti, Piero1 aSchirmbeck, Reinhold1 aMartín-Montalvo, Alejandro1 aMeda, Paolo1 aSoria, Bernat1 aBermúdez-Silva, Francisco-Javier1 aSt-Onge, Luc1 aGauthier, Benoit, R uhttps://www.clinbioinfosspa.es/content/lrh-1-agonism-favours-immune-islet-dialogue-which-protects-against-diabetes-mellitus02954nas a2200541 4500008004100000022001400041245008900055210006900144260000900213300001300222490000700235520138200242653001001624653000901634653001801643653001101661653002901672653003201701653002601733653001101759653001401770653002901784653000901813653001601822653001301838653002201851653001801873653001401891653002701905100002101932700003101953700002001984700002402004700002402028700002602052700001602078700001902094700001902113700002502132700002002157700001902177700002002196700002002216700002402236700002002260700001902280856011302299 2018 eng d a1932-620300aThe modular network structure of the mutational landscape of Acute Myeloid Leukemia.0 amodular network structure of the mutational landscape of Acute M c2018 ae02029260 v133 aAcute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.
10aAdult10aAged10aCytodiagnosis10aFemale10aGene Regulatory Networks10aGenetic Association Studies10aGenetic Heterogeneity10aHumans10aKaryotype10aLeukemia, Myeloid, Acute10aMale10aMiddle Aged10amutation10aNeoplasm Proteins10aNucleophosmin10aPrognosis10awhole exome sequencing1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aSuch, Esperanza1 aGarcía-Alonso, Luz1 aLiquori, Alessandro1 aLópez-Pavía, María1 aLLop, Marta1 aAlonso, Carmen1 aBarragán, Eva1 aGómez-Seguí, Inés1 aNeef, Alexander1 aHervás, David1 aMontesinos, Pau1 aSanz, Guillermo1 aSanz, Miguel, Angel1 aDopazo, Joaquin1 aCervera, José uhttps://www.clinbioinfosspa.es/content/modular-network-structure-mutational-landscape-acute-myeloid-leukemia02380nas a2200313 4500008004100000022001400041245011300055210006900168260001600237300000800253490000700261520133500268653001201603653002301615653003001638653004201668653001301710653002701723653001801750653002801768100002101796700002201817700002201839700002101861700002101882700002001903700001901923856012401942 2017 eng d a1471-210500aATGC transcriptomics: a web-based application to integrate, explore and analyze de novo transcriptomic data.0 aATGC transcriptomics a webbased application to integrate explore c2017 Feb 22 a1210 v183 aBACKGROUND: In the last years, applications based on massively parallelized RNA sequencing (RNA-seq) have become valuable approaches for studying non-model species, e.g., without a fully sequenced genome. RNA-seq is a useful tool for detecting novel transcripts and genetic variations and for evaluating differential gene expression by digital measurements. The large and complex datasets resulting from functional genomic experiments represent a challenge in data processing, management, and analysis. This problem is especially significant for small research groups working with non-model species.
RESULTS: We developed a web-based application, called ATGC transcriptomics, with a flexible and adaptable interface that allows users to work with new generation sequencing (NGS) transcriptomic analysis results using an ontology-driven database. This new application simplifies data exploration, visualization, and integration for a better comprehension of the results.
CONCLUSIONS: ATGC transcriptomics provides access to non-expert computer users and small research groups to a scalable storage option and simple data integration, including database administration and management. The software is freely available under the terms of GNU public license at http://atgcinta.sourceforge.net .
10aAnimals10aDatabases, Genetic10aGene Expression Profiling10aHigh-Throughput Nucleotide Sequencing10aInternet10aSequence Analysis, RNA10aTranscriptome10aUser-Computer Interface1 aGonzalez, Sergio1 aClavijo, Bernardo1 aRivarola, Máximo1 aMoreno, Patricio1 aFernandez, Paula1 aDopazo, Joaquin1 aPaniego, Norma uhttps://www.clinbioinfosspa.es/content/atgc-transcriptomics-web-based-application-integrate-explore-and-analyze-de-novo01430nas a2200481 4500008004100000022001400041245007200055210006900127260001500196300001400211490000800225653000900233653002400242653003700266653003400303653001900337653001000356653002900366653001100395653002200406653002800428653001100456653001600467653001300483100002100496700002100517700002800538700002700566700002600593700002000619700002000639700002000659700002900679700002000708700002600728700002800754700002200782700002400804700002000828700002100848700002500869856005400894 2017 eng d a1533-440600aGGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates.0 aGGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonat c2017 05 04 a1794-17950 v37610aAged10aAmino Acid Sequence10aBone Density Conservation Agents10aDimethylallyltranstransferase10aDiphosphonates10aExome10aFarnesyltranstransferase10aFemale10aFemoral Fractures10aGeranyltranstransferase10aHumans10aMiddle Aged10amutation1 aRoca-Ayats, Neus1 aBalcells, Susana1 aGarcia-Giralt, Natàlia1 aFalcó-Mascaró, Maite1 aMartínez-Gil, Núria1 aAbril, Josep, F1 aUrreizti, Roser1 aDopazo, Joaquin1 aQuesada-Gómez, José, M1 aNogués, Xavier1 aMellibovsky, Leonardo1 aPrieto-Alhambra, Daniel1 aDunford, James, E1 aJavaid, Muhammad, K1 aRussell, Graham1 aGrinberg, Daniel1 aDíez-Pérez, Adolfo uhttp://www.nejm.org/doi/full/10.1056/NEJMc161280402585nas a2200349 4500008004100000022001400041245014600055210006900201260001500270300001200285490000700297520142200304653001201726653001501738653002001753653002001773653003501793653003001828653002101858653002401879653002301903653001201926653001601938653001801954653002101972100002301993700002902016700002002045700001702065700001902082856013402101 2017 eng d a1460-219900aGlobal Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types.0 aGlobal Transcriptome Analysis of Primary Cerebrocortical Cells I c2017 01 01 a706-7170 v273 aThyroid hormones, thyroxine, and triiodothyronine (T3) are crucial for cerebral cortex development acting through regulation of gene expression. To define the transcriptional program under T3 regulation, we have performed RNA-Seq of T3-treated and untreated primary mouse cerebrocortical cells. The expression of 1145 genes or 7.7% of expressed genes was changed upon T3 addition, of which 371 responded to T3 in the presence of cycloheximide indicating direct transcriptional regulation. The results were compared with available transcriptomic datasets of defined cellular types. In this way, we could identify targets of T3 within genes enriched in astrocytes and neurons, in specific layers including the subplate, and in specific neurons such as prepronociceptin, cholecystokinin, or cortistatin neurons. The subplate and the prepronociceptin neurons appear as potentially major targets of T3 action. T3 upregulates mostly genes related to cell membrane events, such as G-protein signaling, neurotransmission, and ion transport and downregulates genes involved in nuclear events associated with the M phase of cell cycle, such as chromosome organization and segregation. Remarkably, the transcriptomic changes induced by T3 sustain the transition from fetal to adult patterns of gene expression. The results allow defining in molecular terms the elusive role of thyroid hormones on neocortical development.
10aAnimals10aAstrocytes10aCells, Cultured10aCerebral Cortex10aFluorescent Antibody Technique10aGene Expression Profiling10aMice, 129 Strain10aMice, Inbred BALB C10aMice, Inbred C57BL10aNeurons10aPiperazines10aTranscriptome10aTriiodothyronine1 aGil-Ibañez, Pilar1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aBernal, Juan1 aMorte, Beatriz uhttps://www.clinbioinfosspa.es/content/global-transcriptome-analysis-primary-cerebrocortical-cells-identification-genes-regulated02298nas a2200361 4500008004100000022001400041245004600055210004400101260001500145300001400160490000700174520132500181653002201506653001801528653001101546653001301557653001301570653002801583100001801611700001701629700002101646700002301667700002301690700002201713700001601735700001701751700001901768700001801787700002001805700002001825700002001845856007101865 2017 eng d a1362-496200aHGVA: the Human Genome Variation Archive.0 aHGVA the Human Genome Variation Archive c2017 07 03 aW189-W1940 v453 aHigh-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets.
10aGenetic Variation10aGenome, Human10aHumans10aInternet10aSoftware10aUser-Computer Interface1 aLopez, Javier1 aColl, Jacobo1 aHaimel, Matthias1 aKandasamy, Swaathi1 aTárraga, Joaquín1 aFurio-Tari, Pedro1 aBari, Wasim1 aBleda, Marta1 aRueda, Antonio1 aGräf, Stefan1 aRendon, Augusto1 aDopazo, Joaquin1 aMedina, Ignacio uhttps://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx44503013nas a2200433 4500008004100000022001400041245016000055210006900215260001300284300001200297490000700309520160000316653001601916653003801932653001501970653001701985653001902002653002702021653001502048653002602063653002602089653001002115100002402125700002402149700001902173700002002192700002202212700002102234700002202255700002902277700002002306700001802326700002002344700002402364700001902388700002102407700001902428856013202447 2017 eng d a1573-502800aIntegration of transcriptomic and metabolic data reveals hub transcription factors involved in drought stress response in sunflower (Helianthus annuus L.).0 aIntegration of transcriptomic and metabolic data reveals hub tra c2017 Jul a549-5640 v943 aBy integration of transcriptional and metabolic profiles we identified pathways and hubs transcription factors regulated during drought conditions in sunflower, useful for applications in molecular and/or biotechnological breeding. Drought is one of the most important environmental stresses that effects crop productivity in many agricultural regions. Sunflower is tolerant to drought conditions but the mechanisms involved in this tolerance remain unclear at the molecular level. The aim of this study was to characterize and integrate transcriptional and metabolic pathways related to drought stress in sunflower plants, by using a system biology approach. Our results showed a delay in plant senescence with an increase in the expression level of photosynthesis related genes as well as higher levels of sugars, osmoprotectant amino acids and ionic nutrients under drought conditions. In addition, we identified transcription factors that were upregulated during drought conditions and that may act as hubs in the transcriptional network. Many of these transcription factors belong to families implicated in the drought response in model species. The integration of transcriptomic and metabolomic data in this study, together with physiological measurements, has improved our understanding of the biological responses during droughts and contributes to elucidate the molecular mechanisms involved under this environmental condition. These findings will provide useful biotechnological tools to improve stress tolerance while maintaining crop yield under restricted water availability.
10aChlorophyll10aGene Expression Regulation, Plant10aHelianthus10aPlant Leaves10aPlant Proteins10aProtein Array Analysis10aRNA, Plant10aStress, Physiological10aTranscription Factors10aWater1 aMoschen, Sebastián1 aDi Rienzo, Julio, A1 aHiggins, Janet1 aTohge, Takayuki1 aWatanabe, Mutsumi1 aGonzalez, Sergio1 aRivarola, Máximo1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aHopp, Esteban1 aHoefgen, Rainer1 aFernie, Alisdair, R1 aPaniego, Norma1 aFernandez, Paula1 aHeinz, Ruth, A uhttps://www.clinbioinfosspa.es/content/integration-transcriptomic-and-metabolic-data-reveals-hub-transcription-factors-involved02565nas a2200541 4500008004100000022001400041245008600055210006900141260001200210300001200222490000700234520094000241653002801181653001201209653002801221653001001249653004201259653001301301653001101314653003101325653000901356653001301365653001401378653003301392653002801425100002201453700001701475700002501492700003201517700002201549700001801571700002101589700002001610700002401630700003401654700001901688700002001707700002901727700002501756700001901781700002001800700001901820700001801839700001701857700001901874700001901893856011101912 2017 eng d a1098-100400aMutations in TRAPPC11 are associated with a congenital disorder of glycosylation.0 aMutations in TRAPPC11 are associated with a congenital disorder c2017 02 a148-1510 v383 aCongenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders.
10aAbnormalities, Multiple10aAlleles10aAmino Acid Substitution10aBrain10aCongenital Disorders of Glycosylation10aGenotype10aHumans10aMagnetic Resonance Imaging10aMale10amutation10aPhenotype10aVesicular Transport Proteins10aWhole Genome Sequencing1 aMatalonga, Leslie1 aBravo, Miren1 aSerra-Peinado, Carla1 aGarcía-Pelegrí, Elisabeth1 aUgarteburu, Olatz1 aVidal, Silvia1 aLlambrich, Maria1 aQuintana, Ester1 aFuster-Jorge, Pedro1 aGonzalez-Bravo, Maria, Nieves1 aBeltran, Sergi1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aFoulquier, François1 aMatthijs, Gert1 aMills, Philippa1 aRibes, Antonia1 aEgea, Gustavo1 aBriones, Paz1 aTort, Frederic1 aGirós, Marisa uhttps://www.clinbioinfosspa.es/content/mutations-trappc11-are-associated-congenital-disorder-glycosylation01960nas a2200325 4500008004100000022001400041245009200055210006900147260001600216300000800232490000700240520091900247653001801166653002001184653002001204653004201224653001101266653001301277653002801290653002201318100002101340700002301361700002301384700002201407700002401429700002001453700001901473700002001492856012201512 2017 eng d a1471-210500aVISMapper: ultra-fast exhaustive cartography of viral insertion sites for gene therapy.0 aVISMapper ultrafast exhaustive cartography of viral insertion si c2017 Sep 20 a4210 v183 aBACKGROUND: The possibility of integrating viral vectors to become a persistent part of the host genome makes them a crucial element of clinical gene therapy. However, viral integration has associated risks, such as the unintentional activation of oncogenes that can result in cancer. Therefore, the analysis of integration sites of retroviral vectors is a crucial step in developing safer vectors for therapeutic use.
RESULTS: Here we present VISMapper, a vector integration site analysis web server, to analyze next-generation sequencing data for retroviral vector integration sites. VISMapper can be found at: http://vismapper.babelomics.org .
CONCLUSIONS: Because it uses novel mapping algorithms VISMapper is remarkably faster than previous available programs. It also provides a useful graphical interface to analyze the integration sites found in the genomic context.
10aBase Sequence10aGenetic Therapy10aGenetic Vectors10aHigh-Throughput Nucleotide Sequencing10aHumans10aInternet10aUser-Computer Interface10aVirus Integration1 aJuanes, José, M1 aGallego, Asunción1 aTárraga, Joaquín1 aChaves, Felipe, J1 aMarin-Garcia, Pablo1 aMedina, Ignacio1 aArnau, Vicente1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/vismapper-ultra-fast-exhaustive-cartography-viral-insertion-sites-gene-therapy03542nas a2200649 4500008004100000022001400041245010900055210006900164260001600233300000700249490000700256520162800263653001601891653001701907653000801924100001901932700002001951700002201971700002501993700002502018700002202043700001702065700002102082700002502103700001902128700002202147700002002169700002102189700001902210700001802229700001802247700002202265700002302287700001802310700002002328700001602348700002602364700001702390700002202407700001702429700002202446700002102468700003202489700002802521700002302549700002902572700002502601700001802626700001902644700002502663700002602688700002302714700001902737700003402756700002402790856007802814 2017 eng d a1474-760X00aWhole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.0 aWhole exome sequencing coupled with unbiased functional analysis c2017 Mar 08 a480 v183 aBACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.10aHirschprung10aRare Disease10aWES1 aGui, Hongsheng1 aSchriemer, Duco1 aCheng, William, W1 aChauhan, Rajendra, K1 aAntiňolo, Guillermo1 aBerrios, Courtney1 aBleda, Marta1 aBrooks, Alice, S1 aBrouwer, Rutger, W W1 aBurns, Alan, J1 aCherny, Stacey, S1 aDopazo, Joaquin1 aEggen, Bart, J L1 aGriseri, Paola1 aJalloh, Binta1 aLe, Thuy-Linh1 aLui, Vincent, C H1 aLuzón-Toro, Berta1 aMatera, Ivana1 aNgan, Elly, S W1 aPelet, Anna1 aRuiz-Ferrer, Macarena1 aSham, Pak, C1 aShepherd, Iain, T1 aSo, Man-Ting1 aSribudiani, Yunia1 aTang, Clara, S M1 avan den Hout, Mirjam, C G N1 avan der Linde, Herma, C1 avan Ham, Tjakko, J1 avan IJcken, Wilfred, F J1 aVerheij, Joke, B G M1 aAmiel, Jeanne1 aBorrego, Salud1 aCeccherini, Isabella1 aChakravarti, Aravinda1 aLyonnet, Stanislas1 aTam, Paul, K H1 aGarcia-Barceló, Maria-Mercè1 aHofstra, Robert, Mw uhttp://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-601877nas a2200577 4500008004100000245010800041210006900149260001600218490000700234100001900241700002000260700002300280700002600303700002500329700002200354700001700376700002200393700002700415700002000442700002300462700002000485700002300505700001900528700001800547700001800565700002400583700002300607700001800630700002200648700001600670700002600686700001800712700002300730700001700753700002200770700002300792700003500815700002900850700002400879700003100903700002800934700001800962700001900980700002500999700002601024700002301050700002101073700003401094700002701128856014401155 2017 eng d00aWhole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes0 aWhole exome sequencing coupled with unbiased functional analysis cJan-12-20170 v181 aGui, Hongsheng1 aSchriemer, Duco1 aCheng, William, W.1 aChauhan, Rajendra, K.1 aAntiňolo, Guillermo1 aBerrios, Courtney1 aBleda, Marta1 aBrooks, Alice, S.1 aBrouwer, Rutger, W. W.1 aBurns, Alan, J.1 aCherny, Stacey, S.1 aDopazo, Joaquin1 aEggen, Bart, J. L.1 aGriseri, Paola1 aJalloh, Binta1 aLe, Thuy-Linh1 aLui, Vincent, C. H.1 aLuzón-Toro, Berta1 aMatera, Ivana1 aNgan, Elly, S. W.1 aPelet, Anna1 aRuiz-Ferrer, Macarena1 aSham, Pak, C.1 aShepherd, Iain, T.1 aSo, Man-Ting1 aSribudiani, Yunia1 aTang, Clara, S. M.1 avan den Hout, Mirjam, C. G. N.1 avan der Linde, Herma, C.1 avan Ham, Tjakko, J.1 avan IJcken, Wilfred, F. J.1 aVerheij, Joke, B. G. M.1 aAmiel, Jeanne1 aBorrego, Salud1 aCeccherini, Isabella1 aChakravarti, Aravinda1 aLyonnet, Stanislas1 aTam, Paul, K. H.1 aGarcia-Barceló, Maria-Mercè1 aHofstra, Robert, M. W. uhttp://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf03274nas a2200469 4500008004100000022001400041245010000055210006900155260001600224520184400240653001202084653000802096653001802104653002402122653001902146653000802165100002102173700001902194700001702213700002402230700002302254700002902277700002302306700002302329700002102352700001902373700002202392700003302414700002302447700001602470700002602486700002802512700002002540700002002560700002702580700002002607700002702627700001902654700002702673700002502700856007902725 2016 eng d a1537-171900a267 Spanish exomes reveal population-specific differences in disease-related genetic variation.0 a267 Spanish exomes reveal populationspecific differences in dise c2016 Jan 133 aRecent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalogue of local variability motivated the whole exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including about 10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies in order to distinguish real disease associations from population-specific polymorphisms.10adisease10aNGS10apolymorphisms10aPopulation genomics10aprioritization10aSNP1 aDopazo, Joaquín1 aAmadoz, Alicia1 aBleda, Marta1 aGarcía-Alonso, Luz1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aRodriguez, Juan, A1 aDaub, Josephine, T1 aMuntané, Gerard1 aRueda, Antonio1 aVela-Boza, Alicia1 aLópez-Domingo, Francisco, J1 aFlorido, Javier, P1 aArce, Pablo1 aRuiz-Ferrer, Macarena1 aMéndez-Vidal, Cristina1 aArnold, Todd, E1 aSpleiss, Olivia1 aAlvarez-Tejado, Miguel1 aNavarro, Arcadi1 aBhattacharya, Shomi, S1 aBorrego, Salud1 aSantoyo-López, Javier1 aAntiňolo, Guillermo uhttps://mbe.oxfordjournals.org/content/early/2016/02/17/molbev.msw005.full01971nas a2200301 4500008004100000022001400041245010200055210006900157260001500226520100600241653002101247653002201268653002601290653001901316653002101335653002601356653001501382653002401397100002401421700002101445700001901466700001801485700002001503700001901523700003101542700002101573856007501594 2016 eng d a1362-496200aActionable pathways: interactive discovery of therapeutic targets using signaling pathway models.0 aActionable pathways interactive discovery of therapeutic targets c2016 May 23 aThe discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org.10aactionable genes10aDisease mechanism10adrug action mechanism10aDrug discovery10apathway analysis10apersonalized medicine10asignalling10atherapeutic targets1 aSalavert, Francisco1 aHidago, Marta, R1 aAmadoz, Alicia1 aCubuk, Cankut1 aMedina, Ignacio1 aCrespo, Daniel1 aCarbonell-Caballero, José1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/early/2016/05/02/nar.gkw369.full02635nas a2200361 4500008004100000022001400041245014600055210006900201260001500270520148500285653002401770653000801794653001501802653000801817653001101825653001801836653002601854100001901880700002901899700001801928700002001946700002401966700002401990700002102014700001902035700002102054700003102075700003202106700002302138700002002161700002102181856007102202 2016 eng d a1943-781100aAssessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.0 aAssessment of Targeted NextGeneration Sequencing as a Tool for t c2016 Jan 23 aCharcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies.10aCharcot-Marie-Tooth10aCMT10aDiagnostic10aNGS10aPanels10arare diseases10aTargeted resequencing1 aLupo, Vincenzo1 aGarcia-Garcia, Francisco1 aSancho, Paula1 aTello, Cristina1 aGarcía-Romero, Mar1 aVillarreal, Liliana1 aAlberti, Antonia1 aSivera, Rafael1 aDopazo, Joaquín1 aPascual-Pascual, Samuel, I1 aMárquez-Infante, Celedonio1 aCasasnovas, Carlos1 aSevilla, Teresa1 aEspinós, Carmen uhttp://www.sciencedirect.com/science/article/pii/S152515781500261501158nas a2200313 4500008004100000245011100041210006900152260001600221490000600237100002000243700003400263700002700297700002700324700002200351700002400373700002500397700002100422700001900443700002000462700002300482700002200505700001900527700003300546700002000579700002300599700002000622700002100642856018100663 2016 eng d00aExtension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq)0 aExtension of human lncRNA transcripts by RACE coupled with longr cJan-11-20160 v71 aLagarde, Julien1 aUszczynska-Ratajczak, Barbara1 aSantoyo-López, Javier1 aGonzalez, Jose, Manuel1 aTapanari, Electra1 aMudge, Jonathan, M.1 aSteward, Charles, A.1 aWilming, Laurens1 aTanzer, Andrea1 aHowald, Cédric1 aChrast, Jacqueline1 aVela-Boza, Alicia1 aRueda, Antonio1 aLopez-Domingo, Francisco, J.1 aDopazo, Joaquin1 aReymond, Alexandre1 aGuigó, Roderic1 aHarrow, Jennifer uhttp://www.nature.com/articles/ncomms12339http://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms1233902094nas a2200349 4500008004100000022001400041245011200055210006900167260000900236300001000245490000600255520101800261100002001279700003401299700002701333700002701360700002201387700002301409700002401432700002101456700001901477700002001496700002301516700002201539700001901561700003301580700002001613700002301633700002001656700002101676856004701697 2016 eng d a2041-172300aExtension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq).0 aExtension of human lncRNA transcripts by RACE coupled with longr c2016 a123390 v73 aLong non-coding RNAs (lncRNAs) constitute a large, yet mostly uncharacterized fraction of the mammalian transcriptome. Such characterization requires a comprehensive, high-quality annotation of their gene structure and boundaries, which is currently lacking. Here we describe RACE-Seq, an experimental workflow designed to address this based on RACE (rapid amplification of cDNA ends) and long-read RNA sequencing. We apply RACE-Seq to 398 human lncRNA genes in seven tissues, leading to the discovery of 2,556 on-target, novel transcripts. About 60% of the targeted loci are extended in either 5’ or 3’, often reaching genomic hallmarks of gene boundaries. Analysis of the novel transcripts suggests that lncRNAs are as long, have as many exons and undergo as much alternative splicing as protein-coding genes, contrary to current assumptions. Overall, we show that RACE-Seq is an effective tool to annotate an organism’s deep transcriptome, and compares favourably to other targeted sequencing techniques.1 aLagarde, Julien1 aUszczynska-Ratajczak, Barbara1 aSantoyo-López, Javier1 aGonzalez, Jose, Manuel1 aTapanari, Electra1 aMudge, Jonathan, M1 aSteward, Charles, A1 aWilming, Laurens1 aTanzer, Andrea1 aHowald, Cédric1 aChrast, Jacqueline1 aVela-Boza, Alicia1 aRueda, Antonio1 aLópez-Domingo, Francisco, J1 aDopazo, Joaquin1 aReymond, Alexandre1 aGuigó, Roderic1 aHarrow, Jennifer uhttp://www.nature.com/articles/ncomms1233901698nas a2200337 4500008004100000022001400041245007000055210006800125260001300193300001100206490000700217520067800224653001300902653004200915653001100957653003200968653002701000653001801027100001401045700001601059700001701075700001801092700001901110700001601129700002301145700002301168700002601191700002501217700001401242856010401256 2016 eng d a1756-166300aHighly sensitive and ultrafast read mapping for RNA-seq analysis.0 aHighly sensitive and ultrafast read mapping for RNAseq analysis c2016 Apr a93-1000 v233 aAs sequencing technologies progress, the amount of data produced grows exponentially, shifting the bottleneck of discovery towards the data analysis phase. In particular, currently available mapping solutions for RNA-seq leave room for improvement in terms of sensitivity and performance, hindering an efficient analysis of transcriptomes by massive sequencing. Here, we present an innovative approach that combines re-engineering, optimization and parallelization. This solution results in a significant increase of mapping sensitivity over a wide range of read lengths and substantial shorter runtimes when compared with current RNA-seq mapping methods available.
10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aSensitivity and Specificity10aSequence Analysis, RNA10aTranscriptome1 aMedina, I1 aTárraga, J1 aMartínez, H1 aBarrachina, S1 aCastillo, M, I1 aPaschall, J1 aSalavert-Torres, J1 aBlanquer-Espert, I1 aHernández-García, V1 aQuintana-Ortí, E, S1 aDopazo, J uhttps://www.clinbioinfosspa.es/content/highly-sensitive-and-ultrafast-read-mapping-rna-seq-analysis00587nas a2200157 4500008004100000245007900041210006900120260001600189490000700205100002300212700002300235700001900258700002000277700002000297856011200317 2016 eng d00aHPG pore: an efficient and scalable framework for nanopore sequencing data0 aHPG pore an efficient and scalable framework for nanopore sequen cJan-12-20160 v171 aTárraga, Joaquín1 aGallego, Asunción1 aArnau, Vicente1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://www.biomedcentral.com/1471-2105/17/107http://link.springer.com/content/pdf/10.1186/s12859-016-0966-001901nas a2200241 4500008004100000022001400041245008000055210006900135260000900204300000800213490000700221520123600228653001101464653000801475653001301483653000801496100002301504700002301527700001901550700002001569700002001589856005001609 2016 eng d a1471-210500aHPG pore: an efficient and scalable framework for nanopore sequencing data.0 aHPG pore an efficient and scalable framework for nanopore sequen c2016 a1070 v173 aBACKGROUND: The use of nanopore technologies is expected to spread in the future because they are portable and can sequence long fragments of DNA molecules without prior amplification. The first nanopore sequencer available, the MinION™ from Oxford Nanopore Technologies, is a USB-connected, portable device that allows real-time DNA analysis. In addition, other new instruments are expected to be released soon, which promise to outperform the current short-read technologies in terms of throughput. Despite the flood of data expected from this technology, the data analysis solutions currently available are only designed to manage small projects and are not scalable. RESULTS: Here we present HPG Pore, a toolkit for exploring and analysing nanopore sequencing data. HPG Pore can run on both individual computers and in the Hadoop distributed computing framework, which allows easy scale-up to manage the large amounts of data expected to result from extensive use of nanopore technologies in the future. CONCLUSIONS: HPG Pore allows for virtually unlimited sequencing data scalability, thus guaranteeing its continued management in near future scenarios. HPG Pore is available in GitHub at http://github.com/opencb/hpg-pore .10ahadoop10aHPC10ananopore10aNGS1 aTárraga, Joaquín1 aGallego, Asunción1 aArnau, Vicente1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://www.biomedcentral.com/1471-2105/17/10702499nas a2200505 4500008004100000022001400041245008800055210006900143260001600212300000900228490000600237520111400243653001001357653000901367653002201376653002001398653001601418653001101434653001101445653000901456653001601465653003101481653002201512653002601534100002201560700001201582700001301594700001301607700001401620700002301634700001801657700001701675700002301692700002001715700002001735700001401755700001401769700001301783700001601796700001201812700001401824700001601838700001601854856012301870 2016 eng d a2158-318800aHuman DNA methylomes of neurodegenerative diseases show common epigenomic patterns.0 aHuman DNA methylomes of neurodegenerative diseases show common e c2016 Jan 19 ae7180 v63 aDifferent neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.
10aAdult10aAged10aAged, 80 and over10aDNA Methylation10aEpigenomics10aFemale10aHumans10aMale10aMiddle Aged10aneurodegenerative diseases10aPrefrontal Cortex10aTissue Array Analysis1 aSanchez-Mut, J, V1 aHeyn, H1 aVidal, E1 aMoran, S1 aSayols, S1 aDelgado-Morales, R1 aSchultz, M, D1 aAnsoleaga, B1 aGarcia-Esparcia, P1 aPons-Espinal, M1 ade Lagran, M, M1 aDopazo, J1 aRabano, A1 aAvila, J1 aDierssen, M1 aLott, I1 aFerrer, I1 aEcker, J, R1 aEsteller, M uhttps://www.clinbioinfosspa.es/content/human-dna-methylomes-neurodegenerative-diseases-show-common-epigenomic-patterns03226nas a2200697 4500008004100000022001400041245013600055210006900191260001500260300001000275490000600285520117300291653000901464653001201473653002601485653002001511653001901531653003801550653001801588653002801606653001001634653001701644653001101661653003101672653002101703653002501724653001501749653001101764653000901775653000901784653001601793653003601809653003201845653001101877653002401888653003601912653002501948653001001973653002101983653002602004100001402030700002402044700001602068700001602084700001702100700002402117700002702141700002402168700002102192700001302213700002302226700001402249700002702263700002002290700002302310700001402333700002402347700001402371700001302385856013002398 2016 eng d a2045-232200aIdentification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.0 aIdentification of the Photoreceptor Transcriptional CoRepressor c2016 10 13 a353700 v63 aRetinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.
10aAged10aAnimals10aCo-Repressor Proteins10aCodon, Nonsense10aCohort Studies10aComparative Genomic Hybridization10aConsanguinity10aDNA Mutational Analysis10aExome10aEye Proteins10aFemale10aGene Expression Regulation10aGenes, Recessive10aHomeodomain Proteins10aHomozygote10aHumans10aMale10aMice10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aRetina10aRetinal Dystrophies10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aSpain10aTrans-Activators10aTranscription Factors1 aCorton, M1 aAvila-Fernández, A1 aCampello, L1 aSánchez, M1 aBenavides, B1 aLópez-Molina, M, I1 aFernández-Sánchez, L1 aSánchez-Alcudia, R1 ada Silva, L, R J1 aReyes, N1 aMartín-Garrido, E1 aZurita, O1 aSan José, Fernández-1 aPérez-Carro, R1 aGarcía-García, F1 aDopazo, J1 aGarcía-Sandoval, B1 aCuenca, N1 aAyuso, C uhttps://www.clinbioinfosspa.es/content/identification-photoreceptor-transcriptional-co-repressor-samd11-novel-cause-autosomal02761nas a2200397 4500008004100000022001400041245012200055210006900177260001600246300001000262490000600272520143100278653001201709653002401721653003101745653002801776653001701804653001701821653003201838653002601870653002001896653004201916653001101958653001301969653001401982653002401996100002302020700002802043700002502071700003302096700003602129700002002165700001902185700002502204856013402229 2016 eng d a2045-232200aImproving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.0 aImproving the management of Inherited Retinal Dystrophies by tar c2016 Apr 01 a239100 v63 aNext-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73% of IRD patients ranging from 50% for autosomal dominant cases, 75% for syndromic cases, 83% for autosomal recessive cases, and 100% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management.
10aAlleles10aComputer Simulation10aDNA Copy Number Variations10aDNA Mutational Analysis10aEye Proteins10aGene Library10aGenetic Association Studies10aGenetic Heterogeneity10aGenetic Therapy10aHigh-Throughput Nucleotide Sequencing10aHumans10amutation10aPhenotype10aRetinal Dystrophies1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aRomero-Pérez, Laura1 adel Pozo, María, González-1 ade la Rúa, Enrique, Rodríguez1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttps://www.clinbioinfosspa.es/content/improving-management-inherited-retinal-dystrophies-targeted-sequencing-population-specific02434nas a2200289 4500008004100000022001400041245005500055210005400110260001500164300001200179490000700191520155100198653002601749653003001775653001801805653002901823653004201852653001101894653001401905653001401919653003101933100002901964700002201993700002002015700002002035856008902055 2016 eng d a1367-481100aIntegrated gene set analysis for microRNA studies.0 aIntegrated gene set analysis for microRNA studies c2016 09 15 a2809-160 v323 aMOTIVATION: Functional interpretation of miRNA expression data is currently done in a three step procedure: select differentially expressed miRNAs, find their target genes, and carry out gene set overrepresentation analysis Nevertheless, major limitations of this approach have already been described at the gene level, while some newer arise in the miRNA scenario.Here, we propose an enhanced methodology that builds on the well-established gene set analysis paradigm. Evidence for differential expression at the miRNA level is transferred to a gene differential inhibition score which is easily interpretable in terms of gene sets or pathways. Such transferred indexes account for the additive effect of several miRNAs targeting the same gene, and also incorporate cancellation effects between cases and controls. Together, these two desirable characteristics allow for more accurate modeling of regulatory processes.
RESULTS: We analyze high-throughput sequencing data from 20 different cancer types and provide exhaustive reports of gene and Gene Ontology-term deregulation by miRNA action.
AVAILABILITY AND IMPLEMENTATION: The proposed methodology was implemented in the Bioconductor library mdgsa http://bioconductor.org/packages/mdgsa For the purpose of reproducibility all of the scripts are available at https://github.com/dmontaner-papers/gsa4mirna
CONTACT: : david.montaner@gmail.com
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
10aComputational Biology10aGene Expression Profiling10aGene ontology10aGene Regulatory Networks10aHigh-Throughput Nucleotide Sequencing10aHumans10aMicroRNAs10aNeoplasms10aReproducibility of Results1 aGarcia-Garcia, Francisco1 aPanadero, Joaquin1 aDopazo, Joaquin1 aMontaner, David uhttps://www.clinbioinfosspa.es/content/integrated-gene-set-analysis-microrna-studies03254nas a2200493 4500008004100000022001400041245010800055210006900163260001300232300001100245490000700256520165600263653004101919653003001960653003801990653001802028653001702046653001502063653000902078653001702087653004402104653001702148653003302165653001902198653002602217100002402243700002602267700002402293700002802317700002002345700002202365700002102387700002102408700002202429700002902451700002002480700002702500700002002527700002402547700001902571700002102590700001902611856013002630 2016 eng d a1467-765200aIntegrating transcriptomic and metabolomic analysis to understand natural leaf senescence in sunflower.0 aIntegrating transcriptomic and metabolomic analysis to understan c2016 Feb a719-340 v143 aLeaf senescence is a complex process, which has dramatic consequences on crop yield. In sunflower, gap between potential and actual yields reveals the economic impact of senescence. Indeed, sunflower plants are incapable of maintaining their green leaf area over sustained periods. This study characterizes the leaf senescence process in sunflower through a systems biology approach integrating transcriptomic and metabolomic analyses: plants being grown under both glasshouse and field conditions. Our results revealed a correspondence between profile changes detected at the molecular, biochemical and physiological level throughout the progression of leaf senescence measured at different plant developmental stages. Early metabolic changes were detected prior to anthesis and before the onset of the first senescence symptoms, with more pronounced changes observed when physiological and molecular variables were assessed under field conditions. During leaf development, photosynthetic activity and cell growth processes decreased, whereas sucrose, fatty acid, nucleotide and amino acid metabolisms increased. Pathways related to nutrient recycling processes were also up-regulated. Members of the NAC, AP2-EREBP, HB, bZIP and MYB transcription factor families showed high expression levels, and their expression level was highly correlated, suggesting their involvement in sunflower senescence. The results of this study thus contribute to the elucidation of the molecular mechanisms involved in the onset and progression of leaf senescence in sunflower leaves as well as to the identification of candidate genes involved in this process.
10aGas Chromatography-Mass Spectrometry10aGene Expression Profiling10aGene Expression Regulation, Plant10aGene ontology10aGenes, Plant10aHelianthus10aIons10ametabolomics10aOligonucleotide Array Sequence Analysis10aPlant Leaves10aPrincipal Component Analysis10aRNA, Messenger10aTranscription Factors1 aMoschen, Sebastián1 aLuoni, Sofía, Bengoa1 aDi Rienzo, Julio, A1 aCaro, María, Del Pilar1 aTohge, Takayuki1 aWatanabe, Mutsumi1 aHollmann, Julien1 aGonzalez, Sergio1 aRivarola, Máximo1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aHopp, Horacio, Esteban1 aHoefgen, Rainer1 aFernie, Alisdair, R1 aPaniego, Norma1 aFernandez, Paula1 aHeinz, Ruth, A uhttps://www.clinbioinfosspa.es/content/integrating-transcriptomic-and-metabolomic-analysis-understand-natural-leaf-senescence02864nas a2200433 4500008004100000022001400041245013500055210006900190260000900259300001300268490000700281520145800288653001001746653002901756653001801785653001101803653001901814653003501833653001301868653001801881653003601899653003101935100002101966700003101987700002402018700002002042700002902062700001902091700001902110700002602129700001602155700001902171700002502190700002002215700002002235700002002255700001902275856013602294 2016 eng d a1932-620300aThe Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.0 aMutational Landscape of Acute Promyelocytic Leukemia Reveals an c2016 ae01483460 v113 aPreliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.
10aExome10aGene Regulatory Networks10aGenome, Human10aHumans10aINDEL Mutation10aLeukemia, Promyelocytic, Acute10amutation10aMutation Rate10aPolymorphism, Single Nucleotide10aReproducibility of Results1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aGarcía-Alonso, Luz1 aSuch, Esperanza1 aJiménez-Almazán, Jorge1 aVidal, Enrique1 aBarragán, Eva1 aLópez-Pavía, María1 aLLop, Marta1 aMartín, Iván1 aGómez-Seguí, Inés1 aMontesinos, Pau1 aSanz, Miguel, A1 aDopazo, Joaquin1 aCervera, José uhttps://www.clinbioinfosspa.es/content/mutational-landscape-acute-promyelocytic-leukemia-reveals-interacting-network-co-occurrences03507nas a2200517 4500008004100000022001400041245007400055210006900129260001300198300001000211490000800221520209300229653001002322653000902332653001202341653001002353653003202363653001102395653002002406653001102426653001102437653000902448653000902457653001602466653001302482653001302495653001402508653001802522653001602540653002602556653001602582100002002598700001902618700002902637700001802666700001902684700002502703700002402728700003102752700001802783700002002801700002202821700002002843700002102863856010502884 2016 eng d a1460-215600aMutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.0 aMutations in the MORC2 gene cause axonal CharcotMarieTooth disea c2016 Jan a62-720 v1393 aCharcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.
10aAdult10aAged10aAnimals10aAxons10aCharcot-Marie-Tooth Disease10aFemale10agene expression10aHumans10aInfant10aMale10aMice10aMiddle Aged10amutation10aPedigree10aPhenotype10aSciatic Nerve10aSural Nerve10aTranscription Factors10aYoung Adult1 aSevilla, Teresa1 aLupo, Vincenzo1 aMartínez-Rubio, Dolores1 aSancho, Paula1 aSivera, Rafael1 aChumillas, María, J1 aGarcía-Romero, Mar1 aPascual-Pascual, Samuel, I1 aMuelas, Nuria1 aDopazo, Joaquin1 aVílchez, Juan, J1 aPalau, Francesc1 aEspinós, Carmen uhttps://www.clinbioinfosspa.es/content/mutations-morc2-gene-cause-axonal-charcot-marie-tooth-disease02426nas a2200325 4500008004100000022001400041245006600055210006400121260001300185300001000198490000700208520140200215653002501617653003401642653003701676653001101713653002201724653002101746653003601767653002301803100002101826700001701847700002001864700002201884700003201906700001901938700002201957700002101979856010002000 2016 eng d a2363-891500aProgress in pharmacogenetics: consortiums and new strategies.0 aProgress in pharmacogenetics consortiums and new strategies c2016 Mar a17-230 v313 aPharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.
10aCooperative Behavior10aGenome-Wide Association Study10aHigh-Throughput Screening Assays10aHumans10aPatient Care Team10apharmacogenetics10aPolymorphism, Single Nucleotide10aPrecision Medicine1 aMaroñas, Olalla1 aLatorre, Ana1 aDopazo, Joaquin1 aPirmohamed, Munir1 aRodríguez-Antona, Cristina1 aSiest, Gérard1 aCarracedo, Ángel1 aLLerena, Adrián uhttps://www.clinbioinfosspa.es/content/progress-pharmacogenetics-consortiums-and-new-strategies02961nas a2200505 4500008004100000022001400041245008800055210006900143260001300212300001000225490000900235520151700244653001501761653001701776653001001793653002101803653002101824653001001845653001101855653004201866653001101908653001101919653002801930653000901958653001301967653001301980653001401993653001402007653002302021100002002044700002102064700001902085700002902104700002302133700002202156700002202178700001902200700001902219700002002238700001702258700002302275700002102298700002102319856011502340 2016 eng d a1552-483300aScreening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.0 aScreening of CD96 and ASXL1 in 11 patients with Opitz C or Bohri c2016 Jan a24-310 v170A3 aOpitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases.
10aAdolescent10aAntigens, CD10aChild10aChild, Preschool10aCraniosynostoses10aExome10aFemale10aHigh-Throughput Nucleotide Sequencing10aHumans10aInfant10aIntellectual Disability10aMale10amutation10aPedigree10aPhenotype10aPrognosis10aRepressor Proteins1 aUrreizti, Roser1 aRoca-Ayats, Neus1 aTrepat, Judith1 aGarcia-Garcia, Francisco1 aAlemán, Alejandro1 aOrteschi, Daniela1 aMarangi, Giuseppe1 aNeri, Giovanni1 aOpitz, John, M1 aDopazo, Joaquin1 aCormand, Bru1 aVilageliu, Lluïsa1 aBalcells, Susana1 aGrinberg, Daniel uhttps://www.clinbioinfosspa.es/content/screening-cd96-and-asxl1-11-patients-opitz-c-or-bohring-opitz-syndromes03446nas a2200277 4500008004100000022001400041245011600055210006900171260001300240300001000253490000600263520251800269100001902787700002102806700002002827700002202847700001802869700001902887700001702906700002202923700002002945700002402965700001902989700002903008856013103037 2016 eng d a2212-877800aStress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis.0 aStressinduced activation of brown adipose tissue prevents obesit c2016 Jan a19-330 v53 aBACKGROUND: Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.
METHODS: We used wt and triple β1,β2,β3-Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.
RESULTS: Departing from our initial observation that βARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the βARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and β-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.
CONCLUSION: Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to βARs agonists for the activation of human BAT.
1 aRazzoli, Maria1 aFrontini, Andrea1 aGurney, Allison1 aMondini, Eleonora1 aCubuk, Cankut1 aKatz, Liora, S1 aCero, Cheryl1 aBolan, Patrick, J1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aCinti, Saverio1 aBartolomucci, Alessandro uhttps://www.clinbioinfosspa.es/content/stress-induced-activation-brown-adipose-tissue-prevents-obesity-conditions-low-adaptive01578nas a2200253 4500008004100000022001400041245006500055210006300120260001500183300001100198490000700209520080700216653002601023653001301049653001301062100002401075700002401099700002101123700002001144700001701164700002001181700002001201856010301221 2016 eng d a1367-481100aWeb-based network analysis and visualization using CellMaps.0 aWebbased network analysis and visualization using CellMaps c2016 10 01 a3041-30 v323 aUNLABELLED: : CellMaps is an HTML5 open-source web tool that allows displaying, editing, exploring and analyzing biological networks as well as integrating metadata into them. Computations and analyses are remotely executed in high-end servers, and all the functionalities are available through RESTful web services. CellMaps can easily be integrated in any web page by using an available JavaScript API.
AVAILABILITY AND IMPLEMENTATION: The application is available at: http://cellmaps.babelomics.org/ and the code can be found in: https://github.com/opencb/cell-maps The client is implemented in JavaScript and the server in C and Java.
CONTACT: jdopazo@cipf.es
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
10aBiochemical Phenomena10aInternet10aSoftware1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aSánchez, Rubén1 aAlonso, Roberto1 aBleda, Marta1 aMedina, Ignacio1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/web-based-network-analysis-and-visualization-using-cellmaps01932nas a2200253 4500008004100000022001400041245011000055210006900165260001600234300001400250490000700264520114400271653000801415653001301423653001501436653002001451100003601471700002401507700003001531700002301561700002001584700002101604856005301625 2015 eng d a1362-496200aAssessing the impact of mutations found in next generation sequencing data over human signaling pathways.0 aAssessing the impact of mutations found in next generation seque c2015 Apr 16 aW270-W2750 v433 aModern sequencing technologies produce increasingly detailed data on genomic variation. However, conventional methods for relating either individual variants or mutated genes to phenotypes present known limitations given the complex, multigenic nature of many diseases or traits. Here we present PATHiVar, a web-based tool that integrates genomic variation data with gene expression tissue information. PATHiVar constitutes a new generation of genomic data analysis methods that allow studying variants found in next generation sequencing experiment in the context of signaling pathways. Simple Boolean models of pathways provide detailed descriptions of the impact of mutations in cell functionality so as, recurrences in functionality failures can easily be related to diseases, even if they are produced by mutations in different genes. Patterns of changes in signal transmission circuits, often unpredictable from individual genes mutated, correspond to patterns of affected functionalities that can be related to complex traits such as disease progression, drug response, etc. PATHiVar is available at: http://pathivar.babelomics.org.10aNGS10apathways10asignalling10aSystems biology1 aHernansaiz-Ballesteros, Rosa, D1 aSalavert, Francisco1 aSebastián-Leon, Patricia1 aAlemán, Alejandro1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/43/W1/W27002445nas a2200469 4500008004100000022001400041245008300055210006900138260001600207300001400223490000700237520108700244653001501331653002101346653002201367653001601389653002101405653000801426653001201434653002001446653002001466100002001486700002401506700002901530700003101559700001701590700002401607700002301631700002201654700002401676700002101700700001801721700002201739700001901761700003601780700002301816700002301839700002001862700002001882700002001902856005301922 2015 eng d a1362-496200aBabelomics 5.0: functional interpretation for new generations of genomic data.0 aBabelomics 50 functional interpretation for new generations of g c2015 Apr 20 aW117-W1210 v433 aBabelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.10ababelomics10adata integration10agene set analysis10ainteractome10anetwork analysis10aNGS10aRNA-seq10aSystems biology10atranscriptomics1 aAlonso, Roberto1 aSalavert, Francisco1 aGarcia-Garcia, Francisco1 aCarbonell-Caballero, José1 aBleda, Marta1 aGarcía-Alonso, Luz1 aSanchis-Juan, Alba1 aPerez-Gil, Daniel1 aMarin-Garcia, Pablo1 aSánchez, Rubén1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aHernansaiz-Ballesteros, Rosa, D1 aAlemán, Alejandro1 aTárraga, Joaquín1 aMontaner, David1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://nar.oxfordjournals.org/content/43/W1/W11703376nas a2200793 4500008004100000022001400041245011500055210006900170260001600239520112300255653001101378653000801389653002001397100001901417700002601436700001201462700001801474700002201492700002701514700002201541700002201563700001901585700002901604700002301633700002001656700002001676700002301696700002501719700002201744700002201766700002101788700004001809700001201849700001701861700001201878700001601890700001901906700001801925700002101943700001601964700002001980700002402000700002002024700001802044700001302062700001702075700001802092700002102110700002402131700002002155700002102175700001702196700002102213700002502234700002102259700001902280700001902299700002102318700001602339700001402355700001702369700001502386700001302401700003102414700002102445700002102466700002002487856007502507 2015 eng d a1548-710500aCombining tumor genome simulation with crowdsourcing to benchmark somatic single-nucleotide-variant detection.0 aCombining tumor genome simulation with crowdsourcing to benchmar c2015 May 183 aThe detection of somatic mutations from cancer genome sequences is key to understanding the genetic basis of disease progression, patient survival and response to therapy. Benchmarking is needed for tool assessment and improvement but is complicated by a lack of gold standards, by extensive resource requirements and by difficulties in sharing personal genomic information. To resolve these issues, we launched the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, a crowdsourced benchmark of somatic mutation detection algorithms. Here we report the BAMSurgeon tool for simulating cancer genomes and the results of 248 analyses of three in silico tumors created with it. Different algorithms exhibit characteristic error profiles, and, intriguingly, false positives show a trinucleotide profile very similar to one found in human tumors. Although the three simulated tumors differ in sequence contamination (deviation from normal cell sequence) and in subclonality, an ensemble of pipelines outperforms the best individual pipeline in all cases. BAMSurgeon is available at https://github.com/adamewing/bamsurgeon/.10acancer10aNGS10avariant calling1 aEwing, Adam, D1 aHoulahan, Kathleen, E1 aHu, Yin1 aEllrott, Kyle1 aCaloian, Cristian1 aYamaguchi, Takafumi, N1 aBare, Christopher1 aP’ng, Christine1 aWaggott, Daryl1 aSabelnykova, Veronica, Y1 aKellen, Michael, R1 aNorman, Thea, C1 aHaussler, David1 aFriend, Stephen, H1 aStolovitzky, Gustavo1 aMargolin, Adam, A1 aStuart, Joshua, M1 aBoutros, Paul, C1 aparticipants, ICGC-TCGA, DREAM Soma1 aXi, Liu1 aDewal, Ninad1 aFan, Yu1 aWang, Wenyi1 aWheeler, David1 aWilm, Andreas1 aTing, Grace, Hui1 aLi, Chenhao1 aBertrand, Denis1 aNagarajan, Niranjan1 aChen, Qing-Rong1 aHsu, Chih-Hao1 aHu, Ying1 aYan, Chunhua1 aKibbe, Warren1 aMeerzaman, Daoud1 aCibulskis, Kristian1 aRosenberg, Mara1 aBergelson, Louis1 aKiezun, Adam1 aRadenbaugh, Amie1 aSertier, Anne-Sophie1 aFerrari, Anthony1 aTonton, Laurie1 aBhutani, Kunal1 aHansen, Nancy, F1 aWang, Difei1 aSong, Lei1 aLai, Zhongwu1 aLiao, Yang1 aShi, Wei1 aCarbonell-Caballero, José1 aDopazo, Joaquín1 aLau, Cheryl, C K1 aGuinney, Justin uhttp://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.3407.html02945nas a2200217 4500008004100000022001400041245012100055210006900176260001500245520217400260100003602434700003402470700002102504700002702525700002002552700002202572700002102594700002502615700001602640856007102656 2015 eng d a1878-589100aComparative gene expression study of the vestibular organ of the Igf1 deficient mouse using whole-transcript arrays.0 aComparative gene expression study of the vestibular organ of the c2015 Sep 13 aThe auditory and vestibular organs form the inner ear and have a common developmental origin. Insulin like growth factor 1 (IGF-1) has a central role in the development of the cochlea and maintenance of hearing. Its deficiency causes sensorineural hearing loss in man and mice. During chicken early development, IGF-1 modulates neurogenesis of the cochleovestibular ganglion but no further studies have been conducted to explore the potential role of IGF-1 in the vestibular system. In this study we have compared the whole transcriptome of the vestibular organ from wild type and Igf1(-/-) mice at different developmental and postnatal times. RNA was prepared from E18.5, P15 and P90 vestibular organs of Igf1(-/-) and Igf1(+/+) mice and the transcriptome analysed in triplicates using Affymetrix® Mouse Gene 1.1 ST Array Plates. These plates are whole-transcript arrays that include probes to measure both messenger (mRNA) and long intergenic non-coding RNA transcripts (lincRNA), with a coverage of over 28 thousand coding transcripts and over 7 thousands non-coding transcripts. Given the complexity of the data we used two different methods VSN-RMA and mmBGX to analyse and compare the data. This is to better evaluate the number of false positives and to quantify uncertainty of low signals. We identified a number of differentially expressed genes that we described using functional analysis and validated using RT-qPCR. The morphology of the vestibular organ did not show differences between genotypes and no evident alterations were observed in the vestibular sensory areas of the null mice. However, well-defined cellular alterations were found in the vestibular neurons with respect their number and size. Although these mice did not show a dramatic vestibular phenotype, we conducted a functional analysis on differentially expressed genes between genotypes and across time. This was with the aim to identify new pathways that are involved in the development of the vestibular organ as well as pathways that maybe affected by the lack of IGF-1 and be associated to the morphological changes of the vestibular neurons that we observed in the Igf1(-/-) mice.1 ade la Rosa, Lourdes, Rodríguez1 aSánchez-Calderón, Hortensia1 aContreras, Julio1 aMurillo-Cuesta, Silvia1 aFalagan, Sandra1 aAvendaño, Carlos1 aDopazo, Joaquín1 aVarela-Nieto, Isabel1 aMilo, Marta uhttp://www.sciencedirect.com/science/article/pii/S037859551500183501828nas a2200253 4500008004100000022001400041245007200055210006900127260001700196300001300213490000700226520106800233653000801301653000801309653002301317100002101340700002301361700002001384700002301404700002201427700002001449700003001469856007501499 2015 eng d a1557-996400aConcurrent and Accurate Short Read Mapping on Multicore Processors.0 aConcurrent and Accurate Short Read Mapping on Multicore Processo c2015 Sep-Oct a995-10070 v123 aWe introduce a parallel aligner with a work-flow organization for fast and accurate mapping of RNA sequences on servers equipped with multicore processors. Our software, [Formula: see text] ([Formula: see text] is an open-source application. The software is available at http://www.opencb.org, exploits a suffix array to rapidly map a large fraction of the RNA fragments (reads), as well as leverages the accuracy of the Smith-Waterman algorithm to deal with conflictive reads. The aligner is enhanced with a careful strategy to detect splice junctions based on an adaptive division of RNA reads into small segments (or seeds), which are then mapped onto a number of candidate alignment locations, providing crucial information for the successful alignment of the complete reads. The experimental results on a platform with Intel multicore technology report the parallel performance of [Formula: see text], on RNA reads of 100-400 nucleotides, which excels in execution time/sensitivity to state-of-the-art aligners such as TopHat 2+Bowtie 2, MapSplice, and STAR.10aHPC10aNGS10ashort real mapping1 aMartinez, Hector1 aTárraga, Joaquín1 aMedina, Ignacio1 aBarrachina, Sergio1 aCastillo, Maribel1 aDopazo, Joaquin1 aQuintana-Orti, Enrique, S uhttp://ieeexplore.ieee.org/xpl/articleDetails.jsp?tp=&arnumber=701000503282nas a2200445 4500008004100000022001400041245015900055210006900214260001600283300000900299490000800308520183200316653001002148653000902158653001102167653004102178653002302219653003002242653004602272653001802318653003402336653001702370653001102387653001602398653002002414653001302434653004402447653001202491653003402503653002402537100002302561700002502584700001602609700002302625700001302648700001402661700001602675700001302691856013202704 2015 eng d a1879-003800aDeregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.0 aDeregulation of key signaling pathways involved in oocyte matura c2015 Oct 15 a52-70 v5713 aFMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.
10aAdult10aAged10aFemale10aFragile X Mental Retardation Protein10aFragile X Syndrome10aGene Expression Profiling10aGene Expression Regulation, Developmental10aGene ontology10aGenome-Wide Association Study10aHeterozygote10aHumans10aMiddle Aged10aModels, Genetic10amutation10aOligonucleotide Array Sequence Analysis10aOocytes10aPrimary Ovarian Insufficiency10aSignal Transduction1 aAlvarez-Mora, M, I1 aRodriguez-Revenga, L1 aMadrigal, I1 aGarcía-García, F1 aDuran, M1 aDopazo, J1 aEstivill, X1 aMilà, M uhttps://www.clinbioinfosspa.es/content/deregulation-key-signaling-pathways-involved-oocyte-maturation-fmr1-premutation-carriers02466nas a2200445 4500008004100000022001400041245006900055210006200124260001300186300001200199490000700211520128200218653001001500653000901510653002201519653001001541653003201551653003601583653001001619653001101629653001101640653000901651653001601660653001301676653001301689653001401702653003001716653001601746100001501762700001401777700002301791700001201814700002001826700001501846700001401861700001901875700001301894700001601907856009701923 2015 eng d a1468-133100aThe EGR2 gene is involved in axonal Charcot-Marie-Tooth disease.0 aEGR2 gene is involved in axonal CharcotMarieTooth disease c2015 Dec a1548-550 v223 aBACKGROUND AND PURPOSE: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype.
METHODS: The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays.
RESULTS: A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression.
CONCLUSIONS: This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.
10aAdult10aAged10aAged, 80 and over10aAxons10aCharcot-Marie-Tooth Disease10aEarly Growth Response Protein 210aExome10aFemale10aHumans10aMale10aMiddle Aged10amutation10aPedigree10aPhenotype10aSeverity of Illness Index10aYoung Adult1 aSevilla, T1 aSivera, R1 aMartínez-Rubio, D1 aLupo, V1 aChumillas, M, J1 aCalpena, E1 aDopazo, J1 aVílchez, J, J1 aPalau, F1 aEspinós, C uhttps://www.clinbioinfosspa.es/content/egr2-gene-involved-axonal-charcot-marie-tooth-disease02225nas a2200265 4500008004100000022001400041245012800055210006900183260001300252300001200265490000800277520128900285100002301574700002801597700002501625700002001650700002001670700001901690700002501709700002301734700002501757700002501782700002101807856013101828 2015 eng d a1600-072200aFamily-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate.0 aFamilybased genomewide association study in Patagonia confirms t c2015 Oct a381-3840 v1233 aThe etiology of cleft lip with or without cleft palate (CL±P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X-linked syndromes [midline 1 (MID1), oral-facial-digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL±P. We attempted to confirm the role of X-linked genes in the etiology of isolated CL±P in a South American population through a family-based genome-wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL±P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL±P. Four genomic segments were identified, two of which showed a statistically significant association with CL±P. One is an 11-kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7 kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL±P. The MID1 and OFD1 genes were not included in the four potential CL±P-associated X-chromosome genomic segments.
1 aFonseca, Renata, F1 ade Carvalho, Flávia, M1 aPoletta, Fernando, A1 aMontaner, David1 aDopazo, Joaquin1 aMereb, Juan, C1 aMoreira, Miguel, A M1 aSeuanez, Hector, N1 aVieira, Alexandre, R1 aCastilla, Eduardo, E1 aOrioli, Iêda, M uhttps://www.clinbioinfosspa.es/content/family-based-genome-wide-association-study-patagonia-confirms-association-dmd-locus-and02556nas a2200301 4500008004100000022001400041245008500055210006900140260001600209300000700225490000700232520160800239653001501847653001801862653001301880653004201893653001101935653002301946653002701969653001301996100002002009700002002029700002302049700002002072700002002092700002202112856012002134 2015 eng d a1471-210500aFast inexact mapping using advanced tree exploration on backward search methods.0 aFast inexact mapping using advanced tree exploration on backward c2015 Jan 28 a180 v163 aBACKGROUND: Short sequence mapping methods for Next Generation Sequencing consist on a combination of seeding techniques followed by local alignment based on dynamic programming approaches. Most seeding algorithms are based on backward search alignment, using the Burrows Wheeler Transform, the Ferragina and Manzini Index or Suffix Arrays. All these backward search algorithms have excellent performance, but their computational cost highly increases when allowing errors. In this paper, we discuss an inexact mapping algorithm based on pruning strategies for search tree exploration over genomic data.
RESULTS: The proposed algorithm achieves a 13x speed-up over similar algorithms when allowing 6 base errors, including insertions, deletions and mismatches. This algorithm can deal with 400 bps reads with up to 9 errors in a high quality Illumina dataset. In this example, the algorithm works as a preprocessor that reduces by 55% the number of reads to be aligned. Depending on the aligner the overall execution time is reduced between 20-40%.
CONCLUSIONS: Although not intended as a complete sequence mapping tool, the proposed algorithm could be used as a preprocessing step to modern sequence mappers. This step significantly reduces the number reads to be aligned, accelerating overall alignment time. Furthermore, this algorithm could be used for accelerating the seeding step of already available sequence mappers. In addition, an out-of-core index has been implemented for working with large genomes on systems without expensive memory configurations.
10aAlgorithms10aGenome, Human10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aSequence Alignment10aSequence Analysis, DNA10aSoftware1 aSalavert, José1 aTomás, Andrés1 aTárraga, Joaquín1 aMedina, Ignacio1 aDopazo, Joaquin1 aBlanquer, Ignacio uhttps://www.clinbioinfosspa.es/content/fast-inexact-mapping-using-advanced-tree-exploration-backward-search-methods01498nas a2200289 4500008004100000022001400041245014900055210006900204260000800273300000700281490000600288520057300294100002300867700001700890700001900907700002400926700002600950700002000976700002800996700002701024700002701051700002001078700002501098700002001123700001901143856004601162 2015 eng d a1755-879400aIdentification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas0 aIdentification of epistatic interactions through genomewide asso cDec a830 v83 aThe molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.1 aLuzón-Toro, Berta1 aBleda, Marta1 aNavarro, Elena1 aGarcía-Alonso, Luz1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aMartín-Sánchez, Marta1 aGonzalez, Cristina, Y.1 aFernández, Raquel, M.1 aTorroglosa, Ana1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttps://doi.org/10.1186/s12920-015-0160-702478nas a2200325 4500008004100000022001400041245015000055210006900205260000900274300000700283490000600290520144200296653001401738653000901752653001901761100002301780700001701803700001901820700002401839700002601863700002001889700002801909700002601937700002601963700002001989700002502009700002002034700001902054856007902073 2015 eng d a1755-879400aIdentification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.0 aIdentification of epistatic interactions through genomewide asso c2015 a830 v83 aBACKGROUND: The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk. METHODS: We carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease. RESULTS: We have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression. CONCLUSIONS: Overall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.10aepistasis10aGWAS10aThyroid cancer1 aLuzón-Toro, Berta1 aBleda, Marta1 aNavarro, Elena1 aGarcía-Alonso, Luz1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aMartín-Sánchez, Marta1 aGonzalez, Cristina, Y1 aFernández, Raquel, M1 aTorroglosa, Ana1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-702283nas a2200253 4500008004100000022001400041245009200055210006900147260001600216300001400232490000700246520154200253653001101795653000801806653001601814653000801830100002301838700002001861700002101881700001701902700002001919700002101939856006901960 2015 eng d a1367-481100aA Parallel and Sensitive Software Tool for Methylation Analysis on Multicore Platforms.0 aParallel and Sensitive Software Tool for Methylation Analysis on c2015 Jun 10 a3130-31380 v313 aMOTIVATION: DNA methylation analysis suffers from very long processing time, since the advent of Next-Generation Sequencers (NGS) has shifted the bottleneck of genomic studies from the sequencers that obtain the DNA samples to the software that performs the analysis of these samples. The existing software for methylation analysis does not seem to scale efficiently neither with the size of the dataset nor with the length of the reads to be analyzed. Since it is expected that the sequencers will provide longer and longer reads in the near future, efficient and scalable methylation software should be developed. RESULTS: We present a new software tool, called HPG-Methyl, which efficiently maps bisulfite sequencing reads on DNA, analyzing DNA methylation. The strategy used by this software consists of leveraging the speed of the Burrows-Wheeler Transform to map a large number of DNA fragments (reads) rapidly, as well as the accuracy of the Smith-Waterman algorithm, which is exclusively employed to deal with the most ambiguous and shortest reads. Experimental results on platforms with Intel multicore processors show that HPGMethyl significantly outperforms in both execution time and sensitivity state-of-the-art software such as Bismark, BS-Seeker or BSMAP, particularly for long bisulfite reads. AVAILABILITY: Software in the form of C libraries and functions, together with instructions to compile and execute this software. Available by sftp to anonymous@clariano.uv.es (password "anonymous"). CONTACT: Juan.Orduna@uv.es.10aBS-seq10aHPC10amethylation10aNGS1 aTárraga, Joaquín1 aPérez, Mariano1 aOrduña, Juan, M1 aDuato, José1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://bioinformatics.oxfordjournals.org/content/31/19/3130.long02147nas a2200301 4500008004100000022001400041245009600055210006900151260001600220520124900236100002101485700002401506700001401530700001401544700002201558700001701580700001701597700001701614700002301631700001701654700001801671700001501689700001901704700001801723700001501741700001801756856007101774 2015 eng d a1546-169600aPrediction of human population responses to toxic compounds by a collaborative competition.0 aPrediction of human population responses to toxic compounds by a c2015 Aug 103 aThe ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson’s r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.1 aEduati, Federica1 aMangravite, Lara, M1 aWang, Tao1 aTang, Hao1 aBare, Christopher1 aHuang, Ruili1 aNorman, Thea1 aKellen, Mike1 aMenden, Michael, P1 aYang, Jichen1 aZhan, Xiaowei1 aZhong, Rui1 aXiao, Guanghua1 aXia, Menghang1 aAbdo, Nour1 aKosyk, Oksana uhttp://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3299.html02330nas a2200265 4500008004100000022001400041245012000055210006900175260001300244300001300257490000700270520140800277653002301685653001301708653003201721653004301753100001901796700001901815700001601834700002401850700002001874700002401894700001501918856013101933 2015 eng d a1362-496200aPTMcode v2: a resource for functional associations of post-translational modifications within and between proteins.0 aPTMcode v2 a resource for functional associations of posttransla c2015 Jan aD494-5020 v433 aThe post-translational regulation of proteins is mainly driven by two molecular events, their modification by several types of moieties and their interaction with other proteins. These two processes are interdependent and together are responsible for the function of the protein in a particular cell state. Several databases focus on the prediction and compilation of protein-protein interactions (PPIs) and no less on the collection and analysis of protein post-translational modifications (PTMs), however, there are no resources that concentrate on describing the regulatory role of PTMs in PPIs. We developed several methods based on residue co-evolution and proximity to predict the functional associations of pairs of PTMs that we apply to modifications in the same protein and between two interacting proteins. In order to make data available for understudied organisms, PTMcode v2 (http://ptmcode.embl.de) includes a new strategy to propagate PTMs from validated modified sites through orthologous proteins. The second release of PTMcode covers 19 eukaryotic species from which we collected more than 300,000 experimentally verified PTMs (>1,300,000 propagated) of 69 types extracting the post-translational regulation of >100,000 proteins and >100,000 interactions. In total, we report 8 million associations of PTMs regulating single proteins and over 9.4 million interplays tuning PPIs.
10aDatabases, Protein10aInternet10aProtein Interaction Mapping10aProtein Processing, Post-Translational1 aMinguez, Pablo1 aLetunic, Ivica1 aParca, Luca1 aGarcía-Alonso, Luz1 aDopazo, Joaquin1 aHuerta-Cepas, Jaime1 aBork, Peer uhttps://www.clinbioinfosspa.es/content/ptmcode-v2-resource-functional-associations-post-translational-modifications-within-and02536nas a2200361 4500008004100000022001400041245008000055210006900135260001300204300001300217490000800230520137100238653001801609653004901627653003401676653001701710653001101727653002801738653002301766653001301789653002501802653002701827653001001854100003301864700002301897700002801920700003301948700002201981700002002003700001902023700002502042856010702067 2015 eng d a1552-483300aRe-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.0 aReevaluation casts doubt on the pathogenicity of homozygous USH2 c2015 Jul a1597-6000 v1673 aMutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.
10aBase Sequence10aCyclic Nucleotide Phosphodiesterases, Type 610aExtracellular Matrix Proteins10aGene Library10aHumans10aMolecular Sequence Data10aMutation, Missense10aPedigree10aRetinitis pigmentosa10aSequence Analysis, DNA10aSpain1 aDel Pozo, María, González-1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aMontero-de-Espinosa, Ignacio1 aMillán, José, M1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttps://www.clinbioinfosspa.es/content/re-evaluation-casts-doubt-pathogenicity-homozygous-ush2a-pc759f02545nas a2200253 4500008004100000022001400041245011200055210006900167260001300236300001100249490000700260520175500267100001902022700002002041700001702061700002002078700001702098700002102115700002302136700002202159700001802181700002102199856007102220 2015 eng d a1872-914200aTherapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides.0 aTherapeutic targets for olive pollen allergy defined by gene mar c2015 Apr a252-610 v643 aTwo regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation-related genes. These results open new research ways to the regulation of allergy by Oleaceae family members.1 aCalzada, David1 aAguerri, Miriam1 aBaos, Selene1 aMontaner, David1 aMata, Manuel1 aDopazo, Joaquín1 aQuiralte, Joaquín1 aFlorido, Fernando1 aLahoz, Carlos1 aCárdaba, Blanca uhttp://www.sciencedirect.com/science/article/pii/S016158901400335602872nas a2200373 4500008004100000022001400041245013900055210006900194260001600263300001400279490000700293520162700300100003001927700002401957700001801981700003201999700002002031700001802051700002802069700002202097700003402119700002602153700003302179700002802212700002702240700001802267700002902285700002002314700002802334700001902362700002002381700001802401856007902419 2015 eng d a1460-208300aWhole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations.0 aWhole Exome Sequencing Reveals ZNF408 as a New Gene Associated W c2015 Apr 16 a4037-40480 v243 aRetinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alex1 aFernadez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W1 aCuenca, Nicolas1 aAyuso, Carmen uhttp://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract03598nas a2200601 4500008004100000022001400041245013900055210006900194260001600263300001200279490000700291520163400298653002401932653001201956653002501968653002301993653001402016653002502030653001002055653003402065653004202099653001502141653001102156653002802167653002002195653001302215653001102228653003702239653003602276653002502312653002602337100003002363700002402393700001802417700003202435700002002467700002302487700002902510700002202539700003402561700002602595700003302621700002802654700002702682700001802709700002902727700002002756700002802776700002102804700002002825700001802845856013302863 2015 eng d a1460-208300aWhole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.0 aWholeexome sequencing reveals ZNF408 as a new gene associated wi c2015 Jul 15 a4037-480 v243 aRetinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.
10aAmino Acid Sequence10aAnimals10aChlorocebus aethiops10aChromosome Mapping10aCOS Cells10aDNA-Binding Proteins10aExome10aGenome-Wide Association Study10aHigh-Throughput Nucleotide Sequencing10aHomozygote10aHumans10aMolecular Sequence Data10aMutant Proteins10aPedigree10aRetina10aRetinal Cone Photoreceptor Cells10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aTranscription Factors1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alejandro1 aFernandez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W J1 aCuenca, Nicolas1 aAyuso, Carmen uhttps://www.clinbioinfosspa.es/content/whole-exome-sequencing-reveals-znf408-new-gene-associated-autosomal-recessive-retinitis-001441nas a2200265 4500008004100000022001400041245009700055210006900152260001600221300001400237490000700251520057300258653000800831653004300839100002300882700001900905700002100924700001700945700001900962700002700981700002901008700002101037700002001058856009701078 2014 eng d a1367-481100aAcceleration of short and long DNA read mapping without loss of accuracy using suffix array.0 aAcceleration of short and long DNA read mapping without loss of c2014 Aug 20 a3396-33980 v303 aHPG Aligner applies suffix arrays for DNA read mapping. This implementation produces a highly sensitive and extremely fast mapping of DNA reads that scales up almost linearly with read length. The approach presented here is faster (over 20x for long reads) and more sensitive (over 98% in a wide range of read lengths) than the current, state-of-the-art mappers. HPG Aligner is not only an optimal alternative for current sequencers but also the only solution available to cope with longer reads and growing throughputs produced by forthcoming sequencing technologies.10aNGS10ashort read mapping. HPC. suffix arrays1 aTárraga, Joaquín1 aArnau, Vicente1 aMartinez, Hector1 aMoreno, Raul1 aCazorla, Diego1 aSalavert-Torres, José1 aBlanquer-Espert, Ignacio1 aDopazo, Joaquín1 aMedina, Ignacio uhttp://bioinformatics.oxfordjournals.org/content/early/2014/08/19/bioinformatics.btu553.long02168nas a2200289 4500008004100000022001400041245017000055210006900225260000900294300000800303490000600311520111200317100002701429700001601456700002901472700002601501700002901527700001901556700002101575700002901596700002701625700002001652700002401672700002401696700002601720856013201746 2014 eng d a2234-943X00aThe Activation of the Sox2 RR2 Pluripotency Transcriptional Reporter in Human Breast Cancer Cell Lines is Dynamic and Labels Cells with Higher Tumorigenic Potential.0 aActivation of the Sox2 RR2 Pluripotency Transcriptional Reporter c2014 a3080 v43 aThe striking similarity displayed at the mechanistic level between tumorigenesis and the generation of induced pluripotent stem cells and the fact that genes and pathways relevant for embryonic development are reactivated during tumor progression highlights the link between pluripotency and cancer. Based on these observations, we tested whether it is possible to use a pluripotency-associated transcriptional reporter, whose activation is driven by the SRR2 enhancer from the Sox2 gene promoter (named S4+ reporter), to isolate cancer stem cells (CSCs) from breast cancer cell lines. The S4+ pluripotency transcriptional reporter allows the isolation of cells with enhanced tumorigenic potential and its activation was switched on and off in the cell lines studied, reflecting a plastic cellular process. Microarray analysis comparing the populations in which the reporter construct is active versus inactive showed that positive cells expressed higher mRNA levels of cytokines (IL-8, IL-6, TNF) and genes (such as ATF3, SNAI2, and KLF6) previously related with the CSC phenotype in breast cancer.
1 aIglesias, Juan, Manuel1 aLeis, Olatz1 aRuiz, Estíbaliz, Pérez1 aBarrie, Juan, Gumuzio1 aGarcia-Garcia, Francisco1 aAduriz, Ariane1 aBeloqui, Izaskun1 aHernandez-Garcia, Susana1 aLopez-Mato, Maria, Paz1 aDopazo, Joaquin1 aPandiella, Atanasio1 aMenendez, Javier, A1 aMartin, Angel, Garcia uhttps://www.clinbioinfosspa.es/content/activation-sox2-rr2-pluripotency-transcriptional-reporter-human-breast-cancer-cell-lines02676nas a2200541 4500008004100000022001400041245013100055210006900186260000900255300000900264490000600273520115300279653001201432100002001444700002001464700001601484700001701500700002501517700001601542700002001558700001801578700002101596700001801617700002001635700002001655700002101675700001401696700001501710700001801725700001901743700002601762700002701788700002701815700001601842700001301858700002101871700002601892700001801918700001601936700001801952700001501970700001501985700001302000700001502013700001302028700001602041856007702057 2014 eng d a2041-172300aAssessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures.0 aAssessing technical performance in differential gene expression c2014 a51250 v53 aThere is a critical need for standard approaches to assess, report and compare the technical performance of genome-scale differential gene expression experiments. Here we assess technical performance with a proposed standard ’dashboard’ of metrics derived from analysis of external spike-in RNA control ratio mixtures. These control ratio mixtures with defined abundance ratios enable assessment of diagnostic performance of differentially expressed transcript lists, limit of detection of ratio (LODR) estimates and expression ratio variability and measurement bias. The performance metrics suite is applicable to analysis of a typical experiment, and here we also apply these metrics to evaluate technical performance among laboratories. An interlaboratory study using identical samples shared among 12 laboratories with three different measurement processes demonstrates generally consistent diagnostic power across 11 laboratories. Ratio measurement variability and bias are also comparable among laboratories for the same measurement process. We observe different biases for measurement processes using different mRNA-enrichment protocols.10aRNA-seq1 aMunro, Sarah, A1 aLund, Steven, P1 aPine, Scott1 aBinder, Hans1 aClevert, Djork-Arné1 aConesa, Ana1 aDopazo, Joaquin1 aFasold, Mario1 aHochreiter, Sepp1 aHong, Huixiao1 aJafari, Nadereh1 aKreil, David, P1 aLabaj, Paweł, P1 aLi, Sheng1 aLiao, Yang1 aLin, Simon, M1 aMeehan, Joseph1 aMason, Christopher, E1 aSantoyo-López, Javier1 aSetterquist, Robert, A1 aShi, Leming1 aShi, Wei1 aSmyth, Gordon, K1 aStralis-Pavese, Nancy1 aSu, Zhenqiang1 aTong, Weida1 aWang, Charles1 aWang, Jian1 aXu, Joshua1 aYe, Zhan1 aYang, Yong1 aYu, Ying1 aSalit, Marc uhttp://www.nature.com/ncomms/2014/140925/ncomms6125/full/ncomms6125.html02750nas a2200217 4500008004100000022001400041245011000055210006900165260000900234300001100243490000600254520206500260100002702325700002002352700002402372700001602396700002102412700001902433700002802452856005202480 2014 eng d a1932-620300aCombined genetic and high-throughput strategies for molecular diagnosis of inherited retinal dystrophies.0 aCombined genetic and highthroughput strategies for molecular dia c2014 ae884100 v93 aMost diagnostic laboratories are confronted with the increasing demand for molecular diagnosis from patients and families and the ever-increasing genetic heterogeneity of visual disorders. Concerning Retinal Dystrophies (RD), almost 200 causative genes have been reported to date, and most families carry private mutations. We aimed to approach RD genetic diagnosis using all the available genetic information to prioritize candidates for mutational screening, and then restrict the number of cases to be analyzed by massive sequencing. We constructed and optimized a comprehensive cosegregation RD-chip based on SNP genotyping and haplotype analysis. The RD-chip allows to genotype 768 selected SNPs (closely linked to 100 RD causative genes) in a single cost-, time-effective step. Full diagnosis was attained in 17/36 Spanish pedigrees, yielding 12 new and 12 previously reported mutations in 9 RD genes. The most frequently mutated genes were USH2A and CRB1. Notably, RD3-up to now only associated to Leber Congenital Amaurosis- was identified as causative of Retinitis Pigmentosa. The main assets of the RD-chip are: i) the robustness of the genetic information that underscores the most probable candidates, ii) the invaluable clues in cases of shared haplotypes, which are indicative of a common founder effect, and iii) the detection of extended haplotypes over closely mapping genes, which substantiates cosegregation, although the assumptions in which the genetic analysis is based could exceptionally lead astray. The combination of the genetic approach with whole exome sequencing (WES) greatly increases the diagnosis efficiency, and revealed novel mutations in USH2A and GUCY2D. Overall, the RD-chip diagnosis efficiency ranges from 16% in dominant, to 80% in consanguineous recessive pedigrees, with an average of 47%, well within the upper range of massive sequencing approaches, highlighting the validity of this time- and cost-effective approach whilst high-throughput methodologies become amenable for routine diagnosis in medium sized labs.1 ade Castro-Miró, Marta1 aPomares, Esther1 aLorés-Motta, Laura1 aTonda, Raul1 aDopazo, Joaquín1 aMarfany, Gemma1 aGonzàlez-Duarte, Roser uhttp://dx.plos.org/10.1371/journal.pone.008841001916nas a2200253 4500008004100000022001400041245013800055210006900193260001600262300001400278490000700292520118400299653000801483653001201491653000901503100001101512700001601523700000501539700001501544700000501559700001601564700001101580856007101591 2014 eng d a1546-169600aA comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium.0 acomprehensive assessment of RNAseq accuracy reproducibility and c2014 Aug 24 a903–9140 v323 aWe present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.10aNGS10aRNA-seq10aSEQC1 aSu, Z.1 aLabaj, P.P.1 a1 aDopazo, J.1 a1 aMason, C.E.1 aShi, L uhttp://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.2957.html02423nas a2200433 4500008004100000022001400041245008500055210006900140260001500209300001400224490000700238520117700245653001501422653001601437653003101453100002001484700002201504700001901526700001901545700001701564700002201581700001901603700002601622700001801648700002301666700002201689700002101711700002001732700001801752700002001770700003001790700002301820700002501843700002001868700002001888700001301908700002001921856004801941 2014 eng d a1538-744500aA Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition.0 aComprehensive DNA Methylation Profile of EpithelialtoMesenchymal c2014 Aug 8 a5608–190 v743 aEpithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-to-epithelial transition (MET). The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype. Herein, we obtained the DNA methylomes at single-base resolution of MDCK cells undergoing epithelial-to-mesenchymal transition (EMT) and translated the identified differentially methylated regions (DMRs) to human breast cancer cells undergoing a gain of migratory and invasive capabilities associated with the EMT phenotype. We noticed dynamic and reversible changes of DNA methylation, both on promoter sequences and gene-bodies in association with transcription regulation of EMT-related genes. Most importantly, the identified DNA methylation markers of EMT were present in primary mammary tumors in association with the epithelial or the mesenchymal phenotype of the studied breast cancer samples.10aMethyl-Seq10aMethylomics10aNext Generation Sequencing1 aCarmona, Javier1 aDavalos, Veronica1 aVidal, Enrique1 aGomez, Antonio1 aHeyn, Holger1 aHashimoto, Yutaka1 aVizoso, Miguel1 aMartinez-Cardus, Anna1 aSayols, Sergi1 aFerreira, Humberto1 aSanchez-Mut, Jose1 aMoran, Sebastian1 aMargeli, Mireia1 aCastella, Eva1 aBerdasco, Maria1 aStefansson, Olafur, Andri1 aEyfjord, Jorunn, E1 aGonzalez-Suarez, Eva1 aDopazo, Joaquin1 aOrozco, Modesto1 aGut, Ivo1 aEsteller, Manel uhttp://www.ncbi.nlm.nih.gov/pubmed/2510642702369nas a2200265 4500008004100000022001400041245009900055210006900154260001300223300001100236490000600247520144900253100003301702700002801735700002701763700002201790700002301812700001901835700002401854700003201878700002001910700001901930700002501949856012901974 2014 eng d a2324-926900aDeciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.0 aDeciphering intrafamilial phenotypic variability by exome sequen c2014 Mar a124-330 v23 aBardet-Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing-based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick-Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.
1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aSantoyo-López, Javier1 aVela-Boza, Alicia1 aBravo-Gil, Nereida1 aRueda, Antonio1 aGarcía-Alonso, Luz1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttps://www.clinbioinfosspa.es/content/deciphering-intrafamilial-phenotypic-variability-exome-sequencing-bardet-biedl-family02250nas a2200241 4500008004100000245010000041210006900141300001200210490000600222520144700228100003301675700002801708700002701736700002201763700002301785700001901808700002401827700003201851700002101883700001901904700002501923856006001948 2014 eng d00aDeciphering intrafamilial phenotypic variability by exome sequencing in a Bardet–Biedl family0 aDeciphering intrafamilial phenotypic variability by exome sequen a124-1330 v23 aBardet–Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing–based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick–Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aSantoyo-López, Javier1 aVela-Boza, Alicia1 aBravo-Gil, Nereida1 aRueda, Antonio1 aGarcía-Alonso, Luz1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquín1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://onlinelibrary.wiley.com/doi/10.1002/mgg3.50/full02780nas a2200445 4500008004100000022001400041245012000055210006900175260000900244300001200253490000600265520144600271653001501717653001001732653002401742653001801766653001001784653002701794653002801821653001001849653001101859653001101870653001101881653002501892653000901917653001601926653002801942653001301970653001301983653002401996653001402020100003302034700002802067700002302095700002202118700002002140700001902160700002502179856013002204 2014 eng d a1932-620300aExome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.0 aExome sequencing reveals novel and recurrent mutations with clin c2014 ae1161760 v93 aThis study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.
10aAdolescent10aAdult10aAmino Acid Sequence10aBase Sequence10aChild10aChromosome Segregation10aDNA Mutational Analysis10aExome10aFamily10aFemale10aHumans10aInheritance Patterns10aMale10aMiddle Aged10aMolecular Sequence Data10amutation10aPedigree10aRetinal Dystrophies10aRhodopsin1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 aVela-Boza, Alicia1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttps://www.clinbioinfosspa.es/content/exome-sequencing-reveals-novel-and-recurrent-mutations-clinical-significance-inherited01989nas a2200181 4500008004100000245008700041210006900128300001400197490000800211520142000219100001901639700001801658700001801676700001501694700001501709700001701724856006601741 2014 eng d00aMolecular interactions between sugar beet and Polymyxa betae during its life cycle0 aMolecular interactions between sugar beet and Polymyxa betae dur a244–2560 v1643 aPolymyxa betae is a biotrophic obligate sugar beet parasite that belongs to plasmodiophorids. The infection of sugar beet roots by this parasite is asymptomatic, except when it transmits Beet necrotic yellow vein virus (BNYVV), the causal agent of rhizomania. To date, there has been little work on P. betae–sugar beet molecular interactions, mainly because of the obligate nature of the parasite and also because research on rhizomania has tended to focus on the virus. In this study, we investigated these interactions through differential transcript analysis, using suppressive subtractive hybridization. The analysis included 76 P. betae and 120 sugar beet expressed sequence tags (ESTs). The expression of selected ESTs from both organisms was monitored during the protist life cycle, revealing a potential role of two P. betae proteins, profilin and a Von Willebrand factor domain-containing protein, in the early phase of infection. This study also revealed an over-expression of some sugar beet genes involved in defence, such as those encoding PR proteins, stress resistance proteins or lectins, especially during the plasmodial stage of the P. betae life cycle. In addition to providing new information on the molecular aspects of P. betae–sugar beet interactions, this study also enabled previously unknown ESTs of P. betae to be sequenced, thus enhancing our knowledge of the genome of this protist.1 aDesoignies, N.1 aCarbonell, J.1 aMoreau, J.-S.1 aConesa, A.1 aDopazo, J.1 aLegrève, A. uhttp://onlinelibrary.wiley.com/doi/10.1111/aab.12095/abstract02492nas a2200577 4500008004100000022001400041245006100055210005800116260001500174300001600189490000700205520082400212653000801036653001901044653001701063100001801080700002101098700002101119700002801140700002301168700001701191700002201208700002201230700003001252700001601282700002001298700002601318700002901344700002201373700002201395700002001417700002901437700002701466700002101493700001701514700002201531700002101553700002401574700002201598700002901620700002701649700002001676700002001696700002501716700002101741700002001762700001601782700002801798700002101826856006701847 2014 eng d a1098-100400aA New Overgrowth Syndrome is Due to Mutations in RNF125.0 aNew Overgrowth Syndrome is Due to Mutations in RNF125 c2014 Sep 5 a1436–14410 v353 aOvergrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known overgrowth syndrome. We identified one de novo deletion and three missense mutations in RNF125 in six patients from 4 families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycaemia and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors. This article is protected by copyright. All rights reserved.10aNGS10aprioritization10aRare Disease1 aTenorio, Jair1 aMansilla, Alicia1 aValencia, María1 aMartínez-Glez, Víctor1 aRomanelli, Valeria1 aArias, Pedro1 aCastrejón, Nerea1 aPoletta, Fernando1 aGuillén-Navarro, Encarna1 aGordo, Gema1 aMansilla, Elena1 aGarcía-Santiago, Fé1 aGonzález-Casado, Isabel1 aVallespín, Elena1 aPalomares, María1 aMori, María, A1 aSantos-Simarro, Fernando1 aGarcía-Miñaur, Sixto1 aFernández, Luis1 aMena, Rocío1 aBenito-Sanz, Sara1 aDel Pozo, Angela1 aSilla, Juan, Carlos1 aIbañez, Kristina1 aLópez-Granados, Eduardo1 aMartín-Trujillo, Alex1 aMontaner, David1 aHeath, Karen, E1 aCampos-Barros, Angel1 aDopazo, Joaquín1 aNevado, Julián1 aMonk, David1 aRuiz-Pérez, Víctor, L1 aLapunzina, Pablo uhttp://onlinelibrary.wiley.com/doi/10.1002/humu.22689/abstract01770nas a2200229 4500008004100000022001400041245007700055210006900132260001500201300001000216490000700226520109900233100001501332700002301347700001201370700002501382700001701407700001501424700001301439700001601452856007201468 2014 eng d a1873-236400aA novel locus for a hereditary recurrent neuropathy on chromosome 21q21.0 anovel locus for a hereditary recurrent neuropathy on chromosome c2014 May 9 a660-50 v243 aHereditary recurrent neuropathies are uncommon. Disorders with a known molecular basis falling within this group include hereditary neuropathy with liability to pressure palsies (HNPP) due to the deletion of the PMP22 gene or to mutations in this same gene, and hereditary neuralgic amyotrophy (HNA) caused by mutations in the SEPT9 gene. We report a three-generation family presenting a hereditary recurrent neuropathy without pathological changes in either PMP22 or SEPT9 genes. We performed a genome-wide mapping, which yielded a locus of 12.4Mb on chromosome 21q21. The constructed haplotype fully segregated with the disease and we found significant evidence of linkage. After mutational screening of genes located within this locus, encoding for proteins and microRNAs, as well as analysis of large deletions/insertions, we identified 71 benign polymorphisms. Our findings suggest a novel genetic locus for a recurrent hereditary neuropathy of which the molecular defect remains elusive. Our results further underscore the clinical and genetic heterogeneity of this group of neuropathies.1 aCalpena, E1 aMartínez-Rubio, D1 aArpa, J1 aGarcía-Peñas, J, J1 aMontaner, D.1 aDopazo, J.1 aPalau, F1 aEspinós, C uhttp://www.sciencedirect.com/science/article/pii/S0960896614001060#03765nas a2200397 4500008004100000022001400041245013500055210006900190260001600259300000800275490000700283520244800290653002602738653001802764653002502782653002802807653001702835653002102852653003202873653001102905653002702916653003602943653002302979653001303002653001403015653001103029653002503040100002803065700002303093700003303116700002203149700002003171700001903191700002503210856013203235 2014 eng d a1471-215600aNovel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.0 aNovel RP1 mutations and a recurrent BBS1 variant explain the coe c2014 Dec 14 a1430 v153 aBACKGROUND: Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).
RESULTS: Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.
CONCLUSIONS: The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.
10aBardet-Biedl Syndrome10aBase Sequence10aCase-Control Studies10aDNA Mutational Analysis10aEye Proteins10aGenes, Recessive10aGenetic Association Studies10aHumans10aMicrosatellite Repeats10aMicrotubule-Associated Proteins10aMutation, Missense10aPedigree10aPhenotype10aRetina10aRetinitis pigmentosa1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 adel Pozo, María, González-1 aVela-Boza, Alicia1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttps://www.clinbioinfosspa.es/content/novel-rp1-mutations-and-recurrent-bbs1-variant-explain-co-existence-two-distinct-retinal03075nas a2200385 4500008004100000022001400041245005700055210005600112260000900168300000700177490001400184520197500198653002202173653001502195653002002210653003002230653002902260653002002289653001502309653003002324653001602354653001202370653002902382653002002411653001402431100002102445700001802466700002002484700001802504700002002522700002102542700002002563700001602583856009002599 2014 eng d a1752-050900aPathway network inference from gene expression data.0 aPathway network inference from gene expression data c2014 aS70 v8 Suppl 23 aBACKGROUND: The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules.
RESULTS: We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example.
CONCLUSIONS: PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network's topology obtained for the yeast cell cycle data.
10aAlzheimer Disease10aCell Cycle10aDNA Replication10aGene Expression Profiling10aGene Regulatory Networks10aGluconeogenesis10aGlycolysis10aOxidative Phosphorylation10aProteolysis10aPurines10aSaccharomyces cerevisiae10aSystems biology10aUbiquitin1 aPonzoni, Ignacio1 aNueda, María1 aTarazona, Sonia1 aGötz, Stefan1 aMontaner, David1 aDussaut, Julieta1 aDopazo, Joaquin1 aConesa, Ana uhttps://www.clinbioinfosspa.es/content/pathway-network-inference-gene-expression-data02479nas a2200205 4500008004100000022001400041245013400055210006900189260001600258520174200274100002202016700002902038700002902067700001802096700001902114700002302133700002002156700002202176856007502198 2014 eng d a1460-243100aProgrammed cell death activated by Rose Bengal in Arabidopsis thaliana cell suspension cultures requires functional chloroplasts.0 aProgrammed cell death activated by Rose Bengal in Arabidopsis th c2014 Apr 103 aLight-grown Arabidopsis thaliana cell suspension culture (ACSC) were subjected to mild photooxidative damage with Rose Bengal (RB) with the aim of gaining a better understanding of singlet oxygen-mediated defence responses in plants. Additionally, ACSC were treated with H2O2 at concentrations that induced comparable levels of protein oxidation damage. Under low to medium light conditions, both RB and H2O2 treatments activated transcriptional defence responses and inhibited photosynthetic activity, but they differed in that programmed cell death (PCD) was only observed in cells treated with RB. When dark-grown ACSC were subjected to RB in the light, PCD was suppressed, indicating that the singlet oxygen-mediated signalling pathway in ACSC requires functional chloroplasts. Analysis of up-regulated transcripts in light-grown ACSC, treated with RB in the light, showed that both singlet oxygen-responsive transcripts and transcripts with a key role in hormone-activated PCD (i.e. ethylene and jasmonic acid) were present. A co-regulation analysis proved that ACSC treated with RB exhibited higher correlation with the conditional fluorescence (flu) mutant than with other singlet oxygen-producing mutants or wild-type plants subjected to high light. However, there was no evidence for the up-regulation of EDS1, suggesting that activation of PCD was not associated with the EXECUTER- and EDS1-dependent signalling pathway described in the flu mutant. Indigo Carmine and Methylene Violet, two photosensitizers unable to enter chloroplasts, did not activate transcriptional defence responses in ACSC; however, whether this was due to their location or to their inherently low singlet oxygen quantum efficiencies was not determined.1 aGutiérrez, Jorge1 aGonzález-Pérez, Sergio1 aGarcia-Garcia, Francisco1 aDaly, Cara, T1 aLorenzo, Oscar1 aRevuelta, José, L1 aMcCabe, Paul, F1 aArellano, Juan, B uhttp://jxb.oxfordjournals.org/content/early/2014/04/09/jxb.eru151.long02925nas a2200409 4500008004100000022001400041245011400055210006900169260001300238300001000251490000700261520165700268653001201925653001501937653001101952653003901963653001802002653001902020653001202039653003102051653001302082653000902095653001402104653001602118653002702134653002402161653001802185100002102203700002502224700003102249700001602280700002002296700001802316700002502334700003202359856012402391 2014 eng d a1096-093700aSequencing and functional analysis of the genome of a nematode egg-parasitic fungus, Pochonia chlamydosporia.0 aSequencing and functional analysis of the genome of a nematode e c2014 Apr a69-800 v653 aPochonia chlamydosporia is a worldwide-distributed soil fungus with a great capacity to infect and destroy the eggs and kill females of plant-parasitic nematodes. Additionally, it has the ability to colonize endophytically roots of economically-important crop plants, thereby promoting their growth and eliciting plant defenses. This multitrophic behavior makes P. chlamydosporia a potentially useful tool for sustainable agriculture approaches. We sequenced and assembled ∼41 Mb of P. chlamydosporia genomic DNA and predicted 12,122 gene models, of which many were homologous to genes of fungal pathogens of invertebrates and fungal plant pathogens. Predicted genes (65%) were functionally annotated according to Gene Ontology, and 16% of them found to share homology with genes in the Pathogen Host Interactions (PHI) database. The genome of this fungus is highly enriched in genes encoding hydrolytic enzymes, such as proteases, glycoside hydrolases and carbohydrate esterases. We used RNA-Seq technology in order to identify the genes expressed during endophytic behavior of P. chlamydosporia when colonizing barley roots. Functional annotation of these genes showed that hydrolytic enzymes and transporters are expressed during endophytism. This structural and functional analysis of the P. chlamydosporia genome provides a starting point for understanding the molecular mechanisms involved in the multitrophic lifestyle of this fungus. The genomic information provided here should also prove useful for enhancing the capabilities of this fungus as a biocontrol agent of plant-parasitic nematodes and as a plant growth-promoting organism.
10aAnimals10aAscomycota10aFemale10aGene Expression Regulation, Fungal10aGene ontology10aGenome, Fungal10aHordeum10aHost-Pathogen Interactions10aNematoda10aOvum10aPhylogeny10aPlant Roots10aSequence Analysis, DNA10aSignal Transduction10aTranscriptome1 aLarriba, Eduardo1 aJaime, María, D L A1 aCarbonell-Caballero, José1 aConesa, Ana1 aDopazo, Joaquin1 aNislow, Corey1 aMartín-Nieto, José1 aLopez-Llorca, Luis, Vicente uhttps://www.clinbioinfosspa.es/content/sequencing-and-functional-analysis-genome-nematode-egg-parasitic-fungus-pochonia03200nas a2200517 4500008004100000022001400041245017300055210006900228260001300297300001000310490000700320520152000327653003201847653003101879653001601910653001101926653000901937653002301946653002801969653001501997653002002012100002802032700002302060700001602083700002402099700002502123700002102148700001902169700002202188700002102210700002002231700002002251700002202271700001902293700002102312700002802333700002202361700002002383700001702403700002702420700002602447700002102473700002402494700002802518856013602546 2014 eng d a1098-100400aTwo novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.0 aTwo novel mutations in the BCKDK branchedchain ketoacid dehydrog c2014 Apr a470-70 v353 aInactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.
10aAmino Acids, Branched-Chain10aDevelopmental Disabilities10aFibroblasts10aHumans10aMale10aMutation, Missense10aNervous System Diseases10aPediatrics10aProtein Kinases1 aGarcía-Cazorla, Angels1 aOyarzabal, Alfonso1 aFort, Joana1 aRobles, Concepción1 aCastejón, Esperanza1 aRuiz-Sala, Pedro1 aBodoy, Susanna1 aMerinero, Begoña1 aLopez-Sala, Anna1 aDopazo, Joaquin1 aNunes, Virginia1 aUgarte, Magdalena1 aArtuch, Rafael1 aPalacín, Manuel1 aRodríguez-Pombo, Pilar1 aAlcaide, Patricia1 aNavarrete, Rosa1 aSanz, Paloma1 aFont-Llitjós, Mariona1 aVilaseca, Ma, Antonia1 aOrmaizabal, Aida1 aPristoupilova, Anna1 aAgulló, Sergi, Beltran uhttps://www.clinbioinfosspa.es/content/two-novel-mutations-bckdk-branched-chain-keto-acid-dehydrogenase-kinase-gene-are-responsible02611nas a2200313 4500008004100000022001400041245017200055210006900227260001600296300001000312490000700322520157100329100002801900700002301928700001601951700002401967700002501991700002102016700001902037700002202056700002102078700002102099700002002120700002202140700001902162700002102181700002802202856006702230 2014 eng d a1098-100400aTwo Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients.0 aTwo Novel Mutations in the BCKDK Gene BranchedChain KetoAcid Deh c2014 Jan 21 a470-70 v353 aInactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain keto-acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients’ clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention. This article is protected by copyright. All rights reserved.1 aGarcía-Cazorla, Angels1 aOyarzabal, Alfonso1 aFort, Joana1 aRobles, Concepción1 aCastejón, Esperanza1 aRuiz-Sala, Pedro1 aBodoy, Susanna1 aMerinero, Begoña1 aLopez-Sala, Anna1 aDopazo, Joaquín1 aNunes, Virginia1 aUgarte, Magdalena1 aArtuch, Rafael1 aPalacín, Manuel1 aRodríguez-Pombo, Pilar uhttp://onlinelibrary.wiley.com/doi/10.1002/humu.22513/abstract00806nas a2200241 4500008004100000245008100041210006900122260000700191300000800198490000600206100003000212700001900242700001900261700001600280700002000296700001900316700001900335700003200354700002400386700002000410700002000430856011400450 2014 eng d00aUnderstanding disease mechanisms with models of signaling pathway activities0 aUnderstanding disease mechanisms with models of signaling pathwa c10 a1210 v81 aSebastián-Leon, Patricia1 aVidal, Enrique1 aMinguez, Pablo1 aConesa, Ana1 aTarazona, Sonia1 aAmadoz, Alicia1 aArmero, Carmen1 aTorres, Francisco, Salavert1 aVidal-Puig, Antonio1 aMontaner, David1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/understanding-disease-mechanisms-models-signaling-pathway-activities-102249nas a2200313 4500008004100000022001400041245008200055210006900137260001600206300000800222490000600230520134100236653002201577653001201599653001501611653002001626100003001646700001901676700001901695700001601714700002001730700001901750700001901769700002401788700002401812700002001836700002101856856005801877 2014 eng d a1752-050900aUnderstanding disease mechanisms with models of signaling pathway activities.0 aUnderstanding disease mechanisms with models of signaling pathwa c2014 Oct 25 a1210 v83 aBackgroundUnderstanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine.ResultsHere we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets.ConclusionsThe proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.10aDisease mechanism10apathway10asignalling10aSystems biology1 aSebastián-Leon, Patricia1 aVidal, Enrique1 aMinguez, Pablo1 aConesa, Ana1 aTarazona, Sonia1 aAmadoz, Alicia1 aArmero, Carmen1 aSalavert, Francisco1 aVidal-Puig, Antonio1 aMontaner, David1 aDopazo, Joaquín uhttp://www.biomedcentral.com/1752-0509/8/121/abstract01799nas a2200217 4500008004100000022001400041245013800055210006900193260001600262300001200278490000700290520106000297653001501357653003501372653000801407100002301415700002901438700002001467700002101487856007301508 2014 eng d a1362-496200aA web tool for the design and management of panels of genes for targeted enrichment and massive sequencing for clinical applications.0 aweb tool for the design and management of panels of genes for ta c2014 May 26 aW83-W870 v423 aDisease targeted sequencing is gaining importance as a powerful and cost-effective application of high throughput sequencing technologies to the diagnosis. However, the lack of proper tools to process the data hinders its extensive adoption. Here we present TEAM, an intuitive and easy-to-use web tool that fills the gap between the predicted mutations and the final diagnostic in targeted enrichment sequencing analysis. The tool searches for known diagnostic mutations, corresponding to a disease panel, among the predicted patient’s variants. Diagnostic variants for the disease are taken from four databases of disease-related variants (HGMD-public, HUMSAVAR, ClinVar and COSMIC.) If no primary diagnostic variant is found, then a list of secondary findings that can help to establish a diagnostic is produced. TEAM also provides with an interface for the definition of and customization of panels, by means of which, genes and mutations can be added or discarded to adjust panel definitions. TEAM is freely available at: http://team.babelomics.org.10aDiagnostic10aTargeted enrichment sequencing10aWES1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2486162602033nas a2200205 4500008004100000022001400041245013200055210006900187260001500256300001300271490000700284520134300291653002401634100002301658700002901681700002401710700002001734700002101754856005201775 2014 eng d a1362-496200aA web-based interactive framework to assist in the prioritization of disease candidate genes in whole-exome sequencing studies.0 awebbased interactive framework to assist in the prioritization o c2014 May 6 aW88-W93.0 v423 aWhole-exome sequencing has become a fundamental tool for the discovery of disease-related genes of familial diseases and the identification of somatic driver variants in cancer. However, finding the causal mutation among the enormous background of individual variability in a small number of samples is still a big challenge. Here we describe a web-based tool, BiERapp, which efficiently helps in the identification of causative variants in family and sporadic genetic diseases. The program reads lists of predicted variants (nucleotide substitutions and indels) in affected individuals or tumor samples and controls. In family studies, different modes of inheritance can easily be defined to filter out variants that do not segregate with the disease along the family. Moreover, BiERapp integrates additional information such as allelic frequencies in the general population and the most popular damaging scores to further narrow down the number of putative variants in successive filtering steps. BiERapp provides an interactive and user-friendly interface that implements the filtering strategy used in the context of a large-scale genomic project carried out by the Spanish Network for Research in Rare Diseases (CIBERER) in which more than 800 exomes have been analyzed. BiERapp is freely available at: http://bierapp.babelomics.org/10aNGS. prioritization1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aSalavert, Francisco1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/42/W1/W8801651nas a2200193 4500008004100000245012700041210006900168260001600237520097000253100002101223700002301244700002701267700001801294700002701312700002001339700002001359700002101379856005701400 2013 eng d00aAssessing Differential Expression Measurements by Highly Parallel Pyrosequencing and DNA Microarrays: A Comparative Study.0 aAssessing Differential Expression Measurements by Highly Paralle c2011 Sep 153 aAbstract To explore the feasibility of pyrosequencing for quantitative differential gene expression analysis we have performed a comparative study of the results of the sequencing experiments to those obtained by a conventional DNA microarray platform. A conclusion from our analysis is that, over a threshold of 35 normalized reads per gene, the measurements of gene expression display a good correlation with the references. The observed concordance between pyrosequencing and DNA microarray platforms beyond the threshold was of 0.8, measured as a Pearson’s correlation coefficient. In differential gene expression the initial aim is the quantification the differences among transcripts when comparing experimental conditions. Thus, even in a scenario of low coverage the concordance in the measurements is quite acceptable. On the other hand, the comparatively longer read size obtained by pyrosequencing allows detecting unconventional splicing forms.
1 aAriño, Joaquín1 aCasamayor, Antonio1 aPérez, Julián, Perez1 aPedrola, Laia1 aAlvarez-Tejado, Miguel1 aMarbà, Martina1 aSantoyo, Javier1 aDopazo, Joaquín uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545353/02299nas a2200253 4500008004100000022001400041245013400055210006900189260001600258520136900274100003001643700002601673700002901699700002201728700001801750700003401768700001901802700002001821700001801841700002101859700002101880700001701901856012701918 2013 eng d a1949-255300aCapturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer.0 aCapturing the biological impact of CDKN2A and MC1R genes as an e c2013 Dec 163 aGermline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development.1 aPuig-Butille, Joan, Anton1 aEscamez, Maria, José1 aGarcia-Garcia, Francisco1 aTell-Marti, Gemma1 aFabra, Angels1 aMartínez-Santamaría, Lucía1 aBadenas, Celia1 aAguilera, Paula1 aPevida, Marta1 aDopazo, Joaquín1 aDel Rio, Marcela1 aPuig, Susana uhttp://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=1444&path%5B%5D=182402642nas a2200397 4500008004100000022001400041245009900055210006900154260000900223300001100232490000600243520136900249653003101618653001601649653002501665653002601690653002501716653003001741653002901771653001801800653001101818653003401829653002701863653002601890100001801916700002601934700002401960700002001984700001702004700001902021700002002040700002002060700001602080700001802096856013002114 2013 eng d a1932-620300aDefining the genomic signature of totipotency and pluripotency during early human development.0 aDefining the genomic signature of totipotency and pluripotency d c2013 ae621350 v83 aThe genetic mechanisms governing human pre-implantation embryo development and the in vitro counterparts, human embryonic stem cells (hESCs), still remain incomplete. Previous global genome studies demonstrated that totipotent blastomeres from day-3 human embryos and pluripotent inner cell masses (ICMs) from blastocysts, display unique and differing transcriptomes. Nevertheless, comparative gene expression analysis has revealed that no significant differences exist between hESCs derived from blastomeres versus those obtained from ICMs, suggesting that pluripotent hESCs involve a new developmental progression. To understand early human stages evolution, we developed an undifferentiation network signature (UNS) and applied it to a differential gene expression profile between single blastomeres from day-3 embryos, ICMs and hESCs. This allowed us to establish a unique signature composed of highly interconnected genes characteristic of totipotency (61 genes), in vivo pluripotency (20 genes), and in vitro pluripotency (107 genes), and which are also proprietary according to functional analysis. This systems biology approach has led to an improved understanding of the molecular and signaling processes governing human pre-implantation embryo development, as well as enabling us to comprehend how hESCs might adapt to in vitro culture conditions.
10aBlastocyst Inner Cell Mass10aBlastomeres10aCell Differentiation10aEmbryonic Development10aEmbryonic Stem Cells10aGene Expression Profiling10aGene Regulatory Networks10aGenome, Human10aHumans10aMolecular Sequence Annotation10aPluripotent Stem Cells10aTotipotent Stem Cells1 aGalan, Amparo1 aDiaz-Gimeno, Patricia1 aPoo, Maria, Eugenia1 aValbuena, Diana1 aSanchez, Eva1 aRuiz, Veronica1 aDopazo, Joaquin1 aMontaner, David1 aConesa, Ana1 aSimon, Carlos uhttps://www.clinbioinfosspa.es/content/defining-genomic-signature-totipotency-and-pluripotency-during-early-human-development02843nas a2200349 4500008004100000022001400041245010300055210006900158260001700227300001100244490000700255520180200262653001002064653001102074653003002085653001102115653000902126653001602135653000902151653003302160653003302193100001502226700001502241700001602256700001202272700001502284700001602299700001402315700001302329700001502342856013602357 2013 eng d a0393-974X00aDifferential gene-expression analysis defines a molecular pattern related to olive pollen allergy.0 aDifferential geneexpression analysis defines a molecular pattern c2013 Apr-Jun a337-500 v273 aAnalysis of gene-expression profiles by microarrays is useful for characterization of candidate genes, key regulatory networks, and to define phenotypes or molecular signatures which improve the diagnosis and/or classification of the allergic processes. We have used this approach in the study of olive pollen response in order to find differential molecular markers among responders and non-responders to this allergenic source. Five clinical groups, non-allergic, asymptomatic, allergic but not to olive pollen, untreated-olive-pollen allergic patients and olive-pollen allergic patients (under specific-immunotherapy), were assessed during and outside pollen seasons. Whole-genome gene expression analysis was performed in RNAs extracted from PBMCs. After assessment of data quality and principal components analysis (PCA), differential gene-expression, by multiple testing and, functional analyses by KEGG, for pathways and Gene-Ontology for biological processes were performed. Relevance was defined by fold change and corrected P values (less than 0.05). The most differential genes were validated by qRT-PCR in a larger set of individuals. Interestingly, gene-expression profiling obtained by PCA clearly showed five clusters of samples that correlated with the five clinical groups. Furthermore, differential gene expression and functional analyses revealed differential genes and pathways in the five clinical groups. The 93 most significant genes found were validated, and one set of 35 genes was able to discriminate profiles of olive pollen response. Our results, in addition to providing new information on allergic response, define a possible molecular signature for olive pollen allergy which could be useful for the diagnosis and treatment of this and other sensitizations.
10aAdult10aFemale10aGene Expression Profiling10aHumans10aMale10aMiddle Aged10aOlea10aPrincipal Component Analysis10aRhinitis, Allergic, Seasonal1 aAguerri, M1 aCalzada, D1 aMontaner, D1 aMata, M1 aFlorido, F1 aQuiralte, J1 aDopazo, J1 aLahoz, C1 aCardaba, B uhttps://www.clinbioinfosspa.es/content/differential-gene-expression-analysis-defines-molecular-pattern-related-olive-pollen-allergy00483nas a2200133 4500008004100000022002200041245005800063210005700121300001200178490000600190100002900196700002000225856010400245 2013 eng d a978-84-9858-872-900aDocencia en Estadística: Experiencias de Innovación0 aDocencia en Estadística Experiencias de Innovación a201-2100 v11 aGarcia-Garcia, Francisco1 aMontaner, David uhttps://www.clinbioinfosspa.es/content/docencia-en-estad%C3%ADstica-experiencias-de-innovaci%C3%B3n02468nas a2200325 4500008004100000022001400041245005000055210004800105260001500153300001200168490000700180520163100187653000801818653001801826653001001844653001501854653003101869653000801900653000801908653000801916100002001924700002401944700002101968700002401989700002002013700001902033700001702052700002102069856005202090 2013 eng d a1362-496200aGenome Maps, a new generation genome browser.0 aGenome Maps a new generation genome browser c2013 Jun 8 aW41-W460 v413 aGenome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org.10aBAM10agenome viewer10aHTML510ajavascript10aNext Generation Sequencing10aNGS10aSVG10aVCF1 aMedina, Ignacio1 aSalavert, Francisco1 aSánchez, Rubén1 aDe Maria, Alejandro1 aAlonso, Roberto1 aEscobar, Pablo1 aBleda, Marta1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/41/W1/W4102403nas a2200229 4500008004100000022001400041245013500055210006900190260001600259520156900275100002601844700002301870700002001893700002801913700002901941700002101970700002601991700002902017700002202046700002002068856008502088 2013 eng d a1460-218000aGrape antioxidant dietary fiber (GADF) inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.0 aGrape antioxidant dietary fiber GADF inhibits intestinal polypos c2013 Apr 243 aEpidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin-rich dietary fiber (Grape Antioxidant Dietary Fiber, GADF) on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1 mm (65%), 1-2 mm (67%) and >2 mm (87%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine a decrease of 76%, 81% and 73% was observed respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer.1 aSánchez-Tena, Susana1 aLizarraga, Daneida1 aMiranda, Anibal1 aVinardell, Maria, Pilar1 aGarcia-Garcia, Francisco1 aDopazo, Joaquín1 aTorres, Josep, Lluís1 aSaura-Calixto, Fulgencio1 aCapellà, Gabriel1 aCascante, Marta uhttp://carcin.oxfordjournals.org/content/early/2013/04/23/carcin.bgt140.abstract03047nas a2200481 4500008004100000022001400041245012800055210006900183260001300252300001100265490000700276520158000283653001201863653001701875653001601892653001901908653001501927653002701942653002501969653001801994653002402012653002002036653001302056653001702069653002502086653002202111653002102133653000902154653000902163653001802172653001002190100002602200700002302226700002002249700002402269700002902293700002002322700002102342700002902363700002202392700002002414856013102434 2013 eng d a1460-218000aGrape antioxidant dietary fiber inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.0 aGrape antioxidant dietary fiber inhibits intestinal polyposis in c2013 Aug a1881-80 v343 aEpidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin (PA)-rich dietary fiber [grape antioxidant dietary fiber (GADF)] on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1mm (65%), 1-2mm (67%) and >2mm (87%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine, a decrease of 76, 81 and 73% was observed, respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer.
10aAnimals10aAntioxidants10aBody Weight10aCarcinogenesis10aCell Cycle10aCell Cycle Checkpoints10aColorectal Neoplasms10aDietary Fiber10aDietary Supplements10aDown-Regulation10aG1 Phase10aInflammation10aIntestinal Polyposis10aIntestinal Polyps10aIntestine, Small10aMale10aMice10aTranscriptome10aVitis1 aSánchez-Tena, Susana1 aLizarraga, Daneida1 aMiranda, Anibal1 aVinardell, Maria, P1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aTorres, Josep, L1 aSaura-Calixto, Fulgencio1 aCapellà, Gabriel1 aCascante, Marta uhttps://www.clinbioinfosspa.es/content/grape-antioxidant-dietary-fiber-inhibits-intestinal-polyposis-apcmin-mice-relation-cell02231nas a2200313 4500008004100000022001400041245008600055210006900141260001300210300001100223490000700234520127400241653001201515653001101527653001301538653000901551653002401560653002801584653002401612653001301636653001801649100003001667700002101697700002401718700002101742700002001763700002001783856011401803 2013 eng d a1362-496200aInferring the functional effect of gene expression changes in signaling pathways.0 aInferring the functional effect of gene expression changes in si c2013 Jul aW213-70 v413 aSignaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case-control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/.
10aAnimals10aHumans10aInternet10aMice10aModels, Statistical10aReceptors, Cell Surface10aSignal Transduction10aSoftware10aTranscriptome1 aSebastián-Leon, Patricia1 aCarbonell, José1 aSalavert, Francisco1 aSánchez, Rubén1 aMedina, Ignacio1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/inferring-functional-effect-gene-expression-changes-signaling-pathways02931nas a2200445 4500008004100000022001400041245009600055210006900151260000900220300001100229490000600240520152900246653002101775653001401796653002101810653002301831653002101854653001101875653002001886653003001906653004301936653003001979653001102009653001602020653002602036653002402062653002602086100002702112700002102139700002902160700001602189700003002205700002002235700001702255700001802272700002402290700002002314700002102334856013002355 2013 eng d a1932-620300aMammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin.0 aMammosphere formation in breast carcinoma cell lines depends upo c2013 ae772810 v83 aTumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.
10aBreast Neoplasms10aCadherins10aCell Line, Tumor10aCell Proliferation10aCluster Analysis10aFemale10agene expression10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aGene Knockdown Techniques10aHumans10aMCF-7 Cells10aNeoplastic Stem Cells10aSpheroids, Cellular10aTumor Cells, Cultured1 aIglesias, Juan, Manuel1 aBeloqui, Izaskun1 aGarcia-Garcia, Francisco1 aLeis, Olatz1 aVazquez-Martin, Alejandro1 aEguiara, Arrate1 aCufi, Silvia1 aPavon, Andres1 aMenendez, Javier, A1 aDopazo, Joaquin1 aMartin, Angel, G uhttps://www.clinbioinfosspa.es/content/mammosphere-formation-breast-carcinoma-cell-lines-depends-upon-expression-e-cadherin-002347nas a2200253 4500008004100000245009500041210006900136260004200205300001300247490000600260520152900266100002701795700002101822700002901843700001601872700003001888700002001918700001701938700001801955700002501973700002001998700002202018856005302040 2013 eng d00aMammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin0 aMammosphere Formation in Breast Carcinoma Cell Lines Depends upo bPublic Library of Sciencec2013/10/04 ae77281 -0 v83 aTumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.
1 aIglesias, Juan, Manuel1 aBeloqui, Izaskun1 aGarcia-Garcia, Francisco1 aLeis, Olatz1 aVazquez-Martin, Alejandro1 aEguiara, Arrate1 aCufi, Silvia1 aPavon, Andres1 aMenendez, Javier, A.1 aDopazo, Joaquin1 aMartin, Angel, G. uhttp://dx.doi.org/10.1371%2Fjournal.pone.007728100733nas a2200229 4500008004100000020002200041245006900063210006800132260004000200653002900240653001400269653001300283653001100296653001600307100002700323700001700350700002400367700002100391700002000412700002000432856005100452 2013 eng d a978-3-642-36948-300aMulticore and Cloud-based Solutions for Genomic Variant Analysis0 aMulticore and Cloudbased Solutions for Genomic Variant Analysis aBerlin, HeidelbergbSpringer-Verlag10agenomic variant analysis10amulticore10amutation10aOpenMP10aweb service1 aGonzalez, Cristina, Y.1 aBleda, Marta1 aSalavert, Francisco1 aSánchez, Rubén1 aDopazo, Joaquin1 aMedina, Ignacio uhttp://dx.doi.org/10.1007/978-3-642-36949-0_3002727nas a2200505 4500008004100000022001400041245018900055210006900244260001300313300001000326490000700336520107200343653002801415653001001443653000901453653002201462653001101484653003801495653001101533653003001544653004401574653004301618653001601661653001101677653001701688653005001705653001401755653000901769653001601778653002001794653001401814653003201828653002801860653000901888653001901897653002101916100003001937700001901967700002001986700002002006700002902026700002002055700001702075856012902092 2013 eng d a1600-062500aRole of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.0 aRole of CPI17 in restoring skin homoeostasis in cutaneous field c2013 Jul a494-60 v223 aCutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P = 0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P = 0.012) and IL-1B (P = 0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.
10aAdministration, Topical10aAdult10aAged10aAged, 80 and over10aBiopsy10aDeoxyribodipyrimidine Photo-Lyase10aFemale10aGene Expression Profiling10aGene Expression Regulation, Enzymologic10aGene Expression Regulation, Neoplastic10aHomeostasis10aHumans10aInflammation10aIntracellular Signaling Peptides and Proteins10aLiposomes10aMale10aMiddle Aged10aMuscle Proteins10aPhenotype10aPhosphoprotein Phosphatases10aReactive Oxygen Species10aSkin10aSkin Neoplasms10aUltraviolet Rays1 aPuig-Butille, Joan, Anton1 aMalvehy, Josep1 aPotrony, Miriam1 aTrullas, Carles1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aPuig, Susana uhttps://www.clinbioinfosspa.es/content/role-cpi-17-restoring-skin-homoeostasis-cutaneous-field-cancerization-effects-topical03066nas a2200241 4500008004100000022001400041245015200055210006900207260000900276300001200285490000700297520223800304100002802542700003302570700002202603700002702625700003302652700003202685700002002717700001902737700002502756856004302781 2013 eng d a1090-053500aWhole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.0 aWholeexome sequencing identifies novel compound heterozygous mut c2013 a2187-950 v193 aPURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.1 aMéndez-Vidal, Cristina1 adel Pozo, María, González-1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aLópez-Domingo, Francisco, J1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://www.molvis.org/molvis/v19/2187/02076nas a2200241 4500008004100000022001400041245014000055210006900195260001300264300001200277490000700289520129000296100001701586700002301603700002401626700002401650700002401674700001901698700001901717700002001736700002001756856005801776 2012 eng d a1362-496200aCellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources.0 aCellBase a comprehensive collection of RESTful web services for c2012 Jul aW609-140 v403 aDuring the past years, the advances in high-throughput technologies have produced an unprecedented growth in the number and size of repositories and databases storing relevant biological data. Today, there is more biological information than ever but, unfortunately, the current status of many of these repositories is far from being optimal. Some of the most common problems are that the information is spread out in many small databases; frequently there are different standards among repositories and some databases are no longer supported or they contain too specific and unconnected information. In addition, data size is increasingly becoming an obstacle when accessing or storing biological data. All these issues make very difficult to extract and integrate information from different sources, to analyze experiments or to access and query this information in a programmatic way. CellBase provides a solution to the growing necessity of integration by easing the access to biological data. CellBase implements a set of RESTful web services that query a centralized database containing the most relevant biological data sources. The database is hosted in our servers and is regularly updated. CellBase documentation can be found at http://docs.bioinfo.cipf.es/projects/cellbase.1 aBleda, Marta1 aTárraga, Joaquín1 aDe Maria, Alejandro1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aCelma, Matilde1 aMartin, Ainoha1 aDopazo, Joaquin1 aMedina, Ignacio uhttp://nar.oxfordjournals.org/content/40/W1/W609.long02998nas a2200349 4500008004100000022001400041245015500055210006900210260000900279300001100288490000600299520188000305100002102185700001902206700001702225700002002242700002402262700002202286700002802308700002102336700002002357700002102377700002102398700002302419700002902442700001602471700001802487700002102505700002402526700001902550856007902569 2012 eng d a1932-620300aDevelopment, Characterization and Experimental Validation of a Cultivated Sunflower (Helianthus annuus L.) Gene Expression Oligonucleotide Microarray.0 aDevelopment Characterization and Experimental Validation of a Cu c2012 ae458990 v73 aOligonucleotide-based microarrays with accurate gene coverage represent a key strategy for transcriptional studies in orphan species such as sunflower, H. annuus L., which lacks full genome sequences. The goal of this study was the development and functional annotation of a comprehensive sunflower unigene collection and the design and validation of a custom sunflower oligonucleotide-based microarray. A large scale EST (>130,000 ESTs) curation, assembly and sequence annotation was performed using Blast2GO (www.blast2go.de). The EST assembly comprises 41,013 putative transcripts (12,924 contigs and 28,089 singletons). The resulting Sunflower Unigen Resource (SUR version 1.0) was used to design an oligonucleotide-based Agilent microarray for cultivated sunflower. This microarray includes a total of 42,326 features: 1,417 Agilent controls, 74 control probes for sunflower replicated 10 times (740 controls) and 40,169 different non-control probes. Microarray performance was validated using a model experiment examining the induction of senescence by water deficit. Pre-processing and differential expression analysis of Agilent microarrays was performed using the Bioconductor limma package. The analyses based on p-values calculated by eBayes (p<0.01) allowed the detection of 558 differentially expressed genes between water stress and control conditions; from these, ten genes were further validated by qPCR. Over-represented ontologies were identified using FatiScan in the Babelomics suite. This work generated a curated and trustable sunflower unigene collection, and a custom, validated sunflower oligonucleotide-based microarray using Agilent technology. Both the curated unigene collection and the validated oligonucleotide microarray provide key resources for sunflower genome analysis, transcriptional studies, and molecular breeding for crop improvement.1 aFernandez, Paula1 aSoria, Marcelo1 aBlesa, David1 aDirienzo, Julio1 aMoschen, Sebastián1 aRivarola, Máximo1 aClavijo, Bernardo, Jose1 aGonzalez, Sergio1 aPeluffo, Lucila1 aPríncipi, Dario1 aDosio, Guillermo1 aAguirrezabal, Luis1 aGarcia-Garcia, Francisco1 aConesa, Ana1 aHopp, Esteban1 aDopazo, Joaquín1 aHeinz, Ruth, Amelia1 aPaniego, Norma uhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.004589902621nas a2200325 4500008004100000022001400041245012100055210006900176260001600245300000900261490000700270520154400277653002101821653001901842653002901861653002001890653003401910653001301944653001101957653003201968100002402000700002002024700001902044700001902063700002402082700001902106700002002125700002002145856013002165 2012 eng d a1362-496200aDiscovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.0 aDiscovering the hidden subnetwork component in a ranked list of c2012 Nov 01 ae1580 v403 aGenomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network.
10aBipolar Disorder10aFanconi Anemia10aGene Regulatory Networks10aGenes, Neoplasm10aGenome-Wide Association Study10aGenomics10aHumans10aProtein Interaction Mapping1 aGarcía-Alonso, Luz1 aAlonso, Roberto1 aVidal, Enrique1 aAmadoz, Alicia1 aDe Maria, Alejandro1 aMinguez, Pablo1 aMedina, Ignacio1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/discovering-hidden-sub-network-component-ranked-list-genes-or-proteins-derived-genomic02787nas a2200253 4500008004100000022001400041245015200055210006900207260001600276520178700292100002502079700002602104700002902130700003102159700002802190700002602218700002802244700002702272700003302299700002702332700001602359700002902375856012902404 2012 eng d a1097-021500aExpression profiling shows differential molecular pathways and provides potential new diagnostic biomarkers for colorectal serrated adenocarcinoma.0 aExpression profiling shows differential molecular pathways and p c2012 Jun 143 aSerrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5-8.7% of CRCs. It has been shown that SAC has a poorer prognosis and has different molecular and immunohistochemical features compared to conventional carcinoma (CC) but, to date, only one previous study has analysed its mRNA expression profile by microarray. Using a different microarray platform, we have studied the molecular signature of 11 SACs and compared it with that of 15 matched CC with the aim of discerning the functions which characterize SAC biology and validating, at the mRNA and protein level, the most differentially expressed genes which were also tested using a validation set of 70 SACs and 70 CCs to assess their diagnostic and prognostic values. Microarray data showed a higher representation of morphogenesis-, hypoxia-, cytoskeleton- and vesicle transport-related functions and also an over-expression of fascin1 (actin-bundling protein associated with invasion) and the antiapoptotic gene hippocalcin in SAC all of which were validated both by qPCR and immunohistochemistry. Fascin1 expression was statistically associated with KRAS mutation with 88.6% sensitivity and 85.7% specificity for SAC diagnosis and the positivity of fascin1 or hippocalcin was highly suggestive of SAC diagnosis (sensitivity=100%). Evaluation of these markers in CRCs showing histological and molecular characteristics of high-level microsatellite instability (MSI-H) also helped to distinguish SACs from MSI-H CRCs. Molecular profiling demonstrates that SAC shows activation of distinct signalling pathways and that immunohistochemical fascin1 and hippocalcin expression can be reliably used for its differentiation from other CRC subtypes. © 2012 Wiley Periodicals, Inc.1 aConesa-Zamora, Pablo1 aGarcía-Solano, José1 aGarcia-Garcia, Francisco1 aTurpin, María, Del Carmen1 aTrujillo-Santos, Javier1 aTorres-Moreno, Daniel1 aOviedo-Ramírez, Isabel1 aCarbonell-Muñoz, Rosa1 aMuñoz-Delgado, Encarnación1 aRodriguez-Braun, Edith1 aConesa, Ana1 aPérez-Guillermo, Miguel uhttps://www.clinbioinfosspa.es/content/expression-profiling-shows-differential-molecular-pathways-and-provides-potential-new02975nas a2200313 4500008004100000022001400041245008300055210006900138260000900207300001100216490000600227520199700233653001202230653003302242653001102275653001702286653000902303653001802312653004402330653002502374653001902399653002702418100001902445700001902464700002002483700002002503700002002523856011802543 2012 eng d a1932-620300aExtensive translatome remodeling during ER stress response in mammalian cells.0 aExtensive translatome remodeling during ER stress response in ma c2012 ae359150 v73 aIn this work we have described the translatome of two mammalian cell lines, NIH3T3 and Jurkat, by scoring the relative polysome association of ∼10,000 mRNA under normal and ER stress conditions. We have found that translation efficiencies of mRNA correlated poorly with transcript abundance, although a general tendency was observed so that the highest translation efficiencies were found in abundant mRNA. Despite the differences found between mouse (NIH3T3) and human (Jurkat) cells, both cell types share a common translatome composed by ∼800-900 mRNA that encode proteins involved in basic cellular functions. Upon stress, an extensive remodeling in translatomes was observed so that translation of ∼50% of mRNA was inhibited in both cell types, this effect being more dramatic for those mRNA that accounted for most of the cell translation. Interestingly, we found two subsets comprising 1000-1500 mRNA whose translation resisted or was induced by stress. Translation arrest resistant class includes many mRNA encoding aminoacyl tRNA synthetases, ATPases and enzymes involved in DNA replication and stress response such as BiP. This class of mRNA is characterized by high translation rates in both control and stress conditions. Translation inducible class includes mRNA whose translation was relieved after stress, showing a high enrichment in early response transcription factors of bZIP and zinc finger C2H2 classes. Unlike yeast, a general coordination between changes in translation and transcription upon stress (potentiation) was not observed in mammalian cells. Among the different features of mRNA analyzed, we found a relevant association of translation efficiency with the presence of upstream ATG in the 5'UTR and with the length of coding sequence of mRNA, and a looser association with other parameters such as the length and the G+C content of 5'UTR. A model for translatome remodeling during the acute phase of stress response in mammalian cells is proposed.
10aAnimals10aEndoplasmic Reticulum Stress10aHumans10aJurkat Cells10aMice10aNIH 3T3 Cells10aOligonucleotide Array Sequence Analysis10aProtein Biosynthesis10aRNA, Messenger10aTranscription, Genetic1 aVentoso, Iván1 aKochetov, Alex1 aMontaner, David1 aDopazo, Joaquin1 aSantoyo, Javier uhttps://www.clinbioinfosspa.es/content/extensive-translatome-remodeling-during-er-stress-response-mammalian-cells02491nas a2200373 4500008004100000022001400041245014600055210006900201260001600270300000800286490000600294520125600300653001101556653003801567653003401605653001301639653002501652653001101677653000901688100002701697700001701724700002701741700002001768700002301788700002401811700002001835700002001855700002801875700002001903700002501923700002001948700001901968856013001987 2012 eng d a1750-117200aFour new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease.0 aFour new loci associations discovered by pathwaybased and networ c2012 Dec 28 a1030 v73 aFinding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung's disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.
10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHirschsprung Disease10aHumans10aMale1 aFernández, Raquel, Ma1 aBleda, Marta1 aNúñez-Torres, Rocío1 aMedina, Ignacio1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aTorroglosa, Ana1 aMarbà, Martina1 aEnguix-Riego, Ma, Valle1 aMontaner, David1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttps://www.clinbioinfosspa.es/content/four-new-loci-associations-discovered-pathway-based-and-network-analyses-genome-wide-002193nas a2200289 4500008004100000022001400041245014800055210006900203260001600272300000800288490000600296520126100302100002701563700001701590700002701607700002001634700002301654700002401677700002001701700002001721700002801741700002001769700002501789700002101814700001901835856004901854 2012 eng d a1750-117200aFour new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung’s disease.0 aFour new loci associations discovered by pathwaybased and networ c2012 Dec 28 a1030 v73 aABSTRACT: Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung’s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.1 aFernández, Raquel, Ma1 aBleda, Marta1 aNúñez-Torres, Rocío1 aMedina, Ignacio1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aTorroglosa, Ana1 aMarbà, Martina1 aEnguix-Riego, Ma, Valle1 aMontaner, David1 aAntiňolo, Guillermo1 aDopazo, Joaquín1 aBorrego, Salud uhttp://www.ojrd.com/content/7/1/103/abstract03360nas a2200529 4500008004100000022001400041245009200055210007000147260001300217300001100230490000600241520169800247653001801945653001801963653002301981653001502004653002602019653001302045653001702058653003002075653003002105653001702135653001102152653002102163653002702184653005002211653002202261653001202283653001502295653002702310653001502337653004402352653002102396653002402417100002002441700002402461700001802485700002002503700002902523700002002552700002202572700002302594700002302617700003002640700002202670856013802692 2012 eng d a2629-327700aIL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-κB.0 aIL1β induces mesenchymal stem cells migration and leucocyte chem c2012 Sep a905-160 v83 aMesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1β mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX(3)CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-α, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1β did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1β treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-κβ transcription factor activation with IκB kinase beta (IKKβ) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1β demonstrating that NF-κB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments.
10aCell Adhesion10aCell Movement10aCell Proliferation10aChemokines10aChemotaxis, Leukocyte10aCollagen10aFibronectins10aGene Expression Profiling10aGene Knockdown Techniques10aHEK293 Cells10aHumans10aI-kappa B Kinase10aInflammation Mediators10aIntercellular Signaling Peptides and Proteins10aInterleukin-1beta10aLaminin10aLeukocytes10aMesenchymal Stem Cells10aNF-kappa B10aOligonucleotide Array Sequence Analysis10aRNA Interference10aSignal Transduction1 aCarrero, Rubén1 aCerrada, Inmaculada1 aLledó, Elisa1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aRubio, Mari-Paz1 aTrigueros, César1 aDorronsoro, Akaitz1 aRuiz-Sauri, Amparo1 aMontero, José, Anastasio1 aSepúlveda, Pilar uhttps://www.clinbioinfosspa.es/content/il1%CE%B2-induces-mesenchymal-stem-cells-migration-and-leucocyte-chemotaxis-through-nf-%CE%BAb02001nas a2200313 4500008004100000022001400041245007400055210006900129260001300198300001200211490000700223520105300230653001801283653002301301653001901324653002901343653001301372653001401385653001301399653002601412653001801438100001701456700002001473700002001493700002401513700002401537700002001561856010601581 2012 eng d a1362-496200aInferring the regulatory network behind a gene expression experiment.0 aInferring the regulatory network behind a gene expression experi c2012 Jul aW168-720 v403 aTranscription factors (TFs) and miRNAs are the most important dynamic regulators in the control of gene expression in multicellular organisms. These regulatory elements play crucial roles in development, cell cycling and cell signaling, and they have also been associated with many diseases. The Regulatory Network Analysis Tool (RENATO) web server makes the exploration of regulatory networks easy, enabling a better understanding of functional modularity and network integrity under specific perturbations. RENATO is suitable for the analysis of the result of expression profiling experiments. The program analyses lists of genes and search for the regulators compatible with its activation or deactivation. Tests of single enrichment or gene set enrichment allow the selection of the subset of TFs or miRNAs significantly involved in the regulation of the query genes. RENATO also offers an interactive advanced graphical interface that allows exploring the regulatory network found.RENATO is available at: http://renato.bioinfo.cipf.es/.
10aBinding Sites10aDatabases, Genetic10aFanconi Anemia10aGene Regulatory Networks10aInternet10aMicroRNAs10aSoftware10aTranscription Factors10aTranscriptome1 aBleda, Marta1 aMedina, Ignacio1 aAlonso, Roberto1 aDe Maria, Alejandro1 aSalavert, Francisco1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/inferring-regulatory-network-behind-gene-expression-experiment02674nas a2200313 4500008004100000022001400041245008800055210006900143260001600212300000700228490000600235520174000241653000801981100002101989700001602010700001602026700001902042700002002061700002602081700002002107700002902127700002802156700003302184700001702217700002702234700002502261700002002286856005402306 2012 eng d a1756-994X00aA map of human microRNA variation uncovers unexpectedly high levels of variability.0 amap of human microRNA variation uncovers unexpectedly high level c2012 Aug 20 a620 v43 aABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in healthy population seems an obvious requirement for future research on miRNA-related pathologies. METHODS: Data on 14 populations from the 1000 Genomes Project were analysed, along with new data extracted from 60 exomes of healthy individuals from a southern Spain population, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. RESULTS: Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. CONCLUSIONS: Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.10aNGS1 aCarbonell, José1 aAlloza, Eva1 aArce, Pablo1 aBorrego, Salud1 aSantoyo, Javier1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aJiménez-Almazán, Jorge1 aMéndez-Vidal, Cristina1 adel Pozo, María, González-1 aVela, Alicia1 aBhattacharya, Shomi, S1 aAntiňolo, Guillermo1 aDopazo, Joaquin uhttp://genomemedicine.com/content/4/8/62/abstract02568nas a2200445 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520111500256653001201371653002201383653003901405653002601444653002201470653004401492653001701536653003201553653000901585653002701594653005201621653002101673653002701694653001801721653003201739100002201771700001901793700001501812700002001827700002201847700001901869700002001888700002001908700002201928700002101950700002201971856012901993 2012 eng d a1530-686000aThe protease MT1-MMP drives a combinatorial proteolytic program in activated endothelial cells.0 aprotease MT1MMP drives a combinatorial proteolytic program in ac c2012 Nov a4481-940 v263 aThe mechanism by which proteolytic events translate into biological responses is not well understood. To explore the link of pericellular proteolysis to events relevant to capillary sprouting within the inflammatory context, we aimed at the identification of the collection of substrates of the protease MT1-MMP in endothelial tip cells induced by inflammatory stimuli. We applied quantitative proteomics to endothelial cells (ECs) derived from wild-type and MT1-MMP-null mice to identify the substrate repertoire of this protease in TNF-α-activated ECs. Bioinformatics analysis revealed a combinatorial MT1-MMP proteolytic program, in which combined rather than single substrate processing would determine biological decisions by activated ECs, including chemotaxis, cell motility and adhesion, and vasculature development. MT1-MMP-deficient ECs inefficiently processed several of these substrates (TSP1, CYR61, NID1, and SEM3C), validating the model. This novel concept of MT1-MMP-driven combinatorial proteolysis in angiogenesis might be extendable to proteolytic actions in other cellular contexts.
10aAnimals10aBlotting, Western10aCombinatorial Chemistry Techniques10aComputational Biology10aEndothelial Cells10aGene Expression Regulation, Enzymologic10aInflammation10aMatrix Metalloproteinase 1410aMice10aProtein Array Analysis10aReverse Transcriptase Polymerase Chain Reaction10aRNA Interference10aRNA, Small Interfering10aTranscriptome10aTumor Necrosis Factor-alpha1 aKoziol, Agnieszka1 aGonzalo, Pilar1 aMota, Alba1 aPollán, Angela1 aLorenzo, Cristina1 aColomé, Nuria1 aMontaner, David1 aDopazo, Joaquin1 aArribas, Joaquín1 aCanals, Francesc1 aArroyo, Alicia, G uhttps://www.clinbioinfosspa.es/content/protease-mt1-mmp-drives-combinatorial-proteolytic-program-activated-endothelial-cells01929nas a2200253 4500008004100000022001400041245006800055210006500123260001600188300001100204490000700215520118200222653000801404100003001412700002901442700002101471700001801492700001801510700002001528700002101548700002101569700001601590856006901606 2012 eng d a1367-481100aQualimap: evaluating next-generation sequencing alignment data.0 aQualimap evaluating nextgeneration sequencing alignment data c2012 Oct 15 a2678-90 v283 aMOTIVATION: The sequence alignment/map (SAM) and the binary alignment/map (BAM) formats have become the standard method of representation of nucleotide sequence alignments for next-generation sequencing data. SAM/BAM files usually contain information from tens to hundreds of millions of reads. Often, the sequencing technology, protocol and/or the selected mapping algorithm introduce some unwanted biases in these data. The systematic detection of such biases is a non-trivial task that is crucial to drive appropriate downstream analyses. RESULTS: We have developed Qualimap, a Java application that supports user-friendly quality control of mapping data, by considering sequence features and their genomic properties. Qualimap takes sequence alignment data and provides graphical and statistical analyses for the evaluation of data. Such quality-control data are vital for highlighting problems in the sequencing and/or mapping processes, which must be addressed prior to further analyses. AVAILABILITY: Qualimap is freely available from http://www.qualimap.org. CONTACT: aconesa@cipf.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.10aNGS1 aGarcía-Alcalde, Fernando1 aOkonechnikov, Konstantin1 aCarbonell, José1 aCruz, Luis, M1 aGötz, Stefan1 aTarazona, Sonia1 aDopazo, Joaquín1 aMeyer, Thomas, F1 aConesa, Ana uhttp://bioinformatics.oxfordjournals.org/content/28/20/2678.long01878nas a2200289 4500008004100000022001400041245008700055210006900142260000900211300001100220490000600231520100600237100002701243700002001270700002801290700001901318700002701337700002201364700001801386700002001404700002001424700001801444700002101462700002101483700002001504856006401524 2012 eng d a1748-567300aSelect your SNPs (SYSNPs): a web tool for automatic and massive selection of SNPs.0 aSelect your SNPs SYSNPs a web tool for automatic and massive sel c2012 a324-340 v63 aAssociation studies are the choice approach in the discovery of the genomic basis of complex traits. To carry out such analysis, researchers frequently need to (1) select optimally informative sets of Single Nucleotide Polymorphisms (SNPs) in candidate regions and (2) annotate the results of associations found by means of genome-wide SNP arrays. These are complex tasks, since many criteria have to be considered, including the SNPs’ functional properties, technological information and haplotype frequencies in given populations. SYSNPs implements algorithms that allow for efficient and simultaneous consideration of all the relevant criteria to obtain sets of SNPs that properly cover arbitrarily large lists of genes or genomic regions. Complementarily, SYSNPs allows for comprehensive functional annotation of SNPs linked to any given marker SNP. SYSNPs dramatically reduces the effort needed for SNP selection from days of searching various databases to a few minutes using a simple browser.1 aLorente-Galdos, Belén1 aMedina, Ignacio1 aMorcillo-Suarez, Carlos1 aHeredia, Txema1 aCarreño-Torres, Angel1 aSangrós, Ricardo1 aAlegre, Josep1 aPita, Guillermo1 aVellalta, Gemma1 aMalats, Nuria1 aPisano, David, G1 aDopazo, Joaquín1 aNavarro, Arcadi uhttp://inderscience.metapress.com/content/f76740x8071u513n/02236nas a2200325 4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520119100257653002301448653001101471653001301482653002701495653001401522653003601536653002501572653001301597100002001610700002101630700001801651700002801669700001801697700002001715700002301735700002301758856012901781 2012 eng d a1362-496200aSNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants.0 aSNPeffect 40 online prediction of molecular and structural effec c2012 Jan aD935-90 v403 aSingle nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants.
10aDatabases, Protein10aHumans10aInternet10aMeta-Analysis as Topic10aPhenotype10aPolymorphism, Single Nucleotide10aProtein Conformation10aProteins1 aDe Baets, Greet1 aVan Durme, Joost1 aReumers, Joke1 aMaurer-Stroh, Sebastian1 aVanhee, Peter1 aDopazo, Joaquin1 aSchymkowitz, Joost1 aRousseau, Frederic uhttps://www.clinbioinfosspa.es/content/snpeffect-40-line-prediction-molecular-and-structural-effects-protein-coding-variants03644nas a2200505 4500008004100000022001400041245012700055210006900182260000900251300001100260490000600271520212800277653001902405653001202424653002302436653001802459653002602477653001802503653000802521653001502529653002202544653003002566653002302596653001002619653002402629653002802653653000902681653002202690653001302712653001702725653001802742100001902760700001802779700002102797700001402818700001602832700002402848700002202872700002102894700002202915700001802937700001702955700003002972856013603002 2012 eng d a1932-620300aTranscriptome profiling of the intoxication response of Tenebrio molitor larvae to Bacillus thuringiensis Cry3Aa protoxin.0 aTranscriptome profiling of the intoxication response of Tenebrio c2012 ae346240 v73 aBacillus thuringiensis (Bt) crystal (Cry) proteins are effective against a select number of insect pests, but improvements are needed to increase efficacy and decrease time to mortality for coleopteran pests. To gain insight into the Bt intoxication process in Coleoptera, we performed RNA-Seq on cDNA generated from the guts of Tenebrio molitor larvae that consumed either a control diet or a diet containing Cry3Aa protoxin. Approximately 134,090 and 124,287 sequence reads from the control and Cry3Aa-treated groups were assembled into 1,318 and 1,140 contigs, respectively. Enrichment analyses indicated that functions associated with mitochondrial respiration, signalling, maintenance of cell structure, membrane integrity, protein recycling/synthesis, and glycosyl hydrolases were significantly increased in Cry3Aa-treated larvae, whereas functions associated with many metabolic processes were reduced, especially glycolysis, tricarboxylic acid cycle, and fatty acid synthesis. Microarray analysis was used to evaluate temporal changes in gene expression after 6, 12 or 24 h of Cry3Aa exposure. Overall, microarray analysis indicated that transcripts related to allergens, chitin-binding proteins, glycosyl hydrolases, and tubulins were induced, and those related to immunity and metabolism were repressed in Cry3Aa-intoxicated larvae. The 24 h microarray data validated most of the RNA-Seq data. Of the three intoxication intervals, larvae demonstrated more differential expression of transcripts after 12 h exposure to Cry3Aa. Gene expression examined by three different methods in control vs. Cry3Aa-treated larvae at the 24 h time point indicated that transcripts encoding proteins with chitin-binding domain 3 were the most differentially expressed in Cry3Aa-intoxicated larvae. Overall, the data suggest that T. molitor larvae mount a complex response to Cry3Aa during the initial 24 h of intoxication. Data from this study represent the largest genetic sequence dataset for T. molitor to date. Furthermore, the methods in this study are useful for comparative analyses in organisms lacking a sequenced genome.10aAdministration10aAnimals10aBacterial Proteins10aBase Sequence10aBiosynthetic Pathways10aComplementary10aDNA10aEndotoxins10aEnergy Metabolism10aGene Expression Profiling10aHemolysin Proteins10aLarva10aMicroarray Analysis10aMolecular Sequence Data10aOral10aSequence Analysis10aTenebrio10aTime Factors10aTranscriptome1 aOppert, Brenda1 aDowd, Scot, E1 aBouffard, Pascal1 aLi, Lewyn1 aConesa, Ana1 aLorenzen, Marcé, D1 aToutges, Michelle1 aMarshall, Jeremy1 aHuestis, Diana, L1 aFabrick, Jeff1 aOppert, Cris1 aJurat-Fuentes, Juan, Luis uhttps://www.clinbioinfosspa.es/content/transcriptome-profiling-intoxication-response-tenebrio-molitor-larvae-bacillus-thuringiensis01857nas a2200265 4500008004100000022001400041245011600055210006900171260001600240300001400256490000600270520098400276653003001260653001801290653001001308653000801318100002701326700003001353700002901383700002301412700002001435700002101455700002001476856009501496 2012 eng d a1557-996400aUsing GPUs for the Exact Alignment of Short-read Genetic Sequences by Means of the Burrows–Wheeler Transform.0 aUsing GPUs for the Exact Alignment of Shortread Genetic Sequence c2012 Mar 20 a1245-12560 v93 aGeneral Purpose Graphic Processing Units (GPGPUs) constitute an inexpensive resource for computing-intensive applications that could exploit an intrinsic fine-grain parallelism. This paper presents the design and implementation in GPGPUs of an exact alignment tool for nucleotide sequences based on the Burrows-Wheeler Transform. We compare this algorithm with state-of-the-art implementations of the same algorithm over standard CPUs, and considering the same conditions in terms of I/O. Excluding disk transfers, the implementation of the algorithm in GPUs shows a speedup larger than 12x, when compared to CPU execution. This implementation exploits the parallelism by concurrently searching different sequences on the same reference search tree, maximising memory locality and ensuring a symmetric access to the data. The article describes the behaviour of the algorithm in GPU, showing a good scalability in the performance, only limited by the size of the GPU inner memory.10aBurrows-Wheeler transform10aCPU execution10aGPGPU10aNGS1 aTorres, Jose, Salavert1 aEspert, Ignacio, Blanquer1 aDominguez, Andres, Tomas1 aHernendez, Vicente1 aMedina, Ignacio1 aTerraga, Joaquin1 aDopazo, Joaquin uhttp://ieeexplore.ieee.org.sire.ub.edu/xpl/articleDetails.jsp?reload=true&arnumber=617588802717nas a2200325 4500008004100000022001400041245015600055210006900211260001300280300001000293490000700303520157800310653002801888653002201916653004201938653001301980653003401993653001302027653003602040653001302076653002802089100002002117700002402137700001702161700002402178700002002202700002602222700002002248856012302268 2012 eng d a1362-496200aVARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing.0 aVARIANT Command Line Web service and Web interface for fast and c2012 Jul aW54-80 v403 aThe massive use of Next-Generation Sequencing (NGS) technologies is uncovering an unexpected amount of variability. The functional characterization of such variability, particularly in the most common form of variation found, the Single Nucleotide Variants (SNVs), has become a priority that needs to be addressed in a systematic way. VARIANT (VARIant ANalyis Tool) reports information on the variants found that include consequence type and annotations taken from different databases and repositories (SNPs and variants from dbSNP and 1000 genomes, and disease-related variants from the Genome-Wide Association Study (GWAS) catalog, Online Mendelian Inheritance in Man (OMIM), Catalog of Somatic Mutations in Cancer (COSMIC) mutations, etc). VARIANT also produces a rich variety of annotations that include information on the regulatory (transcription factor or miRNA-binding sites, etc.) or structural roles, or on the selective pressures on the sites affected by the variation. This information allows extending the conventional reports beyond the coding regions and expands the knowledge on the contribution of non-coding or synonymous variants to the phenotype studied. Contrarily to other tools, VARIANT uses a remote database and operates through efficient RESTful Web Services that optimize search and transaction operations. In this way, local problems of installation, update or disk size limitations are overcome without the need of sacrifice speed (thousands of variants are processed per minute). VARIANT is available at: http://variant.bioinfo.cipf.es.
10aDatabases, Nucleic Acid10aGenetic Variation10aHigh-Throughput Nucleotide Sequencing10aInternet10aMolecular Sequence Annotation10amutation10aPolymorphism, Single Nucleotide10aSoftware10aUser-Computer Interface1 aMedina, Ignacio1 aDe Maria, Alejandro1 aBleda, Marta1 aSalavert, Francisco1 aAlonso, Roberto1 aGonzalez, Cristina, Y1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/variant-command-line-web-service-and-web-interface-fast-and-accurate-functional02874nas a2200493 4500008004100000022001400041245007000055210006800125260001600193300001100209490000600220520139500226653001801621653002701639653002101666653004101687653002001728653002401748653000901772653001101781653001801792653004201810653001101852653003701863653001301900653003801913653002701951653001301978100001701991700001902008700001802027700002502045700002102070700002002091700001902111700002602130700002302156700001802179700001602197700002402213700002002237700002002257856010302277 2012 eng d a1559-230800aWhole-genome bisulfite DNA sequencing of a DNMT3B mutant patient.0 aWholegenome bisulfite DNA sequencing of a DNMT3B mutant patient c2012 Jun 01 a542-500 v73 aThe immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated to mutations of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable to analyze single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base pair resolution. Genome-wide we detected a decrease of methylation level of 42%, with the most profound changes occurring in inactive heterochromatic regions, satellite repeats and transposons. Interestingly, transcriptional active loci and ribosomal RNA repeats escaped global hypomethylation. Despite a genome-wide loss of DNA methylation the epigenetic landscape and crucial regulatory structures were conserved. Remarkably, we revealed a mislocated activity of mutant DNMT3B to H3K4me1 loci resulting in hypermethylation of active promoters. Functionally, we could associate alterations in promoter methylation with the ICF syndrome immunodeficient phenotype by detecting changes in genes related to the B-cell receptor mediated maturation pathway.
10aB-Lymphocytes10aCell Line, Transformed10aChild, Preschool10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methylation10aEpigenesis, Genetic10aFace10aFemale10aGenome, Human10aHigh-Throughput Nucleotide Sequencing10aHumans10aImmunologic Deficiency Syndromes10amutation10aPrimary Immunodeficiency Diseases10aSequence Analysis, DNA10aSulfites1 aHeyn, Holger1 aVidal, Enrique1 aSayols, Sergi1 aSanchez-Mut, Jose, V1 aMoran, Sebastian1 aMedina, Ignacio1 aSandoval, Juan1 aSimó-Riudalbas, Laia1 aSzczesna, Karolina1 aHuertas, Dori1 aGatto, Sole1 aMatarazzo, Maria, R1 aDopazo, Joaquin1 aEsteller, Manel uhttps://www.clinbioinfosspa.es/content/whole-genome-bisulfite-dna-sequencing-dnmt3b-mutant-patient02550nas a2200145 4500008004100000245013600041210006900177260000900246300001100255490000600266520201400272100001902286700002002305856007902325 2011 eng d00aAssessing the biological significance of gene expression signatures and co-expression modules by studying their network properties.0 aAssessing the biological significance of gene expression signatu c2011 ae174740 v63 aMicroarray experiments have been extensively used to define signatures, which are sets of genes that can be considered markers of experimental conditions (typically diseases). Paradoxically, in spite of the apparent functional role that might be attributed to such gene sets, signatures do not seem to be reproducible across experiments. Given the close relationship between function and protein interaction, network properties can be used to study to what extent signatures are composed of genes whose resulting proteins show a considerable level of interaction (and consequently a putative common functional role).We have analysed 618 signatures and 507 modules of co-expression in cancer looking for significant values of four main protein-protein interaction (PPI) network parameters: connection degree, cluster coefficient, betweenness and number of components. A total of 3904 gene ontology (GO) modules, 146 KEGG pathways, and 263 Biocarta pathways have been used as functional modules of reference.Co-expression modules found in microarray experiments display a high level of connectivity, similar to the one shown by conventional modules based on functional definitions (GO, KEGG and Biocarta). A general observation for all the classes studied is that the networks formed by the modules improve their topological parameters when an external protein is allowed to be introduced within the paths (up to the 70% of GO modules show network parameters beyond the random expectation). This fact suggests that functional definitions are incomplete and some genes might still be missing. Conversely, signatures are clearly not capturing the altered functions in the corresponding studies. This is probably because the way in which the genes have been selected in the signatures is too conservative. These results suggest that gene selection methods which take into account relationships among genes should be superior to methods that assume independence among genes outside their functional contexts.
1 aMinguez, Pablo1 aDopazo, Joaquin uhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.001747402490nas a2200229 4500008004100000245005800041210005500099260001600154300001200170490000700182520178000189100001801969700001901987700003002006700003102036700002202067700002202089700002102111700001902132700001602151856009302167 2011 eng d00aB2G-FAR, a species centered GO annotation repository.0 aB2GFAR a species centered GO annotation repository c2011 Feb 18 a919-9240 v273 aMOTIVATION: Functional genomics research has expanded enormously in the last decade thanks to the cost-reduction in high-throughput technologies and the development of computational tools that generate, standardize and share information on gene and protein function such as the Gene Ontology (GO). Nevertheless many biologists, especially working with non-model organisms, still suffer from non-existing or low coverage functional annotation, or simply struggle retrieving, summarizing and querying these data. RESULTS: The Blast2GO Functional Annotation Repository (B2G-FAR) is a bioinformatics resource envisaged to provide functional information for otherwise uncharacterized sequence-data and offers data-mining tools to analyze a larger repertoire of species than currently available. This new annotation resource has been created by applying the Blast2GO functional annotation engine in a strongly high-throughput manner to the entire space of public available sequences. The resulting repository contains GO term predictions for over 13.2 million non-redundant protein sequences based on BLAST search alignments from the SIMAP database. We generated GO annotation for approximately 150.000 different taxa making available the 2000 species with the highest coverage through B2G-FAR. A second section within B2G-FAR holds functional annotations for 17 non-model organism Affymetrix GeneChips. Conclusions: B2G-FAR provides easy access to exhaustive functional annotation for 2000 species offering a good balance between quality and quantity, thereby supporting functional genomics research especially in the case of non-model organisms. AVAILABILITY: The annotation resource is available at http://b2gfar.bioinfo.cipf.es. CONTACT: aconesa@cipf.es, sgoetz@cipf.es.
1 aGötz, Stefan1 aArnold, Roland1 aSebastián-Leon, Patricia1 aMartín-Rodríguez, Samuel1 aTischler, Patrick1 aJehl, Marc-André1 aDopazo, Joaquín1 aRattei, Thomas1 aConesa, Ana uhttps://www.clinbioinfosspa.es/content/b2g-far-species-centered-go-annotation-repository02878nas a2200301 4500008004100000245015000041210006900191260001600260300001200276490000700288520183800295100001902133700002202152700002502174700002102199700002002220700002002240700001702260700002102277700002202298700002502320700002102345700002002366700001802386700002102404700002402425856012702449 2011 eng d00aDifferential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice.0 aDifferential Lipid Partitioning Between Adipocytes and Tissue Ma c2011 Jan 24 a797-8090 v603 aOBJECTIVE Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.
1 aPrieur, Xavier1 aMok, Crystal, Y L1 aVelagapudi, Vidya, R1 aNúñez, Vanessa1 aFuentes, Lucía1 aMontaner, David1 aIshikawa, Ko1 aCamacho, Alberto1 aBarbarroja, Nuria1 aO’Rahilly, Stephen1 aSethi, Jaswinder1 aDopazo, Joaquin1 aOresic, Matej1 aRicote, Mercedes1 aVidal-Puig, Antonio uhttps://www.clinbioinfosspa.es/content/differential-lipid-partitioning-between-adipocytes-and-tissue-macrophages-modulates01382nas a2200313 4500008004100000245005700041210005500098260001300153300001300166490000600179520044900185100001700634700002200651700002700673700002200700700002000722700002200742700001800764700001900782700001700801700003300818700002800851700002000879700002600899700002500925700001600950700002100966856008100987 2011 eng d00aDiscovery of an ebolavirus-like filovirus in europe.0 aDiscovery of an ebolaviruslike filovirus in europe c2011 Oct ae10023040 v73 aFiloviruses, amongst the most lethal of primate pathogens, have only been reported as natural infections in sub-Saharan Africa and the Philippines. Infections of bats with the ebolaviruses and marburgviruses do not appear to be associated with disease. Here we report identification in dead insectivorous bats of a genetically distinct filovirus, provisionally named Lloviu virus, after the site of detection, Cueva del Lloviu, in Spain.
1 aNegredo, Ana1 aPalacios, Gustavo1 aVázquez-Morón, Sonia1 aGonzález, Félix1 aDopazo, Hernán1 aMolero, Francisca1 aJuste, Javier1 aQuetglas, Juan1 aSavji, Nazir1 aMartínez, Maria, de la Cruz1 aHerrera, Jesus, Enrique1 aPizarro, Manuel1 aHutchison, Stephen, K1 aEchevarría, Juan, E1 aLipkin, Ian1 aTenorio, Antonio uhttps://www.clinbioinfosspa.es/content/discovery-ebolavirus-filovirus-europe03520nas a2200493 4500008004100000022001400041245012700055210006900182260001600251300000700267490000600274520197600280653001202256653002302268653001802291653001602309653002002325653001102345653003102356653002902387653002302416653002802439653000902467653001202476653002402488653002002512653001502532653002402547653002702571653003602598100001802634700003002652700002302682700002902705700002102734700002002755700001902775700001602794700001602810700002002826700002402846700002302870856013302893 2011 eng d a1755-879400aEarly peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.0 aEarly peroxisome proliferatoractivated receptor gamma regulated c2011 Dec 30 a860 v43 aBACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion
RESULTS: Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.
CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.
10aAnimals10aCell Proliferation10aCell Survival10aCholesterol10aDown-Regulation10aFemale10aGene Expression Regulation10aGene Knockout Techniques10aInsulin Resistance10aInsulin-Secreting Cells10aMice10aobesity10aOxidation-Reduction10aPhosphorylation10aPPAR gamma10aSignal Transduction10aTranscription, Genetic10aTransforming Growth Factor beta1 aVivas, Yurena1 aMartinez-Garcia, Cristina1 aIzquierdo, Adriana1 aGarcia-Garcia, Francisco1 aCallejas, Sergio1 aVelasco, Ismael1 aCampbell, Mark1 aRos, Manuel1 aDopazo, Ana1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aMedina-Gomez, Gema uhttps://www.clinbioinfosspa.es/content/early-peroxisome-proliferator-activated-receptor-gamma-regulated-genes-involved-expansion00694nas a2200193 4500008004100000022001400041245010000055210006900155260000900224300000800233490000700241520001400248100002100262700002600283700001600309700002000325700002100345856013400366 2011 eng d a1471-222900aFortunella margarita Transcriptional Reprogramming Triggered by Xanthomonas citri subsp. citri.0 aFortunella margarita Transcriptional Reprogramming Triggered by c2011 a1590 v113 aABSTRACT:1 aKhalaf, Abeer, A1 aGmitter, Frederick, G1 aConesa, Ana1 aDopazo, Joaquin1 aMoore, Gloria, A uhttps://www.clinbioinfosspa.es/content/fortunella-margarita-transcriptional-reprogramming-triggered-xanthomonas-citri-subsp-citri03591nas a2200649 4500008004100000022001400041245019000055210006900245260001600314300001200330490000700342520147500349653001801824653002201842653001201864653004901876653002501925653001401950653001701964653002101981653002502002653002002027653001902047653003002066653002902096653001102125653000902136653001802145653002802163653002802191653005202219653002902271653002402300653003002324653004802354653001802402100001402420700001802434700003002452700001602482700002002498700002002518700001702538700002402555700001902579700001902598700002802617700002002645700001902665700002802684700001802712700002202730700002002752700002002772700001902792856013002811 2011 eng d a1460-208300aLarge-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.0 aLargescale transcriptional profiling and functional assays revea c2011 Dec 15 a4932-460 v203 aUnderstanding the transcriptional cues that direct differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells to defined and functional cell types is essential for future clinical applications. In this study, we have compared transcriptional profiles of haematopoietic progenitors derived from hESCs at various developmental stages of a feeder- and serum-free differentiation method and show that the largest transcriptional changes occur during the first 4 days of differentiation. Data mining on the basis of molecular function revealed Rho-GTPase signalling as a key regulator of differentiation. Inhibition of this pathway resulted in a significant reduction in the numbers of emerging haematopoietic progenitors throughout the differentiation window, thereby uncovering a previously unappreciated role for Rho-GTPase signalling during human haematopoietic development. Our analysis indicated that SCL was the 11th most upregulated transcript during the first 4 days of the hESC differentiation process. Overexpression of SCL in hESCs promoted differentiation to meso-endodermal lineages, the emergence of haematopoietic and erythro-megakaryocytic progenitors and accelerated erythroid differentiation. Importantly, intrasplenic transplantation of SCL-overexpressing hESC-derived haematopoietic cells enhanced recovery from induced acute anaemia without significant cell engraftment, suggesting a paracrine-mediated effect.
10aAcute Disease10aAnemia, Hemolytic10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aCell Differentiation10aCell Line10aCell Lineage10aCluster Analysis10aEmbryonic Stem Cells10aErythroid Cells10aFlow Cytometry10aGene Expression Profiling10aHematopoietic Stem Cells10aHumans10aMice10aMyeloid Cells10aParacrine Communication10aProto-Oncogene Proteins10aReverse Transcriptase Polymerase Chain Reaction10arho GTP-Binding Proteins10aSignal Transduction10aStem Cell Transplantation10aT-Cell Acute Lymphocytic Leukemia Protein 110aTranscriptome1 aYung, Sun1 aLedran, Maria1 aMoreno-Gimeno, Inmaculada1 aConesa, Ana1 aMontaner, David1 aDopazo, Joaquin1 aDimmick, Ian1 aSlater, Nicholas, J1 aMarenah, Lamin1 aReal, Pedro, J1 aParaskevopoulou, Iliana1 aBisbal, Viviana1 aBurks, Deborah1 aSantibanez-Koref, Mauro1 aMoreno, Ruben1 aMountford, Joanne1 aMenendez, Pablo1 aArmstrong, Lyle1 aLako, Majlinda uhttps://www.clinbioinfosspa.es/content/large-scale-transcriptional-profiling-and-functional-assays-reveal-important-roles-rho01043nas a2200229 4500008004100000245010000041210006900141260001300210300001100223490000700234520022900241100002600470700002500496700002500521700002200546700002300568700003700591700002200628700001600650700001800666856012900684 2011 eng d00aModeling human endometrial decidualization from the interaction between proteome and secretome.0 aModeling human endometrial decidualization from the interaction c2011 Mar a706-160 v963 aDecidualization of the human endometrium, which involves morphological and biochemical modifications of the endometrial stromal cells (ESCs), is a prerequisite for adequate trophoblast invasion and placenta formation.
1 aGarrido-Gomez, Tamara1 aDominguez, Francisco1 aLopez, Juan, Antonio1 aCamafeita, Emilio1 aQuiñonero, Alicia1 aMartinez-Conejero, Jose, Antonio1 aPellicer, Antonio1 aConesa, Ana1 aSimon, Carlos uhttps://www.clinbioinfosspa.es/content/modeling-human-endometrial-decidualization-interaction-between-proteome-and-secretome02924nas a2200433 4500008004100000022001400041245013300055210006900188260000900257300001100266490000600277520154700283653001201830653002801842653001001870653002201880653001101902653002301913653001101936653001201947653001301959653001301972653002301985653004402008653003002052653003102082653002502113653001802138100003302156700001902189700002202208700002002230700002002250700002002270700002002290700002002310700002502330856013502355 2011 eng d a1932-620300aMutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.0 aMutation screening of multiple genes in Spanish patients with au c2011 ae278940 v63 aRetinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing.
10aAlleles10aDNA Mutational Analysis10aExons10aGenetic Variation10aGenome10aHispanic or Latino10aHumans10aIntrons10aLanguage10amutation10aMutation, Missense10aOligonucleotide Array Sequence Analysis10aPolymerase Chain Reaction10aReproducibility of Results10aRetinitis pigmentosa10aUnited States1 adel Pozo, María, González-1 aBorrego, Salud1 aBarragán, Isabel1 aPieras, Juan, I1 aSantoyo, Javier1 aMatamala, Nerea1 aNaranjo, Belén1 aDopazo, Joaquin1 aAntiňolo, Guillermo uhttps://www.clinbioinfosspa.es/content/mutation-screening-multiple-genes-spanish-patients-autosomal-recessive-retinitis-pigmentosa02486nas a2200277 4500008004100000022001400041245007400055210006900129260000900198300001100207490000600218520162800224653002201852653002301874653001301897653001301910653003401923653002801957100002301985700002402008700001602032700002002048700001902068700001902087856010202106 2011 eng d a1932-620300amyKaryoView: a light-weight client for visualization of genomic data.0 amyKaryoView a lightweight client for visualization of genomic da c2011 ae263450 v63 aThe Distributed Annotation System (DAS) is a protocol for easy sharing and integration of biological annotations. In order to visualize feature annotations in a genomic context a client is required. Here we present myKaryoView, a simple light-weight DAS tool for visualization of genomic annotation. myKaryoView has been specifically configured to help analyse data derived from personal genomics, although it can also be used as a generic genome browser visualization. Several well-known data sources are provided to facilitate comparison of known genes and normal variation regions. The navigation experience is enhanced by simultaneous rendering of different levels of detail across chromosomes. A simple interface is provided to allow searches for any SNP, gene or chromosomal region. User-defined DAS data sources may also be added when querying the system. We demonstrate myKaryoView capabilities for adding user-defined sources with a set of genetic profiles of family-related individuals downloaded directly from 23andMe. myKaryoView is a web tool for visualization of genomic data specifically designed for direct-to-consumer genomic data that uses publicly available data distributed throughout the Internet. It does not require data to be held locally and it is capable of rendering any feature as long as it conforms to DAS specifications. Configuration and addition of sources to myKaryoView can be done through the interface. Here we show a proof of principle of myKaryoView's ability to display personal genomics data with 23andMe genome data sources. The tool is available at: http://mykaryoview.com.
10aComputer Graphics10aDatabases, Genetic10aGenomics10aInternet10aMolecular Sequence Annotation10aUser-Computer Interface1 aJimenez, Rafael, C1 aSalazar, Gustavo, A1 aGel, Bernat1 aDopazo, Joaquin1 aMulder, Nicola1 aCorpas, Manuel uhttps://www.clinbioinfosspa.es/content/mykaryoview-light-weight-client-visualization-genomic-data01895nas a2200181 4500008004100000245013100041210006900172260001300241300001100254490000700265520119300272100002401465700002201489700002201511700002501533700002101558856013401579 2011 eng d00aN-glycosylation efficiency is determined by the distance to the C-terminus and the amino acid preceding an Asn-Ser-Thr sequon.0 aNglycosylation efficiency is determined by the distance to the C c2011 Jan a179-860 v203 aN-glycosylation is the most common and versatile protein modification. In eukaryotic cells, this modification is catalyzed cotranslationally by the enzyme oligosaccharyltransferase, which targets the β-amide of the asparagine in an Asn-Xaa-Ser/Thr consensus sequon (where Xaa is any amino acid but proline) in nascent proteins as they enter the endoplasmic reticulum. Because modification of the glycosylation acceptor site on membrane proteins occurs in a compartment-specific manner, the presence of glycosylation is used to indicate membrane protein topology. Moreover, glycosylation sites can be added to gain topological information. In this study, we explored the determinants of N-glycosylation with the in vitro transcription/translation of a truncated model protein in the presence of microsomes and surveyed 25,488 glycoproteins, of which 2,533 glycosylation sites had been experimentally validated. We found that glycosylation efficiency was dependent on both the distance to the C-terminus and the nature of the amino acid that preceded the consensus sequon. These findings establish a broadly applicable method for membrane protein tagging in topological studies.
1 aBañó-Polo, Manuel1 aBaldin, Francesca1 aTamborero, Silvia1 aMarti-Renom, Marc, A1 aMingarro, Ismael uhttps://www.clinbioinfosspa.es/content/n-glycosylation-efficiency-determined-distance-c-terminus-and-amino-acid-preceding-asn-ser02025nas a2200349 4500008004100000022001400041245011700055210006900172260001300241300001100254490000700265520090400272653002501176653001301201653001301214653001401227653002301241653001301264100002101277700002101298700002301319700002001342700002101362700001701383700002401400700003301424700002401457700002001481700002001501700002001521856013401541 2011 eng d a1362-496200aPhylemon 2.0: a suite of web-tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing.0 aPhylemon 20 a suite of webtools for molecular evolution phylogen c2011 Jul aW470-40 v393 aPhylemon 2.0 is a new release of the suite of web tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing. It has been designed as a response to the increasing demand of molecular sequence analyses for experts and non-expert users. Phylemon 2.0 has several unique features that differentiates it from other similar web resources: (i) it offers an integrated environment that enables evolutionary analyses, format conversion, file storage and edition of results; (ii) it suggests further analyses, thereby guiding the users through the web server; and (iii) it allows users to design and save phylogenetic pipelines to be used over multiple genes (phylogenomics). Altogether, Phylemon 2.0 integrates a suite of 30 tools covering sequence alignment reconstruction and trimming; tree reconstruction, visualization and manipulation; and evolutionary hypotheses testing.
10aEvolution, Molecular10aGenomics10aInternet10aPhylogeny10aSequence Alignment10aSoftware1 aSánchez, Rubén1 aSerra, François1 aTárraga, Joaquín1 aMedina, Ignacio1 aCarbonell, José1 aPulido, Luis1 aDe Maria, Alejandro1 aCapella-Gutíerrez, Salvador1 aHuerta-Cepas, Jaime1 aGabaldón, Toni1 aDopazo, Joaquin1 aDopazo, Hernán uhttps://www.clinbioinfosspa.es/content/phylemon-20-suite-web-tools-molecular-evolution-phylogenetics-phylogenomics-and-hypotheses01461nas a2200253 4500008004100000245009300041210006900134260000900203300000700212490000700219520063100226100002300857700001500880700001900895700002300914700002800937700001500965700001700980700002100997700002401018700002001042700002001062856012501082 2011 eng d00aRecent human evolution has shaped geographical differences in susceptibility to disease.0 aRecent human evolution has shaped geographical differences in su c2011 a550 v123 aSearching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.
1 aMarigorta, Urko, M1 aLao, Oscar1 aCasals, Ferran1 aCalafell, Francesc1 aMorcillo-Suarez, Carlos1 aFaria, Rui1 aBosch, Elena1 aSerra, François1 aBertranpetit, Jaume1 aDopazo, Hernán1 aNavarro, Arcadi uhttps://www.clinbioinfosspa.es/content/recent-human-evolution-has-shaped-geographical-differences-susceptibility-disease02327nas a2200241 4500008004100000245007500041210006900116260001300185300001100198490000700209520154000216100002401756700003301780700002101813700001901834700003501853700002001888700001801908700002701926700002001953700001701973856009501990 2011 eng d00aRole of tomato BRANCHED1-like genes in the control of shoot branching.0 aRole of tomato BRANCHED1like genes in the control of shoot branc c2011 Aug a701-140 v673 aIn angiosperms, shoot branching greatly determines overall plant architecture and affects fundamental aspects of plant life. Branching patterns are determined by genetic pathways conserved widely across angiosperms. In Arabidopsis thaliana (Brassicaceae, Rosidae) BRANCHED1 (BRC1) plays a central role in this process, acting locally to arrest axillary bud growth. In tomato (Solanum lycopersicum, Solanaceae, Asteridae) we have identified two BRC1-like paralogues, SlBRC1a and SlBRC1b. These genes are expressed in arrested axillary buds and both are down-regulated upon bud activation, although SlBRC1a is transcribed at much lower levels than SlBRC1b. Alternative splicing of SlBRC1a renders two transcripts that encode two BRC1-like proteins with different C-t domains due to a 3’-terminal frameshift. The phenotype of loss-of-function lines suggests that SlBRC1b has retained the ancestral role of BRC1 in shoot branch suppression. We have isolated the BRC1a and BRC1b genes of other Solanum species and have studied their evolution rates across the lineages. These studies indicate that, after duplication of an ancestral BRC1-like gene, BRC1b genes continued to evolve under a strong purifying selection that was consistent with the conserved function of SlBRC1b in shoot branching control. In contrast, the coding sequences of Solanum BRC1a genes have evolved at a higher evolution rate. Branch-site tests indicate that this difference does not reflect relaxation but rather positive selective pressure for adaptation.
1 aMartín-Trillo, Mar1 aGrandío, Eduardo, González1 aSerra, François1 aMarcel, Fabien1 aRodríguez-Buey, María, Luisa1 aSchmitz, Gregor1 aTheres, Klaus1 aBendahmane, Abdelhafid1 aDopazo, Hernán1 aCubas, Pilar uhttps://www.clinbioinfosspa.es/content/role-tomato-branched1-genes-control-shoot-branching01872nas a2200145 4500008004100000245008600041210006900127260001300196300001000209490000700219520134300226100001701569700002501586856011501611 2011 eng d00aStructure determination of genomic domains by satisfaction of spatial restraints.0 aStructure determination of genomic domains by satisfaction of sp c2011 Jan a25-350 v193 aThe three-dimensional (3D) architecture of a genome is non-random and known to facilitate the spatial colocalization of regulatory elements with the genes they regulate. Determining the 3D structure of a genome may therefore probe an essential step in characterizing how genes are regulated. Currently, there are several experimental and theoretical approaches that aim at determining the 3D structure of genomes and genomic domains; however, approaches integrating experiments and computation to identify the most likely 3D folding of a genome at medium to high resolutions have not been widely explored. Here, we review existing methodologies and propose that the integrative modeling platform ( http://www.integrativemodeling.org ), a computational package developed for structurally characterizing protein assemblies, could be used for integrating diverse experimental data towards the determination of the 3D architecture of genomic domains and entire genomes at unprecedented resolution. Our approach, through the visualization of looping interactions between distal regulatory elements, will allow for the characterization of global chromatin features and their relation to gene expression. We illustrate our work by outlining the recent determination of the 3D architecture of the α-globin domain in the human genome.
1 aBaù, Davide1 aMarti-Renom, Marc, A uhttps://www.clinbioinfosspa.es/content/structure-determination-genomic-domains-satisfaction-spatial-restraints01797nas a2200217 4500008004100000245010400041210007000145260001300215300001100228490000700239520104100246100001701287700002001304700002101324700002201345700001501367700002401382700001601406700002501422856013201447 2011 eng d00aThe three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules.0 athreedimensional folding of the αglobin gene domain reveals form c2011 Jan a107-140 v183 aWe developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the α-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the α-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy.
1 aBaù, Davide1 aSanyal, Amartya1 aLajoie, Bryan, R1 aCapriotti, Emidio1 aByron, Meg1 aLawrence, Jeanne, B1 aDekker, Job1 aMarti-Renom, Marc, A uhttps://www.clinbioinfosspa.es/content/three-dimensional-folding-%CE%B1-globin-gene-domain-reveals-formation-chromatin-globules02554nas a2200361 4500008004100000245014100041210006900182260001600251300003100267490000700298520145100305653001501756653002001771653001501791653001001806653000801816653000901824100002001833700002101853700001701874700002101891700001801912700001601930700002301946700002901969700002701998700002002025700002302045700002002068700002002088700002102108856006302129 2010 eng d00aBabelomics: an integrative platform for the analysis of transcriptomics, proteomics and genomic data with advanced functional profiling.0 aBabelomics an integrative platform for the analysis of transcrip c2010 May 16 aW210-W213. Featured in NAR0 v383 aBabelomics is a response to the growing necessity of integrating and analyzing different types of genomic data in an environment that allows an easy functional interpretation of the results. Babelomics includes a complete suite of methods for the analysis of gene expression data that include normalization (covering most commercial platforms), pre-processing, differential gene expression (case-controls, multiclass, survival or continuous values), predictors, clustering; large-scale genotyping assays (case controls and TDTs, and allows population stratification analysis and correction). All these genomic data analysis facilities are integrated and connected to multiple options for the functional interpretation of the experiments. Different methods of functional enrichment or gene set enrichment can be used to understand the functional basis of the experiment analyzed. Many sources of biological information, which include functional (GO, KEGG, Biocarta, Reactome, etc.), regulatory (Transfac, Jaspar, ORegAnno, miRNAs, etc.), text-mining or protein-protein interaction modules can be used for this purpose. Finally a tool for the de novo functional annotation of sequences has been included in the system. This provides support for the functional analysis of non-model species. Mirrors of Babelomics or command line execution of their individual components are now possible. Babelomics is available at http://www.babelomics.org.
10ababelomics10agene expression10agenotyping10agepas10aGSA10aGWAS1 aMedina, Ignacio1 aCarbonell, José1 aPulido, Luis1 aMadeira, Sara, C1 aGoetz, Stefan1 aConesa, Ana1 aTárraga, Joaquín1 aPascual-Montano, Alberto1 aNogales-Cadenas, Ruben1 aSantoyo, Javier1 aGarcía, Francisco1 aMarbà, Martina1 aMontaner, David1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/38/suppl_2/W210.full02778nas a2200385 4500008004100000245011100041210006900152260001300221300001000234490000700244520152200251100002301773700002601796700001901822700002401841700002701865700002901892700002001921700002001941700002801961700001901989700002302008700002402031700002002055700001602075700002302091700001902114700002002133700002002153700002002173700002002193700002502213700002302238856013102261 2010 eng d00aChanges in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.0 aChanges in the pattern of DNA methylation associate with twin di c2010 Feb a170-90 v203 aMonozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.
1 aJavierre, Biola, M1 aFernandez, Agustin, F1 aRichter, Julia1 aAl-Shahrour, Fatima1 aMartin-Subero, Ignacio1 aRodriguez-Ubreva, Javier1 aBerdasco, Maria1 aFraga, Mario, F1 aO’Hanlon, Terrance, P1 aRider, Lisa, G1 aJacinto, Filipe, V1 aLopez-Longo, Javier1 aDopazo, Joaquin1 aForn, Marta1 aPeinado, Miguel, A1 aCarreño, Luis1 aSawalha, Amr, H1 aHarley, John, B1 aSiebert, Reiner1 aEsteller, Manel1 aMiller, Frederick, W1 aBallestar, Esteban uhttps://www.clinbioinfosspa.es/content/changes-pattern-dna-methylation-associate-twin-discordance-systemic-lupus-erythematosus03411nas a2200529 4500008004100000022001400041245007000055210006900125260000900194300000800203490000700211520186600218653000902084653002102093653001602114653002002130653002402150653001102174653003002185653001502215653001302230653001102243653001802254653001602272653001302288653002102301653004402322653002102366653003302387100002302420700002502443700001902468700001902487700002002506700002202526700002002548700002602568700002002594700002002614700002202634700002602656700001902682700002002701700002802721700002702749856010502776 2010 eng d a1465-542X00aDNA methylation epigenotypes in breast cancer molecular subtypes.0 aDNA methylation epigenotypes in breast cancer molecular subtypes c2010 aR770 v123 aINTRODUCTION: Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes.
METHODS: Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis.
RESULTS: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors.
CONCLUSIONS: Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.
10aAged10aBreast Neoplasms10aCpG Islands10aDNA Methylation10aEpigenesis, Genetic10aFemale10aGene Expression Profiling10aGenes, p5310aGenotype10aHumans10aKi-67 Antigen10aMiddle Aged10amutation10aNeoplasm Grading10aOligonucleotide Array Sequence Analysis10aReceptor, ErbB-210aTumor Suppressor Protein p531 aBediaga, Naiara, G1 aAcha-Sagredo, Amelia1 aGuerra, Isabel1 aViguri, Amparo1 aAlbaina, Carmen1 aDiaz, Irune, Ruiz1 aRezola, Ricardo1 aAlberdi, Maria, Jesus1 aDopazo, Joaquin1 aMontaner, David1 aRenobales, Mertxe1 aFernandez, Agustin, F1 aField, John, K1 aFraga, Mario, F1 aLiloglou, Triantafillos1 ade Pancorbo, Marian, M uhttps://www.clinbioinfosspa.es/content/dna-methylation-epigenotypes-breast-cancer-molecular-subtypes03760nas a2200625 4500008004100000022001400041245009800055210006900153260001600222300001100238490000600249520178700255653001002042653004902052653001102101653002102112653004902133653002502182653002902207653002402236653002802260653001102288653001902299653003802318653003402356653001302390653002302403653001102426653001502437653001102452653003602463653003702499653002902536653003802565653002002603653002002623653002002643653001702663100002102680700002002701700002402721700002702745700002102772700002202793700002202815700002502837700001702862700002002879700002102899700001902920700001902939700002102958700002602979856012903005 2010 eng d a1932-620300aExploring the link between germline and somatic genetic alterations in breast carcinogenesis.0 aExploring the link between germline and somatic genetic alterati c2010 Nov 22 ae140780 v53 aRecent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.
10aAdult10aBone Morphogenetic Protein Receptors, Type I10aBreast10aBreast Neoplasms10aCalcium-Calmodulin-Dependent Protein Kinases10aCase-Control Studies10aCyclin-Dependent Kinases10aDisease Progression10aEstrogen Receptor alpha10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGerm-Line Mutation10aHumans10aOdds Ratio10aPoland10aPolymorphism, Single Nucleotide10aProtein Serine-Threonine Kinases10aProtein-Tyrosine Kinases10aReceptor Protein-Tyrosine Kinases10aReceptor, EphA310aReceptor, EphA710aReceptor, EphB110aRisk Factors1 aBonifaci, Núria1 aGórski, Bohdan1 aMasojć, Bartlomiej1 aWokołorczyk, Dominika1 aJakubowska, Anna1 aDębniak, Tadeusz1 aBerenguer, Antoni1 aMusach, Jordi, Serra1 aBrunet, Joan1 aDopazo, Joaquin1 aNarod, Steven, A1 aLubiński, Jan1 aLázaro, Conxi1 aCybulski, Cezary1 aPujana, Miguel, Angel uhttps://www.clinbioinfosspa.es/content/exploring-link-between-germline-and-somatic-genetic-alterations-breast-carcinogenesis03102nas a2200325 4500008004100000245012300041210006900164260001600233520197300249100001902222700001902241700002402260700002102284700001702305700003102322700002002353700003002373700002502403700002402428700001902452700001902471700002102490700002602511700002402537700002902561700001802590700002002608700001902628856012902647 2010 eng d00aFine-scale evolution: genomic, phenotypic and ecological differentiation in two coexisting Salinibacter ruber strains.0 aFinescale evolution genomic phenotypic and ecological differenti c2010 Feb 183 aGenomic and metagenomic data indicate a high degree of genomic variation within microbial populations, although the ecological and evolutive meaning of this microdiversity remains unknown. Microevolution analyses, including genomic and experimental approaches, are so far very scarce for non-pathogenic bacteria. In this study, we compare the genomes, metabolomes and selected ecological traits of the strains M8 and M31 of the hyperhalophilic bacterium Salinibacter ruber that contain ribosomal RNA (rRNA) gene and intergenic regions that are identical in sequence and were simultaneously isolated from a Mediterranean solar saltern. Comparative analyses indicate that S. ruber genomes present a mosaic structure with conserved and hypervariable regions (HVRs). The HVRs or genomic islands, are enriched in transposases, genes related to surface properties, strain-specific genes and highly divergent orthologous. However, the many indels outside the HVRs indicate that genome plasticity extends beyond them. Overall, 10% of the genes encoded in the M8 genome are absent from M31 and could stem from recent acquisitions. S. ruber genomes also harbor 34 genes located outside HVRs that are transcribed during standard growth and probably derive from lateral gene transfers with Archaea preceding the M8/M31 divergence. Metabolomic analyses, phage susceptibility and competition experiments indicate that these genomic differences cannot be considered neutral from an ecological perspective. The results point to the avoidance of competition by micro-niche adaptation and response to viral predation as putative major forces that drive microevolution within these Salinibacter strains. In addition, this work highlights the extent of bacterial functional diversity and environmental adaptation, beyond the resolution of the 16S rRNA and internal transcribed spacers regions.The ISME Journal advance online publication, 18 February 2010; doi:10.1038/ismej.2010.6.
1 aPeña, Arantxa1 aTeeling, Hanno1 aHuerta-Cepas, Jaime1 aSantos, Fernando1 aYarza, Pablo1 aBrito-Echeverría, Jocelyn1 aLucio, Marianna1 aSchmitt-Kopplin, Philippe1 aMeseguer, Inmaculada1 aSchenowitz, Chantal1 aDossat, Carole1 aBarbe, Valerie1 aDopazo, Joaquín1 aRosselló-Mora, Ramon1 aSchüler, Margarete1 aGlöckner, Frank, Oliver1 aAmann, Rudolf1 aGabaldón, Toni1 aAntón, Josefa uhttps://www.clinbioinfosspa.es/content/fine-scale-evolution-genomic-phenotypic-and-ecological-differentiation-two-coexisting02604nas a2200229 4500008004100000245010300041210006900144260001500213300001200228490000800240520175600248100002902004700003802033700002802071700002902099700001802128700002002146700002002166700002302186700003002209856013502239 2010 eng d00aFM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status.0 aFM19G11 a new hypoxiainducible factor HIF modulator affects stem c2010 Jan 8 a1333-420 v2853 aThe biology of the alpha subunits of hypoxia-inducible factors (HIFalpha) has expanded from their role in angiogenesis to their current position in the self-renewal and differentiation of stem cells. The results reported in this article show the discovery of FM19G11, a novel chemical entity that inhibits HIFalpha proteins that repress target genes of the two alpha subunits, in various tumor cell lines as well as in adult and embryonic stem cell models from rodents and humans, respectively. FM19G11 inhibits at nanomolar range the transcriptional and protein expression of Oct4, Sox2, Nanog, and Tgf-alpha undifferentiating factors, in adult rat and human embryonic stem cells, FM19G11 activity occurs in ependymal progenitor stem cells from rats (epSPC), a cell model reported for spinal cord regeneration, which allows the progression of oligodendrocyte cell differentiation in a hypoxic environment, has created interest in its characterization for pharmacological research. Experiments using small interfering RNA showed a significant depletion in Sox2 protein only in the case of HIF2alpha silencing, but not in HIF1alpha-mediated ablation. Moreover, chromatin immunoprecipitation data, together with the significant presence of functional hypoxia response element consensus sequences in the promoter region of Sox2, strongly validated that this factor behaves as a target gene of HIF2alpha in epSPCs. FM19G11 causes a reduction of overall histone acetylation with significant repression of p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation. Arrays carried out in the presence and absence of the inhibitor showed the predominant involvement of epigenetic-associated events mediated by the drug.
1 aMoreno-Manzano, Victoria1 aRodríguez-Jiménez, Francisco, J1 aAceña-Bonilla, Jose, L1 aFustero-Lardíes, Santos1 aErceg, Slaven1 aDopazo, Joaquin1 aMontaner, David1 aStojkovic, Miodrag1 aSánchez-Puelles, Jose, M uhttps://www.clinbioinfosspa.es/content/fm19g11-new-hypoxia-inducible-factor-hif-modulator-affects-stem-cell-differentiation-status01719nas a2200229 4500008004100000022001400041245009600055210006900151260001300220300001000233490000600243520095200249653003101201653002901232653001301261653002001274653001301294653002001307100001901327700002001346856012301366 2010 eng d a1744-838700aFunctional genomics and networks: new approaches in the extraction of complex gene modules.0 aFunctional genomics and networks new approaches in the extractio c2010 Feb a55-630 v73 aThe engine that makes the cell work is made of an intricate network of molecular interactions. Nowadays, the elements and relationships of this complex network can be studied with several types of high-throughput techniques. The dream of having a global picture of the cell from different perspectives that can jointly explain cell behavior is, at least technically, feasible. However, this task can only be accomplished by filling the gap between data and information. The availability of methods capable of accurately managing, integrating and analyzing the results from these experiments is crucial for this purpose. Here, we review the new challenges raised by the availability of different genomic data, as well as the new proposals presented to cope with the increasing data complexity. Special emphasis is given to approaches that explore the transcriptome trying to describe the modules of genes that account for the traits studied.
10aGene Expression Regulation10aGene Regulatory Networks10aGenomics10aProtein Binding10aProteins10aSystems biology1 aMinguez, Pablo1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/functional-genomics-and-networks-new-approaches-extraction-complex-gene-modules02389nas a2200301 4500008004100000022001400041245010100055210006900156260001600225300001100241490000600252520140600258653001601664653002301680653003001703653001301733653001101746653004401757100001801801700002001819700001801839700002001857700001901877700002401896700002001920700001801940856012901958 2010 eng d a1932-620300aFunctional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysis.0 aFunctional genomics of 5 to 8cell stage human embryos by blastom c2010 Oct 26 ae136150 v53 aBlastomere fate and embryonic genome activation (EGA) during human embryonic development are unsolved areas of high scientific and clinical interest. Forty-nine blastomeres from 5- to 8-cell human embryos have been investigated following an efficient single-cell cDNA amplification protocol to provide a template for high-density microarray analysis. The previously described markers, characteristic of Inner Cell Mass (ICM) (n = 120), stemness (n = 190) and Trophectoderm (TE) (n = 45), were analyzed, and a housekeeping pattern of 46 genes was established. All the human blastomeres from the 5- to 8-cell stage embryo displayed a common gene expression pattern corresponding to ICM markers (e.g., DDX3, FOXD3, LEFTY1, MYC, NANOG, POU5F1), stemness (e.g., POU5F1, DNMT3B, GABRB3, SOX2, ZFP42, TERT), and TE markers (e.g., GATA6, EOMES, CDX2, LHCGR). The EGA profile was also investigated between the 5-6- and 8-cell stage embryos, and compared to the blastocyst stage. Known genes (n = 92) such as depleted maternal transcripts (e.g., CCNA1, CCNB1, DPPA2) and embryo-specific activation (e.g., POU5F1, CDH1, DPPA4), as well as novel genes, were confirmed. In summary, the global single-cell cDNA amplification microarray analysis of the 5- to 8-cell stage human embryos reveals that blastomere fate is not committed to ICM or TE. Finally, new EGA features in human embryogenesis are presented.
10aBlastomeres10aDNA, Complementary10aGene Expression Profiling10aGenomics10aHumans10aOligonucleotide Array Sequence Analysis1 aGalan, Amparo1 aMontaner, David1 aPóo, Eugenia1 aValbuena, Diana1 aRuiz, Veronica1 aAguilar, Cristóbal1 aDopazo, Joaquin1 aSimon, Carlos uhttps://www.clinbioinfosspa.es/content/functional-genomics-5-8-cell-stage-human-embryos-blastomere-single-cell-cdna-analysis03322nas a2200613 4500008004100000022001400041245010400055210006900159260001600228300001100244490000700255520144400262653001901706653001201725653001501737653002801752653002501780653001701805653002501822653002001847653002001867653002501887653002201912653003001934653003101964653001101995653000902006653002602015653003602041653001102077653002702088653000902115653001502124653004102139100002302180700001602203700001902219700003002238700002702268700002102295700002002316700002002336700001702356700002002373700002702393700002202420700001802442700002902460700001802489700002002507700002202527700002302549856013602572 2010 eng d a1549-491800aHypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.0 aHypoxia promotes efficient differentiation of human embryonic st c2010 Mar 31 a407-180 v283 aEarly development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O(2)) as somatic cells. We hypothesized that O(2) levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O(2)) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O(2) levels; after 24 hours at 5% O(2), more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.
10aAngiopoietin-110aAnimals10abiomarkers10aCell Culture Techniques10aCell Differentiation10aCell Hypoxia10aCell Transplantation10aCells, Cultured10aDown-Regulation10aEmbryonic Stem Cells10aEndothelial Cells10aGene Expression Profiling10aGene Expression Regulation10aHumans10aMale10aMyocardial Infarction10aNeovascularization, Physiologic10aOxygen10aPluripotent Stem Cells10aRats10aRats, Nude10aVascular Endothelial Growth Factor A1 aPrado-Lopez, Sonia1 aConesa, Ana1 aArmiñán, Ana1 aMartínez-Losa, Magdalena1 aEscobedo-Lucea, Carmen1 aGandia, Carolina1 aTarazona, Sonia1 aMelguizo, Dario1 aBlesa, David1 aMontaner, David1 aSanz-González, Silvia1 aSepúlveda, Pilar1 aGötz, Stefan1 aO'Connor, José, Enrique1 aMoreno, Ruben1 aDopazo, Joaquin1 aBurks, Deborah, J1 aStojkovic, Miodrag uhttps://www.clinbioinfosspa.es/content/hypoxia-promotes-efficient-differentiation-human-embryonic-stem-cells-functional-endothelium01700nas a2200265 4500008004100000245004500041210004400086260000900130300001300139490000600152520096600158653000801124653001401132100002001146700001601166700002701182700002001209700002001229700002301249700001901272700001901291700002001310700002001330856008401350 2010 eng d00aInitial genomics of the human nucleolus.0 aInitial genomics of the human nucleolus c2010 ae10008890 v63 aWe report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4% of the genome. Bioinformatic evaluation showed that NAD-localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD-specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture.
10aNGS10anucleolus1 aNémeth, Attila1 aConesa, Ana1 aSantoyo-López, Javier1 aMedina, Ignacio1 aMontaner, David1 aPéterfia, Bálint1 aSolovei, Irina1 aCremer, Thomas1 aDopazo, Joaquin1 aLängst, Gernot uhttp://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.100088907842nas a2202545 4500008004100000245014500041210006900186260001300255300001100268490000700279520110300286100001601389700002201405700002201427700002101449700001701470700002301487700001801510700001801528700002601546700001901572700002501591700002201616700002301638700002301661700001801684700001901702700001701721700001201738700002201750700002301772700002301795700001401818700002401832700002001856700001701876700001601893700001701909700002001926700002201946700001701968700001701985700001502002700001602017700001502033700002402048700002102072700001802093700002702111700001802138700002002156700002002176700001902196700001802215700001602233700001702249700001502266700002002281700002102301700001802322700001402340700002402354700002002378700002202398700002002420700002702440700001102467700001402478700001302492700001802505700001702523700002602540700001302566700001302579700002302592700001902615700002202634700002202656700001802678700001902696700002102715700001502736700002102751700001602772700001602788700001702804700002702821700002302848700002102871700001702892700002702909700002002936700001702956700001502973700001402988700002203002700001703024700001903041700001703060700001703077700001503094700002203109700001603131700002703147700002003174700002403194700002003218700002603238700001703264700001503281700001603296700001403312700001703326700002603343700001603369700002203385700001703407700001503424700002103439700003003460700002103490700001903511700001603530700002603546700001203572700002303584700001403607700002303621700002103644700001803665700002003683700002403703700001503727700002403742700002103766700002003787700002103807700001903828700001703847700001103864700001703875700001803892700001303910700001703923700001303940700001403953700001703967700001303984700001903997700003204016700002004048700001904068700001904087700002404106700002004130700002104150700002404171700002104195700002404216700001804240700001904258700001704277700002004294700001704314700002104331700001804352700001704370700001204387700002504399700001904424700002404443700002604467700002504493700001504518700002004533700001704553700001904570700002304589700001604612700002104628700001904649700002004668700001704688700001604705700001504721700001804736700001704754700002204771700001804793700002004811700002504831700002304856700001804879700001504897700001704912700001404929700002204943700002104965700001904986700001605005700001905021700001505040700001205055700001405067700001505081700001705096700001405113700001505127700001505142700001705157700001605174700001605190700002605206856006405232 2010 eng d00aThe MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.0 aMicroArray Quality Control MAQCII study of common practices for c2010 Aug a827-380 v283 aGene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.
1 aShi, Leming1 aCampbell, Gregory1 aJones, Wendell, D1 aCampagne, Fabien1 aWen, Zhining1 aWalker, Stephen, J1 aSu, Zhenqiang1 aChu, Tzu-Ming1 aGoodsaid, Federico, M1 aPusztai, Lajos1 aShaughnessy, John, D1 aOberthuer, André1 aThomas, Russell, S1 aPaules, Richard, S1 aFielden, Mark1 aBarlogie, Bart1 aChen, Weijie1 aDu, Pan1 aFischer, Matthias1 aFurlanello, Cesare1 aGallas, Brandon, D1 aGe, Xijin1 aMegherbi, Dalila, B1 aSymmans, Fraser1 aWang, May, D1 aZhang, John1 aBitter, Hans1 aBrors, Benedikt1 aBushel, Pierre, R1 aBylesjo, Max1 aChen, Minjun1 aCheng, Jie1 aCheng, Jing1 aChou, Jeff1 aDavison, Timothy, S1 aDelorenzi, Mauro1 aDeng, Youping1 aDevanarayan, Viswanath1 aDix, David, J1 aDopazo, Joaquin1 aDorff, Kevin, C1 aElloumi, Fathi1 aFan, Jianqing1 aFan, Shicai1 aFan, Xiaohui1 aFang, Hong1 aGonzaludo, Nina1 aHess, Kenneth, R1 aHong, Huixiao1 aHuan, Jun1 aIrizarry, Rafael, A1 aJudson, Richard1 aJuraeva, Dilafruz1 aLababidi, Samir1 aLambert, Christophe, G1 aLi, Li1 aLi, Yanen1 aLi, Zhen1 aLin, Simon, M1 aLiu, Guozhen1 aLobenhofer, Edward, K1 aLuo, Jun1 aLuo, Wen1 aMcCall, Matthew, N1 aNikolsky, Yuri1 aPennello, Gene, A1 aPerkins, Roger, G1 aPhilip, Reena1 aPopovici, Vlad1 aPrice, Nathan, D1 aQian, Feng1 aScherer, Andreas1 aShi, Tieliu1 aShi, Weiwei1 aSung, Jaeyun1 aThierry-Mieg, Danielle1 aThierry-Mieg, Jean1 aThodima, Venkata1 aTrygg, Johan1 aVishnuvajjala, Lakshmi1 aWang, Sue, Jane1 aWu, Jianping1 aWu, Yichao1 aXie, Qian1 aYousef, Waleed, A1 aZhang, Liang1 aZhang, Xuegong1 aZhong, Sheng1 aZhou, Yiming1 aZhu, Sheng1 aArasappan, Dhivya1 aBao, Wenjun1 aLucas, Anne, Bergstrom1 aBerthold, Frank1 aBrennan, Richard, J1 aBuness, Andreas1 aCatalano, Jennifer, G1 aChang, Chang1 aChen, Rong1 aCheng, Yiyu1 aCui, Jian1 aCzika, Wendy1 aDemichelis, Francesca1 aDeng, Xutao1 aDosymbekov, Damir1 aEils, Roland1 aFeng, Yang1 aFostel, Jennifer1 aFulmer-Smentek, Stephanie1 aFuscoe, James, C1 aGatto, Laurent1 aGe, Weigong1 aGoldstein, Darlene, R1 aGuo, Li1 aHalbert, Donald, N1 aHan, Jing1 aHarris, Stephen, C1 aHatzis, Christos1 aHerman, Damir1 aHuang, Jianping1 aJensen, Roderick, V1 aJiang, Rui1 aJohnson, Charles, D1 aJurman, Giuseppe1 aKahlert, Yvonne1 aKhuder, Sadik, A1 aKohl, Matthias1 aLi, Jianying1 aLi, Li1 aLi, Menglong1 aLi, Quan-Zhen1 aLi, Shao1 aLi, Zhiguang1 aLiu, Jie1 aLiu, Ying1 aLiu, Zhichao1 aMeng, Lu1 aMadera, Manuel1 aMartinez-Murillo, Francisco1 aMedina, Ignacio1 aMeehan, Joseph1 aMiclaus, Kelci1 aMoffitt, Richard, A1 aMontaner, David1 aMukherjee, Piali1 aMulligan, George, J1 aNeville, Padraic1 aNikolskaya, Tatiana1 aNing, Baitang1 aPage, Grier, P1 aParker, Joel1 aParry, Mitchell1 aPeng, Xuejun1 aPeterson, Ron, L1 aPhan, John, H1 aQuanz, Brian1 aRen, Yi1 aRiccadonna, Samantha1 aRoter, Alan, H1 aSamuelson, Frank, W1 aSchumacher, Martin, M1 aShambaugh, Joseph, D1 aShi, Qiang1 aShippy, Richard1 aSi, Shengzhu1 aSmalter, Aaron1 aSotiriou, Christos1 aSoukup, Mat1 aStaedtler, Frank1 aSteiner, Guido1 aStokes, Todd, H1 aSun, Qinglan1 aTan, Pei-Yi1 aTang, Rong1 aTezak, Zivana1 aThorn, Brett1 aTsyganova, Marina1 aTurpaz, Yaron1 aVega, Silvia, C1 aVisintainer, Roberto1 avon Frese, Juergen1 aWang, Charles1 aWang, Eric1 aWang, Junwei1 aWang, Wei1 aWestermann, Frank1 aWilley, James, C1 aWoods, Matthew1 aWu, Shujian1 aXiao, Nianqing1 aXu, Joshua1 aXu, Lei1 aYang, Lun1 aZeng, Xiao1 aZhang, Jialu1 aZhang, Li1 aZhang, Min1 aZhao, Chen1 aPuri, Raj, K1 aScherf, Uwe1 aTong, Weida1 aWolfinger, Russell, D uhttp://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html00628nas a2200133 4500008004100000022001400041245014400055210006900199260001600268300001400284490000700298110002000305856016900325 2010 eng d a1087-015600aThe MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models0 aMicroArray Quality Control MAQCII study of common practices for cJan-08-2010 a827 - 8380 v281 aMAQC Consortium uhttp://www.nature.com/articles/nbt.1665http://www.nature.com/articles/nbt.1665.pdfhttp://www.nature.com/articles/nbt.1665.pdfhttp://www.nature.com/articles/nbt.166502112nas a2200241 4500008004100000022001400041245005600055210005500111260001600166300001100182490000600193520139200199653002301591653003001614653002901644653001801673653001301691653001101704653002401715100002001739700002001759856009101779 2010 eng d a1932-620300aMultidimensional gene set analysis of genomic data.0 aMultidimensional gene set analysis of genomic data c2010 Apr 27 ae103480 v53 aUnderstanding the functional implications of changes in gene expression, mutations, etc., is the aim of most genomic experiments. To achieve this, several functional profiling methods have been proposed. Such methods study the behaviour of different gene modules (e.g. gene ontology terms) in response to one particular variable (e.g. differential gene expression). In spite to the wealth of information provided by functional profiling methods, a common limitation to all of them is their inherent unidimensional nature. In order to overcome this restriction we present a multidimensional logistic model that allows studying the relationship of gene modules with different genome-scale measurements (e.g. differential expression, genotyping association, methylation, copy number alterations, heterozygosity, etc.) simultaneously. Moreover, the relationship of such functional modules with the interactions among the variables can also be studied, which produces novel results impossible to be derived from the conventional unidimensional functional profiling methods. We report sound results of gene sets associations that remained undetected by the conventional one-dimensional gene set analysis in several examples. Our findings demonstrate the potential of the proposed approach for the discovery of new cell functionalities with complex dependences on more than one variable.
10aDatabases, Genetic10aGene Expression Profiling10aGene Regulatory Networks10aGenome, Human10aGenomics10aHumans10aModels, Statistical1 aMontaner, David1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/multidimensional-gene-set-analysis-genomic-data03045nas a2200565 4500008004100000022001400041245009600055210006900151260001300220300001400233490000700247520132400254653002401578653001201602653002501614653002801639653002401667653002501691653001701716653001101733653002101744653002201765653001101787653000901798653002801807653001301835653001301848653003601861653003201897653002501929653001001954653003301964100002201997700001902019700002602038700003302064700002002097700001802117700002302135700002202158700001802180700002402198700001902222700002102241700002202262700002002284700002702304700002502331856012302356 2010 eng d a1098-100400aMutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.0 aMutation spectrum of EYS in Spanish patients with autosomal rece c2010 Nov aE1772-8000 v313 aRetinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.
10aAmino Acid Sequence10aAnimals10aCase-Control Studies10aDNA Mutational Analysis10aDrosophila Proteins10aEvolution, Molecular10aEye Proteins10aFemale10aGenes, Recessive10aGenetic Variation10aHumans10aMale10aMolecular Sequence Data10amutation10aPedigree10aPolymorphism, Single Nucleotide10aProtein Structure, Tertiary10aRetinitis pigmentosa10aSpain10aStructural Homology, Protein1 aBarragán, Isabel1 aBorrego, Salud1 aPieras, Juan, Ignacio1 adel Pozo, María, González-1 aSantoyo, Javier1 aAyuso, Carmen1 aBaiget, Montserrat1 aMillán, José, M1 aMena, Marcela1 aEl-Aziz, Mai, M Abd1 aAudo, Isabelle1 aZeitz, Christina1 aLittink, Karin, W1 aDopazo, Joaquin1 aBhattacharya, Shomi, S1 aAntiňolo, Guillermo uhttps://www.clinbioinfosspa.es/content/mutation-spectrum-eys-spanish-patients-autosomal-recessive-retinitis-pigmentosa01816nas a2200145 4500008004100000245010300041210006900144260001600213300000800229490000700237520125000244100001801494700002401512856013401536 2010 eng d00aQuantifying the relationship between sequence and three-dimensional structure conservation in RNA.0 aQuantifying the relationship between sequence and threedimension c2010 Jun 15 a3220 v113 aABSTRACT: BACKGROUND: In recent years, the number of available RNA structures has rapidly grown reflecting the increased interest on RNA biology. Similarly to the studies carried out two decades ago for proteins, which gave the fundamental grounds for developing comparative protein structure prediction methods, we are now able to quantify the relationship between sequence and structure conservation in RNA. RESULTS: Here we introduce an all-against-all sequence- and three-dimensional (3D) structure-based comparison of a representative set of RNA structures, which have allowed us to quantitatively confirm that: (i) there is a measurable relationship between sequence and structure conservation that weakens for alignments resulting in below 60% sequence identity, (ii) evolution tends to conserve more RNA structure than sequence, and (iii) there is a twilight zone for RNA homology detection. DISCUSSION: The computational analysis here presented quantitatively describes the relationship between sequence and structure for RNA molecules and defines a twilight zone region for detecting RNA homology. Our work could represent the theoretical basis and limitations for future developments in comparative RNA 3D structure prediction.
1 aCapriotti, E.1 aMarti-Renom, M., A. uhttps://www.clinbioinfosspa.es/content/quantifying-relationship-between-sequence-and-three-dimensional-structure-conservation-rna00608nas a2200169 4500008004100000245010100041210006900142300001300211490000600224100002500230700001900255700002700274700001900301700002000320700002000340856007800360 2010 eng d00aSelection upon Genome Architecture: Conservation of Functional Neighborhoods with Changing Genes0 aSelection upon Genome Architecture Conservation of Functional Ne ae10009530 v61 aAl-Shahrour, Fátima1 aMinguez, Pablo1 aMarqués-Bonet, Tomás1 aGazave, Elodie1 aNavarro, Arcadi1 aDopazo, Joaquin uhttp://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.100095301786nas a2200277 4500008004100000022001400041245009200055210006900147260001300216300001200229490000700241520089700248653001501145653003001160653001301190653001301203653001801216653004401234653001301278100002401291700002101315700002001336700002001356700001601376856011601392 2010 eng d a1362-496200aSerial Expression Analysis: a web tool for the analysis of serial gene expression data.0 aSerial Expression Analysis a web tool for the analysis of serial c2010 Jul aW239-450 v383 aSerial transcriptomics experiments investigate the dynamics of gene expression changes associated with a quantitative variable such as time or dosage. The statistical analysis of these data implies the study of global and gene-specific expression trends, the identification of significant serial changes, the comparison of expression profiles and the assessment of transcriptional changes in terms of cellular processes. We have created the SEA (Serial Expression Analysis) suite to provide a complete web-based resource for the analysis of serial transcriptomics data. SEA offers five different algorithms based on univariate, multivariate and functional profiling strategies framed within a user-friendly interface and a project-oriented architecture to facilitate the analysis of serial gene expression data sets from different perspectives. SEA is available at sea.bioinfo.cipf.es.
10aAlgorithms10aGene Expression Profiling10aInternet10aKinetics10aLinear Models10aOligonucleotide Array Sequence Analysis10aSoftware1 aNueda, Maria, José1 aCarbonell, José1 aMedina, Ignacio1 aDopazo, Joaquin1 aConesa, Ana uhttps://www.clinbioinfosspa.es/content/serial-expression-analysis-web-tool-analysis-serial-gene-expression-data02245nas a2200217 4500008004100000245012100041210007100162260001300233300001100246490000700257520147000264100001901734700002201753700001801775700002201793700002001815700001901835700001601854700002301870856013401893 2010 eng d00aSIMAP–a comprehensive database of pre-calculated protein sequence similarities, domains, annotations and clusters.0 aSIMAP–a comprehensive database of precalculated protein sequence c2010 Jan aD223-60 v383 aThe prediction of protein function as well as the reconstruction of evolutionary genesis employing sequence comparison at large is still the most powerful tool in sequence analysis. Due to the exponential growth of the number of known protein sequences and the subsequent quadratic growth of the similarity matrix, the computation of the Similarity Matrix of Proteins (SIMAP) becomes a computational intensive task. The SIMAP database provides a comprehensive and up-to-date pre-calculation of the protein sequence similarity matrix, sequence-based features and sequence clusters. As of September 2009, SIMAP covers 48 million proteins and more than 23 million non-redundant sequences. Novel features of SIMAP include the expansion of the sequence space by including databases such as ENSEMBL as well as the integration of metagenomes based on their consistent processing and annotation. Furthermore, protein function predictions by Blast2GO are pre-calculated for all sequences in SIMAP and the data access and query functions have been improved. SIMAP assists biologists to query the up-to-date sequence space systematically and facilitates large-scale downstream projects in computational biology. Access to SIMAP is freely provided through the web portal for individuals (http://mips.gsf.de/simap/) and for programmatic access through DAS (http://webclu.bio.wzw.tum.de/das/) and Web-Service (http://mips.gsf.de/webservices/services/SimapService2.0?wsdl).
1 aRattei, Thomas1 aTischler, Patrick1 aGötz, Stefan1 aJehl, Marc-André1 aHoser, Jonathan1 aArnold, Roland1 aConesa, Ana1 aMewes, Hans-Werner uhttps://www.clinbioinfosspa.es/content/simap%E2%80%93-comprehensive-database-pre-calculated-protein-sequence-similarities-domains02049nas a2200181 4500008004100000245008700041210006900128260001300197300001100210490000700221520141100228100002401639700002201663700002501685700002101710700001701731856011901748 2009 eng d00aAlignment of multiple protein structures based on sequence and structure features.0 aAlignment of multiple protein structures based on sequence and s c2009 Sep a569-740 v223 aComparing the structures of proteins is crucial to gaining insight into protein evolution and function. Here, we align the sequences of multiple protein structures by a dynamic programming optimization of a scoring function that is a sum of an affine gap penalty and terms dependent on various sequence and structure features (SALIGN). The features include amino acid residue type, residue position, residue accessible surface area, residue secondary structure state and the conformation of a short segment centered on the residue. The multiple alignment is built by following the ’guide’ tree constructed from the matrix of all pairwise protein alignment scores. Importantly, the method does not depend on the exact values of various parameters, such as feature weights and gap penalties, because the optimal alignment across a range of parameter values is found. Using multiple structure alignments in the HOMSTRAD database, SALIGN was benchmarked against MUSTANG for multiple alignments as well as against TM-align and CE for pairwise alignments. On the average, SALIGN produces a 15% improvement in structural overlap over HOMSTRAD and 14% over MUSTANG, and yields more equivalent structural positions than TM-align and CE in 90% and 95% of cases, respectively. The utility of accurate multiple structure alignment is illustrated by its application to comparative protein structure modeling.
1 aMadhusudhan, M., S.1 aWebb, Benjamin, M1 aMarti-Renom, Marc, A1 aEswar, Narayanan1 aSali, Andrej uhttps://www.clinbioinfosspa.es/content/alignment-multiple-protein-structures-based-sequence-and-structure-features01884nas a2200253 4500008004100000245010700041210006900148300001000217490000700227520107700234653001101311653002901322100002101351700002001372700001701392700001401409700001601423700001501439700001401454700002001468700001501488700002101503856010601524 2009 eng d00aAnalysis of chronic lymphotic leukemia transcriptomic profile: differences between molecular subgroups0 aAnalysis of chronic lymphotic leukemia transcriptomic profile di a68-790 v503 aB cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with a variable clinical course. Patients with unmutated IgV(H) gene show a shorter progression-free and overall survival than patients with immunoglobulin heavy chain variable regions (IgV(H)) gene mutated. In addition, BCL6 mutations identify a subgroup of patients with high risk of progression. Gene expression was analysed in 36 early-stage patients using high-density microarrays. Around 150 genes differentially expressed were found according to IgV(H) mutations, whereas no difference was found according to BCL6 mutations. Functional profiling methods allowed us to distinguish KEGG and gene ontology terms showing coordinated gene expression changes across subgroups of CLL. We validated a set of differentially expressed genes according to IgV(H) status, scoring them as putative prognostic markers in CLL. Among them, CRY1, LPL, CD82 and DUSP22 are the ones with at least equal or superior performance to ZAP70 which is actually the most used surrogate marker of IgV(H) status.
10acancer10amicroarray data analysis1 aLewintre, Jantus1 aMartin, Reinoso1 aMontaner, D.1 aMarin, M.1 aTerol, Jose1 aFarras, R.1 aBenet, I.1 aCalvete, J., J.1 aDopazo, J.1 aGarcia-Conde, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1912748202422nas a2200469 4500008004100000022001400041245007800055210006900133260001300202300001300215490000700228520094000235653001001175653002101185653003001206653004101236653002601277653001101303653002101314653002201335653004401357653001901401653001801420653002701438100002001465700003001485700002701515700002501542700002101567700002401588700002801612700002601640700002701666700002401693700002201717700002101739700001501760700002001775700002301795700002101818856011301839 2009 eng d a1029-240300aFunctional signatures identified in B-cell non-Hodgkin lymphoma profiles.0 aFunctional signatures identified in Bcell nonHodgkin lymphoma pr c2009 Oct a1699-7080 v503 aGene-expression profiling in B-cell lymphomas has provided crucial data on specific lymphoma types, which can contribute to the identification of essential lymphoma survival genes and pathways. In this study, the gene-expression profiling data of all major B-cell lymphoma types were analyzed by unsupervised clustering. The transcriptome classification so obtained, was explored using gene set enrichment analysis generating a heatmap for B-cell lymphoma that identifies common lymphoma survival mechanisms and potential therapeutic targets, recognizing sets of coregulated genes and functional pathways expressed in different lymphoma types. Some of the most relevant signatures (stroma, cell cycle, B-cell receptor (BCR)) are shared by multiple lymphoma types or subclasses. A specific attention was paid to the analysis of BCR and coregulated pathways, defining molecular heterogeneity within multiple B-cell lymphoma types.
10aAdult10aCluster Analysis10aGene Expression Profiling10aGene Expression Regulation, Leukemic10aGenetic Heterogeneity10aHumans10aLymphoma, B-Cell10aNeoplasm Proteins10aOligonucleotide Array Sequence Analysis10aRNA, Messenger10aRNA, Neoplasm10aTranscription, Genetic1 aAggarwal, Mohit1 aSánchez-Beato, Margarita1 aGómez-López, Gonzalo1 aAl-Shahrour, Fátima1 aMartínez, Nerea1 aRodríguez, Antonia1 aRuiz-Ballesteros, Elena1 aCamacho, Francisca, I1 aPérez-Rosado, Alberto1 ade la Cueva, Paloma1 aArtiga, María, J1 aPisano, David, G1 aKimby, Eva1 aDopazo, Joaquin1 aVilluendas, Raquel1 aPiris, Miguel, A uhttps://www.clinbioinfosspa.es/content/functional-signatures-identified-b-cell-non-hodgkin-lymphoma-profiles03387nas a2200325 4500008004100000022001400041245007200055210006900127260001600196300000800212490000700220520234600227653001502573653002102588653004402609653002602653653002802679653001102707653003002718653001302748653001102761653004402772653003002816653003102846100002002877700001902897700002502916700002002941856010002961 2009 eng d a1471-216400aGene set internal coherence in the context of functional profiling.0 aGene set internal coherence in the context of functional profili c2009 Apr 27 a1970 v103 aBACKGROUND: Functional profiling methods have been extensively used in the context of high-throughput experiments and, in particular, in microarray data analysis. Such methods use available biological information to define different types of functional gene modules (e.g. gene ontology -GO-, KEGG pathways, etc.) whose representation in a pre-defined list of genes is further studied. In the most popular type of microarray experimental designs (e.g. up- or down-regulated genes, clusters of co-expressing genes, etc.) or in other genomic experiments (e.g. Chip-on-chip, epigenomics, etc.) these lists are composed by genes with a high degree of co-expression. Therefore, an implicit assumption in the application of functional profiling methods within this context is that the genes corresponding to the modules tested are effectively defining sets of co-expressing genes. Nevertheless not all the functional modules are biologically coherent entities in terms of co-expression, which will eventually hinder its detection with conventional methods of functional enrichment.
RESULTS: Using a large collection of microarray data we have carried out a detailed survey of internal correlation in GO terms and KEGG pathways, providing a coherence index to be used for measuring functional module co-regulation. An unexpected low level of internal correlation was found among the modules studied. Only around 30% of the modules defined by GO terms and 57% of the modules defined by KEGG pathways display an internal correlation higher than the expected by chance.This information on the internal correlation of the genes within the functional modules can be used in the context of a logistic regression model in a simple way to improve their detection in gene expression experiments.
CONCLUSION: For the first time, an exhaustive study on the internal co-expression of the most popular functional categories has been carried out. Interestingly, the real level of coexpression within many of them is lower than expected (or even inexistent), which will preclude its detection by means of most conventional functional profiling methods. If the gene-to-function correlation information is used in functional profiling methods, the results obtained improve the ones obtained by conventional enrichment methods.
10aAlgorithms10aBreast Neoplasms10aCarcinoma, Intraductal, Noninfiltrating10aComputational Biology10aDatabases, Nucleic Acid10aFemale10aGene Expression Profiling10aGenomics10aHumans10aOligonucleotide Array Sequence Analysis10aPapillomavirus Infections10aReproducibility of Results1 aMontaner, David1 aMinguez, Pablo1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/gene-set-internal-coherence-context-functional-profiling01715nas a2200265 4500008004100000245014300041210006900184300001300253490000700266520085600273653001501129653001301144653001101157653002701168653000801195100002001203700002001223700002101243700002601264700002101290700002301311700002401334700002001358856007101378 2009 eng d00aGene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies0 aGene setbased analysis of polymorphisms finding pathways or biol aW340-3440 v373 aGenome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/
10ababelomics10agene set10aGESBAP10apathway-based analysis10aSNP1 aMedina, Ignacio1 aMontaner, David1 aBonifaci, Núria1 aPujana, Miguel, Angel1 aCarbonell, José1 aTárraga, Joaquín1 aAl-Shahrour, Fatima1 aDopazo, Joaquin uhttp://nar.oxfordjournals.org/cgi/content/abstract/37/suppl_2/W34002028nas a2200349 4500008004100000022001400041245014400055210006900199260001300268300001100281490000700292520085700299653002501156653002101181653001101202653001001213653002201223653003401245653001101279653003601290653001301326653002801339100002001367700002001387700002101407700002601428700002101454700002301475700002501498700002001523856013501543 2009 eng d a1362-496200aGene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies.0 aGene setbased analysis of polymorphisms finding pathways or biol c2009 Jul aW340-40 v373 aGenome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/.
10aBiological Phenomena10aBreast Neoplasms10aFemale10aGenes10aGenetic Variation10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aSoftware10aUser-Computer Interface1 aMedina, Ignacio1 aMontaner, David1 aBonifaci, Núria1 aPujana, Miguel, Angel1 aCarbonell, José1 aTárraga, Joaquín1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/gene-set-based-analysis-polymorphisms-finding-pathways-or-biological-processes-associated-002548nas a2200241 4500008004100000245006500041210006300106300000900169490000600178520182800184100001302012700002002025700001502045700001402060700001902074700001602093700001502109700001702124700002202141700001302163700002402176856010602200 2009 eng d00aA kernel for open source drug discovery in tropical diseases0 akernel for open source drug discovery in tropical diseases ae4180 v33 aBACKGROUND: Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private-public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues-open source drug discovery-has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such "kernels". METHODOLOGY/PRINCIPAL FINDINGS: HERE, WE USE A COMPUTATIONAL PIPELINE FOR: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other. CONCLUSIONS/SIGNIFICANCE: The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases.1 aOrti, L.1 aCarbajo, R., J.1 aPieper, U.1 aEswar, N.1 aMaurer, S., M.1 aRai, A., K.1 aTaylor, G.1 aTodd, M., H.1 aPineda-Lucena, A.1 aSali, A.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1938128600678nas a2200229 4500008004100000245004900041210004700090300001000137490000700147100001300154700002000167700001500187700001400202700001900216700001600235700001500251700001700266700002200283700001300305700002400318856010600342 2009 eng d00aA kernel for the Tropical Disease Initiative0 akernel for the Tropical Disease Initiative a320-10 v271 aOrti, L.1 aCarbajo, R., J.1 aPieper, U.1 aEswar, N.1 aMaurer, S., M.1 aRai, A., K.1 aTaylor, G.1 aTodd, M., H.1 aPineda-Lucena, A.1 aSali, A.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1935236202308nas a2200325 4500008004100000245009900041210006900140300001200209490000700221520117300228653001501401653003601416653004401452653003601496653009601532653005201628100001501680700001401695700001701709700001601726700001401742700001901756700001501775700001501790700001601805700002401821700001801845700001301863856010601876 2009 eng d00aMODBASE, a database of annotated comparative protein structure models and associated resources0 aMODBASE a database of annotated comparative protein structure mo aD347-540 v373 aMODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models. The models are calculated by MODPIPE, an automated modeling pipeline that relies primarily on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE currently contains 5,152,695 reliable models for domains in 1,593,209 unique protein sequences; only models based on statistically significant alignments and/or models assessed to have the correct fold are included. MODBASE also allows users to calculate comparative models on demand, through an interface to the MODWEB modeling server (http://salilab.org/modweb). Other resources integrated with MODBASE include databases of multiple protein structure alignments (DBAli), structurally defined ligand binding sites (LIGBASE), predicted ligand binding sites (AnnoLyze), structurally defined binary domain interfaces (PIBASE) and annotated single nucleotide polymorphisms and somatic mutations found in human proteins (LS-SNP, LS-Mut). MODBASE models are also available through the Protein Model Portal (http://www.proteinmodelportal.org/).10a*Databases10aMolecular Mutation Polymorphism10aProtein Genomics Humans Ligands *Models10aProtein User-Computer Interface10aSingle Nucleotide Protein Folding Protein Interaction Domains and Motifs *Protein Structure10aTertiary Proteins/genetics *Structural Homology1 aPieper, U.1 aEswar, N.1 aWebb, B., M.1 aEramian, D.1 aKelly, L.1 aBarkan, D., T.1 aCarter, H.1 aMankoo, P.1 aKarchin, R.1 aMarti-Renom, M., A.1 aDavis, F., P.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1894828202280nas a2200169 4500008004100000245007900041210006900120520169500189653002001884100001501904700001601919700001801935700002401953700001301977700001401990856010602004 2009 eng d00aModLink+: Improving fold recognition by using protein-protein interactions0 aModLink Improving fold recognition by using proteinprotein inter3 aMOTIVATION: Several strategies have been developed to predict the fold of a target protein sequence, most of which are based on aligning the target sequence to other sequences of known structure. Previously, we demonstrated that the consideration of protein-protein interactions significantly increases the accuracy of fold assignment compared to PSI-BLAST sequence comparisons. A drawback of our method was the low number of proteins to which a fold could be assigned. Here, we present an improved version of the method that addresses this limitation. We also compare our method to other state-of-the-art fold assignment methodologies. RESULTS: Our approach (ModLink+) has been tested on 3,716 proteins with domain folds classified in the Structural Classification Of Proteins (SCOP) as well as known interacting partners in the Database of Interacting Proteins (DIP). For this test set, the ratio of success (PPV) on fold assignment increases from 75% for PSI-BLAST, 83% for HHSearch and 81% for PRC to more than 90% for ModLink+ at the e-value cutoff of 10(-3). Under this e-value, ModLink+ can assign a fold to 30-45% of the proteins in the test set, while our previous method could cover less than 25%. When applied to 6,384 proteins with unknown fold in the yeast proteome, ModLink+ combined with PSI-BLAST assigns a fold for domains in 3,738 proteins, while PSI-BLAST alone only covers 2,122 proteins, HHSearch 2,969 and PRC 2,826 proteins, using a threshold e-value that would represent a PPV higher than 82% for each method in the test set. AVAILABILITY: The ModLink+ server is freely accessible in the World Wide Web at http://sbi.imim.es/modlink/. CONTACT: boliva@imim.es.
10aprotein folding1 aFornes, O.1 aAragues, R.1 aEspadaler, J.1 aMarti-Renom, M., A.1 aSali, A.1 aOliva, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1935710000709nas a2200181 4500008004100000022001400041245013200055210006900187300000800256490000600264100002600270700001600296700001800312700002000330700002200350700001900372856013600391 2009 eng d a1756-050000aParallel changes in gene expression in peripheral blood mononuclear cells and the brain after maternal separation in the mouse.0 aParallel changes in gene expression in peripheral blood mononucl a1950 v21 avan Heerden, Johan, H1 aConesa, Ana1 aStein, Dan, J1 aMontaner, David1 aRussell, Vivienne1 aIlling, Nicola uhttps://www.clinbioinfosspa.es/content/parallel-changes-gene-expression-peripheral-blood-mononuclear-cells-and-brain-after-maternal00658nas a2200241 4500008004100000245004000041210003900081300001200120490000600132100001400138700001600152700001400168700001600182700001500198700001800213700001500231700002100246700002200267700001500289700002200304700001500326856007500341 2009 eng d00aPere Alberch: Originator of EvoDevo0 aPere Alberch Originator of EvoDevo a351-3530 v31 aReiss, JO1 aBurke, A, C1 aArcher, C1 aDe Renzi, M1 aDopazo, H.1 aEtxeberria, A1 aGale, E, A1 aHinchliffe, J, R1 ade la Rosa, Nuño1 aRose, C, S1 aRasskin-Gutman, D1 aMüller, G uhttps://www.clinbioinfosspa.es/content/pere-alberch-originator-evodevo00912nas a2200265 4500008004100000245010100041210006900142260000700211100002100218700002100239700002000260700002200280700001800302700002200320700002200342700002000364700002000384700001400404700001900418700001900437700001800456700002400474700001800498856013000516 2009 eng d00aPeripheral blood cells transcriptome to study new biomarkers for myocardial infarction follow up0 aPeripheral blood cells transcriptome to study new biomarkers for c061 aSilbiger, Vivian1 aLuchessi, André1 aHirata, Rosario1 aCarracedo, Ángel1 aBrión, Maria1 aNeto, Lidio, Lima1 aPastorelli, C, P.1 aDopazo, Joaquin1 aMontaner, David1 aGarcia, F1 aSampaio, M, P.1 aPereira, M, P.1 aSantos, E, S.1 aArmaganijan, Dikran1 aHirata, Mario uhttps://www.clinbioinfosspa.es/content/peripheral-blood-cells-transcriptome-study-new-biomarkers-myocardial-infarction-follow00491nas a2200157 4500008004100000022002900041245004900070210004900119260003900168300001200207100001600219700001500235700001600250700001800266856004900284 2009 eng d a1605663980, 97816056639800aProtein Interactions for Functional Genomics0 aProtein Interactions for Functional Genomics aHershey, USAbIdea Group Inc (IGI) a223-2381 aMinguez, P.1 aDopazo, J.1 aLi, Xiao-Li1 aNg, See-Kiong uhttp://books.google.es/books?id=pNyCy5GsqtkC01599nas a2200145 4500008004100000245006100041210006000102300001100162520114400173653000801317653001801325100002201343700002401365856006401389 2009 eng d00aSARA: a server for function annotation of RNA structures0 aSARA a server for function annotation of RNA structures agkp4333 aRecent interest in non-coding RNA transcripts has resulted in a rapid increase of deposited RNA structures in the Protein Data Bank. However, a characterization and functional classification of the RNA structure and function space have only been partially addressed. Here, we introduce the SARA program for pair-wise alignment of RNA structures as a web server for structure-based RNA function assignment. The SARA server relies on the SARA program, which aligns two RNA structures based on a unit-vector root-mean-square approach. The likely accuracy of the SARA alignments is assessed by three different P-values estimating the statistical significance of the sequence, secondary structure and tertiary structure identity scores, respectively. Our benchmarks, which relied on a set of 419 RNA structures with known SCOR structural class, indicate that at a negative logarithm of mean P-value higher or equal than 2.5, SARA can assign the correct or a similar SCOR class to 81.4% and 95.3% of the benchmark set, respectively. The SARA server is freely accessible via the World Wide Web at http://sgu.bioinfo.cipf.es/services/SARA/.
10aRNA10aRNA structure1 aCapriotti, Emidio1 aMarti-Renom, M., A. uhttp://nar.oxfordjournals.org/cgi/content/abstract/gkp433v102586nas a2200193 4500008004100000245013300041210006900174520188100243653001502124653002302139653002202162100002202184700001502206700001502221700001402236700001902250700001702269856010602286 2009 eng d00aSexual selection drives weak positive selection in protamine genes and high promoter divergence, enhancing sperm competitiveness0 aSexual selection drives weak positive selection in protamine gen3 aPhenotypic adaptations may be the result of changes in gene structure or gene regulation, but little is known about the evolution of gene expression. In addition, it is unclear whether the same selective forces may operate at both levels simultaneously. Reproductive proteins evolve rapidly, but the underlying selective forces promoting such rapid changes are still a matter of debate. In particular, the role of sexual selection in driving positive selection among reproductive proteins remains controversial, whereas its potential influence on changes in promoter regions has not been explored. Protamines are responsible for maintaining DNA in a compacted form in chromosomes in sperm and the available evidence suggests that they evolve rapidly. Because protamines condense DNA within the sperm nucleus, they influence sperm head shape. Here, we examine the influence of sperm competition upon protamine 1 and protamine 2 genes and their promoters, by comparing closely related species of Mus that differ in relative testes size, a reliable indicator of levels of sperm competition. We find evidence of positive selection in the protamine 2 gene in the species with the highest inferred levels of sperm competition. In addition, sperm competition levels across all species are strongly associated with high divergence in protamine 2 promoters that, in turn, are associated with sperm swimming speed. We suggest that changes in protamine 2 promoters are likely to enhance sperm swimming speed by making sperm heads more hydrodynamic. Such phenotypic changes are adaptive because sperm swimming speed may be a major determinant of fertilization success under sperm competition. Thus, when species have diverged recently, few changes in gene-coding sequences are found, while high divergence in promoters seems to be associated with the intensity of sexual selection.
10aAdaptation10apositive selection10asperm competition1 aMartin-Coello, J.1 aDopazo, H.1 aArbiza, L.1 aAusio, J.1 aRoldan, E., R.1 aGomendio, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1936473501737nas a2200277 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520083000253653002201083653003701105653002301142653001101165653001301176653003201189653001301221100001901234700001801253700002001271700002501291700002001316856012301336 2009 eng d a1362-496200aSNOW, a web-based tool for the statistical analysis of protein-protein interaction networks.0 aSNOW a webbased tool for the statistical analysis of proteinprot c2009 Jul aW109-140 v373 aUnderstanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today's biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.
10aComputer Graphics10aData Interpretation, Statistical10aDatabases, Protein10aHumans10aInternet10aProtein Interaction Mapping10aSoftware1 aMinguez, Pablo1 aGötz, Stefan1 aMontaner, David1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/snow-web-based-tool-statistical-analysis-protein-protein-interaction-networks-001472nas a2200205 4500008004100000245009600041210006900137300001300206490000700219520083200226653001601058653001201074653000901086100001901095700001301114700002001127700002401147700002001171856007501191 2009 eng d00aSNOW, a web-based tool for the statistical analysis of protein-protein interaction networks0 aSNOW a webbased tool for the statistical analysis of proteinprot aW109-1140 v373 aUnderstanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today’s biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.
10ainteractome10anetwork10asnow1 aMinguez, Pablo1 aGotz, S.1 aMontaner, David1 aAl-Shahrour, Fatima1 aDopazo, Joaquin uhttp://nar.oxfordjournals.org/content/early/2009/05/19/nar.gkp402.full00479nas a2200157 4500008004100000245004000041210004000081250000800121260003700129653003000166100002400196700001800220700001900238700001500257856004900272 2009 eng d00aStructural Comparison and Alignment0 aStructural Comparison and Alignment a2nd aNew Jersey. USAbWiley-Blackwell10aStructural Bioinformatics1 aMarti-Renom, M., A.1 aCapriotti, E.1 aShindyalov, I.1 aBourne, P. uhttp://www.amazon.com/gp/product/0470181052/00387nas a2200109 4500008004100000245004800041210004800089260005700137100001800194700002400212856004100236 2008 eng d00aAssessment of protein structure predictions0 aAssessment of protein structure predictions aNew Jersey, USAbWorld Scientific Publishing Company1 aCapriotti, E.1 aMarti-Renom, M., A. uhttp://www.amazon.com/dp/9812778772/02142nas a2200253 4500008004100000245010200041210006900143300001100212490000700223520138600230653001501616653002401631100002401655700001801679700001601697700001401713700001501727700001601742700002001758700001501778700001701793700001501810856006301825 2008 eng d00aBabelomics: advanced functional profiling of transcriptomics, proteomics and genomics experiments0 aBabelomics advanced functional profiling of transcriptomics prot aW341-60 v363 aWe present a new version of Babelomics, a complete suite of web tools for the functional profiling of genome scale experiments, with new and improved methods as well as more types of functional definitions. Babelomics includes different flavours of conventional functional enrichment methods as well as more advanced gene set analysis methods that makes it a unique tool among the similar resources available. In addition to the well-known functional definitions (GO, KEGG), Babelomics includes new ones such as Biocarta pathways or text mining-derived functional terms. Regulatory modules implemented include transcriptional control (Transfac, CisRed) and other levels of regulation such as miRNA-mediated interference. Moreover, Babelomics allows for sub-selection of terms in order to test more focused hypothesis. Also gene annotation correspondence tables can be imported, which allows testing with user-defined functional modules. Finally, a tool for the ’de novo’ functional annotation of sequences has been included in the system. This allows using yet unannotated organisms in the program. Babelomics has been extensively re-engineered and now it includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. Babelomics is available at http://www.babelomics.org.
10ababelomics10afuntional profiling1 aAl-Shahrour, Fatima1 aCarbonell, J.1 aMinguez, P.1 aGoetz, S.1 aConesa, A.1 aTarraga, J.1 aMedina, Ignacio1 aAlloza, E.1 aMontaner, D.1 aDopazo, J. uhttp://nar.oxfordjournals.org/content/36/suppl_2/W341.long02872nas a2200241 4500008004100000245013000041210006900171300000700240490000600247520211000253653001302363653000902376653000802385100001702393700001802410700001302428700001402441700002002455700001502475700001502490700001902505856010602524 2008 eng d00aBiological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes0 aBiological processes properties and molecular wiring diagrams of a620 v13 aABSTRACT: BACKGROUND: Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. METHODS: We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. RESULTS: First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk. CONCLUSION: This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.
10agene set10aGWAS10aSNP1 aBonifaci, N.1 aBerenguer, A.1 aDiez, J.1 aReina, O.1 aMedina, Ignacio1 aDopazo, J.1 aMoreno, V.1 aPujana, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1909423002659nas a2200253 4500008004100000245010800041210006900149300001000218490000700228520165100235653006101886653019201947100001402139700001302153700001302166700001802179700001702197700001502214700002002229700001602249700001502265700001902280856010602299 2008 eng d00aCLEAR-test: combining inference for differential expression and variability in microarray data analysis0 aCLEARtest combining inference for differential expression and va a33-450 v413 aA common goal of microarray experiments is to detect genes that are differentially expressed under distinct experimental conditions. Several statistical tests have been proposed to determine whether the observed changes in gene expression are significant. The t-test assigns a score to each gene on the basis of changes in its expression relative to its estimated variability, in such a way that genes with a higher score (in absolute values) are more likely to be significant. Most variants of the t-test use the complete set of genes to influence the variance estimate for each single gene. However, no inference is made in terms of the variability itself. Here, we highlight the problem of low observed variances in the t-test, when genes with relatively small changes are declared differentially expressed. Alternatively, the z-test could be used although, unlike the t-test, it can declare differentially expressed genes with high observed variances. To overcome this, we propose to combine the z-test, which focuses on large changes, with a chi(2) test to evaluate variability. We call this procedure CLEAR-test and we provide a combined p-value that offers a compromise between both aspects. Analysis of three publicly available microarray datasets reveals the greater performance of the CLEAR-test relative to the t-test and alternative methods. Finally, empirical and simulated data analyses demonstrate the greater reproducibility and statistical power of the CLEAR-test and z-test with respect to current alternative methods. In addition, the CLEAR-test improves the z-test by capturing reproducible genes with high variability.
10a*Algorithms Artificial Intelligence *Data Interpretation10aStatistical Gene Expression Profiling/*methods Gene Expression Regulation/*physiology Oligonucleotide Array Sequence Analysis/*methods Proteome/*metabolism Signal Transduction/*physiology1 aValls, J.1 aGrau, M.1 aSole, X.1 aHernandez, P.1 aMontaner, D.1 aDopazo, J.1 aPeinado, M., A.1 aCapella, G.1 aMoreno, V.1 aPujana, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1759700903014nas a2200229 4500008004100000245012600041210006900167300001200236490000700248520187400255653014702129653025902276100002302535700001602558700001502574700002002589700001802609700002002627700001702647700001402664856010602678 2008 eng d00aControlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications0 aControlled ovarian stimulation induces a functional genomic dela a4500-100 v933 aCONTEXT: Controlled ovarian stimulation induces morphological, biochemical, and functional genomic modifications of the human endometrium during the window of implantation. OBJECTIVE: Our objective was to compare the gene expression profile of the human endometrium in natural vs. controlled ovarian stimulation cycles throughout the early-mid secretory transition using microarray technology. METHOD: Microarray data from 49 endometrial biopsies obtained from LH+1 to LH+9 (n=25) in natural cycles and from human chorionic gonadotropin (hCG) +1 to hCG+9 in controlled ovarian stimulation cycles (n=24) were analyzed using different methods, such as clustering, profiling of biological processes, and selection of differentially expressed genes, as implemented in Gene Expression Pattern Analysis Suite and Babelomics programs. RESULTS: Endometria from natural cycles followed different genomic patterns compared with controlled ovarian stimulation cycles in the transition from the pre-receptive (days LH/hCG+1 until LH/hCG+5) to the receptive phase (day LH+7/hCG+7). Specifically, we have demonstrated the existence of a 2-d delay in the activation/repression of two clusters composed by 218 and 133 genes, respectively, on day hCG+7 vs. LH+7. Many of these delayed genes belong to the class window of implantation genes affecting basic biological processes in the receptive endometrium. CONCLUSIONS: These results demonstrate that gene expression profiling of the endometrium is different between natural and controlled ovarian stimulation cycles in the receptive phase. Identification of these differentially regulated genes can be used to understand the different developmental profiles of receptive endometrium during controlled ovarian stimulation and to search for the best controlled ovarian stimulation treatment in terms of minimal endometrial impact.
10aAlgorithms Chorionic Gonadotropin/genetics Endometrium/cytology/pathology/*physiology/physiopathology Female Gene Expression Regulation Genome10aHuman Glutathione Peroxidase/genetics Humans Insulin-Like Growth Factor Binding Proteins/genetics Luteal Phase/physiology Luteinizing Hormone/genetics Menstrual Cycle Oligonucleotide Array Sequence Analysis Ovulation Induction/*methods RNA/genetics/isola1 aHorcajadas, J., A.1 aMinguez, P.1 aDopazo, J.1 aEsteban, F., J.1 aDominguez, F.1 aGiudice, L., C.1 aPellicer, A.1 aSimon, C. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1869787000550nas a2200157 4500008004100000245007400041210006900115260002300184300001200207100001800219700001200237700001600249700001600265700001300281856009800294 2008 eng d00aThe core of a minimal gene set: insights from natural reduced genomes0 acore of a minimal gene set insights from natural reduced genomes aUSAbThe MIT Press a347-3661 aGabaldón, T.1 aGil, R.1 aPeretó, J.1 aLatorre, A.1 aMoya, A. uhttps://www.clinbioinfosspa.es/content/core-minimal-gene-set-insights-natural-reduced-genomes01778nas a2200229 4500008004100000245010300041210006900144300001100213490000700224520087500231653007101106653013601177100001501313700001201328700002201340700001801362700001301380700001701393700001701410700001501427856010601442 2008 eng d00aDirect functional assessment of the composite phenotype through multivariate projection strategies0 aDirect functional assessment of the composite phenotype through a373-830 v923 aWe present a novel approach for the analysis of transcriptomics data that integrates functional annotation of gene sets with expression values in a multivariate fashion, and directly assesses the relation of functional features to a multivariate space of response phenotypical variables. Multivariate projection methods are used to obtain new correlated variables for a set of genes that share a given function. These new functional variables are then related to the response variables of interest. The analysis of the principal directions of the multivariate regression allows for the identification of gene function features correlated with the phenotype. Two different transcriptomics studies are used to illustrate the statistical and interpretative aspects of the methodology. We demonstrate the superiority of the proposed method over equivalent approaches.
10aBreast Neoplasms/genetics Computational Biology/*methods Databases10aGenetic Female Gene Expression Profiling/*statistics & numerical data Humans Mathematical Computing Multivariate Analysis Phenotype1 aConesa, A.1 aBro, R.1 aGarcia-Garcia, F.1 aPrats, J., M.1 aGotz, S.1 aKjeldahl, K.1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1865288801951nas a2200337 4500008004100000022001400041245010400055210006900159260001300228300001100241490000700252520087500259653002101134653002601155653002301181653001101204653003001215653001101245653002701256653002601283653001401309100001601323700001601339700002901355700002501384700001801409700002001427700002001447700002001467856012601487 2008 eng d a1089-864600aDirect functional assessment of the composite phenotype through multivariate projection strategies.0 aDirect functional assessment of the composite phenotype through c2008 Dec a373-830 v923 aWe present a novel approach for the analysis of transcriptomics data that integrates functional annotation of gene sets with expression values in a multivariate fashion, and directly assesses the relation of functional features to a multivariate space of response phenotypical variables. Multivariate projection methods are used to obtain new correlated variables for a set of genes that share a given function. These new functional variables are then related to the response variables of interest. The analysis of the principal directions of the multivariate regression allows for the identification of gene function features correlated with the phenotype. Two different transcriptomics studies are used to illustrate the statistical and interpretative aspects of the methodology. We demonstrate the superiority of the proposed method over equivalent approaches.
10aBreast Neoplasms10aComputational Biology10aDatabases, Genetic10aFemale10aGene Expression Profiling10aHumans10aMathematical Computing10aMultivariate Analysis10aPhenotype1 aConesa, Ana1 aBro, Rasmus1 aGarcia-Garcia, Francisco1 aPrats, José, Manuel1 aGötz, Stefan1 aKjeldahl, Karin1 aMontaner, David1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/direct-functional-assessment-composite-phenotype-through-multivariate-projection-001187nas a2200145 4500008004100000245013100041210006900172300000800241490000600249520062400255100001900879700001300898700002400911856010600935 2008 eng d00aEvolutionary potentials: structure specific knowledge-based potentials exploiting the evolutionary record of sequence homologs0 aEvolutionary potentials structure specific knowledgebased potent aR680 v93 aABSTRACT: We introduce a new type of knowledge-based potentials for protein structure prediction, called ’evolutionary potentials’, which are derived using a single experimental protein structure and all three-dimensional models of its homologous sequences. The new potentials have been benchmarked against other knowledge-based potentials, resulting in a significant increase in accuracy for model assessment. In contrast to standard knowledge-based potentials, we propose that evolutionary potentials capture key determinants of thermodynamic stability and specific sequence constraints required for fast folding.1 aPanjkovich, A.1 aMelo, F.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1839751702205nas a2200301 4500008004100000245007600041210006900117300001200186490000700198520130100205653001001506653002901516100001601545700002001561700001801581700002101599700001601620700001501636700002401651700002301675700001401698700001601712700002201728700001501750700001701765700001501782856010601797 2008 eng d00aGEPAS, a web-based tool for microarray data analysis and interpretation0 aGEPAS a webbased tool for microarray data analysis and interpret aW308-140 v363 aGene Expression Profile Analysis Suite (GEPAS) is one of the most complete and extensively used web-based packages for microarray data analysis. During its more than 5 years of activity it has continuously been updated to keep pace with the state-of-the-art in the changing microarray data analysis arena. GEPAS offers diverse analysis options that include well established as well as novel algorithms for normalization, gene selection, class prediction, clustering and functional profiling of the experiment. New options for time-course (or dose-response) experiments, microarray-based class prediction, new clustering methods and new tests for differential expression have been included. The new pipeliner module allows automating the execution of sequential analysis steps by means of a simple but powerful graphic interface. An extensive re-engineering of GEPAS has been carried out which includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. GEPAS is nowadays the most quoted web tool in its field and it is extensively used by researchers of many countries and its records indicate an average usage rate of 500 experiments per day. GEPAS, is available at http://www.gepas.org.
10agepas10amicroarray data analysis1 aTarraga, J.1 aMedina, Ignacio1 aCarbonell, J.1 aHuerta-Cepas, J.1 aMinguez, P.1 aAlloza, E.1 aAl-Shahrour, Fatima1 aVegas-Azcarate, S.1 aGoetz, S.1 aEscobar, P.1 aGarcia-Garcia, F.1 aConesa, A.1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1850880602503nas a2200385 4500008004100000022001400041245007700055210006900132260001600201300001200217490000700229520130100236653002201537653003701559653003001596653001301626653001301639653004401652653001301696100002301709700002001732700002101752700002401773700001901797700001601816700002501832700002801857700001801885700001901903700002901922700001601951700002001967700002001987856011002007 2008 eng d a1362-496200aGEPAS, a web-based tool for microarray data analysis and interpretation.0 aGEPAS a webbased tool for microarray data analysis and interpret c2008 Jul 01 aW308-140 v363 aGene Expression Profile Analysis Suite (GEPAS) is one of the most complete and extensively used web-based packages for microarray data analysis. During its more than 5 years of activity it has continuously been updated to keep pace with the state-of-the-art in the changing microarray data analysis arena. GEPAS offers diverse analysis options that include well established as well as novel algorithms for normalization, gene selection, class prediction, clustering and functional profiling of the experiment. New options for time-course (or dose-response) experiments, microarray-based class prediction, new clustering methods and new tests for differential expression have been included. The new pipeliner module allows automating the execution of sequential analysis steps by means of a simple but powerful graphic interface. An extensive re-engineering of GEPAS has been carried out which includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. GEPAS is nowadays the most quoted web tool in its field and it is extensively used by researchers of many countries and its records indicate an average usage rate of 500 experiments per day. GEPAS, is available at http://www.gepas.org.
10aComputer Graphics10aDose-Response Relationship, Drug10aGene Expression Profiling10aInternet10aKinetics10aOligonucleotide Array Sequence Analysis10aSoftware1 aTárraga, Joaquín1 aMedina, Ignacio1 aCarbonell, José1 aHuerta-Cepas, Jaime1 aMinguez, Pablo1 aAlloza, Eva1 aAl-Shahrour, Fátima1 aVegas-Azcárate, Susana1 aGoetz, Stefan1 aEscobar, Pablo1 aGarcia-Garcia, Francisco1 aConesa, Ana1 aMontaner, David1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/gepas-web-based-tool-microarray-data-analysis-and-interpretation-002702nas a2200253 4500008004100000245013300041210006900174300001100243490000700254520167500261653004701936653002901983653012302012653010502135100001602240700001402256700002002270700002102290700001802311700001502329700001702344700002002361856006702381 2008 eng d00aJoint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases0 aJoint annotation of coding and noncoding single nucleotide polym aD825-90 v363 aSingle nucleotide polymorphisms (SNPs) are, together with copy number variation, the primary source of variation in the human genome. SNPs are associated with altered response to drug treatment, susceptibility to disease and other phenotypic variation. Furthermore, during genetic screens for disease-associated mutations in groups of patients and control individuals, the distinction between disease causing mutation and polymorphism is often unclear. Annotation of the functional and structural implications of single nucleotide changes thus provides valuable information to interpret and guide experiments. The SNPeffect and PupaSuite databases are now synchronized to deliver annotations for both non-coding and coding SNP, as well as annotations for the SwissProt set of human disease mutations. In addition, SNPeffect now contains predictions of Tango2: an improved aggregation detector, and Waltz: a novel predictor of amyloid-forming sequences, as well as improved predictors for regions that are recognized by the Hsp70 family of chaperones. The new PupaSuite version incorporates predictions for SNPs in silencers and miRNAs including their targets, as well as additional methods for predicting SNPs in TFBSs and splice sites. Also predictions for mouse and rat genomes have been added. In addition, a PupaSuite web service has been developed to enable data access, programmatically. The combined database holds annotations for 4,965,073 regulatory as well as 133,505 coding human SNPs and 14,935 disease mutations, and phenotypic descriptions of 43,797 human proteins and is accessible via http://snpeffect.vib.be and http://pupasuite.bioinfo.cipf.es/.
10aAmino Acid Substitution Animals *Databases10aGenetic Genetic Diseases10aInborn/genetics HSP70 Heat-Shock Proteins/metabolism Humans Internet Mice MicroRNAs/metabolism *Mutation *Polymorphism10aSingle Nucleotide Proteins/chemistry/genetics RNA Splice Sites Rats Transcription Factors/metabolism1 aReumers, J.1 aConde, L.1 aMedina, Ignacio1 aMaurer-Stroh, S.1 aVan Durme, J.1 aDopazo, J.1 aRousseau, F.1 aSchymkowitz, J. uhttp://nar.oxfordjournals.org/cgi/content/full/36/suppl_1/D82502961nas a2200409 4500008004100000022001400041245013400055210006900189260001300258300001100271490000700282520167500289653002801964653001201992653002302004653002902027653003002056653001102086653001302097653000902110653001402119653001302133653003602146653001302182653000902195653002102204653002602225100001802251700001702269700002002286700002802306700002102334700002002355700002302375700002302398856013002421 2008 eng d a1362-496200aJoint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases.0 aJoint annotation of coding and noncoding single nucleotide polym c2008 Jan aD825-90 v363 aSingle nucleotide polymorphisms (SNPs) are, together with copy number variation, the primary source of variation in the human genome. SNPs are associated with altered response to drug treatment, susceptibility to disease and other phenotypic variation. Furthermore, during genetic screens for disease-associated mutations in groups of patients and control individuals, the distinction between disease causing mutation and polymorphism is often unclear. Annotation of the functional and structural implications of single nucleotide changes thus provides valuable information to interpret and guide experiments. The SNPeffect and PupaSuite databases are now synchronized to deliver annotations for both non-coding and coding SNP, as well as annotations for the SwissProt set of human disease mutations. In addition, SNPeffect now contains predictions of Tango2: an improved aggregation detector, and Waltz: a novel predictor of amyloid-forming sequences, as well as improved predictors for regions that are recognized by the Hsp70 family of chaperones. The new PupaSuite version incorporates predictions for SNPs in silencers and miRNAs including their targets, as well as additional methods for predicting SNPs in TFBSs and splice sites. Also predictions for mouse and rat genomes have been added. In addition, a PupaSuite web service has been developed to enable data access, programmatically. The combined database holds annotations for 4,965,073 regulatory as well as 133,505 coding human SNPs and 14,935 disease mutations, and phenotypic descriptions of 43,797 human proteins and is accessible via http://snpeffect.vib.be and http://pupasuite.bioinfo.cipf.es/.
10aAmino Acid Substitution10aAnimals10aDatabases, Genetic10aGenetic Diseases, Inborn10aHSP70 Heat-Shock Proteins10aHumans10aInternet10aMice10aMicroRNAs10amutation10aPolymorphism, Single Nucleotide10aProteins10aRats10aRNA Splice Sites10aTranscription Factors1 aReumers, Joke1 aConde, Lucia1 aMedina, Ignacio1 aMaurer-Stroh, Sebastian1 aVan Durme, Joost1 aDopazo, Joaquin1 aRousseau, Frederic1 aSchymkowitz, Joost uhttps://www.clinbioinfosspa.es/content/joint-annotation-coding-and-non-coding-single-nucleotide-polymorphisms-and-mutations-003141nas a2200313 4500008004100000245013000041210006900171300001200240490000700252520169500259653011401954653003602068653016902104653009402273653012702367100002202494700002602516700001402542700001602556700003002572700001702602700001702619700002002636700001502656700001702671700001602688700001702704856010602721 2008 eng d00aMolecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information0 aMolecular profiling related to poor prognosis in thyroid carcino a1554-610 v273 aUndifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.
10aAdenoma/genetics/metabolism/pathology Adolescent Adult Aged Carcinoma/genetics/metabolism/pathology Carcinoma10aBiological/*genetics/metabolism10aNeoplasm/genetics/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Thyroid Neoplasms/classification/*genetics/metabolism Tumor Markers10aNeoplastic Humans Male Middle Aged *Oligonucleotide Array Sequence Analysis Prognosis RNA10aPapillary/genetics/metabolism/pathology Cell Differentiation Female *Gene Expression Profiling *Gene Expression Regulation1 aMontero-Conde, C.1 aMartin-Campos, J., M.1 aLerma, E.1 aGimenez, G.1 aMartinez-Guitarte, J., L.1 aCombalia, N.1 aMontaner, D.1 aMatias-Guiu, X.1 aDopazo, J.1 ade Leiva, A.1 aRobledo, M.1 aMauricio, D. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1787390803272nas a2200517 4500008004100000022001400041245013100055210006900186260001600255300001200271490000700283520168900290653001201979653001501991653001002006653000902016653002202025653001402047653002502061653002502086653001102111653003002122653004302152653001102195653000902206653001602215653004402231653001402275653005202289653001802341653002402359653002202383100002102405700002502426700001302451700001502464700002902479700001702508700001602525700002002541700001402561700001602575700001502591700001602606856013202622 2008 eng d a1476-559400aMolecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information.0 aMolecular profiling related to poor prognosis in thyroid carcino c2008 Mar 06 a1554-610 v273 aUndifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.
10aAdenoma10aAdolescent10aAdult10aAged10aBiomarkers, Tumor10aCarcinoma10aCarcinoma, Papillary10aCell Differentiation10aFemale10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aHumans10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aPrognosis10aReverse Transcriptase Polymerase Chain Reaction10aRNA, Neoplasm10aSignal Transduction10aThyroid Neoplasms1 aMontero-Conde, C1 aMartín-Campos, J, M1 aLerma, E1 aGimenez, G1 aMartínez-Guitarte, J, L1 aCombalía, N1 aMontaner, D1 aMatías-Guiu, X1 aDopazo, J1 ade Leiva, A1 aRobledo, M1 aMauricio, D uhttps://www.clinbioinfosspa.es/content/molecular-profiling-related-poor-prognosis-thyroid-carcinoma-combining-gene-expression-002031nas a2200253 4500008004100000245009200041210006900133300000800202490000600210520096700216653008801183653004501271653013401316653003101450653007301481100001801554700001401572700001501586700001901601700001301620700002401633700001401657856010601671 2008 eng d00aPrediction of enzyme function by combining sequence similarity and protein interactions0 aPrediction of enzyme function by combining sequence similarity a a2490 v93 aBACKGROUND: A number of studies have used protein interaction data alone for protein function prediction. Here, we introduce a computational approach for annotation of enzymes, based on the observation that similar protein sequences are more likely to perform the same function if they share similar interacting partners. RESULTS: The method has been tested against the PSI-BLAST program using a set of 3,890 protein sequences from which interaction data was available. For protein sequences that align with at least 40% sequence identity to a known enzyme, the specificity of our method in predicting the first three EC digits increased from 80% to 90% at 80% coverage when compared to PSI-BLAST. CONCLUSION: Our method can also be used in proteins for which homologous sequences with known interacting partners can be detected. Thus, our method could increase 10% the specificity of genome-wide enzyme predictions based on sequence matching by PSI-BLAST alone.10aAmino Acid *Software Structure-Activity Relationship Substrate Specificity/genetics10aAmino Acid Sequence/physiology Databases10aAutomated Predictive Value of Tests Protein Interaction Mapping Proteins/analysis/metabolism Sequence Alignment Sequence Analysis10aProtein *Sequence Homology10aProtein Enzymes/analysis/*metabolism Fuzzy Logic Pattern Recognition1 aEspadaler, J.1 aEswar, N.1 aQuerol, E.1 aAviles, F., X.1 aSali, A.1 aMarti-Renom, M., A.1 aOliva, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1850556202322nas a2200181 4500008004100000245005400041210005300095300001100148490000700159520158000166653005701746653002101803653014101824653002701965100001801992700002402010856010602034 2008 eng d00aRNA structure alignment by a unit-vector approach0 aRNA structure alignment by a unitvector approach ai112-80 v243 aMOTIVATION: The recent discovery of tiny RNA molecules such as microRNAs and small interfering RNA are transforming the view of RNA as a simple information transfer molecule. Similar to proteins, the native three-dimensional structure of RNA determines its biological activity. Therefore, classifying the current structural space is paramount for functionally annotating RNA molecules. The increasing numbers of RNA structures deposited in the PDB requires more accurate, automatic and benchmarked methods for RNA structure comparison. In this article, we introduce a new algorithm for RNA structure alignment based on a unit-vector approach. The algorithm has been implemented in the SARA program, which results in RNA structure pairwise alignments and their statistical significance. RESULTS: The SARA program has been implemented to be of general applicability even when no secondary structure can be calculated from the RNA structures. A benchmark against the ARTS program using a set of 1275 non-redundant pairwise structure alignments results in inverted approximately 6% extra alignments with at least 50% structurally superposed nucleotides and base pairs. A first attempt to perform RNA automatic functional annotation based on structure alignments indicates that SARA can correctly assign the deepest SCOR classification to >60% of the query structures. AVAILABILITY: The SARA program is freely available through a World Wide Web server http://sgu.bioinfo.cipf.es/services/SARA/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.10aAlgorithms Base Sequence Computer Simulation *Models10aChemical *Models10aMolecular Molecular Sequence Data Nucleic Acid Conformation RNA/*chemistry/*ultrastructure Sequence Alignment/*methods Sequence Analysis10aRNA/*methods *Software1 aCapriotti, E.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1868981103454nas a2200877 4500008004100000022001400041245006300055210006200118260001300180300001000193490000700203520101900210653001201229653002301241653002301264653001101287653001501298653002701313653001401340653003601354653002801390653000901418653002501427653002701452110002001479700001801499700001701517700003001534700001701564700002401581700001501605700001801620700002401638700002001662700001701682700001801699700001901717700001601736700002401752700002001776700001901796700002101815700001901836700001601855700001701871700001901888700001801907700001701925700002201942700001701964700001901981700001802000700002302018700001802041700002002059700002002079700001802099700002102117700003402138700002202172700002102194700002302215700002202238700002302260700002002283700002002303700002202323700002202345700002002367700002002387700001802407700002002425700001902445700002002464856009202484 2008 eng d a1546-171800aSNP and haplotype mapping for genetic analysis in the rat.0 aSNP and haplotype mapping for genetic analysis in the rat c2008 May a560-60 v403 aThe laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.
10aAnimals10aChromosome Mapping10aDatabases, Genetic10aGenome10aHaplotypes10aLinkage Disequilibrium10aPhylogeny10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRats10aRats, Inbred Strains10aRecombination, Genetic1 aSTAR Consortium1 aSaar, Kathrin1 aBeck, Alfred1 aBihoreau, Marie-Thérèse1 aBirney, Ewan1 aBrocklebank, Denise1 aChen, Yuan1 aCuppen, Edwin1 aDemonchy, Stephanie1 aDopazo, Joaquin1 aFlicek, Paul1 aFoglio, Mario1 aFujiyama, Asao1 aGut, Ivo, G1 aGauguier, Dominique1 aGuigó, Roderic1 aGuryev, Victor1 aHeinig, Matthias1 aHummel, Oliver1 aJahn, Niels1 aKlages, Sven1 aKren, Vladimir1 aKube, Michael1 aKuhl, Heiner1 aKuramoto, Takashi1 aKuroki, Yoko1 aLechner, Doris1 aLee, Young-Ae1 aLopez-Bigas, Nuria1 aLathrop, Mark1 aMashimo, Tomoji1 aMedina, Ignacio1 aMott, Richard1 aPatone, Giannino1 aPerrier-Cornet, Jeanne-Antide1 aPlatzer, Matthias1 aPravenec, Michal1 aReinhardt, Richard1 aSakaki, Yoshiyuki1 aSchilhabel, Markus1 aSchulz, Herbert1 aSerikawa, Tadao1 aShikhagaie, Medya1 aTatsumoto, Shouji1 aTaudien, Stefan1 aToyoda, Atsushi1 aVoigt, Birger1 aZelenika, Diana1 aZimdahl, Heike1 aHubner, Norbert uhttps://www.clinbioinfosspa.es/content/snp-and-haplotype-mapping-genetic-analysis-rat-003097nas a2200757 4500008004100000245006200041210006200103300001000165490000700175520101900182653004201201653001201243653007801255653004301333653006701376100001301443700001301456700002101469700001501490700002001505700001301525700001501538700001701553700001501570700001501585700001501600700001701615700001601632700001701648700001401665700001501679700001501694700001501709700001301724700001501737700001301752700001301765700001301778700001701791700001501808700001601823700001601839700002001855700002001875700001601895700002001911700001301931700001501944700002701959700001601986700001702002700001802019700001502037700001902052700001502071700001702086700001902103700001802122700001602140700001502156700001402171700001702185700001602202700001502218856010602233 2008 eng d00aSNP and haplotype mapping for genetic analysis in the rat0 aSNP and haplotype mapping for genetic analysis in the rat a560-60 v403 aThe laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.
10aAnimals Chromosome Mapping *Databases10aGenetic10aGenetic Genome *Haplotypes Linkage Disequilibrium Phylogeny *Polymorphism10aInbred Strains/*genetics Recombination10aSingle Nucleotide *Quantitative Trait Loci Rats/*genetics Rats1 aSaar, K.1 aBeck, A.1 aBihoreau, M., T.1 aBirney, E.1 aBrocklebank, D.1 aChen, Y.1 aCuppen, E.1 aDemonchy, S.1 aDopazo, J.1 aFlicek, P.1 aFoglio, M.1 aFujiyama, A.1 aGut, I., G.1 aGauguier, D.1 aGuigo, R.1 aGuryev, V.1 aHeinig, M.1 aHummel, O.1 aJahn, N.1 aKlages, S.1 aKren, V.1 aKube, M.1 aKuhl, H.1 aKuramoto, T.1 aKuroki, Y.1 aLechner, D.1 aLee, Y., A.1 aLopez-Bigas, N.1 aLathrop, G., M.1 aMashimo, T.1 aMedina, Ignacio1 aMott, R.1 aPatone, G.1 aPerrier-Cornet, J., A.1 aPlatzer, M.1 aPravenec, M.1 aReinhardt, R.1 aSakaki, Y.1 aSchilhabel, M.1 aSchulz, H.1 aSerikawa, T.1 aShikhagaie, M.1 aTatsumoto, S.1 aTaudien, S.1 aToyoda, A.1 aVoigt, B.1 aZelenika, D.1 aZimdahl, H.1 aHubner, N. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1844359403447nas a2200253 4500008004100000245010700041210006900148300001200217490000700229520238400236653019002620653008902810100001402899700002402913700001702937700001602954700001502970700001602985700002403001700002603025700001703051700001903068856010603087 2008 eng d00aTime course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush0 aTime course profiling of the retinal transcriptome after optic n a1050-630 v143 aPURPOSE: A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT). METHODS: RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naive and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.). RESULTS: Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naive and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling. CONCLUSIONS: This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.10aAnimals Cell Death Cluster Analysis Female *Gene Expression Profiling Gene Expression Regulation *Nerve Crush Optic Nerve/*metabolism/*pathology Optic Nerve Injuries/*genetics Rats Rats10aSprague-Dawley Reproducibility of Results Retina/*metabolism/*pathology Time Factors1 aAgudo, M.1 aPerez-Marin, M., C.1 aLonngren, U.1 aSobrado, P.1 aConesa, A.1 aCanovas, I.1 aSalinas-Navarro, M.1 aMiralles-Imperial, J.1 aHallbook, F.1 aVidal-Sanz, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1855298003144nas a2200277 4500008004100000245020600041210006900247300001200316490000700328520162000335653020401955653006002159653012202219653025902341100001602600700001502616700001502631700001402646700001502660700001802675700001802693700001702711700001702728700001502745856010602760 2008 eng d00aTranscriptome analysis provides new insights into liver changes induced in the rat upon dietary administration of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole0 aTranscriptome analysis provides new insights into liver changes a2616-280 v463 aTranscriptomics was performed to gain insight into mechanisms of food additives butylated hydroxytoluene (BHT), curcumin (CC), propyl gallate (PG), and thiabendazole (TB), additives for which interactions in the liver can not be excluded. Additives were administered in diets for 28 days to Sprague-Dawley rats and cDNA microarray experiments were performed on hepatic RNA. BHT induced changes in the expression of 10 genes, including phase I (CYP2B1/2; CYP3A9; CYP2C6) and phase II metabolism (GST mu2). The CYP2B1/2 and GST expression findings were confirmed by real time RT-PCR, western blotting, and increased GST activity towards DCNB. CC altered the expression of 12 genes. Three out of these were related to peroxisomes (phytanoyl-CoA dioxygenase, enoyl-CoA hydratase; CYP4A3). Increased cyanide insensitive palmitoyl-CoA oxidation was observed, suggesting that CC is a weak peroxisome proliferator. TB changed the expression of 12 genes, including CYP1A2. In line, CYP1A2 protein expression was increased. The expression level of five genes, associated with p53 was found to change upon TB treatment, including p53 itself, GADD45alpha, DN-7, protein kinase C beta and serum albumin. These array experiments led to the novel finding that TB is capable of inducing p53 at the protein level, at least at the highest dose levels employed above the current NOAEL. The expression of eight genes changed upon PG administration. This study shows the value of gene expression profiling in food toxicology in terms of generating novel hypotheses on the mechanisms of action of food additives in relation to pathology.10aAnimals Aryl Hydrocarbon Hydroxylases/metabolism Body Weight/drug effects Butylated Hydroxytoluene/toxicity Curcumin/toxicity Cytochrome P-450 CYP1A2/metabolism Cytochrome P-450 CYP2B1/metabolism DNA10aComplementary/biosynthesis/genetics Data Interpretation10aSprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Steroid Hydroxylases/metabolism Thiabendazole/toxicity10aStatistical *Diet Food Additives/*toxicity Gene Expression/drug effects *Gene Expression Profiling Glutathione Transferase/metabolism Liver/*drug effects Male Organ Size/drug effects Oxidation-Reduction Palmitoyl Coenzyme A/metabolism Propyl Gallate/toxi1 aStierum, R.1 aConesa, A.1 aHeijne, W.1 aOmmen, B.1 aJunker, K.1 aScott, M., P.1 aPrice, R., J.1 aMeredith, C.1 aLake, B., G.1 aGroten, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1853937703094nas a2200385 4500008004100000022001400041245013400055210006900189260001300258300001200271490000700283520182800290653001502118653001002133653002602143653002302169653002802192653002502220653003802245653002202283653001802305653001102323653001802334653001902352653003602371653001302407653003302420100002202453700002102475700001802496700002002514700002002534700002502554856012902579 2008 eng d a1098-100400aUse of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans.0 aUse of estimated evolutionary strength at the codon level improv c2008 Jan a198-2040 v293 aPredicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.
10aAlgorithms10aCodon10aComputational Biology10aDatabases, Protein10aDNA Mutational Analysis10aEvolution, Molecular10aGenetic Predisposition to Disease10aGenetic Variation10aGenome, Human10aHumans10aIduronic Acid10aPoint Mutation10aPolymorphism, Single Nucleotide10aProteins10aTumor Suppressor Protein p531 aCapriotti, Emidio1 aArbiza, Leonardo1 aCasadio, Rita1 aDopazo, Joaquin1 aDopazo, Hernán1 aMarti-Renom, Marc, A uhttps://www.clinbioinfosspa.es/content/use-estimated-evolutionary-strength-codon-level-improves-prediction-disease-related-002909nas a2200241 4500008004100000245013300041210006900174300001200243490000700255520182100262653009602083653009302179653007402272653002302346653008902369100001802458700001502476700001602491700001502507700001502522700002402537856010602561 2008 eng d00aUse of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans0 aUse of estimated evolutionary strength at the codon level improv a198-2040 v293 aPredicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.10aAlgorithms Codon/genetics Computational Biology/*methods *DNA Mutational Analysis Databases10aHuman Humans Iduronic Acid/analogs & derivatives/metabolism *Point Mutation Polymorphism10aMolecular *Genetic Predisposition to Disease Genetic Variation Genome10aProtein *Evolution10aSingle Nucleotide Proteins/chemistry/*genetics Tumor Suppressor Protein p53/genetics1 aCapriotti, E.1 aArbiza, L.1 aCasadio, R.1 aDopazo, J.1 aDopazo, H.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1793514803856nas a2200385 4500008004100000245011000041210006900151300000700220490000600227520253000233653016602763653002902929653009302958100001403051700001503065700002203080700001503102700001403117700001503131700001303146700001503159700001403174700001503188700002103203700001303224700001403237700001503251700001703266700001903283700001503302700001603317700001703333700001403350856010603364 2007 eng d00aAnalysis of 13000 unique Citrus clusters associated with fruit quality, production and salinity tolerance0 aAnalysis of 13000 unique Citrus clusters associated with fruit q a310 v83 aBACKGROUND: Improvement of Citrus, the most economically important fruit crop in the world, is extremely slow and inherently costly because of the long-term nature of tree breeding and an unusual combination of reproductive characteristics. Aside from disease resistance, major commercial traits in Citrus are improved fruit quality, higher yield and tolerance to environmental stresses, especially salinity. RESULTS: A normalized full length and 9 standard cDNA libraries were generated, representing particular treatments and tissues from selected varieties (Citrus clementina and C. sinensis) and rootstocks (C. reshni, and C. sinenis x Poncirus trifoliata) differing in fruit quality, resistance to abscission, and tolerance to salinity. The goal of this work was to provide a large expressed sequence tag (EST) collection enriched with transcripts related to these well appreciated agronomical traits. Towards this end, more than 54000 ESTs derived from these libraries were analyzed and annotated. Assembly of 52626 useful sequences generated 15664 putative transcription units distributed in 7120 contigs, and 8544 singletons. BLAST annotation produced significant hits for more than 80% of the hypothetical transcription units and suggested that 647 of these might be Citrus specific unigenes. The unigene set, composed of 13000 putative different transcripts, including more than 5000 novel Citrus genes, was assigned with putative functions based on similarity, GO annotations and protein domains CONCLUSION: Comparative genomics with Arabidopsis revealed the presence of putative conserved orthologs and single copy genes in Citrus and also the occurrence of both gene duplication events and increased number of genes for specific pathways. In addition, phylogenetic analysis performed on the ammonium transporter family and glycosyl transferase family 20 suggested the existence of Citrus paralogs. Analysis of the Citrus gene space showed that the most important metabolic pathways known to affect fruit quality were represented in the unigene set. Overall, the similarity analyses indicated that the sequences of the genes belonging to these varieties and rootstocks were essentially identical, suggesting that the differential behaviour of these species cannot be attributed to major sequence divergences. This Citrus EST assembly contributes both crucial information to discover genes of agronomical interest and tools for genetic and genomic analyses, such as the development of new markers and microarrays.10aAcclimatization/*genetics Amino Acid Motifs Citrus/*genetics Cluster Analysis Expressed Sequence Tags Fruit/genetics Gene Duplication *Gene Expression Regulation10aPlant Gene Library Genes10aPlant Genomics Molecular Sequence Data Multigene Family Phylogeny *Salts/adverse effects1 aTerol, J.1 aConesa, A.1 aColmenero, J., M.1 aCercos, M.1 aTadeo, F.1 aAgusti, J.1 aAlos, E.1 aAndres, F.1 aSoler, G.1 aBrumos, J.1 aIglesias, D., J.1 aGotz, S.1 aLegaz, F.1 aArgout, X.1 aCourtois, B.1 aOllitrault, P.1 aDossat, C.1 aWincker, P.1 aMorillon, R.1 aTalon, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1725432702500nas a2200253 4500008004100000245008800041210006900129300000700198490001400205520139900219653007701618653005701695653019901752653003901951653002701990100002402017700001402041700002402055700001802079700001502097700001502112700001302127856010602140 2007 eng d00aThe AnnoLite and AnnoLyze programs for comparative annotation of protein structures0 aAnnoLite and AnnoLyze programs for comparative annotation of pro aS40 v8 Suppl 43 aBACKGROUND: Advances in structural biology, including structural genomics, have resulted in a rapid increase in the number of experimentally determined protein structures. However, about half of the structures deposited by the structural genomics consortia have little or no information about their biological function. Therefore, there is a need for tools for automatically and comprehensively annotating the function of protein structures. We aim to provide such tools by applying comparative protein structure annotation that relies on detectable relationships between protein structures to transfer functional annotations. Here we introduce two programs, AnnoLite and AnnoLyze, which use the structural alignments deposited in the DBAli database. DESCRIPTION: AnnoLite predicts the SCOP, CATH, EC, InterPro, PfamA, and GO terms with an average sensitivity of 90% and average precision of 80%. AnnoLyze predicts ligand binding site and domain interaction patches with an average sensitivity of 70% and average precision of 30%, correctly localizing binding sites for small molecules in 95% of its predictions. CONCLUSION: The AnnoLite and AnnoLyze programs for comparative annotation of protein structures can reliably and automatically annotate new protein structures. The programs are fully accessible via the Internet as part of the DBAli suite of tools at http://salilab.org/DBAli/.10a*Algorithms Amino Acid Sequence Confidence Intervals Data Interpretation10aAmino Acid *Software Structure-Activity Relationship10aProtein Information Storage and Retrieval/methods Molecular Sequence Data Proteins/*chemistry/classification/*metabolism Sensitivity and Specificity Sequence Alignment/*methods Sequence Analysis10aProtein/*methods Sequence Homology10aStatistical *Databases1 aMarti-Renom, M., A.1 aRossi, A.1 aAl-Shahrour, Fatima1 aDavis, F., P.1 aPieper, U.1 aDopazo, J.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1757014703226nas a2200433 4500008004100000245012400041210006900165300001100234490000700245520156900252653002601821653003101847653001201878653013601890653023502026653003902261100002202300700002202322700001802344700001702362700001602379700001402395700001502409700001902424700001402443700001602457700002402473700002302497700002302520700001802543700001602561700002302577700001602600700002002616700001502636700001902651700001602670856010602686 2007 eng d00aAssociation study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma0 aAssociation study of 69 genes in the ret pathway identifies lowp a9561-70 v673 aTo date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases.10a80 and over Carcinoma10aAdolescent Adult Aged Aged10aGenetic10aGenetic Proto-Oncogene Proteins c-ret/*genetics/metabolism Signal Transduction Thyroid Neoplasms/*genetics/metabolism Transcription10aMedullary/*genetics/metabolism Case-Control Studies Cyclin-Dependent Kinase Inhibitor p15/biosynthesis/genetics Female Genetic Predisposition to Disease Germ-Line Mutation Haplotypes Humans Male Middle Aged Penetrance Polymorphism10aSingle Nucleotide Promoter Regions1 aRuiz-Llorente, S.1 aMontero-Conde, C.1 aMilne, R., L.1 aMoya, C., M.1 aCebrian, A.1 aLeton, R.1 aCascon, A.1 aMercadillo, F.1 aLanda, I.1 aBorrego, S.1 ade Nanclares, Perez1 aAlvarez-Escola, C.1 aDiaz-Perez, J., A.1 aCarracedo, A.1 aUrioste, M.1 aGonzalez-Neira, A.1 aBenitez, J.1 aSantisteban, P.1 aDopazo, J.1 aPonder, B., A.1 aRobledo, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1790906702608nas a2200217 4500008004100000245009500041210006900136300001200205490000600217520172500223653008401948653002102032653012902053653002102182100001602203700001302219700001402232700002402246700001402270856010602284 2007 eng d00aCharacterization of protein hubs by inferring interacting motifs from protein interactions0 aCharacterization of protein hubs by inferring interacting motifs a1761-710 v33 aThe characterization of protein interactions is essential for understanding biological systems. While genome-scale methods are available for identifying interacting proteins, they do not pinpoint the interacting motifs (e.g., a domain, sequence segments, a binding site, or a set of residues). Here, we develop and apply a method for delineating the interacting motifs of hub proteins (i.e., highly connected proteins). The method relies on the observation that proteins with common interaction partners tend to interact with these partners through a common interacting motif. The sole input for the method are binary protein interactions; neither sequence nor structure information is needed. The approach is evaluated by comparing the inferred interacting motifs with domain families defined for 368 proteins in the Structural Classification of Proteins (SCOP). The positive predictive value of the method for detecting proteins with common SCOP families is 75% at sensitivity of 10%. Most of the inferred interacting motifs were significantly associated with sequence patterns, which could be responsible for the common interactions. We find that yeast hubs with multiple interacting motifs are more likely to be essential than hubs with one or two interacting motifs, thus rationalizing the previously observed correlation between essentiality and the number of interacting partners of a protein. We also find that yeast hubs with multiple interacting motifs evolve slower than the average protein, contrary to the hubs with one or two interacting motifs. The proposed method will help us discover unknown interacting motifs and provide biological insights about protein hubs and their roles in interaction networks.10aAmino Acid Motifs Amino Acid Sequence Binding Sites Computer Simulation *Models10aChemical *Models10aMolecular Molecular Sequence Data Protein Binding Protein Interaction Mapping/*methods Proteins/*chemistry Sequence Analysis10aProtein/*methods1 aAragues, R.1 aSali, A.1 aBonet, J.1 aMarti-Renom, M., A.1 aOliva, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1794170502301nas a2200421 4500008004100000022001400041245005300055210005100108260001300159300001100172490000700183520104700190653001501237653002401252653002601276653003701302653002301339653001301362653002801375653002501403653001301428653002701441653002301468653003101491653003401522653001301556653003601569100002501605700001901630700002201649700001801671700002101689700001901710700002501729700002001754700001701774856008801791 2007 eng d a1362-496200aDBAli tools: mining the protein structure space.0 aDBAli tools mining the protein structure space c2007 Jul aW393-70 v353 aThe DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.
10aAlgorithms10aAmino Acid Sequence10aComputational Biology10aData Interpretation, Statistical10aDatabases, Protein10aInternet10aMolecular Sequence Data10aProtein Conformation10aProteins10aPseudomonas aeruginosa10aSequence Alignment10aSequence Analysis, Protein10aSequence Homology, Amino Acid10aSoftware10aStructure-Activity Relationship1 aMarti-Renom, Marc, A1 aPieper, Ursula1 aMadhusudhan, M, S1 aRossi, Andrea1 aEswar, Narayanan1 aDavis, Fred, P1 aAl-Shahrour, Fátima1 aDopazo, Joaquin1 aSali, Andrej uhttps://www.clinbioinfosspa.es/content/dbali-tools-mining-protein-structure-space-002151nas a2200277 4500008004100000245005200041210005100093300001100144490000700155520104000162653008701202653005701289653019401346653003901540653002701579100002401606700001501630700002401645700001401669700001401683700001801697700002401715700001501739700001301754856010601767 2007 eng d00aDBAli tools: mining the protein structure space0 aDBAli tools mining the protein structure space aW393-70 v353 aThe DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.10a*Algorithms Amino Acid Sequence Computational Biology/*methods Data Interpretation10aAmino Acid *Software Structure-Activity Relationship10aProtein Internet Molecular Sequence Data Protein Conformation Proteins/*chemistry/classification/*metabolism Pseudomonas aeruginosa/*metabolism Sequence Alignment/*methods Sequence Analysis10aProtein/*methods Sequence Homology10aStatistical *Databases1 aMarti-Renom, M., A.1 aPieper, U.1 aMadhusudhan, M., S.1 aRossi, A.1 aEswar, N.1 aDavis, F., P.1 aAl-Shahrour, Fatima1 aDopazo, J.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1747851302784nas a2200301 4500008004100000245006900041210006800110300000800178490000600186520165900192653002501851653002201876653001901898653006101917653007001978653003402048653013602082100001802218700002102236700001702257700002402274700001402298700001402312700001602326700001502342700001902357856010602376 2007 eng d00aEvidence for systems-level molecular mechanisms of tumorigenesis0 aEvidence for systemslevel molecular mechanisms of tumorigenesis a1850 v83 aBACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth. RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis. CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.10a*Cell Transformation10aBiological Models10aGenetic Models10aMessenger/metabolism Signal Transduction Systems Biology10aNeoplastic *Gene Expression Profiling *Gene Expression Regulation10aNeoplastic Humans Male Models10aStatistical Neoplasm Proteins/*physiology Neoplasms/etiology/*genetics Prostatic Neoplasms/genetics Protein Interaction Mapping RNA1 aHernandez, P.1 aHuerta-Cepas, J.1 aMontaner, D.1 aAl-Shahrour, Fatima1 aValls, J.1 aGomez, L.1 aCapella, G.1 aDopazo, J.1 aPujana, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1758491502990nas a2200421 4500008004100000022001400041245007000055210006800125260001600193300000800209490000600217520169900223653003601922653003001958653004301988653001102031653000902042653002302051653002002074653002402094653002202118653001402140653002402154653003202178653001902210653002402229653002002253100002202273700002402295700002002319700002502339700001602364700001702380700002202397700002002419700002602439856010302465 2007 eng d a1471-216400aEvidence for systems-level molecular mechanisms of tumorigenesis.0 aEvidence for systemslevel molecular mechanisms of tumorigenesis c2007 Jun 20 a1850 v83 aBACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth.
RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis.
CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.
10aCell Transformation, Neoplastic10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aHumans10aMale10aModels, Biological10aModels, Genetic10aModels, Statistical10aNeoplasm Proteins10aNeoplasms10aProstatic Neoplasms10aProtein Interaction Mapping10aRNA, Messenger10aSignal Transduction10aSystems biology1 aHernández, Pilar1 aHuerta-Cepas, Jaime1 aMontaner, David1 aAl-Shahrour, Fátima1 aValls, Joan1 aGómez, Laia1 aCapellà, Gabriel1 aDopazo, Joaquin1 aPujana, Miguel, Angel uhttps://www.clinbioinfosspa.es/content/evidence-systems-level-molecular-mechanisms-tumorigenesis-002196nas a2200217 4500008004100000245016500041210006900206300001000275490000700285520140700292653001501699653003501714100002401749700001601773700001601789700002001805700001501825700001701840700001501857856010601872 2007 eng d00aFatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments0 aFatiGO a functional profiling tool for genomic data Integration aW91-60 v353 aThe ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.
10ababelomics10afunctional enrichment analysys1 aAl-Shahrour, Fatima1 aMinguez, P.1 aTarraga, J.1 aMedina, Ignacio1 aAlloza, E.1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1747850402680nas a2200385 4500008004100000022001400041245016600055210006900221260001300290300001000303490000700313520140700320653002201727653001201749653001801761653002601779653003001805653001001835653001301845653001101858653001301869653004401882653002601926653001301952653002401965653002601989100002502015700001902040700002302059700002002082700001602102700002002118700002002138856013602158 2007 eng d a1362-496200aFatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments.0 aFatiGO a functional profiling tool for genomic data Integration c2007 Jul aW91-60 v353 aThe ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.
10aAmino Acid Motifs10aAnimals10aBinding Sites10aComputational Biology10aGene Expression Profiling10aGenes10aGenomics10aHumans10aInternet10aOligonucleotide Array Sequence Analysis10aProgramming Languages10aSoftware10aSystems Integration10aTranscription Factors1 aAl-Shahrour, Fátima1 aMinguez, Pablo1 aTárraga, Joaquín1 aMedina, Ignacio1 aAlloza, Eva1 aMontaner, David1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/fatigo-functional-profiling-tool-genomic-data-integration-functional-annotation-regulatory-002519nas a2200337 4500008004100000022001400041245007300055210006900128260001600197300000800213490000600221520148900227653001501716653002301731653002401754653003001778653002301808653002101831653002401852653001301876653002001889653002801909100002501937700002101962700002001983700002402003700001902027700002002046700002002066856009502086 2007 eng d a1471-210500aFrom genes to functional classes in the study of biological systems.0 aFrom genes to functional classes in the study of biological syst c2007 Apr 03 a1140 v83 aBACKGROUND: With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed.
RESULTS: Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics.
CONCLUSION: Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.
10aAlgorithms10aChromosome Mapping10aComputer Simulation10aGene Expression Profiling10aModels, Biological10aMultigene Family10aSignal Transduction10aSoftware10aSystems biology10aUser-Computer Interface1 aAl-Shahrour, Fátima1 aArbiza, Leonardo1 aDopazo, Hernán1 aHuerta-Cepas, Jaime1 aMinguez, Pablo1 aMontaner, David1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/genes-functional-classes-study-biological-systems-002367nas a2200229 4500008004100000245007200041210006900113300000800182490000600190520145600196653010501652653001501757653013601772100002401908700001501932700001501947700002101962700001601983700001701999700001502016856010602031 2007 eng d00aFrom genes to functional classes in the study of biological systems0 aFrom genes to functional classes in the study of biological syst a1140 v83 aBACKGROUND: With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed. RESULTS: Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics. CONCLUSION: Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.
10aAlgorithms Chromosome Mapping/*methods Computer Simulation Gene Expression Profiling/methods *Models10ababelomics10aBiological Multigene Family/*physiology Signal Transduction/*physiology *Software Systems Biology/*methods *User-Computer Interface1 aAl-Shahrour, Fatima1 aArbiza, L.1 aDopazo, H.1 aHuerta-Cepas, J.1 aMinguez, P.1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1740759601696nas a2200193 4500008004100000245009300041210006900134300001000203490000600213520105200219653001501271100001401286700001701300700002401317700001601341700002401357700001501381856010601396 2007 eng d00aFunctional profiling and gene expression analysis of chromosomal copy number alterations0 aFunctional profiling and gene expression analysis of chromosomal a432-50 v13 aContrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma.
10ababelomics1 aConde, L.1 aMontaner, D.1 aBurguet-Castell, J.1 aTarraga, J.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1759793501771nas a2200205 4500008004100000022001400041245009400055210006900149260001600218300001000234490000600244520105200250100001701302700002001319700002701339700002301366700002501389700002001414856013101434 2007 eng d a0973-206300aFunctional profiling and gene expression analysis of chromosomal copy number alterations.0 aFunctional profiling and gene expression analysis of chromosomal c2007 Apr 10 a432-50 v13 aContrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma.
1 aConde, Lucia1 aMontaner, David1 aBurguet-Castell, Jordi1 aTárraga, Joaquín1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/functional-profiling-and-gene-expression-analysis-chromosomal-copy-number-alterations-001608nas a2200193 4500008004100000245008900041210006900130300001100199490000700210520077100217653003900988653001501027653019401042100001601236700002401252700001701276700001501293856010601308 2007 eng d00aFunctional profiling of microarray experiments using text-mining derived bioentities0 aFunctional profiling of microarray experiments using textmining a3098-90 v233 aMOTIVATION: The increasing use of microarray technologies brought about a parallel demand in methods for the functional interpretation of the results. Beyond the conventional functional annotations for genes, such as gene ontology, pathways, etc. other sources of information are still to be exploited. Text-mining methods allow extracting informative terms (bioentities) with different functional, chemical, clinical, etc. meanings, that can be associated to genes. We show how to use these associations within an appropriate statistical framework and how to apply them through easy-to-use, web-based environments to the functional interpretation of microarray experiments. Functional enrichment and gene set enrichment tests using bioentities are presented.
10aArtificial Intelligence *Databases10ababelomics10aProtein Gene Expression Profiling/*methods Information Storage and Retrieval/*methods *Natural Language Processing Proteins/*classification/*metabolism Research/*methods Systems Integration1 aMinguez, P.1 aAl-Shahrour, Fatima1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1785541501723nas a2200277 4500008004100000022001400041245009000055210006900145260001600214300001100230490000700241520077800248653002801026653002301054653003001077653003801107653003201145653001301177653002001190653002401210100001901234700002501253700002001278700002001298856012701318 2007 eng d a1367-481100aFunctional profiling of microarray experiments using text-mining derived bioentities.0 aFunctional profiling of microarray experiments using textmining c2007 Nov 15 a3098-90 v233 aMOTIVATION: The increasing use of microarray technologies brought about a parallel demand in methods for the functional interpretation of the results. Beyond the conventional functional annotations for genes, such as gene ontology, pathways, etc. other sources of information are still to be exploited. Text-mining methods allow extracting informative terms (bioentities) with different functional, chemical, clinical, etc. meanings, that can be associated to genes. We show how to use these associations within an appropriate statistical framework and how to apply them through easy-to-use, web-based environments to the functional interpretation of microarray experiments. Functional enrichment and gene set enrichment tests using bioentities are presented.
10aArtificial Intelligence10aDatabases, Protein10aGene Expression Profiling10aInformation Storage and Retrieval10aNatural Language Processing10aProteins10aResearch Design10aSystems Integration1 aMinguez, Pablo1 aAl-Shahrour, Fátima1 aMontaner, David1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/functional-profiling-microarray-experiments-using-text-mining-derived-bioentities-002059nas a2200385 4500008004100000022001400041245012300055210006900178260001300247300001000260490000700270520079500277653001201072653002101084653002601105653002201131653003001153653001101183653001301194653002001207653003101227653004401258653002601302653001301328653002401341653002801365100001701393700002001410700002701430700002301457700002001480700002501500700002001525856012801545 2007 eng d a1362-496200aISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling.0 aISACGH a webbased environment for the analysis of Array CGH and c2007 Jul aW81-50 v353 aWe present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.
10aAnimals10aCluster Analysis10aComputational Biology10aComputer Graphics10aGene Expression Profiling10aHumans10aInternet10aModels, Genetic10aNucleic Acid Hybridization10aOligonucleotide Array Sequence Analysis10aProgramming Languages10aSoftware10aSystems Integration10aUser-Computer Interface1 aConde, Lucia1 aMontaner, David1 aBurguet-Castell, Jordi1 aTárraga, Joaquín1 aMedina, Ignacio1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/isacgh-web-based-environment-analysis-array-cgh-and-gene-expression-which-includes-001792nas a2200217 4500008004100000245012200041210006900163300001000232490000700242520078800249653013601037653016501173100001401338700001701352700002401369700001601393700002001409700002401429700001501453856010601468 2007 eng d00aISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling0 aISACGH a webbased environment for the analysis of Array CGH and aW81-50 v353 aWe present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.10aAnimals Cluster Analysis Computational Biology/*methods Computer Graphics Gene Expression Profiling/*methods Humans Internet Models10aGenetic *Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis/*methods Programming Languages *Software Systems Integration User-Computer Interface1 aConde, L.1 aMontaner, D.1 aBurguet-Castell, J.1 aTarraga, J.1 aMedina, Ignacio1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1746849900491nas a2200157 4500008004100000022002200041245005800063210005800121260002100179300001200200490000700212100001700219700002400236700001500260856005800275 2007 eng d a978-3-540-71991-500aNew Trends in the Analysis of Functional Genomic Data0 aNew Trends in the Analysis of Functional Genomic Data aBerlinbSpringer a576-5800 v121 aMontaner, D.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.springerlink.com/content/m62p07r8111004vr/02437nas a2200265 4500008004100000245009200041210006900133300001100202490000700213520143600220653005301656653002601709653002201735653005701757653004501814653008601859100001601945700002001961700001501981700002101996700001802017700001502035700001502050856010602065 2007 eng d00aPhylemon: a suite of web tools for molecular evolution, phylogenetics and phylogenomics0 aPhylemon a suite of web tools for molecular evolution phylogenet aW38-420 v353 aPhylemon is an online platform for phylogenetic and evolutionary analyses of molecular sequence data. It has been developed as a web server that integrates a suite of different tools selected among the most popular stand-alone programs in phylogenetic and evolutionary analysis. It has been conceived as a natural response to the increasing demand of data analysis of many experimental scientists wishing to add a molecular evolution and phylogenetics insight into their research. Tools included in Phylemon cover a wide yet selected range of programs: from the most basic for multiple sequence alignment to elaborate statistical methods of phylogenetic reconstruction including methods for evolutionary rates analyses and molecular adaptation. Phylemon has several features that differentiates it from other resources: (i) It offers an integrated environment that enables the direct concatenation of evolutionary analyses, the storage of results and handles required data format conversions, (ii) Once an outfile is produced, Phylemon suggests the next possible analyses, thus guiding the user and facilitating the integration of multi-step analyses, and (iii) users can define and save complete pipelines for specific phylogenetic analysis to be automatically used on many genes in subsequent sessions or multiple genes in a single session (phylogenomics). The Phylemon web server is available at http://phylemon.bioinfo.cipf.es.10aAnimals Computational Biology/*methods Databases10aDNA Sequence Analysis10aGenetic Evolution10aMolecular Genetic Techniques Humans *Internet Models10aProtein Software User-Computer Interface10aStatistical *Phylogeny Programming Languages Sequence Alignment Sequence Analysis1 aTarraga, J.1 aMedina, Ignacio1 aArbiza, L.1 aHuerta-Cepas, J.1 aGabaldón, T.1 aDopazo, J.1 aDopazo, H. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1745234601384nas a2200193 4500008004100000245007300041210006900114300001000183490000700193520078700200653001500987653001001002653001501012100002001027700001701047700001601064700001501080856009501095 2007 eng d00aProphet, a web-based tool for class prediction using microarray data0 aProphet a webbased tool for class prediction using microarray da a390-10 v233 aSample classification and class prediction is the aim of many gene expression studies. We present a web-based application, Prophet, which builds prediction rules and allows using them for further sample classification. Prophet automatically chooses the best classifier, along with the optimal selection of genes, using a strategy that renders unbiased cross-validated errors. Prophet is linked to different microarray data analysis modules, and includes a unique feature: the possibility of performing the functional interpretation of the molecular signature found. Availability: Prophet can be found at the URL http://prophet.bioinfo.cipf.es/ or within the GEPAS package at http://www.gepas.org/ Supplementary information: http://gepas.bioinfo.cipf.es/tutorial/prophet.html.
10ababelomics10agepas10apredictors1 aMedina, Ignacio1 aMontaner, D.1 aTarraga, J.1 aDopazo, J. uhttp://bioinformatics.oxfordjournals.org/cgi/content/full/23/3/390?view=long&pmid=1713858701778nas a2200205 4500008004100000245007500041210006900116300001300185490000800198520097700206653011101183653003901294653004101333100002001374700001401394700002401408700001701432700001701449856010601466 2007 eng d00aProtein translocation into peroxisomes by ring-shaped import receptors0 aProtein translocation into peroxisomes by ringshaped import rece a4795-8020 v5813 aFolded and functional proteins destined for translocation from the cytosol into the peroxisomal matrix are recognized by two different peroxisomal import receptors, Pex5p and Pex7p. Both cargo-loaded receptors dock on the same translocon components, followed by cargo release and receptor recycling, as part of the complete translocation process. Recent structural and functional evidence on the Pex5p receptor has provided insight on the molecular requirements of specific cargo recognition, while the remaining processes still remain largely elusive. Comparison of experimental structures of Pex5p and a structural model of Pex7p reveal that both receptors are built by ring-like arrangements with cargo binding sites, central to the respective structures. Although, molecular insight into the complete peroxisomal translocon still remains to be determined, emerging data allow to deduce common molecular principles that may hold for other translocation systems as well.10aAmino Acid Sequence Binding Sites Humans Molecular Sequence Data Peroxisomes/*metabolism Protein Structure10aCytoplasmic and Nuclear/*chemistry10aTertiary Protein Transport Receptors1 aStanley, W., A.1 aFodor, K.1 aMarti-Renom, M., A.1 aSchliebs, W.1 aWilmanns, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1788404202657nas a2200277 4500008004100000245007600041210006900117300001200186490000600198520157700204653011001781653008001891653001701971653001801988653005402006653006902060100001802129700002102147700001502168700001802183700001402201700001802215700002102233700001902254856010602273 2007 eng d00aSpatial differentiation in the vegetative mycelium of Aspergillus niger0 aSpatial differentiation in the vegetative mycelium of Aspergillu a2311-220 v63 aFungal mycelia are exposed to heterogenic substrates. The substrate in the central part of the colony has been (partly) degraded, whereas it is still unexplored at the periphery of the mycelium. We here assessed whether substrate heterogeneity is a main determinant of spatial gene expression in colonies of Aspergillus niger. This question was addressed by analyzing whole-genome gene expression in five concentric zones of 7-day-old maltose- and xylose-grown colonies. Expression profiles at the periphery and the center were clearly different. More than 25% of the active genes showed twofold differences in expression between the inner and outermost zones of the colony. Moreover, 9% of the genes were expressed in only one of the five concentric zones, showing that a considerable part of the genome is active in a restricted part of the colony only. Statistical analysis of expression profiles of colonies that had either been or not been transferred to fresh xylose-containing medium showed that differential expression in a colony is due to the heterogeneity of the medium (e.g., genes involved in secretion, genes encoding proteases, and genes involved in xylose metabolism) as well as to medium-independent mechanisms (e.g., genes involved in nitrate metabolism and genes involved in cell wall synthesis and modification). Thus, we conclude that the mycelia of 7-day-old colonies of A. niger are highly differentiated. This conclusion is also indicated by the fact that distinct zones of the colony grow and secrete proteins, even after transfer to fresh medium.10aAspergillus niger/*metabolism Cell Wall/metabolism Fungal Proteins/metabolism *Gene Expression Regulation10aBiological Mycelium/*metabolism Oligonucleotide Array Sequence Analysis RNA10aFungal Genes10aFungal Genome10aFungal Glucans/chemistry Maltose/chemistry Models10aFungal Time Factors Trans-Activators/metabolism Xylose/chemistry1 aLevin, A., M.1 ade Vries, R., P.1 aConesa, A.1 ade Bekker, C.1 aTalon, M.1 aMenke, H., H.1 avan Peij, N., N.1 aWosten, H., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1795151302088nas a2200217 4500008004100000245006100041210006100102300001200163490000800175520132100183653013101504653002201635653001601657100001801673700001601691700001601707700001201723700001601735700001301751856010601764 2007 eng d00aStructural analyses of a hypothetical minimal metabolism0 aStructural analyses of a hypothetical minimal metabolism a1751-620 v3623 aBy integrating data from comparative genomics and large-scale deletion studies, we previously proposed a minimal gene set comprising 206 protein-coding genes. To evaluate the consistency of the metabolism encoded by such a minimal genome, we have carried out a series of computational analyses. Firstly, the topology of the minimal metabolism was compared with that of the reconstructed networks from natural bacterial genomes. Secondly, the robustness of the metabolic network was evaluated by simulated mutagenesis and, finally, the stoichiometric consistency was assessed by automatically deriving the steady-state solutions from the reaction set. The results indicated that the proposed minimal metabolism presents stoichiometric consistency and that it is organized as a complex power-law network with topological parameters falling within the expected range for a natural metabolism of its size. The robustness analyses revealed that most random mutations do not alter the topology of the network significantly, but do cause significant damage by preventing the synthesis of several compounds or compromising the stoichiometric consistency of the metabolism. The implications that these results have on the origins of metabolic complexity and the theoretical design of an artificial minimal cell are discussed.10a*Cell Physiological Phenomena Cells/*metabolism Cluster Analysis *Computer Simulation *Metabolic Networks and Pathways *Models10aBiological Models10aStatistical1 aGabaldón, T.1 aPeretó, J.1 aMontero, F.1 aGil, R.1 aLatorre, A.1 aMoya, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1751002201951nas a2200265 4500008004100000245009000041210006900131300001200200490000800212520099700220653008201217653001201299653011301311100001501424700001501439700001601454700001401470700001601484700001501500700001501515700001901530700001501549700001501564856010601579 2007 eng d00aTranscriptional response of Citrus aurantifolia to infection by Citrus tristeza virus0 aTranscriptional response of Citrus aurantifolia to infection by a298-3060 v3673 aChanges in gene expression of Mexican lime plants in response to infection with a severe (T305) or a mild (T385) isolate of Citrus tristeza virus (CTV) were analyzed using a cDNA microarray containing 12,672 probes to 6875 different citrus genes. Statistically significant (P<0.01) expression changes of 334 genes were detected in response to infection with isolate T305, whereas infection with T385 induced no significant change. Induced genes included 145 without significant similarity with known sequences and 189 that were classified in seven functional categories. Genes related with response to stress and defense were the main category and included 28% of the genes induced. Selected transcription changes detected by microarray analysis were confirmed by quantitative real-time RT-PCR. Changes detected in the transcriptome upon infecting lime with T305 may be associated either with symptom expression, with a strain-specific defense mechanism, or with a general response to stress.10aCitrus/*genetics/physiology/virology Closterovirus/genetics/*physiology Genes10aGenetic10aPlant Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction *Transcription1 aGandia, M.1 aConesa, A.1 aAncillo, G.1 aGadea, J.1 aForment, J.1 aPallas, V.1 aFlores, R.1 aDuran-Vila, N.1 aMoreno, P.1 aGuerri, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1761743102187nas a2200157 4500008004100000245009000041210006900131300001100200490000700211520142200218653023401640653001201874100001301886700002401899856010601923 2006 eng d00aAccuracy of sequence alignment and fold assessment using reduced amino acid alphabets0 aAccuracy of sequence alignment and fold assessment using reduced a986-950 v633 aReduced or simplified amino acid alphabets group the 20 naturally occurring amino acids into a smaller number of representative protein residues. To date, several reduced amino acid alphabets have been proposed, which have been derived and optimized by a variety of methods. The resulting reduced amino acid alphabets have been applied to pattern recognition, generation of consensus sequences from multiple alignments, protein folding, and protein structure prediction. In this work, amino acid substitution matrices and statistical potentials were derived based on several reduced amino acid alphabets and their performance assessed in a large benchmark for the tasks of sequence alignment and fold assessment of protein structure models, using as a reference frame the standard alphabet of 20 amino acids. The results showed that a large reduction in the total number of residue types does not necessarily translate into a significant loss of discriminative power for sequence alignment and fold assessment. Therefore, some definitions of a few residue types are able to encode most of the relevant sequence/structure information that is present in the 20 standard amino acids. Based on these results, we suggest that the use of reduced amino acid alphabets may allow to increasing the accuracy of current substitution matrices and statistical potentials for the prediction of protein structure of remote homologs.10aAmino Acid Sequence Amino Acids/*chemistry/classification/*metabolism Consensus Sequence Molecular Sequence Data Oxidation-Reduction *Protein Folding Proteins/*chemistry/*metabolism Sequence Alignment/*methods Structural Homology10aProtein1 aMelo, F.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1650624301445nas a2200253 4500008004100000245010300041210006900144300001100213490000700224520068700231653001500918653002500933100002400958700001600982700001600998700001701014700001501031700002301046700001401069700001701083700001301100700001501113856006301128 2006 eng d00aBABELOMICS: a systems biology perspective in the functional annotation of genome-scale experiments0 aBABELOMICS a systems biology perspective in the functional annot aW472-60 v343 aWe present a new version of Babelomics, a complete suite of web tools for functional analysis of genome-scale experiments, with new and improved tools. New functionally relevant terms have been included such as CisRed motifs or bioentities obtained by text-mining procedures. An improved indexing has considerably speeded up several of the modules. An improved version of the FatiScan method for studying the coordinate behaviour of groups of functionally related genes is presented, along with a similar tool, the Gene Set Enrichment Analysis. Babelomics is now more oriented to test systems biology inspired hypotheses. Babelomics can be found at http://www.babelomics.org.
10ababelomics10afunctional profiling1 aAl-Shahrour, Fatima1 aMinguez, P.1 aTarraga, J.1 aMontaner, D.1 aAlloza, E.1 aVaquerizas, J., M.1 aConde, L.1 aBlaschke, C.1 aVera, J.1 aDopazo, J. uhttp://nar.oxfordjournals.org/content/34/suppl_2/W472.long02005nas a2200253 4500008004100000245005800041210005800099300001300157490001400170520105600184653008801240653002101328653012901349653003101478100001401509700001301523700002401536700002401560700001601584700001701600700001501617700001301632856010601645 2006 eng d00aComparative protein structure modeling using Modeller0 aComparative protein structure modeling using Modeller aUnit 5 60 vChapter 53 aFunctional characterization of a protein sequence is one of the most frequent problems in biology. This task is usually facilitated by accurate three-dimensional (3-D) structure of the studied protein. In the absence of an experimentally determined structure, comparative or homology modeling can sometimes provide a useful 3-D model for a protein that is related to at least one known protein structure. Comparative modeling predicts the 3-D structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described.10aAlgorithms Amino Acid Sequence Computer Simulation Crystallography/*methods *Models10aChemical *Models10aMolecular Molecular Sequence Data Protein Conformation Protein Folding Proteins/*chemistry/*ultrastructure Sequence Analysis10aProtein/*methods *Software1 aEswar, N.1 aWebb, B.1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aEramian, D.1 aShen, M., Y.1 aPieper, U.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1842876702131nas a2200217 4500008004100000245007200041210006900113300001200182490000700194520144000201653001201641653002101653653003601674100001601710700001701726700001401743700001301757700001301770700002401783856010601807 2006 eng d00aA composite score for predicting errors in protein structure models0 acomposite score for predicting errors in protein structure model a1653-660 v153 aReliable prediction of model accuracy is an important unsolved problem in protein structure modeling. To address this problem, we studied 24 individual assessment scores, including physics-based energy functions, statistical potentials, and machine learning-based scoring functions. Individual scores were also used to construct approximately 85,000 composite scoring functions using support vector machine (SVM) regression. The scores were tested for their abilities to identify the most native-like models from a set of 6000 comparative models of 20 representative protein structures. Each of the 20 targets was modeled using a template of <30% sequence identity, corresponding to challenging comparative modeling cases. The best SVM score outperformed all individual scores by decreasing the average RMSD difference between the model identified as the best of the set and the model with the lowest RMSD (DeltaRMSD) from 0.63 A to 0.45 A, while having a higher Pearson correlation coefficient to RMSD (r=0.87) than any other tested score. The most accurate score is based on a combination of the DOPE non-hydrogen atom statistical potential; surface, contact, and combined statistical potentials from MODPIPE; and two PSIPRED/DSSP scores. It was implemented in the SVMod program, which can now be applied to select the final model in various modeling problems, including fold assignment, target-template alignment, and loop modeling.10a*Models10aMolecular Models10aTheoretical Proteins/*chemistry1 aEramian, D.1 aShen, M., Y.1 aDevos, D.1 aMelo, F.1 aSali, A.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1675160602539nas a2200265 4500008004100000245016000041210006900201300001200270490000700282520126500289653009401554653019301648653013501841653002601976100002102002700001702023700001902040700002002059700001502079700001502094700002002109700001802129700002002147856010602167 2006 eng d00aDevelopment of the GENIPOL European flounder (Platichthys flesus) microarray and determination of temporal transcriptional responses to cadmium at low dose0 aDevelopment of the GENIPOL European flounder Platichthys flesus a6479-880 v403 aWe have constructed a high density, 13 270-clone cDNA array for the sentinel fish species European flounder (Platichthys flesus), combining clones from suppressive subtractive hybridization and a liver cDNA library; DNA sequences of 5211 clones were determined. Fish were treated by single intraperitoneal injection with 50 micrograms cadmium chloride per kilogram body weight, a dose relevant to environmental exposures, and hepatic gene expression changes were determined at 1, 2, 4, 8, and 16 days postinjection in comparison to saline-treated controls. Gene expression responses were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). Blast2GO gene ontology analysis highlighted a general induction of the unfolded protein response, response to oxidative stress, protein synthesis, transport, and degradation pathways, while apoptosis, cell cycle, cytoskeleton, and cytokine genes were also affected. Transcript levels of cytochrome P450 1A (CYP1A) were repressed and vitellogenin altered, real-time PCR showed induction of metallothionein. We thus describe the establishment of a useful resource for ecotoxicogenomics and the determination of the temporal molecular responses to cadmium, a prototypical heavy metal pollutant.10aAnimals Cadmium Chloride/administration & dosage/*pharmacology Dose-Response Relationship10aDevelopmental/drug effects Liver/drug effects/growth & development/metabolism Oligonucleotide Array Sequence Analysis/*methods Reverse Transcriptase Polymerase Chain Reaction Transcription10aDrug Environmental Monitoring/methods Flounder/*genetics/growth & development Gene Expression Profiling Gene Expression Regulation10aGenetic/*drug effects1 aWilliams, T., D.1 aDiab, A., M.1 aGeorge, S., G.1 aGodfrey, R., E.1 aSabine, V.1 aConesa, A.1 aMinchin, S., D.1 aWatts, P., C.1 aChipman, J., K. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1712058402830nas a2200277 4500008004100000245011000041210006900151300001100220490000700231520162300238653016301861653002002024653018602044653004602230100001802276700001402294700002302308700001802331700001402349700001702363700001502380700001902395700001602414700001602430856010602446 2006 eng d00aERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping0 aERCC4 associated with breast cancer risk a twostage casecontrol a9420-70 v663 aThe failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.10a80 and over Breast Neoplasms/epidemiology/*genetics/pathology Case-Control Studies DNA-Binding Proteins/genetics/*physiology Female Finland/epidemiology Genes10aAdult Aged Aged10aRecessive Genetic Predisposition to Disease Genotype Humans Introns/genetics Linkage Disequilibrium Middle Aged Neoplasm Proteins/genetics/*physiology Neoplasm Staging *Polymorphism10aSingle Nucleotide Risk Spain/epidemiology1 aMilne, R., L.1 aRibas, G.1 aGonzalez-Neira, A.1 aFagerholm, R.1 aSalas, A.1 aGonzalez, E.1 aDopazo, J.1 aNevanlinna, H.1 aRobledo, M.1 aBenitez, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1701859602404nas a2200157 4500008004100000245009100041210006900132300001000201490000700211520184000218653001502058100001602073700002402089700001502113856011802128 2006 eng d00aA function-centric approach to the biological interpretation of microarray time-series0 afunctioncentric approach to the biological interpretation of mic a57-660 v173 aThe interpretation of microarray experiments is commonly addressed by means a two-step approach in which the relevant genes are firstly selected uniquely on the basis of their experimental values (ignoring their coordinate behaviors) and in a second step their functional properties are studied to hypothesize about the biological roles they are fulfilling in the cell. Recently, different methods (e.g. GSEA or FatiScan) have been proposed to study the coordinate behavior of blocks of functionally-related genes. These methods study the distribution of functional information across lists of genes ranked according their different experimental values in a static situation, such as the comparison between two classes (e.g. healthy controls versus diseased cases). Nevertheless there is no an equivalent way of studying a dynamic situation from a functional point of view. We present a method for the functional analysis of microarrays series in which the experiments display autocorrelation between successive points (e.g. time series, dose-response experiments, etc.) The method allows to recover the dynamics of the molecular roles fulfilled by the genes along the series which provides a novel approach to functional interpretation of such experiments. The method finds blocks of functionally-related genes which are significantly and coordinately over-expressed at different points of the series. This method draws inspiration from systems biology given that the analysis does not focus on individual properties of genes but on collective behaving blocks of functionally-related genes. The FatiScan algorithm used in the method proposed is available at: http://fatiscan.bioinfo.cipf.es, or within the Babelomics suite: http://www.babelomics.org. Additional material is available at: http://bioinfo.cipf.es/data/plasmodium.
10ababelomics1 aMinguez, P.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttps://www.clinbioinfosspa.es/content/function-centric-approach-biological-interpretation-microarray-time-series03074nas a2200325 4500008004100000245011200041210006900153300001100222490000700233520182100240653001102061653002302072653009602095653012202191653006602313653004102379653002302420100001402443700001602457700001302473700001402486700002602500700002402526700001902550700001502569700001602584700002102600700002102621856010602642 2006 eng d00aIdentification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma0 aIdentification of overexpressed genes in frequently gainedamplif a184-910 v913 aBACKGROUND AND OBJECTIVES: Multiple myeloma (MM) is a malignancy characterized by clonal expansion of plasma cells. In 50% of the cases, the neoplastic transformation begins with a chromosomal translocation that juxtaposes the IGH gene locus to an oncogene. Gene copy number changes are also frequent in MM but less characterized than in other neoplasias. We aimed to characterize genes that are amplified and overexpressed in human myeloma cell lines (HMCL) to provide putative molecular targets for MM therapy. DESIGN AND METHODS: Nine HMCL were characterized by fluorescent in situ hybridization, comparative genomic hybridization (CGH) and cDNA microarrays for gene expression profiling and copy number changes. RESULTS: After defining the IGH-translocations present in the cell lines, we conducted expression-profiling analysis. Supervised analysis identified 166 genes with significantly different expression among the cell lines harboring MMSET/FGFR3 (4p16), MAF (16q) and CCND1 (11q13) rearrangements. Array-CGH was then performed. Five chromosomes recurrently affected by gains/amplifications in primary samples and cell lines were analyzed in detail. Sixty amplified and overexpressed genes were found and 25 (42%) of them were only overexpressed when amplified; moreover, six showed a significant association between overexpression and gain/amplification. We also found co-amplification and overexpression for genes located within the same amplicons, such as MALT1 and BCL2. INTERPRETATION AND CONCLUSIONS: Parallel analysis of gene copy numbers and expression levels by cDNA microarray in MM allowed efficient identification of genes whose expression levels are elevated because of increased copy number. This is the first time that MALT1 and BCL2 have been shown to be overexpressed and amplified in MM.10aB-Cell10aCaspases Cell Line10aHuman *Gene Amplification Gene Dosage Gene Expression Profiling *Gene Expression Regulation10aMarginal Zone/genetics Multiple Myeloma/*genetics Neoplasm Proteins/genetics Proto-Oncogene Proteins c-bcl-2/genetics10aNeoplasm Humans Immunoglobulin Heavy Chains/genetics Lymphoma10aNeoplastic Gene Rearrangement *Genes10aTumor *Chromosomes1 aLargo, C.1 aAlvarez, S.1 aSaez, B.1 aBlesa, D.1 aMartin-Subero, J., I.1 aGonzalez-Garcia, I.1 aBrieva, J., A.1 aDopazo, J.1 aSiebert, R.1 aCalasanz, M., J.1 aCigudosa, J., C. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1646130202048nas a2200157 4500008004100000245010400041210006900145300001200214490000700226520134600233653015401579100001401733700002401747700001301771856010601784 2006 eng d00aLocalization of binding sites in protein structures by optimization of a composite scoring function0 aLocalization of binding sites in protein structures by optimizat a2366-800 v153 aThe rise in the number of functionally uncharacterized protein structures is increasing the demand for structure-based methods for functional annotation. Here, we describe a method for predicting the location of a binding site of a given type on a target protein structure. The method begins by constructing a scoring function, followed by a Monte Carlo optimization, to find a good scoring patch on the protein surface. The scoring function is a weighted linear combination of the z-scores of various properties of protein structure and sequence, including amino acid residue conservation, compactness, protrusion, convexity, rigidity, hydrophobicity, and charge density; the weights are calculated from a set of previously identified instances of the binding-site type on known protein structures. The scoring function can easily incorporate different types of information useful in localization, thus increasing the applicability and accuracy of the approach. To test the method, 1008 known protein structures were split into 20 different groups according to the type of the bound ligand. For nonsugar ligands, such as various nucleotides, binding sites were correctly identified in 55%-73% of the cases. The method is completely automated (http://salilab.org/patcher) and can be applied on a large scale in a structural genomics setting.10aAmino Acid Sequence Binding Sites Biomechanics Hydrophobicity Ligands *Monte Carlo Method Protein Conformation Proteins/*chemistry Static Electricity1 aRossi, A.1 aMarti-Renom, M., A.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1696364502671nas a2200349 4500008004100000245009900041210006900140300001100209490000700220520147800227653002901705653002701734653004401761653005601805653004001861653008301901100001501984700001401999700001802013700001602031700002402047700001402071700002402085700001602109700001702125700001602142700001702158700001402175700001302189700001302202856010602215 2006 eng d00aMODBASE: a database of annotated comparative protein structure models and associated resources0 aMODBASE a database of annotated comparative protein structure mo aD291-50 v343 aMODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models for all available protein sequences that can be matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, and improvements in the software for calculating the models. MODBASE currently contains 3 094 524 reliable models for domains in 1 094 750 out of 1 817 889 unique protein sequences in the UniProt database (July 5, 2005); only models based on statistically significant alignments and models assessed to have the correct fold despite insignificant alignments are included. MODBASE also allows users to generate comparative models for proteins of interest with the automated modeling server MODWEB (http://salilab.org/modweb). Our other resources integrated with MODBASE include comprehensive databases of multiple protein structure alignments (DBAli, http://salilab.org/dbali), structurally defined ligand binding sites and structurally defined binary domain interfaces (PIBASE, http://salilab.org/pibase) as well as predictions of ligand binding sites, interactions between yeast proteins, and functional consequences of human nsSNPs (LS-SNP, http://salilab.org/LS-SNP).10aBinding Sites *Databases10aMolecular Polymorphism10aProtein Humans Internet Ligands *Models10aProtein Systems Integration User-Computer Interface10aSingle Nucleotide Protein Structure10aTertiary Proteins/*chemistry/genetics/metabolism Software *Structural Homology1 aPieper, U.1 aEswar, N.1 aDavis, F., P.1 aBraberg, H.1 aMadhusudhan, M., S.1 aRossi, A.1 aMarti-Renom, M., A.1 aKarchin, R.1 aWebb, B., M.1 aEramian, D.1 aShen, M., Y.1 aKelly, L.1 aMelo, F.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1638186901882nas a2200313 4500008004100000245005200041210005100093300001200144490000700156520100300163653001001166653002901176100001701205700001601222700002101238700001601259700002301275700001401298700001601312700001301328700001801341700001401359700001901373700001501392700001601407700002401423700001501447856010601462 2006 eng d00aNext station in microarray data analysis: GEPAS0 aNext station in microarray data analysis GEPAS aW486-910 v343 aThe Gene Expression Profile Analysis Suite (GEPAS) has been running for more than four years. During this time it has evolved to keep pace with the new interests and trends in the still changing world of microarray data analysis. GEPAS has been designed to provide an intuitive although powerful web-based interface that offers diverse analysis options from the early step of preprocessing (normalization of Affymetrix and two-colour microarray experiments and other preprocessing options), to the final step of the functional annotation of the experiment (using Gene Ontology, pathways, PubMed abstracts etc.), and include different possibilities for clustering, gene selection, class prediction and array-comparative genomic hybridization management. GEPAS is extensively used by researchers of many countries and its records indicate an average usage rate of 400 experiments per day. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://www.gepas.org.
10agepas10amicroarray data analysis1 aMontaner, D.1 aTarraga, J.1 aHuerta-Cepas, J.1 aBurguet, J.1 aVaquerizas, J., M.1 aConde, L.1 aMinguez, P.1 aVera, J.1 aMukherjee, S.1 aValls, J.1 aPujana, M., A.1 aAlloza, E.1 aHerrero, J.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1684505602791nas a2200193 4500008004100000245009800041210006900139300001200208490000800220520199800228653005602226653012802282100001302410700001802423700002402441700001302465700001302478856010602491 2006 eng d00aRefinement of protein structures by iterative comparative modeling and CryoEM density fitting0 aRefinement of protein structures by iterative comparative modeli a1655-680 v3573 aWe developed a method for structure characterization of assembly components by iterative comparative protein structure modeling and fitting into cryo-electron microscopy (cryoEM) density maps. Specifically, we calculate a comparative model of a given component by considering many alternative alignments between the target sequence and a related template structure while optimizing the fit of a model into the corresponding density map. The method relies on the previously developed Moulder protocol that iterates over alignment, model building, and model assessment. The protocol was benchmarked using 20 varied target-template pairs of known structures with less than 30% sequence identity and corresponding simulated density maps at resolutions from 5A to 25A. Relative to the models based on the best existing sequence profile alignment methods, the percentage of C(alpha) atoms that are within 5A of the corresponding C(alpha) atoms in the superposed native structure increases on average from 52% to 66%, which is half-way between the starting models and the models from the best possible alignments (82%). The test also reveals that despite the improvements in the accuracy of the fitness function, this function is still the bottleneck in reducing the remaining errors. To demonstrate the usefulness of the protocol, we applied it to the upper domain of the P8 capsid protein of rice dwarf virus that has been studied by cryoEM at 6.8A. The C(alpha) root-mean-square deviation of the model based on the remotely related template, bluetongue virus VP7, improved from 8.7A to 6.0A, while the best possible model has a C(alpha) RMSD value of 5.3A. Moreover, the resulting model fits better into the cryoEM density map than the initial template structure. The method is being implemented in our program MODELLER for protein structure modeling by satisfaction of spatial restraints and will be applicable to the rapidly increasing number of cryoEM density maps of macromolecular assemblies.10aAmino Acid Sequence Cryoelectron Microscopy *Models10aMolecular Molecular Sequence Data Plant Viruses/chemistry *Protein Conformation Software Viral Proteins/*chemistry/genetics1 aTopf, M.1 aBaker, M., L.1 aMarti-Renom, M., A.1 aChiu, W.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1649020702859nas a2200301 4500008004100000245009400041210006900135300001300204490000800217520172300225653007401948653002202022653001902044653002402063653002802087653002002115653015502135653002502290100001502315700001402330700001702344700001602361700002202377700002202399700001502421700001502436856010602451 2006 eng d00aSelective pressures at a codon-level predict deleterious mutations in human disease genes0 aSelective pressures at a codonlevel predict deleterious mutation a1390-4040 v3583 aDeleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome.10aAmino Acid Sequence Amino Acid Substitution Codon/*genetics Databases10aGenetic Evolution10aGenetic Models10aHuman Humans Models10aInborn/*genetics Genome10aMolecular Genes10aMolecular Molecular Sequence Data *Mutation Neoplasms/genetics Proteins/genetics *Selection (Genetics) Tumor Suppressor Protein p53/chemistry/genetics10ap53 Genetic Diseases1 aArbiza, L.1 aDuchi, S.1 aMontaner, D.1 aBurguet, J.1 aPantoja-Uceda, D.1 aPineda-Lucena, A.1 aDopazo, J.1 aDopazo, H. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1658474602070nas a2200205 4500008004100000245006600041210006500107300001100172490000700183520128000190653004201470653002501512653010401537653004001641100002401681700002401705700001601729700001301745856010601758 2006 eng d00aVariable gap penalty for protein sequence-structure alignment0 aVariable gap penalty for protein sequencestructure alignment a129-330 v193 aThe penalty for inserting gaps into an alignment between two protein sequences is a major determinant of the alignment accuracy. Here, we present an algorithm for finding a globally optimal alignment by dynamic programming that can use a variable gap penalty (VGP) function of any form. We also describe a specific function that depends on the structural context of an insertion or deletion. It penalizes gaps that are introduced within regions of regular secondary structure, buried regions, straight segments and also between two spatially distant residues. The parameters of the penalty function were optimized on a set of 240 sequence pairs of known structure, spanning the sequence identity range of 20-40%. We then tested the algorithm on another set of 238 sequence pairs of known structures. The use of the VGP function increases the number of correctly aligned residues from 81.0 to 84.5% in comparison with the optimized affine gap penalty function; this difference is statistically significant according to Student’s t-test. We estimate that the new algorithm allows us to produce comparative models with an additional approximately 7 million accurately modeled residues in the approximately 1.1 million proteins that are detectably related to a known structure.10aAlgorithms Amino Acid Sequence Models10aAmino Acid *Software10aMolecular Molecular Sequence Data Proteins/*chemistry Sequence Alignment/*methods Sequence Analysis10aProtein/*methods *Sequence Homology1 aMadhusudhan, M., S.1 aMarti-Renom, M., A.1 aSanchez, R.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1642384602090nas a2200193 4500008004100000245012600041210006900167300001100236490000700247520144700254653001501701653002501716100002401741700001601765700002301781700001401804700001501818856006301833 2005 eng d00aBABELOMICS: a suite of web tools for functional annotation and analysis of groups of genes in high-throughput experiments0 aBABELOMICS a suite of web tools for functional annotation and an aW460-40 v333 aWe present Babelomics, a complete suite of web tools for the functional analysis of groups of genes in high-throughput experiments, which includes the use of information on Gene Ontology terms, interpro motifs, KEGG pathways, Swiss-Prot keywords, analysis of predicted transcription factor binding sites, chromosomal positions and presence in tissues with determined histological characteristics, through five integrated modules: FatiGO (fast assignment and transference of information), FatiWise, transcription factor association test, GenomeGO and tissues mining tool, respectively. Additionally, another module, FatiScan, provides a new procedure that integrates biological information in combination with experimental results in order to find groups of genes with modest but coordinate significant differential behaviour. FatiScan is highly sensitive and is capable of finding significant asymmetries in the distribution of genes of common function across a list of ordered genes even if these asymmetries were not extreme. The strong multiple-testing nature of the contrasts made by the tools is taken into account. All the tools are integrated in the gene expression analysis package GEPAS. Babelomics is the natural evolution of our tool FatiGO (which analysed almost 22,000 experiments during the last year) to include more sources on information and new modes of using it. Babelomics can be found at http://www.babelomics.org.
10ababelomics10afunctional profiling1 aAl-Shahrour, Fatima1 aMinguez, P.1 aVaquerizas, J., M.1 aConde, L.1 aDopazo, J. uhttp://nar.oxfordjournals.org/content/33/suppl_2/W460.long02167nas a2200301 4500008004100000245008600041210006900127300001100196490000700207520100200214653012701216653002601343653013701369653003901506653001801545100002001563700001901583700001901602700001901621700001401640700002401654700001701678700001801695700001301713700001901726700001401745856010601759 2005 eng d00aThe C-type lectin fold as an evolutionary solution for massive sequence variation0 aCtype lectin fold as an evolutionary solution for massive sequen a886-920 v123 aOnly few instances are known of protein folds that tolerate massive sequence variation for the sake of binding diversity. The most extensively characterized is the immunoglobulin fold. We now add to this the C-type lectin (CLec) fold, as found in the major tropism determinant (Mtd), a retroelement-encoded receptor-binding protein of Bordetella bacteriophage. Variation in Mtd, with its approximately 10(13) possible sequences, enables phage adaptation to Bordetella spp. Mtd is an intertwined, pyramid-shaped trimer, with variable residues organized by its CLec fold into discrete receptor-binding sites. The CLec fold provides a highly static scaffold for combinatorial display of variable residues, probably reflecting a different evolutionary solution for balancing diversity against stability from that in the immunoglobulin fold. Mtd variants are biased toward the receptor pertactin, and there is evidence that the CLec fold is used broadly for sequence variation by related retroelements.10aAmino Acid Sequence Bacterial Outer Membrane Proteins/*chemistry Bacteriophages/*metabolism Bordetella/*virology Evolution10aBordetella/*chemistry10aC-Type/*chemistry Molecular Sequence Data Protein Conformation Protein Folding Viral Proteins/*chemistry/*genetics Virulence Factors10aMolecular Genetic Variation Genome10aViral Lectins1 aMcMahon, S., A.1 aMiller, J., L.1 aLawton, J., A.1 aKerkow, D., E.1 aHodes, A.1 aMarti-Renom, M., A.1 aDoulatov, S.1 aNarayanan, E.1 aSali, A.1 aMiller, J., F.1 aGhosh, P. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1617032402245nas a2200253 4500008004100000245008600041210006900127300001100196490000800207520134200215653001501557653003601572653012101608653002301729100001801752700001601770700001401786700002401800700001501824700001901839700001301858700001401871856010601885 2005 eng d00aDetecting remotely related proteins by their interactions and sequence similarity0 aDetecting remotely related proteins by their interactions and se a7151-60 v1023 aThe function of an uncharacterized protein is usually inferred either from its homology to, or its interactions with, characterized proteins. Here, we use both sequence similarity and protein interactions to identify relationships between remotely related protein sequences. We rely on the fact that homologous sequences share similar interactions, and, therefore, the set of interacting partners of the partners of a given protein is enriched by its homologs. The approach was bench-marked by assigning the fold and functional family to test sequences of known structure. Specifically, we relied on 1,434 proteins with known folds, as defined in the Structural Classification of Proteins (SCOP) database, and with known interacting partners, as defined in the Database of Interacting Proteins (DIP). For this subset, the specificity of fold assignment was increased from 54% for position-specific iterative BLAST to 75% for our approach, with a concomitant increase in sensitivity for a few percentage points. Similarly, the specificity of family assignment at the e-value threshold of 10(-8) was increased from 70% to 87%. The proposed method would be a useful tool for large-scale automated discovery of remote relationships between protein sequences, given its unique reliance on sequence similarity and protein-protein interactions.10aAmino Acid10aComputational Biology Databases10aMolecular Protein Conformation Protein Folding Proteins/*genetics/*metabolism Proteomics/*methods *Sequence Homology10aProtein *Evolution1 aEspadaler, J.1 aAragues, R.1 aEswar, N.1 aMarti-Renom, M., A.1 aQuerol, E.1 aAviles, F., X.1 aSali, A.1 aOliva, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1588337203705nas a2200805 4500008004100000245010800041210006900149300001100218490000700229520133100236653002501567653010901592653000801701653010501709653007501814100001601889700001401905700001501919700001701934700001501951700001501966700001301981700001501994700001602009700002002025700001502045700002102060700001502081700001802096700001502114700002902129700001502158700001702173700001502190700002802205700001502233700001602248700001402264700002602278700001602304700001502320700002102335700001602356700001902372700002002391700001702411700002702428700001702455700001502472700001602487700001502503700002502518700002002543700001302563700001602576700002202592700001302614700001602627700001402643700001402657700001402671700001402685700001502699700001502714700001602729700001402745700001702759700001702776856010602793 2005 eng d00aDevelopment of a citrus genome-wide EST collection and cDNA microarray as resources for genomic studies0 aDevelopment of a citrus genomewide EST collection and cDNA micro a375-910 v573 aA functional genomics project has been initiated to approach the molecular characterization of the main biological and agronomical traits of citrus. As a key part of this project, a citrus EST collection has been generated from 25 cDNA libraries covering different tissues, developmental stages and stress conditions. The collection includes a total of 22,635 high-quality ESTs, grouped in 11,836 putative unigenes, which represent at least one third of the estimated number of genes in the citrus genome. Functional annotation of unigenes which have Arabidopsis orthologues (68% of all unigenes) revealed gene representation in every major functional category, suggesting that a genome-wide EST collection was obtained. A Citrus clementina Hort. ex Tan. cv. Clemenules genomic library, that will contribute to further characterization of relevant genes, has also been constructed. To initiate the analysis of citrus transcriptome, we have developed a cDNA microarray containing 12,672 probes corresponding to 6875 putative unigenes of the collection. Technical characterization of the microarray showed high intra- and inter-array reproducibility, as well as a good range of sensitivity. We have also validated gene expression data achieved with this microarray through an independent technique such as RNA gel blot analysis.10aCitrus/*genetics DNA10aComplementary/chemistry/genetics *Expressed Sequence Tags Gene Expression Profiling Gene Library *Genome10aDNA10aPlant Genomics/*methods Molecular Sequence Data Oligonucleotide Array Sequence Analysis/*methods RNA10aPlant/genetics/metabolism Reproducibility of Results Sequence Analysis1 aForment, J.1 aGadea, J.1 aHuerta, L.1 aAbizanda, L.1 aAgusti, J.1 aAlamar, S.1 aAlos, E.1 aAndres, F.1 aArribas, R.1 aBeltran, J., P.1 aBerbel, A.1 aBlazquez, M., A.1 aBrumos, J.1 aCanas, L., A.1 aCercos, M.1 aColmenero-Flores, J., M.1 aConesa, A.1 aEstables, B.1 aGandia, M.1 aGarcia-Martinez, J., L.1 aGimeno, J.1 aGisbert, A.1 aGomez, G.1 aGonzalez-Candelas, L.1 aGranell, A.1 aGuerri, J.1 aLafuente, M., T.1 aMadueno, F.1 aMarcos, J., F.1 aMarques, M., C.1 aMartinez, F.1 aMartinez-Godoy, M., A.1 aMiralles, S.1 aMoreno, P.1 aNavarro, L.1 aPallas, V.1 aPerez-Amador, M., A.1 aPerez-Valle, J.1 aPons, C.1 aRodrigo, I.1 aRodriguez, P., L.1 aRoyo, C.1 aSerrano, R.1 aSoler, G.1 aTadeo, F.1 aTalon, M.1 aTerol, J.1 aTrenor, M.1 aVaello, L.1 aVicente, O.1 aVidal, Ch1 aZacarias, L.1 aConejero, V. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1583012802188nas a2200241 4500008004100000245009500041210006900136300001200205490000700217520141200224653001001636653002901646100002301675700001401698700002001712700001601732700001601748700002101764700002401785700001601809700001501825856010601840 2005 eng d00aGEPAS, an experiment-oriented pipeline for the analysis of microarray gene expression data0 aGEPAS an experimentoriented pipeline for the analysis of microar aW616-200 v333 aThe Gene Expression Profile Analysis Suite, GEPAS, has been running for more than three years. With >76,000 experiments analysed during the last year and a daily average of almost 300 analyses, GEPAS can be considered a well-established and widely used platform for gene expression microarray data analysis. GEPAS is oriented to the analysis of whole series of experiments. Its design and development have been driven by the demands of the biomedical community, probably the most active collective in the field of microarray users. Although clustering methods have obviously been implemented in GEPAS, our interest has focused more on methods for finding genes differentially expressed among distinct classes of experiments or correlated to diverse clinical outcomes, as well as on building predictors. There is also a great interest in CGH-arrays which fostered the development of the corresponding tool in GEPAS: InSilicoCGH. Much effort has been invested in GEPAS for developing and implementing efficient methods for functional annotation of experiments in the proper statistical framework. Thus, the popular FatiGO has expanded to a suite of programs for functional annotation of experiments, including information on transcription factor binding sites, chromosomal location and tissues. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://www.gepas.org.
10agepas10amicroarray data analysis1 aVaquerizas, J., M.1 aConde, L.1 aYankilevich, P.1 aCabezon, A.1 aMinguez, P.1 aDiaz-Uriarte, R.1 aAl-Shahrour, Fatima1 aHerrero, J.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1598054802687nas a2200337 4500008004100000245010400041210006900145300001000214490000700224520138200231653003401613653006501647653002501712653001001737653003201747653003301779653003201812653019101844100001502035700002202050700002602072700001602098700002502114700001402139700002202153700001602175700001502191700002102206700001602227856010602243 2005 eng d00aA novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma0 anovel candidate region linked to development of both pheochromoc a260-80 v423 aAlthough the histologic distinction between pheochromocytomas and head and neck paragangliomas is clear, little is known about the genetic differences between them. To date, various sets of genes have been found to be involved in inherited susceptibility to developing both tumor types, but the genes involved in sporadic pathogenesis are still unknown. To define new candidate regions, we performed CGH analysis on 29 pheochromocytomas and on 24 paragangliomas mainly of head and neck origin (20 of 24), which allowed us to differentiate between the two tumor types. Loss of 3q was significantly more frequent in pheochromocytomas, and loss of 1q appeared only in paragangliomas. We also found gain of 11q13 to be a significantly frequent alteration in malignant cases of both types. In addition, recurrent loss of 8p22-23 was found in 62% of pheochromocytomas (including all malignant cases) versus in 33% of paragangliomas, suggesting that this region contains candidate genes involved in the pathogenesis of this abnormality. Using FISH analysis on tissue microarrays, we confirmed genomic deletion of this region in 55% of pheochromocytomas compared to 12% of paragangliomas. Loss of 8p22-23 appears to be an important event in the sporadic development of these tumors, and additional molecular studies are necessary to identify candidate genes in this chromosomal region.10a80 and over Child Chromosomes10aAdolescent Adrenal Gland Neoplasms/*genetics Adult Aged Aged10aBiological/*genetics10aHuman10aPair 1/genetics Chromosomes10aPair 11/genetics Chromosomes10aPair 3/genetics Chromosomes10aPair 8/genetics Female Gene Deletion Head and Neck Neoplasms/*genetics Humans Male Middle Aged Nucleic Acid Hybridization Paraganglioma/*genetics Pheochromocytoma/*genetics Tumor Markers1 aCascon, A.1 aRuiz-Llorente, S.1 aRodriguez-Perales, S.1 aHonrado, E.1 aMartinez-Ramirez, A.1 aLeton, R.1 aMontero-Conde, C.1 aBenitez, J.1 aDopazo, J.1 aCigudosa, J., C.1 aRobledo, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1560934702881nas a2200397 4500008004100000245016800041210006900209300001200278490000700290520143600297653010101733653002201834653001001856653008301866653003301949653003301982653003302015653003202048653005102080100001602131700002102147700001502168700001602183700001602199700001602215700001602231700001802247700001602265700001402281700001302295700002102308700001502329700001702344700001602361856010602377 2005 eng d00aA predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation0 apredictor based on the somatic genomic changes of the BRCA1BRCA2 a1146-530 v113 aThe genetic changes underlying in the development and progression of familial breast cancer are poorly understood. To identify a somatic genetic signature of tumor progression for each familial group, BRCA1, BRCA2, and non-BRCA1/BRCA2 (BRCAX) tumors, by high-resolution comparative genomic hybridization, we have analyzed 77 tumors previously characterized for BRCA1 and BRCA2 germ line mutations. Based on a combination of the somatic genetic changes observed at the six most different chromosomal regions and the status of the estrogen receptor, we developed using random forests a molecular classifier, which assigns to a given tumor a probability to belong either to the BRCA1 or to the BRCA2 class. Because 76.5% (26 of 34) of the BRCAX cases were classified with our predictor to the BRCA1 class with a probability of >50%, we analyzed the BRCA1 promoter region for aberrant methylation in all the BRCAX cases. We found that 15 of the 34 BRCAX analyzed tumors had hypermethylation of the BRCA1 gene. When we considered the predictor, we observed that all the cases with this epigenetic event were assigned to the BRCA1 class with a probability of >50%. Interestingly, 84.6% of the cases (11 of 13) assigned to the BRCA1 class with a probability >80% had an aberrant methylation of the BRCA1 promoter. This fact suggests that somatic BRCA1 inactivation could modify the profile of tumor progression in most of the BRCAX cases.10aBRCA1 Protein/*genetics BRCA2 Protein/*genetics Breast Neoplasms/*genetics/pathology Chromosomes10aGenetic/*genetics10aHuman10aHuman Humans Male Mutation Nucleic Acid Hybridization/methods Promoter Regions10aPair 12/genetics Chromosomes10aPair 15/genetics Chromosomes10aPair 18/genetics Chromosomes10aPair 2/genetics Chromosomes10aPair 8/genetics *DNA Methylation Female Genome1 aAlvarez, S.1 aDiaz-Uriarte, R.1 aOsorio, A.1 aBarroso, A.1 aMelchor, L.1 aPaz, M., F.1 aHonrado, E.1 aRodriguez, R.1 aUrioste, M.1 aValle, L.1 aDiez, O.1 aCigudosa, J., C.1 aDopazo, J.1 aEsteller, M.1 aBenitez, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1570918202319nas a2200181 4500008004100000245005300041210005300094300001200147490000700159520157000166653006801736653008501804653008101889100002401970700002401994700001302018856010602031 2004 eng d00aAlignment of protein sequences by their profiles0 aAlignment of protein sequences by their profiles a1071-870 v133 aThe accuracy of an alignment between two protein sequences can be improved by including other detectably related sequences in the comparison. We optimize and benchmark such an approach that relies on aligning two multiple sequence alignments, each one including one of the two protein sequences. Thirteen different protocols for creating and comparing profiles corresponding to the multiple sequence alignments are implemented in the SALIGN command of MODELLER. A test set of 200 pairwise, structure-based alignments with sequence identities below 40% is used to benchmark the 13 protocols as well as a number of previously described sequence alignment methods, including heuristic pairwise sequence alignment by BLAST, pairwise sequence alignment by global dynamic programming with an affine gap penalty function by the ALIGN command of MODELLER, sequence-profile alignment by PSI-BLAST, Hidden Markov Model methods implemented in SAM and LOBSTER, pairwise sequence alignment relying on predicted local structure by SEA, and multiple sequence alignment by CLUSTALW and COMPASS. The alignment accuracies of the best new protocols were significantly better than those of the other tested methods. For example, the fraction of the correctly aligned residues relative to the structure-based alignment by the best protocol is 56%, which can be compared with the accuracies of 26%, 42%, 43%, 48%, 50%, 49%, 43%, and 43% for the other methods, respectively. The new method is currently applied to large-scale comparative protein structure modeling of all known sequences.10a*Algorithms Amino Acid Sequence Computational Biology Databases10aProtein Markov Chains Molecular Sequence Data *Protein Folding Protein Structure10aTertiary Proteins/*chemistry *Sequence Alignment Sequence Homology *Software1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1504473602177nas a2200313 4500008004100000245013500041210006900176260001500245300001200260490000700272520116700279100003001446700002301476700001901499700002001518700002701538700002701565700002101592700001901613700001601632700002101648700002401669700002401693700002001717700002201737700001801759700002001777856006601797 2004 eng d00aExpression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes.0 aExpression profiling of Tcell lymphomas differentiates periphera c2004 Aug 1 a4971-820 v103 aPURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.
1 aMartinez-Delgado, Beatriz1 aMeléndez, Barbara1 aCuadros, Marta1 aAlvarez, Javier1 aCastrillo, Jose, Maria1 aDe La Parte, Ana, Ruiz1 aMollejo, Manuela1 aBellas, Carmen1 aDiaz, Ramon1 aLombardía, Luis1 aAl-Shahrour, Fatima1 aDomínguez, Orlando1 aCascon, Alberto1 aRobledo, Mercedes1 aRivas, Carmen1 aBenitez, Javier uhttp://clincancerres.aacrjournals.org/content/10/15/4971.long02990nas a2200325 4500008004100000245013600041210006900177300001100246490000700257520176100264653001602025653002602041653001002067653003402077653003402111653011302145653008802258100001702346700002102363700001602384700002502400700002702425700001502452700002102467700001402488700001502502700002502517700001602542856010602558 2004 eng d00aGene expression analysis of chromosomal regions with gain or loss of genetic material detected by comparative genomic hybridization0 aGene expression analysis of chromosomal regions with gain or los a353-650 v413 aComparative genomic hybridization (CGH) has been widely used to detect copy number alterations in cancer and to identify regions containing candidate tumor-responsible genes; however, gene expression changes have been described only in highly amplified regions (amplicons). To study the overall impact of slight copy number changes on gene expression, we analyzed 16 T-cell lymphomas by using CGH and a custom-designed cDNA microarray containing 7,657 genes and expressed sequence tags related to tumorigenesis. We evaluated mean gene expression and variability within CGH-altered regions and explored the relationship between the effects of the gene and its position within these regions. Minimally overlapping CGH candidate areas (6q25, 13q21-q22, and 19q13.1) revealed a weak relationship between altered genomic content and gene expression. However, some candidate genes showed modified expression within these regions in the majority of tumors; these candidate genes were evaluated and confirmed in another independent series of 23 T-cell lymphomas by use of the same cDNA microarray and by FISH on a tissue microarray. When all the CGH regions detected for each tumor were considered, we found a significant increase or decrease in the mean expression of the genes contained in gained or lost regions, respectively. In addition, we found that the expression of a gene was dependent not only on its position within an altered region but also on its own mechanism of regulation: genes in the same altered region responded very differently to the gain or loss of genetic material. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience.wiley.com/jpages/1045-2257/suppmat/index.html.10aChromosomes10aFluorescence Lymphoma10aHuman10aPair 13/*genetics Chromosomes10aPair 19/*genetics Chromosomes10aPair 6/*genetics Expressed Sequence Tags *Gene Dosage Gene Expression Profiling Humans In Situ Hybridization10aT-Cell/*genetics Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis1 aMelendez, B.1 aDiaz-Uriarte, R.1 aCuadros, M.1 aMartinez-Ramirez, A.1 aFernandez-Piqueras, J.1 aDopazo, A.1 aCigudosa, J., C.1 aRivas, C.1 aDopazo, J.1 aMartinez-Delgado, B.1 aBenitez, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1538226103269nas a2200337 4500008004100000245010000041210006900141300001200210490000700222520201600229653008002245653005102325653005202376653014002428100001502568700001402583700001602597700002402613700001802637700001902655700001702674700001402691700002402705700001402729700001302743700001902756700001802775700001902793700001302812856010602825 2004 eng d00aMODBASE, a database of annotated comparative protein structure models, and associated resources0 aMODBASE a database of annotated comparative protein structure mo aD217-220 v323 aMODBASE (http://salilab.org/modbase) is a relational database of annotated comparative protein structure models for all available protein sequences matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on the MODELLER package for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE uses the MySQL relational database management system for flexible querying and CHIMERA for viewing the sequences and structures (http://www.cgl.ucsf.edu/chimera/). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, as well as improvements in the software for calculating the models. For ease of access, MODBASE is organized into different data sets. The largest data set contains 1,26,629 models for domains in 659,495 out of 1,182,126 unique protein sequences in the complete Swiss-Prot/TrEMBL database (August 25, 2003); only models based on alignments with significant similarity scores and models assessed to have the correct fold despite insignificant alignments are included. Another model data set supports target selection and structure-based annotation by the New York Structural Genomics Research Consortium; e.g. the 53 new structures produced by the consortium allowed us to characterize structurally 24,113 sequences. MODBASE also contains binding site predictions for small ligands and a set of predicted interactions between pairs of modeled sequences from the same genome. Our other resources associated with MODBASE include a comprehensive database of multiple protein structure alignments (DBALI, http://salilab.org/dbali) as well as web servers for automated comparative modeling with MODPIPE (MODWEB, http://salilab. org/modweb), modeling of loops in protein structures (MODLOOP, http://salilab.org/modloop) and predicting functional consequences of single nucleotide polymorphisms (SNPWEB, http://salilab. org/snpweb).10aAmino Acid Sequence Animals Binding Sites *Computational Biology *Databases10aMolecular Molecular Sequence Data Polymorphism10aProtein Genomics Humans Internet Ligands Models10aSingle Nucleotide Protein Binding Protein Conformation Proteins/*chemistry/genetics Sequence Alignment Software User-Computer Interface1 aPieper, U.1 aEswar, N.1 aBraberg, H.1 aMadhusudhan, M., S.1 aDavis, F., P.1 aStuart, A., C.1 aMirkovic, N.1 aRossi, A.1 aMarti-Renom, M., A.1 aFiser, A.1 aWebb, B.1 aGreenblatt, D.1 aHuang, C., C.1 aFerrin, T., E.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1468139802102nas a2200217 4500008004100000245007500041210006900116300001200185490000700197520140300204653001001607653002901617100001601646700002301662700002401685700001401709700001501723700002501738700001501763856010601778 2004 eng d00aNew challenges in gene expression data analysis and the extended GEPAS0 aNew challenges in gene expression data analysis and the extended aW485-910 v323 aSince the first papers published in the late nineties, including, for the first time, a comprehensive analysis of microarray data, the number of questions that have been addressed through this technique have both increased and diversified. Initially, interest focussed on genes coexpressing across sets of experimental conditions, implying, essentially, the use of clustering techniques. Recently, however, interest has focussed more on finding genes differentially expressed among distinct classes of experiments, or correlated to diverse clinical outcomes, as well as in building predictors. In addition to this, the availability of accurate genomic data and the recent implementation of CGH arrays has made mapping expression and genomic data on the chromosomes possible. There is also a clear demand for methods that allow the automatic transfer of biological information to the results of microarray experiments. Different initiatives, such as the Gene Ontology (GO) consortium, pathways databases, protein functional motifs, etc., provide curated annotations for genes. Whereas many resources on the web focus mainly on clustering methods, GEPAS has evolved to cope with the aforementioned new challenges that have recently arisen in the field of microarray data analysis. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://gepas.bioinfo.cnio.es.
10agepas10amicroarray data analysis1 aHerrero, J.1 aVaquerizas, J., M.1 aAl-Shahrour, Fatima1 aConde, L.1 aMateos, A.1 aDiaz-Uriarte, J., S.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1521543400480nas a2200145 4500008004100000245003100041210003100072300000900103490000600112653006100118100001400179700001700193700001800210856010600228 2004 eng d00aPerceptions about postdocs0 aPerceptions about postdocs a11040 v510aEurope *Fellowships and Scholarships *Research Personnel1 aVella, F.1 aMietchen, D.1 aGabaldón, T. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1557792002302nas a2200205 4500008004100000245012700041210006900168300001100237490000700248520137200255653006101627653007901688653013001767100001701897700002401914700001801938700001301956700002101969856010601990 2004 eng d00aStructure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition0 aStructurebased assessment of missense mutations in human BRCA1 i a3790-70 v643 aThe BRCA1 gene from individuals at risk of breast and ovarian cancers can be screened for the presence of mutations. However, the cancer association of most alleles carrying missense mutations is unknown, thus creating significant problems for genetic counseling. To increase our ability to identify cancer-associated mutations in BRCA1, we set out to use the principles of protein three-dimensional structure as well as the correlation between the cancer-associated mutations and those that abolish transcriptional activation. Thirty-one of 37 missense mutations of known impact on the transcriptional activation function of BRCA1 are readily rationalized in structural terms. Loss-of-function mutations involve nonconservative changes in the core of the BRCA1 C-terminus (BRCT) fold or are localized in a groove that presumably forms a binding site involved in the transcriptional activation by BRCA1; mutations that do not abolish transcriptional activation are either conservative changes in the core or are on the surface outside of the putative binding site. Next, structure-based rules for predicting functional consequences of a given missense mutation were applied to 57 germ-line BRCA1 variants of unknown cancer association. Such a structure-based approach may be helpful in an integrated effort to identify mutations that predispose individuals to cancer.10aBRCA1 Genetic Predisposition to Disease Humans *Mutation10aBRCA1 Protein/*chemistry/genetics Breast Neoplasms/*genetics Female *Genes10aMissense Ovarian Neoplasms/*genetics Pedigree Protein Conformation Structure-Activity Relationship Transcriptional Activation1 aMirkovic, N.1 aMarti-Renom, M., A.1 aWeber, B., L.1 aSali, A.1 aMonteiro, A., N. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1517298502356nas a2200265 4500008004100000245006200041210006200103300001000165490000700175520124200182653003001424653007301454653007501527653004901602653004201651653004301693653005001736653007501786653005801861100001901919700001601938700001501954700001501969856010601984 2003 eng d00aComparing bacterial genomes through conservation profiles0 aComparing bacterial genomes through conservation profiles a991-80 v133 aWe constructed two-dimensional representations of profiles of gene conservation across different genomes using the genome of Escherichia coli as a model. These profiles permit both the visualization at the genome level of different traits in the organism studied and, at the same time, reveal features related to the genomes analyzed (such as defective genomes or genomes that lack a particular system). Conserved genes are not uniformly distributed along the E. coli genome but tend to cluster together. The study of gene distribution patterns across genomes is important for the understanding of how sets of genes seem to be dependent on each other, probably having some functional link. This provides additional evidence that can be used for the elucidation of the function of unannotated genes. Clustering these patterns produces families of genes which can be arranged in a hierarchy of closeness. In this way, functions can be defined at different levels of generality depending on the level of the hierarchy that is studied. The combined study of conservation and phenotypic traits opens up the possibility of defining phenotype/genotype associations, and ultimately inferring the gene or genes responsible for a particular trait.10aBacterial Genotype Models10aBacterial/genetics Cluster Analysis Conserved Sequence/*genetics DNA10aBacterial/genetics Escherichia coli/classification/*genetics Evolution10aBacterial/genetics Gene Order/genetics Genes10aBacterial/genetics/physiology *Genome10aChromosome Mapping/methods Chromosomes10aGenetic Phenotype Phylogeny Sequence Homology10aMolecular Gene Expression Profiling/methods Gene Expression Regulation10aNucleic Acid Species Specificity Terminology as Topic1 aMartin, M., J.1 aHerrero, J.1 aMateos, A.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1269532402057nas a2200301 4500008004100000245006000041210005900101300001100160490000700171520105900178653002501237653001201262653007701274653003201351653007901383100001601462700001901478700002401497700001901521700002401540700001401564700001401578700001401592700001701606700001301623700001301636856010601649 2003 eng d00aEVA: Evaluation of protein structure prediction servers0 aEVA Evaluation of protein structure prediction servers a3311-50 v313 aEVA (http://cubic.bioc.columbia.edu/eva/) is a web server for evaluation of the accuracy of automated protein structure prediction methods. The evaluation is updated automatically each week, to cope with the large number of existing prediction servers and the constant changes in the prediction methods. EVA currently assesses servers for secondary structure prediction, contact prediction, comparative protein structure modelling and threading/fold recognition. Every day, sequences of newly available protein structures in the Protein Data Bank (PDB) are sent to the servers and their predictions are collected. The predictions are then compared to the experimental structures once a week; the results are published on the EVA web pages. Over time, EVA has accumulated prediction results for a large number of proteins, ranging from hundreds to thousands, depending on the prediction method. This large sample assures that methods are compared reliably. As a result, EVA provides useful information to developers as well as users of prediction methods.10aAutomation Databases10aProtein10aProtein Internet *Protein Conformation Protein Folding Protein Structure10aProtein Structural Homology10aSecondary Proteins/chemistry Reproducibility of Results *Sequence Analysis1 aKoh, I., Y.1 aEyrich, V., A.1 aMarti-Renom, M., A.1 aPrzybylski, D.1 aMadhusudhan, M., S.1 aEswar, N.1 aGrana, O.1 aPazos, F.1 aValencia, A.1 aSali, A.1 aRost, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1282431501500nas a2200217 4500008004100000245007700041210006900118300001100187490000700198520080200205653001001007653002901017100001601046700002401062700002101086700001501107700002301122700001601145700001501161856010601176 2003 eng d00aGEPAS: A web-based resource for microarray gene expression data analysis0 aGEPAS A webbased resource for microarray gene expression data an a3461-70 v313 aWe present a web-based pipeline for microarray gene expression profile analysis, GEPAS, which stands for Gene Expression Profile Analysis Suite (http://gepas.bioinfo.cnio.es). GEPAS is composed of different interconnected modules which include tools for data pre-processing, two-conditions comparison, unsupervised and supervised clustering (which include some of the most popular methods as well as home made algorithms) and several tests for differential gene expression among different classes, continuous variables or survival analysis. A multiple purpose tool for data mining, based on Gene Ontology, is also linked to the tools, which constitutes a very convenient way of analysing clustering results. On-line tutorials are available from our main web server (http://bioinfo.cnio.es).
10agepas10amicroarray data analysis1 aHerrero, J.1 aAl-Shahrour, Fatima1 aDiaz-Uriarte, R.1 aMateos, A.1 aVaquerizas, J., M.1 aSantoyo, J.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1282434501742nas a2200217 4500008004100000245007200041210006900113300001000182490000700192520087900199653006301078653004601141653012601187100001801313700001501331700001901346700002401365700001601389700001301405856010601418 2003 eng d00aModView, visualization of multiple protein sequences and structures0 aModView visualization of multiple protein sequences and structur a165-60 v193 aSUMMARY: We describe ModView, a web application for visualization of multiple protein sequences and structures. ModView integrates a multiple structure viewer, a multiple sequence alignment editor, and a database querying engine. It is possible to interactively manipulate hundreds of proteins, to visualize conservative and variable residues, active and binding sites, fragments, and domains in protein families, as well as to display large macromolecular complexes such as ribosomes or viruses. As a Netscape plug-in, ModView can be included in HTML pages along with text and figures, which makes it useful for teaching and presentations. ModView is also suitable as a graphical interface to various databases because it can be controlled through JavaScript commands and called from CGI scripts. AVAILABILITY: ModView is available at http://guitar.rockefeller.edu/modview.10a*Database Management Systems Documentation/methods Imaging10aProtein/*methods *User-Computer Interface10aThree-Dimensional/methods Protein Conformation Proteins/*chemistry/genetics Sequence Alignment/*methods Sequence Analysis1 aIlyin, V., A.1 aPieper, U.1 aStuart, A., C.1 aMarti-Renom, M., A.1 aMcMahan, L.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1249931301823nas a2200289 4500008004100000245006600041210006600107300001200173490000700185520083500192653004601027653002001073653011301093653003201206100001401238700001301252700001701265700001401282700001801296700001501314700001901329700002401348700002401372700001801396700001301414856010601427 2003 eng d00aTools for comparative protein structure modeling and analysis0 aTools for comparative protein structure modeling and analysis a3375-800 v313 aThe following resources for comparative protein structure modeling and analysis are described (http://salilab.org): MODELLER, a program for comparative modeling by satisfaction of spatial restraints; MODWEB, a web server for automated comparative modeling that relies on PSI-BLAST, IMPALA and MODELLER; MODLOOP, a web server for automated loop modeling that relies on MODELLER; MOULDER, a CPU intensive protocol of MODWEB for building comparative models based on distant known structures; MODBASE, a comprehensive database of annotated comparative models for all sequences detectably related to a known structure; MODVIEW, a Netscape plugin for Linux that integrates viewing of multiple sequences and structures; and SNPWEB, a web server for structure-based prediction of the functional impact of a single amino acid substitution.10aAmino Acid *Software *Structural Homology10aInternet Models10aMolecular Protein Folding Proteins/chemistry Reproducibility of Results Sequence Alignment Sequence Homology10aProtein Systems Integration1 aEswar, N.1 aJohn, B.1 aMirkovic, N.1 aFiser, A.1 aIlyin, V., A.1 aPieper, U.1 aStuart, A., C.1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aYerkovich, B.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1282433100720nas a2200181 4500008004100000245013000041210006900171260003000240300001000270653001500280100002400295700001600319700001500335700001600350700002100366700001500387856013600402 2003 eng d00aUsing Gene Ontology on genome-scale studies to find significant associations of biologically relevant terms to group of genes0 aUsing Gene Ontology on genomescale studies to find significant a aNew York, USAbIEEE Press a43-5210ababelomics1 aAl-Shahrour, Fatima1 aHerrero, J.1 aMateos, A.1 aSantoyo, J.1 aDíaz-Uriarte, R1 aDopazo, J. uhttps://www.clinbioinfosspa.es/content/using-gene-ontology-genome-scale-studies-find-significant-associations-biologically-relevant01632nas a2200193 4500008004100000245007600041210006900117300001000186490000700196520078800203653023600991100001701227700001901244700001501263700001501278700001601293700002301309856010601332 2002 eng d00aFilamentous fungi as cell factories for heterologous protein production0 aFilamentous fungi as cell factories for heterologous protein pro a200-60 v203 aFilamentous fungi have been used as sources of metabolites and enzymes for centuries. For about two decades, molecular genetic tools have enabled us to use these organisms to express extra copies of both endogenous and exogenous genes. This review of current practice reveals that molecular tools have enabled several new developments. But it has been process development that has driven the final breakthrough to achieving commercially relevant quantities of protein. Recent research into gene expression in filamentous fungi has explored their wealth of genetic diversity with a view to exploiting them as expression hosts and as a source of new genes. Inevitably, the progress in the ’genomics’ technology will further develop high-throughput technologies for these organisms.10aFermentation/genetics/physiology Fungi/*genetics/*metabolism Humans Interleukin-6/analysis/*biosynthesis/genetics Peroxidases/analysis/*biosynthesis/genetics Protein Conformation Recombinant Proteins/analysis/*biosynthesis/genetics1 aPunt, P., J.1 avan Biezen, N.1 aConesa, A.1 aAlbers, A.1 aMangnus, J.1 avan den Hondel, C. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1194337500792nam a2200169 4500008004100000245017300041210006900214260003900283300001300322100001900335700002600354700001900380700002000399700002000419700002000439856016300459 2002 eng d00aMethods of Microarray Data Analysis IISupervised Neural Networks for Clustering Conditions in DNA Array Data After Reducing Noise by Clustering Gene Expression Profiles0 aMethods of Microarray Data Analysis IISupervised Neural Networks aBostonbKluwer Academic Publishers a91 - 1031 aLin, Simon, M.1 aJohnson, Kimberly, F.1 aMateos, Alvaro1 aHerrero, Javier1 aTamames, Javier1 aDopazo, Joaquin uhttp://www.springerlink.com/index/10.1007/b112982http://link.springer.com/10.1007/0-306-47598-7_7http://www.springerlink.com/index/pdf/10.1007/0-306-47598-7_701632nas a2200193 4500008004100000245007000041210006900111300001100180490000700191520092300198653004001121653008301161100002401244700002401268700001401292700001301306700001301319856010601332 2002 eng d00aReliability of assessment of protein structure prediction methods0 aReliability of assessment of protein structure prediction method a435-400 v103 aThe reliability of ranking of protein structure modeling methods is assessed. The assessment is based on the parametric Student’s t test and the nonparametric Wilcox signed rank test of statistical significance of the difference between paired samples. The approach is applied to the ranking of the comparative modeling methods tested at the fourth meeting on Critical Assessment of Techniques for Protein Structure Prediction (CASP). It is shown that the 14 CASP4 test sequences may not be sufficient to reliably distinguish between the top eight methods, given the model quality differences and their standard deviations. We suggest that CASP needs to be supplemented by an assessment of protein structure prediction methods that is automated, continuous in time, based on several criteria applied to a large number of models, and with quantitative statistical reliability assigned to each characterization.
10a*Computer Simulation Humans *Models10aMolecular *Protein Conformation Proteins/*chemistry Reproducibility of Results1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aFiser, A.1 aRost, B.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1200544100612nas a2200145 4500008004100000245013500041210006900176260002000245300001100265100001500276700001600291700001600307700001500323856012800338 2002 eng d00aSupervised Neural Networks For Clustering Conditions In DNA Array Data After Reducing Noise By Clustering Gene Expression Profiles0 aSupervised Neural Networks For Clustering Conditions In DNA Arra bKluwer Academic a91-1031 aMateos, A.1 aHerrero, J.1 aTamames, J.1 aDopazo, J. uhttps://www.clinbioinfosspa.es/content/supervised-neural-networks-clustering-conditions-dna-array-data-after-reducing-noise02866nas a2200193 4500008004100000245011400041210006900155300001200224490000700236520197100243653025902214100001502473700001502488700001502503700001102518700001702529700002002546856010602566 2002 eng d00aSystematic learning of gene functional classes from DNA array expression data by using multilayer perceptrons0 aSystematic learning of gene functional classes from DNA array ex a1703-150 v123 aRecent advances in microarray technology have opened new ways for functional annotation of previously uncharacterised genes on a genomic scale. This has been demonstrated by unsupervised clustering of co-expressed genes and, more importantly, by supervised learning algorithms. Using prior knowledge, these algorithms can assign functional annotations based on more complex expression signatures found in existing functional classes. Previously, support vector machines (SVMs) and other machine-learning methods have been applied to a limited number of functional classes for this purpose. Here we present, for the first time, the comprehensive application of supervised neural networks (SNNs) for functional annotation. Our study is novel in that we report systematic results for 100 classes in the Munich Information Center for Protein Sequences (MIPS) functional catalog. We found that only 10% of these are learnable (based on the rate of false negatives). A closer analysis reveals that false positives (and negatives) in a machine-learning context are not necessarily "false" in a biological sense. We show that the high degree of interconnections among functional classes confounds the signatures that ought to be learned for a unique class. We term this the "Borges effect" and introduce two new numerical indices for its quantification. Our analysis indicates that classification systems with a lower Borges effect are better suitable for machine learning. Furthermore, we introduce a learning procedure for combining false positives with the original class. We show that in a few iterations this process converges to a gene set that is learnable with considerably low rates of false positives and negatives and contains genes that are biologically related to the original class, allowing for a coarse reconstruction of the interactions between associated biological pathways. We exemplify this methodology using the well-studied tricarboxylic acid cycle.10aAlgorithms Artificial Intelligence Citric Acid Cycle/genetics Cluster Analysis Computational Biology/methods Gene Expression Profiling/*methods/statistics & numerical data Genes/*physiology Genetic Heterogeneity Neural Networks (Computer) Oligonucleotide1 aMateos, A.1 aDopazo, J.1 aJansen, R.1 aTu, Y.1 aGerstein, M.1 aStolovitzky, G. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1242175700641nas a2200133 4500008004100000245018000041210006900221260003200290100001400322700001500336700001600351700001500367856012500382 2002 eng d00aUnsupervised reduction of the dimensionality followed by supervised learning with a perceptron improves the classification of conditions in DNA microarray gene expression data0 aUnsupervised reduction of the dimensionality followed by supervi aMartigny, SwitzerlandbIEEE1 aConde, L.1 aMateos, A.1 aHerrero, J.1 aDopazo, J. uhttp://ieeexplore.ieee.org/document/1030019/http://xplorestaging.ieee.org/ielx5/8007/22134/01030019.pdf?arnumber=103001902774nas a2200313 4500008004100000245014600041210006900187300001300256490000800269520115600277653004801433653003001481653005001511653023501561653012201796653010201918653014402020100002002164700001502184700002102199700002202220700001702242700002402259700001302283700002002296700001902316700001902335856010602354 2002 eng d00aUse of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies0 aUse of single point mutations in domain I of beta 2glycoprotein a7097-1030 v1693 aAutoantibodies against beta(2)-glycoprotein I (beta(2)GPI) appear to be a critical feature of the antiphospholipid syndrome (APS). As determined using domain deletion mutants, human autoantibodies bind to the first of five domains present in beta(2)GPI. In this study the fine detail of the domain I epitope has been examined using 10 selected mutants of whole beta(2)GPI containing single point mutations in the first domain. The binding to beta(2)GPI was significantly affected by a number of single point mutations in domain I, particularly by mutations in the region of aa 40-43. Molecular modeling predicted these mutations to affect the surface shape and electrostatic charge of a facet of domain I. Mutation K19E also had an effect, albeit one less severe and involving fewer patients. Similar results were obtained in two different laboratories using affinity-purified anti-beta(2)GPI in a competitive inhibition ELISA and with whole serum in a direct binding ELISA. This study confirms that anti-beta(2)GPI autoantibodies bind to domain I, and that the charged surface patch defined by residues 40-43 contributes to a dominant target epitope.10aAmino Acid Substitution/genetics Antibodies10aAntibody/genetics Binding10aAntiphospholipid/blood/*metabolism Antibodies10aCompetitive/genetics/immunology Enzyme-Linked Immunosorbent Assay/methods Epitopes/analysis/*immunology/metabolism Glycine/genetics Glycoproteins/biosynthesis/*genetics/*immunology/isolation & purification/metabolism Humans Models10aMolecular Peptide Fragments/genetics/immunology/isolation & purification/metabolism *Point Mutation Protein Structure10aMonoclonal/blood/metabolism Antiphospholipid Syndrome/immunology Arginine/genetics *Binding Sites10aTertiary/genetics Recombinant Proteins/biosynthesis/immunology/isolation & purification/metabolism Static Electricity beta 2-Glycoprotein I1 aIverson, G., M.1 aReddel, S.1 aVictoria, E., J.1 aCockerill, K., A.1 aWang, Y., X.1 aMarti-Renom, M., A.1 aSali, A.1 aMarquis, D., M.1 aKrilis, S., A.1 aLinnik, M., D. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1247114600621nas a2200133 4500008004100000245016500041210006900206260002000275300001200295100001500307700001600322700001500338856013400353 2002 eng d00aUsing perceptrons for supervised classification of DNA microarray samples: obtaining the optimal level of information and finding differentially expressed genes0 aUsing perceptrons for supervised classification of DNA microarra bJ.R. Dorronsoro a577-5821 aMateos, A.1 aHerrero, J.1 aDopazo, J. uhttps://www.clinbioinfosspa.es/content/using-perceptrons-supervised-classification-dna-microarray-samples-obtaining-optimal-level02311nas a2200361 4500008004100000245009500041210006900136300001100205490000600216520111600222653009801338653003901436653003101475653000801506653005901514100001501573700001601588700001601604700001601620700001601636700001601652700001701668700002101685700001501706700002101721700001601742700001401758700001401772700001501786700001601801700002601817856010601843 2001 eng d00aAnnotated draft genomic sequence from a Streptococcus pneumoniae type 19F clinical isolate0 aAnnotated draft genomic sequence from a Streptococcus pneumoniae a99-1250 v73 aThe public availability of numerous microbial genomes is enabling the analysis of bacterial biology in great detail and with an unprecedented, organism-wide and taxon-wide, broad scope. Streptococcus pneumoniae is one of the most important bacterial pathogens throughout the world. We present here sequences and functional annotations for 2.1-Mbp of pneumococcal DNA, covering more than 90% of the total estimated size of the genome. The sequenced strain is a clinical isolate resistant to macrolides and tetracycline. It carries a type 19F capsular locus, but multilocus sequence typing for several conserved genetic loci suggests that the strain sequenced belongs to a pneumococcal lineage that most often expresses a serotype 15 capsular polysaccharide. A total of 2,046 putative open reading frames (ORFs) longer than 100 amino acids were identified (average of 1,009 bp per ORF), including all described two-component systems and aminoacyl tRNA synthetases. Comparisons to other complete, or nearly complete, bacterial genomes were made and are presented in a graphical form for all the predicted proteins.10aBacterial Molecular Sequence Data Pneumococcal Infections/*microbiology Prokaryotic Cells RNA10aBacterial/chemistry/genetics Genes10aBacterial/genetics *Genome10aDNA10aTransfer/metabolism Streptococcus pneumoniae/*genetics1 aDopazo, J.1 aMendoza, A.1 aHerrero, J.1 aCaldara, F.1 aHumbert, Y.1 aFriedli, L.1 aGuerrier, M.1 aGrand-Schenk, E.1 aGandin, C.1 ade Francesco, M.1 aPolissi, A.1 aBuell, G.1 aFeger, G.1 aGarcia, E.1 aPeitsch, M.1 aGarcia-Bustos, J., F. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1144234802134nas a2200241 4500008004100000245005900041210005800100300001100158490000700169520128500176653008301461653003201544653003201576653005801608100001601666700001301682700002401695700001401719700001901733700001901752700001501771856010601786 2001 eng d00aClassification of protein disulphide-bridge topologies0 aClassification of protein disulphidebridge topologies a477-870 v153 aThe preferential occurrence of certain disulphide-bridge topologies in proteins has prompted us to design a method and a program, KNOT-MATCH, for their classification. The program has been applied to a database of proteins with less than 65% homology and more than two disulphide bridges. We have investigated whether there are topological preferences that can be used to group proteins and if these can be applied to gain insight into the structural or functional relationships among them. The classification has been performed by Density Search and Hierarchical Clustering Techniques, yielding thirteen main protein classes from the superimposition and clustering process. It is noteworthy that besides the disulphide bridges, regular secondary structures and loops frequently become correctly aligned. Although the lack of significant sequence similarity among some clustered proteins precludes the easy establishment of evolutionary relationships, the program permits us to find out important structural or functional residues upon the superimposition of two protein structures apparently unrelated. The derived classification can be very useful for finding relationships among proteins which would escape detection by current sequence or topology-based analytical algorithms.10aAlgorithms Computer Simulation Databases as Topic Disulfides/*chemistry Models10aMolecular Protein Structure10aSecondary Protein Structure10aTertiary Proteins/*chemistry/*classification Software1 aMas, J., M.1 aAloy, P.1 aMarti-Renom, M., A.1 aOliva, B.1 ade Llorens, R.1 aAviles, F., X.1 aQuerol, E. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1139474001470nas a2200169 4500008004100000245005400041210005300095300001000148490000700158520082200165653003700987653011501024100002401139700001801163700001301181856010601194 2001 eng d00aDBAli: a database of protein structure alignments0 aDBAli a database of protein structure alignments a746-70 v173 aSUMMARY: The DBAli database includes approximately 35000 alignments of pairs of protein structures from SCOP (Lo Conte et al., Nucleic Acids Res., 28, 257-259, 2000) and CE (Shindyalov and Bourne, Protein Eng., 11, 739-747, 1998). DBAli is linked to several resources, including Compare3D (Shindyalov and Bourne, http://www.sdsc.edu/pb/software.htm, 1999) and ModView (Ilyin and Sali, http://guitar.rockefeller.edu/ModView/, 2001) for visualizing sequence alignments and structure superpositions. A flexible search of DBAli by protein sequence and structure properties allows construction of subsets of alignments suitable for a number of applications, such as benchmarking of sequence-sequence and sequence-structure alignment methods under a variety of conditions. AVAILABILITY: http://guitar.rockefeller.edu/DBAli/10aComputational Biology *Databases10aProtein Proteins/*chemistry/*genetics Sequence Alignment/*statistics & numerical data Software Software Design1 aMarti-Renom, M., A.1 aIlyin, V., A.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1152437901566nas a2200229 4500008004100000245008100041210006900122300001100191490000700202520078900209653007500998100001901073700002401092700001901116700002401135700001401159700001401173700001701187700001301204700001301217856010601230 2001 eng d00aEVA: continuous automatic evaluation of protein structure prediction servers0 aEVA continuous automatic evaluation of protein structure predict a1242-30 v173 aEvaluation of protein structure prediction methods is difficult and time-consuming. Here, we describe EVA, a web server for assessing protein structure prediction methods, in an automated, continuous and large-scale fashion. Currently, EVA evaluates the performance of a variety of prediction methods available through the internet. Every week, the sequences of the latest experimentally determined protein structures are sent to prediction servers, results are collected, performance is evaluated, and a summary is published on the web. EVA has so far collected data for more than 3000 protein chains. These results may provide valuable insight to both developers and users of prediction methods. AVAILABILITY: http://cubic.bioc.columbia.edu/eva. CONTACT: eva@cubic.bioc.columbia.edu10aAutomation Internet *Protein Conformation Proteins/*analysis *Software1 aEyrich, V., A.1 aMarti-Renom, M., A.1 aPrzybylski, D.1 aMadhusudhan, M., S.1 aFiser, A.1 aPazos, F.1 aValencia, A.1 aSali, A.1 aRost, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1175124002532nas a2200229 4500008004100000245015400041210006900195300001000264490000700274520149500281653013001776653009301906653007401999100001802073700001902091700002002110700001702130700001802147700001502165700001602180856010602196 2001 eng d00aIdentification of optimal regions for phylogenetic studies on VP1 gene of foot-and-mouth disease virus: analysis of types A and O Argentinean viruses0 aIdentification of optimal regions for phylogenetic studies on VP a31-450 v323 aAn analysis of the informative content of sequence stretches on the foot-and-mouth disease virus (FMDV) VPI gene was applied to two important viral serotypes: A and O. Several sequence regions were identified to allow the reconstruction of phylogenetic trees equivalent to those derived from the whole VPI gene. The optimal informative regions for sequence windows of 150 to 250 nt were predicted between positions 250 and 550 of the gene. The sequences spanning the 250 nt of the 3’ end (positions 400 to 650), extensively used for FMDV phylogenetic analyses, showed a lower informative content. In spite of this, the use of sequences from this region allowed the derivation of phylogenetic trees for type A and type O FMDVs which showed topologies similar to those previously reported for the whole VP1 gene. When the sequences determined for viruses isolated in Argentina, between 1990 and 1993, were included in these analyses, the results obtained revealed features of the circulation of type A and type O viruses in the field, in the months that preceded the eradication of the disease in this country. Type A viruses were closely related to an Argentinean vaccine strain, and defined an independent cluster within this serotype. Among the type O viruses analysed, two groups were distinguished; one was closely related to the South American vaccine strains, while the other was grouped with viruses of the O3 subtype. In addition, a detailed phylogeny for type A FMDV is presented.10aAmino Acid Sequence Animals Aphthovirus/classification/*genetics Base Sequence Capsid/chemistry/*genetics Capsid Proteins DNA10aComplementary/chemistry Molecular Sequence Data *Phylogeny Polymerase Chain Reaction RNA10aViral/chemistry/genetics Serotyping Viral Proteins/analysis/*genetics1 aNunez, J., I.1 aMartin, M., J.1 aPiccone, M., E.1 aCarrillo, E.1 aPalma, E., L.1 aDopazo, J.1 aSobrino, F. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1125417501950nas a2200229 4500008004100000245009500041210006900136300001000205490000700215520116100222653001401383653005301397653002801450653003701478100001801515700001501533700001901548700001501567700001901582700001301601856010601614 2001 eng d00aPhylogenetic analysis of viroid and viroid-like satellite RNAs from plants: a reassessment0 aPhylogenetic analysis of viroid and viroidlike satellite RNAs fr a155-90 v533 aThe proposed monophyletic origin of a group of subviral plant pathogens (viroids and viroid-like satellite RNAs), as well as the phylogenetic relationships and the resulting taxonomy of these entities, has been recently questioned. The criticism comes from the (apparent) lack of sequence similarity among these RNAs necessary to reliably infer a phylogeny. Here we show that, despite their low overall sequence similarity, a sequence alignment manually adjusted to take into account all the local similarities and the insertions/deletions and duplications/rearrangements described in the literature for viroids and viroid-like satellite RNA, along with the use of an appropriate estimator of genetic distances, constitutes a data set suitable for a phylogenetic reconstruction. When the likelihood-mapping method was applied to this data set, the tree-likeness obtained was higher than that corresponding to a sequence alignment that does not take into consideration the local similarities. In addition, bootstrap analysis also supports the major groups previously proposed and the reconstruction is consistent with the biological properties of this RNAs.10aEvolution10aMolecular *Phylogeny Plant Viruses/*genetics RNA10aSatellite/*genetics RNA10aViral/genetics Viroids/*genetics1 aElena, S., F.1 aDopazo, J.1 ade la Pena, M.1 aFlores, R.1 aDiener, T., O.1 aMoya, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11479686