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-002234nas a2200325 4500008004100000022001400041245014800055210006900203260001600272300001100288490000700299520106600306100002701372700003201399700002401431700001701455700002601472700001901498700002101517700001801538700002201556700001701578700001901595700002901614700002001643700002301663700002301686700002401709856017501733 2023 eng d a2211-124700aDefective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.0 aDefective extracellular matrix remodeling in brown adipose tissu c2023 Jun 13 a1126400 v423 aThe relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.
1 aPellegrinelli, Vanessa1 aFigueroa-Juárez, Elizabeth1 aSamuelson, Isabella1 aU-Din, Mueez1 aRodriguez-Fdez, Sonia1 aVirtue, Samuel1 aLeggat, Jennifer1 aCubuk, Cankut1 aPeirce, Vivian, J1 aNiemi, Tarja1 aCampbell, Mark1 aRodriguez-Cuenca, Sergio1 aDopazo, Joaquin1 aCarobbio, Stefania1 aVirtanen, Kirsi, A1 aVidal-Puig, Antonio uhttps://www.clinbioinfosspa.es/content/defective-extracellular-matrix-remodeling-brown-adipose-tissue-associated-fibro-inflammation-and-reduced-diet-induced-thermogenesis02373nas 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-omicron01970nas a2200157 4500008004100000022001400041245015200055210006900207260001600276520129100292100003001583700002001613700002401633700002001657856013501677 2022 eng d a1460-208300aDiscovering potential interactions between rare diseases and COVID-19 by combining mechanistic models of viral infection with statistical modeling.0 aDiscovering potential interactions between rare diseases and COV c2022 Jan 123 aRecent studies have demonstrated a relevant role of the host genetics in the COVID-19 prognosis. Most of the 7000 rare diseases described to date have a genetic component, typically highly penetrant. However, this vast spectrum of genetic variability remains yet unexplored with respect to possible interactions with COVID-19. Here, a mathematical mechanistic model of the COVID-19 molecular disease mechanism has been used to detect potential interactions between rare disease genes and the COVID-19 infection process and downstream consequences. Out of the 2518 disease genes analyzed, causative of 3854 rare diseases, a total of 254 genes have a direct effect on the COVID-19 molecular disease mechanism and 207 have an indirect effect revealed by a significant strong correlation. This remarkable potential of interaction occurs for more than 300 rare diseases. Mechanistic modeling of COVID-19 disease map has allowed a holistic systematic analysis of the potential interactions between the loss of function in known rare disease genes and the pathological consequences of COVID-19 infection. The results identify links between disease genes and COVID-19 hallmarks and demonstrate the usefulness of the proposed approach for future preventive measures in some rare diseases.
1 aLópez-Sánchez, Macarena1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/discovering-potential-interactions-between-rare-diseases-and-covid-19-combining-mechanistic03233nas 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-patient00616nas a2200157 4500008004100000245013100041210006900172260001600241300000900257490000600266100003100272700002800303700001800331700002000349856008900369 2021 eng d00aDeciphering Genomic Heterogeneity and the Internal Composition of Tumour Activities through a Hierarchical Factorisation Model0 aDeciphering Genomic Heterogeneity and the Internal Composition o cJan-11-2021 a28330 v91 aCarbonell-Caballero, José1 aLópez-Quílez, Antonio1 aConesa, David1 aDopazo, Joaquin uhttps://www.mdpi.com/2227-7390/9/21/2833https://www.mdpi.com/2227-7390/9/21/2833/pdf03083nas 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-tissue01028nas a2200313 4500008004100000022001400041245008100055210006900136260001200205300001400217490000700231653001500238653002600253653002400279653001100303653002300314653002000337653003200357100001500389700002000404700002600424700001700450700002400467700002100491700002600512700002500538710004000563856011100603 2021 eng d a1548-710500aDOME: recommendations for supervised machine learning validation in biology.0 aDOME recommendations for supervised machine learning validation c2021 10 a1122-11270 v1810aAlgorithms10aComputational Biology10aGuidelines as Topic10aHumans10aModels, Biological10aResearch Design10aSupervised Machine Learning1 aWalsh, Ian1 aFishman, Dmytro1 aGarcia-Gasulla, Dario1 aTitma, Tiina1 aPollastri, Gianluca1 aHarrow, Jennifer1 aPsomopoulos, Fotis, E1 aTosatto, Silvio, C E1 aELIXIR Machine Learning Focus Group uhttps://www.clinbioinfosspa.es/content/dome-recommendations-supervised-machine-learning-validation-biology01087nas a2200313 4500008004100000022001400041245014500055210006900200260001500269300000800284490000600292653002800298653001300326653002300339653001100362653002100373653003300394653003100427653001300458653001500471653002400486100002000510700002700530700001600557700002100573700002000594700002400614856013500638 2020 eng d a2059-363500aDrug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection.0 aDrug repurposing for COVID19 using machine learning and mechanis c2020 12 11 a2900 v510aComputational Chemistry10aCOVID-1910adrug repositioning10aHumans10aMachine Learning10aMolecular Docking Simulation10aMolecular Targeted Therapy10aProteins10aSARS-CoV-210aSignal Transduction1 aLoucera, Carlos1 aEsteban-Medina, Marina1 aRian, Kinza1 aFalco, Matias, M1 aDopazo, Joaquin1 aPeña-Chilet, Maria uhttps://www.clinbioinfosspa.es/content/drug-repurposing-covid-19-using-machine-learning-and-mechanistic-models-signal-transduction02824nas 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-metabolic02242nas a2200409 4500008004100000022001400041245006800055210006700123260001300190300001400203490000700217520102100224653001201245653002701257653002701284653001501311653001301326653003001339653000901369653002701378653001201405653002601417653002701443653002601470100001901496700001801515700002001533700002901553700001601582700001501598700002701613700002001640700002001660700002701680700001901707856010601726 2016 eng d a1551-400500aDysfunctional mitochondrial fission impairs cell reprogramming.0 aDysfunctional mitochondrial fission impairs cell reprogramming c2016 Dec a3240-32500 v153 aWe have recently shown that mitochondrial fission is induced early in reprogramming in a Drp1-dependent manner; however, the identity of the factors controlling Drp1 recruitment to mitochondria was unexplored. To investigate this, we used a panel of RNAi targeting factors involved in the regulation of mitochondrial dynamics and we observed that MiD51, Gdap1 and, to a lesser extent, Mff were found to play key roles in this process. Cells derived from Gdap1-null mice were used to further explore the role of this factor in cell reprogramming. Microarray data revealed a prominent down-regulation of cell cycle pathways in Gdap1-null cells early in reprogramming and cell cycle profiling uncovered a G2/M growth arrest in Gdap1-null cells undergoing reprogramming. High-Content analysis showed that this growth arrest was DNA damage-independent. We propose that lack of efficient mitochondrial fission impairs cell reprogramming by interfering with cell cycle progression in a DNA damage-independent manner.
10aAnimals10aCell Cycle Checkpoints10aCellular Reprogramming10aDNA Damage10aG2 Phase10aGene Knockdown Techniques10aMice10aMitochondrial Dynamics10aMitosis10aNerve Tissue Proteins10aPluripotent Stem Cells10aTranscription Factors1 aPrieto, Javier1 aLeón, Marian1 aPonsoda, Xavier1 aGarcia-Garcia, Francisco1 aBort, Roque1 aSerna, Eva1 aBarneo-Muñoz, Manuela1 aPalau, Francesc1 aDopazo, Joaquin1 aLópez-García, Carlos1 aTorres, Josema uhttps://www.clinbioinfosspa.es/content/dysfunctional-mitochondrial-fission-impairs-cell-reprogramming03282nas 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-carriers02351nas a2200229 4500008004100000022001400041245014200055210006900197260001600266520153800282100001701820700002401837700001401861700001401875700001501889700002301904700001401927700001801941700001501959700001501974856013201989 2015 eng d a1523-174700aDifferential Features Between Chronic Skin Inflammatory Diseases Revealed in Skin-Humanized Psoriasis and Atopic Dermatitis Mouse Models.0 aDifferential Features Between Chronic Skin Inflammatory Diseases c2015 Sep 233 aPsoriasis (PS) and atopic dermatitis (AD) are chronic and relapsing inflammatory diseases of the skin affecting a large number of patients worldwide. Psoriasis is characterized by a Th1/Th17 immunological response whereas acute AD lesions exhibit Th2-dominant inflammation. Current single gene and signaling pathways-based models of inflammatory skin diseases are incomplete. Previous work allowed us to model psoriasis in skin-humanized mice through proper combinations of inflammatory cell components and disruption of barrier function. Herein we describe and characterize an animal model for AD using similar bioengineered-based approaches, by intradermal injection of human Th2 lymphocytes in regenerated human skin after partial removal of stratum corneum. In the present work we have extensively compared this model with the previous and an improved version of the PS model, in which Th17/Th1 lymphocytes replace exogenous cytokines. Comparative expression analyses revealed marked differences in specific epidermal proliferation and differentiation markers and immune-related molecules including antimicrobial peptides. Likewise, the composition of the dermal inflammatory infiltrate presented important differences. Availability of accurate and reliable animal models for these diseases will contribute to the understanding of the pathogenesis and provide valuable tools for drug development and testing.Journal of Investigative Dermatology accepted article preview online, 23 September 2015. doi:10.1038/jid.2015.362.
1 aCarretero, M1 aGuerrero-Aspizua, S1 aIllera, N1 aGalvez, V1 aNavarro, M1 aGarcía-García, F1 aDopazo, J1 aJorcano, J, L1 aLarcher, F1 aDel Rio, M uhttps://www.clinbioinfosspa.es/content/differential-features-between-chronic-skin-inflammatory-diseases-revealed-skin-humanized02250nas 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/full02369nas 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-family02642nas 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%B3n02998nas 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-genomic03463nas a2200469 4500008004100000022001400041245011000055210006900165260001600234300000800250490000700258520195800265653002402223653001202247653001802259653002502277653001802302653001802320653001702338653003002355653002202385653001002407653001602417653003102433653002202464653002802486653002102514653001402535653003202549653005202581653002302633653002702656653003402683653001602717653002402733653001102757100002602768700002102794700002002815700002602835856013202861 2012 eng d a1471-214800aDiversification of the expanded teleost-specific toll-like receptor family in Atlantic cod, Gadus morhua.0 aDiversification of the expanded teleostspecific tolllike recepto c2012 Dec 29 a2560 v123 aBACKGROUND: Toll-like receptors (Tlrs) are major molecular pattern recognition receptors of the innate immune system. Atlantic cod (Gadus morhua) is the first vertebrate known to have lost most of the mammalian Tlr orthologues, particularly all bacterial recognising and other cell surface Tlrs. On the other hand, its genome encodes a unique repertoire of teleost-specific Tlrs. The aim of this study was to investigate if these duplicate Tlrs have been retained through adaptive evolution to compensate for the lack of other cell surface Tlrs in the cod genome.
RESULTS: In this study, one tlr21, 12 tlr22 and two tlr23 genes representing the teleost-specific Tlr family have been cloned and characterised in cod. Phylogenetic analysis grouped all tlr22 genes under a single clade, indicating that the multiple cod paralogues have arisen through lineage-specific duplications. All tlrs examined were transcribed in immune-related tissues as well as in stomach, gut and gonads of adult cod and were differentially expressed during early development. These tlrs were also differentially regulated following immune challenge by immersion with Vibrio anguillarum, indicating their role in the immune response. An increase in water temperature from 4 to 12°C was associated with a 5.5-fold down-regulation of tlr22d transcript levels in spleen. Maximum likelihood analysis with different evolution models revealed that tlr22 genes are under positive selection. A total of 24 codons were found to be positively selected, of which 19 are in the ligand binding region of ectodomain.
CONCLUSION: Positive selection pressure coupled with experimental evidence of differential expression strongly support the hypothesis that teleost-specific tlr paralogues in cod are undergoing neofunctionalisation and can recognise bacterial pathogen-associated molecular patterns to compensate for the lack of other cell surface Tlrs.
10aAmino Acid Sequence10aAnimals10aBinding Sites10aEvolution, Molecular10aFish Diseases10aFish Proteins10aGadus morhua10aGene Expression Profiling10aGenetic Variation10aGills10aHead Kidney10aHost-Pathogen Interactions10aModels, Molecular10aMolecular Sequence Data10aMultigene Family10aPhylogeny10aProtein Structure, Tertiary10aReverse Transcriptase Polymerase Chain Reaction10aSelection, Genetic10aSequence Analysis, DNA10aSequence Homology, Amino Acid10aTemperature10aToll-Like Receptors10aVibrio1 aSundaram, Arvind, Y M1 aKiron, Viswanath1 aDopazo, Joaquin1 aFernandes, Jorge, M O uhttps://www.clinbioinfosspa.es/content/diversification-expanded-teleost-specific-toll-receptor-family-atlantic-cod-gadus-morhua02504nas a2200277 4500008004100000022001400041245005900055210005600114260001300170300001200183490000700195520165100202653001501853653002801868653003001896653003101926653001101957653002001968653004401988100002002032700003002052700002002082700002002102700001602122856008802138 2011 eng d a1549-546900aDifferential expression in RNA-seq: a matter of depth.0 aDifferential expression in RNAseq a matter of depth c2011 Dec a2213-230 v213 aNext-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and additional research is needed for understanding how these data respond to differential expression analysis. In this work, we set out to gain insights into the characteristics of RNA-seq data analysis by studying an important parameter of this technology: the sequencing depth. We have analyzed how sequencing depth affects the detection of transcripts and their identification as differentially expressed, looking at aspects such as transcript biotype, length, expression level, and fold-change. We have evaluated different algorithms available for the analysis of RNA-seq and proposed a novel approach--NOISeq--that differs from existing methods in that it is data-adaptive and nonparametric. Our results reveal that most existing methodologies suffer from a strong dependency on sequencing depth for their differential expression calls and that this results in a considerable number of false positives that increases as the number of reads grows. In contrast, our proposed method models the noise distribution from the actual data, can therefore better adapt to the size of the data set, and is more effective in controlling the rate of false discoveries. This work discusses the true potential of RNA-seq for studying regulation at low expression ranges, the noise within RNA-seq data, and the issue of replication.
10aAlgorithms10aExpressed Sequence Tags10aGene Expression Profiling10aGene Expression Regulation10aHumans10aModels, Genetic10aOligonucleotide Array Sequence Analysis1 aTarazona, Sonia1 aGarcía-Alcalde, Fernando1 aDopazo, Joaquin1 aFerrer, Alberto1 aConesa, Ana uhttps://www.clinbioinfosspa.es/content/differential-expression-rna-seq-matter-depth02878nas 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-europe02443nas a2200169 4500008004100000245016300041210006900204260001500273490000600288520172300294100002202017700002902039700002902068700001902097700002202116856013502138 2011 eng d00aDoes singlet oxygen activate cell death in Arabidopsis cell suspension cultures? Analysis of the early transcriptional defence responses to high light stress.0 aDoes singlet oxygen activate cell death in Arabidopsis cell susp c2011 Dec 10 v63 aCan Arabidopsis cell suspension cultures (ACSC) provide a useful working model to investigate genetically-controlled defence responses with signalling cascades starting in chloroplasts? In order to provide a convincing answer, we analysed the early transcriptional profile of Arabidopsis cells at high light (HL). The results showed that ACSC respond to HL in a manner that resembles the singlet oxygen ( ( 1) O 2)-mediated defence responses described for the conditional fluorescent (flu) mutant of Arabidopsis thaliana. The flu mutant is characterized by the accumulation of free protochlorophyllide (Pchlide) in plastids when put into darkness and the subsequent production of ( 1) O 2 when the light is on. In ACSC, ( 1) O 2 is produced in chloroplasts at HL when excess excitation energy flows into photosystem II (PSII). Other reactive oxygen species are also produced in ACSC at HL, but to a lesser extent. When the HL stress ceases, ACSC recovers the initial rate of oxygen evolution and cell growth continues. We can conclude that chloroplasts of ACSC are both photosynthetically active and capable of initiating ( 1) O 2-mediated signalling cascades that activate a broad range of genetically-controlled defence responses. The up-regulation of transcripts associated with the biosynthesis and signalling pathways of OPDA (12-oxophytodienoic acid) and ethylene (ET) suggests that the activated defence responses at HL are governed by these two hormones. In contrast to the flu mutant, the ( 1) O 2-mediated defence responses were independent of the up-regulation of EDS1 (enhanced disease susceptibility) required for the accumulation of salicylic acid (SA) and genetically-controlled cell death.
1 aGutiérrez, Jorge1 aGonzález-Pérez, Sergio1 aGarcia-Garcia, Francisco1 aLorenzo, Oscar1 aArellano, Juan, B uhttps://www.clinbioinfosspa.es/content/does-singlet-oxygen-activate-cell-death-arabidopsis-cell-suspension-cultures-analysis-early03411nas 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-subtypes01951nas 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-001778nas 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=1865288802151nas 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=1747851302301nas 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-002714nas a2200253 4500008004100000245009200041210006900133300001300202490000700215520168800222653010801910653001202018653001902030653005802049653012102107100001802228700001502246700002302261700002202284700001902306700001402325700001502339856010602354 2007 eng d00aDiscovering gene expression patterns in time course microarray experiments by ANOVA-SCA0 aDiscovering gene expression patterns in time course microarray e a1792-8000 v233 aMOTIVATION: Designed microarray experiments are used to investigate the effects that controlled experimental factors have on gene expression and learn about the transcriptional responses associated with external variables. In these datasets, signals of interest coexist with varying sources of unwanted noise in a framework of (co)relation among the measured variables and with the different levels of the studied factors. Discovering experimentally relevant transcriptional changes require methodologies that take all these elements into account. RESULTS: In this work, we develop the application of the Analysis of variance-simultaneous component analysis (ANOVA-SCA) Smilde et al. Bioinformatics, (2005) to the analysis of multiple series time course microarray data as an example of multifactorial gene expression profiling experiments. We denoted this implementation as ASCA-genes. We show how the combination of ANOVA-modeling and a dimension reduction technique is effective in extracting targeted signals from data by-passing structural noise. The methodology is valuable for identifying main and secondary responses associated with the experimental factors and spotting relevant experimental conditions. We additionally propose a novel approach for gene selection in the context of the relation of individual transcriptional patterns to global gene expression signals. We demonstrate the methodology on both real and synthetic datasets. AVAILABILITY: ASCA-genes has been implemented in the statistical language R and is available at http://www.ivia.es/centrodegenomica/bioinformatics.htm. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.10aAlgorithms *Analysis of Variance Computational Biology/*methods Computer Simulation Data Interpretation10aGenetic10aGenetic Models10aStatistical Gene Expression Profiling/*methods Models10aStatistical Oligonucleotide Array Sequence Analysis/*methods Principal Component Analysis Time Factors Transcription1 aNueda, M., J.1 aConesa, A.1 aWesterhuis, J., A.1 aHoefsloot, H., C.1 aSmilde, A., K.1 aTalon, M.1 aFerrer, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1751925002539nas 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=1712058400743nas a2200169 4500008004100000245006300041210006300104300000800167490000600175520016700181653003400348653002200382653003500404100001500439700001300454856010600467 2006 eng d00aDiscovery and hypothesis generation through bioinformatics0 aDiscovery and hypothesis generation through bioinformatics a3070 v73 aA report on the 4th European Conference on Computational Biology and the 6th Spanish Annual Meeting on Bioinformatics, Madrid, Spain, 28 September-1 October 2005.10a*Computational Biology Genome10aGenetic Phylogeny10aHuman *Genomics Humans *Models1 aDopazo, J.1 aAloy, P. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1652222400468nas a2200121 4500008004100000245006300041210006300104260003500167653001500202100001500217700001500232856009900247 2005 eng d00aData analysis and visualisation in genomics and proteomics0 aData analysis and visualisation in genomics and proteomics bWiley, F. Azuaje and J. Dopazo10ababelomics1 aAzuaje, F.1 aDopazo, J. uhttps://www.clinbioinfosspa.es/content/data-analysis-and-visualisation-genomics-and-proteomics00530nas a2200121 4500008004100000245009500041210006900136260003500205100001500240700001500255700001200270856012600282 2005 eng d00aData and Predictive Model Integration: an Overview of Key Concepts, Problems and Solutions0 aData and Predictive Model Integration an Overview of Key Concept bWiley, F. Azuaje and J. Dopazo1 aAzuaje, F.1 aDopazo, J.1 aWang, H uhttps://www.clinbioinfosspa.es/content/data-and-predictive-model-integration-overview-key-concepts-problems-and-solutions02245nas 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=1583012802842nas a2200205 4500008004100000245013300041210006900174300001200243490000700255520183200262653001502094653013902109653003602248653010202284653008402386100002402470700002102494700001502515856010602530 2005 eng d00aDiscovering molecular functions significantly related to phenotypes by combining gene expression data and biological information0 aDiscovering molecular functions significantly related to phenoty a2988-930 v213 aMOTIVATION: The analysis of genome-scale data from different high throughput techniques can be used to obtain lists of genes ordered according to their different behaviours under distinct experimental conditions corresponding to different phenotypes (e.g. differential gene expression between diseased samples and controls, different response to a drug, etc.). The order in which the genes appear in the list is a consequence of the biological roles that the genes play within the cell, which account, at molecular scale, for the macroscopic differences observed between the phenotypes studied. Typically, two steps are followed for understanding the biological processes that differentiate phenotypes at molecular level: first, genes with significant differential expression are selected on the basis of their experimental values and subsequently, the functional properties of these genes are analysed. Instead, we present a simple procedure which combines experimental measurements with available biological information in a way that genes are simultaneously tested in groups related by common functional properties. The method proposed constitutes a very sensitive tool for selecting genes with significant differential behaviour in the experimental conditions tested. RESULTS: We propose the use of a method to scan ordered lists of genes. The method allows the understanding of the biological processes operating at molecular level behind the macroscopic experiment from which the list was generated. This procedure can be useful in situations where it is not possible to obtain statistically significant differences based on the experimental measurements (e.g. low prevalence diseases, etc.). Two examples demonstrate its application in two microarray experiments and the type of information that can be extracted.
10ababelomics10aBiological Neoplasm Proteins/genetics/*metabolism Phenotype Software Structure-Activity Relationship Systems Integration Tumor Markers10aBiological/genetics/*metabolism10aBreast Neoplasms/genetics/*metabolism Computer Simulation *Database Management Systems *Databases10aProtein Documentation/methods Gene Expression Profiling/*methods Humans *Models1 aAl-Shahrour, Fatima1 aDiaz-Uriarte, R.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1584070201390nas a2200169 4500008004100000245006900041210006700110300001100177490000700188520056300195653024500758653005201003100002301055700001501078700002101093856010601114 2004 eng d00aDNMAD: web-based diagnosis and normalization for microarray data0 aDNMAD webbased diagnosis and normalization for microarray data a3656-80 v203 aSUMMARY: We present a web server for Diagnosis and Normalization of MicroArray Data (DNMAD). DNMAD includes several common data transformations such as spatial and global robust local regression or multiple slide normalization, and allows for detecting several kinds of errors that result from the manipulation and the image analysis of the arrays. This tool offers a user-friendly interface, and is completely integrated within the Gene Expression Pattern Analysis Suite (GEPAS). AVAILABILITY: The tool is accessible on-line at http://dnmad.bioinfo.cnio.es.10aAlgorithms Database Management Systems Gene Expression Profiling/*methods/standards Information Storage and Retrieval/*methods *Internet Oligonucleotide Array Sequence Analysis/*methods/standards Sequence Alignment/methods Sequence Analysis10aDNA/*methods *Software *User-Computer Interface1 aVaquerizas, J., M.1 aDopazo, J.1 aDiaz-Uriarte, R. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1524709401470nas 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=11524379