02396nas a2200193 4500008004100000022001400041245017300055210006900228260001600297300001100313520159800324100002301922700003501945700001701980700002101997700002002018700003002038856013402068 2023 eng d a1873-642400aPolystyrene nanoplastics affect transcriptomic and epigenomic signatures of human fibroblasts and derived induced pluripotent stem cells: Implications for human health.0 aPolystyrene nanoplastics affect transcriptomic and epigenomic si c2022 Dec 09 a1208493 a
Plastic pollution is increasing at an alarming rate yet the impact of this pollution on human health is poorly understood. Because human induced pluripotent stem cells (hiPSC) are frequently derived from dermal fibroblasts, these cells offer a powerful platform for the identification of molecular biomarkers of environmental pollution in human cells. Here, we describe a novel proof-of-concept for deriving hiPSC from human dermal fibroblasts deliberately exposed to polystyrene (PS) nanoplastic particles; unexposed hiPSC served as controls. In parallel, unexposed hiPSC were exposed to low and high concentrations of PS nanoparticles. Transcriptomic and epigenomic signatures of all fibroblasts and hiPSCs were defined using RNA-seq and whole genome methyl-seq, respectively. Both PS-treated fibroblasts and derived hiPSC showed alterations in expression of ESRRB and HNF1A genes and circuits involved in the pluripotency of stem cells, as well as in pathways involved in cancer, inflammatory disorders, gluconeogenesis, carbohydrate metabolism, innate immunity, and dopaminergic synapse. Similarly, the expression levels of identified key transcriptional and DNA methylation changes (DNMT3A, ESSRB, FAM133CP, HNF1A, SEPTIN7P8, and TTC34) were significantly affected in both PS-exposed fibroblasts and hiPSC. This study illustrates the power of human cellular models of environmental pollution to narrow down and prioritize the list of candidate molecular biomarkers of environmental pollution. This knowledge will facilitate the deciphering of the origins of environmental diseases.
1 aStojkovic, Miodrag1 aGuzmán, Francisco, Manuel Ort1 aHan, Dongjun1 aStojkovic, Petra1 aDopazo, Joaquin1 aStankovic, Konstantina, M uhttps://www.clinbioinfosspa.es/content/polystyrene-nanoplastics-affect-transcriptomic-and-epigenomic-signatures-human-fibroblasts03091nas 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-components00782nas 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-syndrome04661nas 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-outcomes05186nas 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-tumour02194nas a2200241 4500008004100000022001400041245006800055210006700123260001500190300001200205490000700217520142700224653001901651653002601670653001101696653002301707100002701730700002001757700002201777700002201799700002501821856010601846 2019 eng d a1477-405400aPrecision medicine needs pioneering clinical bioinformaticians.0 aPrecision medicine needs pioneering clinical bioinformaticians c2019 05 21 a752-7660 v203 aSuccess in precision medicine depends on accessing high-quality genetic and molecular data from large, well-annotated patient cohorts that couple biological samples to comprehensive clinical data, which in conjunction can lead to effective therapies. From such a scenario emerges the need for a new professional profile, an expert bioinformatician with training in clinical areas who can make sense of multi-omics data to improve therapeutic interventions in patients, and the design of optimized basket trials. In this review, we first describe the main policies and international initiatives that focus on precision medicine. Secondly, we review the currently ongoing clinical trials in precision medicine, introducing the concept of 'precision bioinformatics', and we describe current pioneering bioinformatics efforts aimed at implementing tools and computational infrastructures for precision medicine in health institutions around the world. Thirdly, we discuss the challenges related to the clinical training of bioinformaticians, and the urgent need for computational specialists capable of assimilating medical terminologies and protocols to address real clinical questions. We also propose some skills required to carry out common tasks in clinical bioinformatics and some tips for emergent groups. Finally, we explore the future perspectives and the challenges faced by precision medicine bioinformatics.
10aCohort Studies10aComputational Biology10aHumans10aPrecision Medicine1 aGómez-López, Gonzalo1 aDopazo, Joaquin1 aCigudosa, Juan, C1 aValencia, Alfonso1 aAl-Shahrour, Fátima uhttps://www.clinbioinfosspa.es/content/precision-medicine-needs-pioneering-clinical-bioinformaticians02570nas 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-sources01876nas a2200181 4500008004100000022001400041245005400055210004800109260001600157300001000173490000600183520137000189100002101559700001701580700003101597700002101628856004501649 2016 eng d a2045-232200aThe pan-cancer pathological regulatory landscape.0 apancancer pathological regulatory landscape c2016 Dec 21 a397090 v63 aDysregulation of the normal gene expression program is the cause of a broad range of diseases, including cancer. Detecting the specific perturbed regulators that have an effect on the generation and the development of the disease is crucial for understanding the disease mechanism and for taking decisions on efficient preventive and curative therapies. Moreover, detecting such perturbations at the patient level is even more important from the perspective of personalized medicine. We applied the Transcription Factor Target Enrichment Analysis, a method that detects the activity of transcription factors based on the quantification of the collective transcriptional activation of their targets, to a large collection of 5607 cancer samples covering eleven cancer types. We produced for the first time a comprehensive catalogue of altered transcription factor activities in cancer, a considerable number of them significantly associated to patient’s survival. Moreover, we described several interesting TFs whose activity do not change substantially in the cancer with respect to the normal tissue but ultimately play an important role in patient prognostic determination, which suggest they might be promising therapeutic targets. An additional advantage of this method is that it allows obtaining personalized TF activity estimations for individual patients.1 aFalco, Matias, M1 aBleda, Marta1 aCarbonell-Caballero, José1 aDopazo, Joaquín uhttp://www.nature.com/articles/srep3970900573nas a2200145 4500008004100000245005300041210004800094260001600142490000600158100002200164700001700186700003100203700002000234856017300254 2016 eng d00aThe pan-cancer pathological regulatory landscape0 apancancer pathological regulatory landscape cJan-12-20160 v61 aFalco, Matias, M.1 aBleda, Marta1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttp://www.nature.com/articles/srep39709http://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep3970902426nas 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-strategies02390nas a2200397 4500008004100000022001400041245007600055210006900131260001300200300001300213490000700226520116000233653001201393653001801405653002201423653002201445653002301467653002401490653002801514653003801542653001101580653002001591653002801611653001301639653002201652653001401674653003601688653003201724653002401756100002401780700002401804700001801828700002001846700001701866856010901883 2015 eng d a1553-735800aA Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.0 aPanCancer Catalogue of Cancer Driver Protein Interaction Interfa c2015 Oct ae10045180 v113 aDespite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated.
10aAnimals10aBase Sequence10aBiomarkers, Tumor10aCatalogs as Topic10aChromosome Mapping10aComputer Simulation10aDNA Mutational Analysis10aGenetic Predisposition to Disease10aHumans10aModels, Genetic10aMolecular Sequence Data10amutation10aNeoplasm Proteins10aNeoplasms10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aSignal Transduction1 aPorta-Pardo, Eduard1 aGarcía-Alonso, Luz1 aHrabe, Thomas1 aDopazo, Joaquin1 aGodzik, Adam uhttps://www.clinbioinfosspa.es/content/pan-cancer-catalogue-cancer-driver-protein-interaction-interfaces02283nas 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.long02086nas a2200253 4500008004100000022001400041245014200055210006900197260001600266300001400282490000700296520127300303653001601576653001101592653001401603653000801617100003101625700002001656700002201676700001801698700001801716700002001734856007801754 2015 eng d a1537-171900aA phylogenetic analysis of 34 chloroplast genomes elucidates the relationships between wild and domestic species within the genus Citrus.0 aphylogenetic analysis of 34 chloroplast genomes elucidates the r c2015 Apr 14 a2015-20350 v323 aCitrus genus includes some of the most important cultivated fruit trees worldwide. Despite being extensively studied because of its commercial relevance, the origin of cultivated citrus species and the history of its domestication still remain an open question. Here we present a phylogenetic analysis of the chloroplast genomes of 34 citrus genotypes which constitutes the most comprehensive and detailed study to date on the evolution and variability of the genus Citrus. A statistical model was used to estimate divergence times between the major citrus groups. Additionally, a complete map of the variability across the genome of different citrus species was produced, including single nucleotide variants, heteroplasmic positions, indels and large structural variants. The distribution of all these variants provided further independent support to the phylogeny obtained. An unexpected finding was the high level of heteroplasmy found in several of the analysed genomes. The use of the complete chloroplast DNA not only paves the way for a better understanding of the phylogenetic relationships within the Citrus genus, but also provides original insights into other elusive evolutionary processes such as chloroplast inheritance, heteroplasmy and gene selection.10achloroplast10acitrus10aPhylogeny10aWGS1 aCarbonell-Caballero, José1 aAlonso, Roberto1 aIbañez, Victoria1 aTerol, Javier1 aTalon, Manuel1 aDopazo, Joaquin uhttp://mbe.oxfordjournals.org/content/early/2015/04/27/molbev.msv082.full02147nas 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-and03075nas 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-data02520nas a2200445 4500008004100000022001400041245009400055210006900149260000900218300001200227490000600239520119500245653001201440653001501452653001901467653001601486653002701502653002101529653001101550653002901561653001601590653001001606653003001616653001501646653001301661653001401674653001201688653001501700100001801715700002801733700003301761700002001794700002901814700001801843700002401861700002001885700002301905700002201928856012401950 2014 eng d a1932-620300aPermanent cardiac sarcomere changes in a rabbit model of intrauterine growth restriction.0 aPermanent cardiac sarcomere changes in a rabbit model of intraut c2014 ae1130670 v93 aBACKGROUND: Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.
METHODS AND RESULTS: IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.
CONCLUSION: The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.
10aAnimals10abiomarkers10aBlood Pressure10aBody Weight10aDisease Models, Animal10aEchocardiography10aFemale10aFetal Growth Retardation10aFetal Heart10aFetus10aGene Expression Profiling10aOrgan Size10aPlacenta10aPregnancy10aRabbits10aSarcomeres1 aTorre, Iratxe1 aGonzález-Tendero, Anna1 aGarcía-Cañadilla, Patricia1 aCrispi, Fátima1 aGarcia-Garcia, Francisco1 aBijnens, Bart1 aIruretagoyena, Igor1 aDopazo, Joaquin1 aAmat-Roldán, Ivan1 aGratacós, Eduard uhttps://www.clinbioinfosspa.es/content/permanent-cardiac-sarcomere-changes-rabbit-model-intrauterine-growth-restriction02479nas 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.long02519nas a2200373 4500008004100000022001400041245006800055210006500123260001500188300000800203490000600211520145200217653000901669653001601678653002101694653002701715100002601742700001701768700002301785700002401808700001901832700002201851700002001873700002401893700001601917700002501933700002301958700002401981700002602005700002502031700002102056700001902077856004902096 2013 eng d a1750-117200aPathways systematically associated to Hirschsprung’s disease.0 aPathways systematically associated to Hirschsprung s disease c2013 Dec 2 a1870 v83 aDespite it has been reported that several loci are involved in Hirschsprung’s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung’s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.10aGWAS10aHirschprung10anetwork analysis10aPathway Based Analysis1 aFernández, Raquel, M1 aBleda, Marta1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aArnold, Stacey1 aSribudiani, Yunia1 aBesmond, Claude1 aLantieri, Francesca1 aDoan, Betty1 aCeccherini, Isabella1 aLyonnet, Stanislas1 aHofstra, Robert, Mw1 aChakravarti, Aravinda1 aAntiňolo, Guillermo1 aDopazo, Joaquín1 aBorrego, Salud uhttp://www.ojrd.com/content/8/1/187/abstract02677nas a2200409 4500008004100000022001400041245006600055210006400121260001600185300000800201490000600209520145600215653001101671653003801682653001301720653002501733653001101758653000901769653003601778100002601814700001701840700002301857700002401880700001901904700002201923700002001945700002401965700001601989700002502005700002302030700002402053700002602077700002502103700002002128700001902148856010002167 2013 eng d a1750-117200aPathways systematically associated to Hirschsprung's disease.0 aPathways systematically associated to Hirschsprungs disease c2013 Dec 02 a1870 v83 aDespite it has been reported that several loci are involved in Hirschsprung's disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung's disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.
10aFemale10aGenetic Predisposition to Disease10aGenotype10aHirschsprung Disease10aHumans10aMale10aPolymorphism, Single Nucleotide1 aFernández, Raquel, M1 aBleda, Marta1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aArnold, Stacey1 aSribudiani, Yunia1 aBesmond, Claude1 aLantieri, Francesca1 aDoan, Betty1 aCeccherini, Isabella1 aLyonnet, Stanislas1 aHofstra, Robert, Mw1 aChakravarti, Aravinda1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttps://www.clinbioinfosspa.es/content/pathways-systematically-associated-hirschsprungs-disease02568nas 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-cells01134nas a2200169 4500008004100000245010300041210006900144260001500213300001000228490000700238520049600245100003000741700002900771700002100800700001600821856012700837 2011 eng d00aPaintomics: a web based tool for the joint visualization of transcriptomics and metabolomics data.0 aPaintomics a web based tool for the joint visualization of trans c2011 Jan 1 a137-90 v273 aThe development of the omics technologies such as transcriptomics, proteomics and metabolomics has made possible the realization of systems biology studies where biological systems are interrogated at different levels of biochemical activity (gene expression, protein activity and/or metabolite concentration). An effective approach to the analysis of these complex datasets is the joined visualization of the disparate biomolecular data on the framework of known biological pathways.
1 aGarcía-Alcalde, Fernando1 aGarcía-López, Federico1 aDopazo, Joaquín1 aConesa, Ana uhttps://www.clinbioinfosspa.es/content/paintomics-web-based-tool-joint-visualization-transcriptomics-and-metabolomics-data02025nas 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-hypotheses01514nas a2200169 4500008004100000245009800041210006900139260001300208300001100221490000700232520088300239100002201122700003201144700002001176700002201196856012601218 2011 eng d00aPhylogenetic and in silico structural analysis of the Parkinson disease-related kinase PINK1.0 aPhylogenetic and in silico structural analysis of the Parkinson c2011 Apr a369-780 v323 aParkinson disease (PD) is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Mutations in PINK1 were shown to cause recessive familial PD, and today are proposed to be associated with the disease via mitochondrial dysfunction and oxidative damage. The PINK1 gene comprises eight exons, which encode a ubiquitously expressed 581 amino acid protein that contains an N-terminal mitochondrial targeting domain and a serine/threonine protein kinase. To better understand the relationship between PINK1 and PD we have first analyzed the evolutionary history of the gene showing its late emergence in evolution. In addition, we have modeled the three-dimensional structure of PINK1 and found some evidences that help to explain the effect of some PD-related mutations in this protein’s function.
1 aCardona, Fernando1 aSánchez-Mut, Jose, Vicente1 aDopazo, Hernán1 aPérez-Tur, Jordi uhttps://www.clinbioinfosspa.es/content/phylogenetic-and-silico-structural-analysis-parkinson-disease-related-kinase-pink101327nas a2200265 4500008004100000245009000041210006900131260000900200300000800209490000700217520047300224100001800697700001900715700002100734700001900755700002600774700002600800700001800826700001600844700002500860700002100885700001600906700002100922856011800943 2011 eng d00aProfiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing.0 aProfiling the venom gland transcriptomes of Costa Rican snakes b c2011 a2590 v123 aA long term research goal of venomics, of applied importance for improving current antivenom therapy, but also for drug discovery, is to understand the pharmacological potential of venoms. Individually or combined, proteomic and transcriptomic studies have demonstrated their feasibility to explore in depth the molecular diversity of venoms. In the absence of genome sequence, transcriptomes represent also valuable searchable databases for proteomic projects.
1 aDurban, Jordi1 aJuárez, Paula1 aAngulo, Yamileth1 aLomonte, Bruno1 aFlores-Diaz, Marietta1 aAlape-Girón, Alberto1 aSasa, Mahmood1 aSanz, Libia1 aGutiérrez, José, M1 aDopazo, Joaquín1 aConesa, Ana1 aCalvete, Juan, J uhttps://www.clinbioinfosspa.es/content/profiling-venom-gland-transcriptomes-costa-rican-snakes-454-pyrosequencing00709nas 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=pNyCy5GsqtkC02003nas a2200181 4500008004100000245007400041210006900115300001100184490000700195520123100202653013101433653008301564100002101647700001401668700001501682700001801697856010601715 2008 eng d00aPhylomeDB: a database for genome-wide collections of gene phylogenies0 aPhylomeDB a database for genomewide collections of gene phylogen aD491-60 v363 aThe complete collection of evolutionary histories of all genes in a genome, also known as phylome, constitutes a valuable source of information. The reconstruction of phylomes has been previously prevented by large demands of time and computer power, but is now feasible thanks to recent developments in computers and algorithms. To provide a publicly available repository of complete phylomes that allows researchers to access and store large-scale phylogenomic analyses, we have developed PhylomeDB. PhylomeDB is a database of complete phylomes derived for different genomes within a specific taxonomic range. All phylomes in the database are built using a high-quality phylogenetic pipeline that includes evolutionary model testing and alignment trimming phases. For each genome, PhylomeDB provides the alignments, phylogentic trees and tree-based orthology predictions for every single encoded protein. The current version of PhylomeDB includes the phylomes of Human, the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli, comprising a total of 32 289 seed sequences with their corresponding alignments and 172 324 phylogenetic trees. PhylomeDB can be publicly accessed at http://phylomedb.bioinfo.cipf.es.10aAncient Humans *Phylogeny Proteins/classification/genetics Saccharomyces cerevisiae/classification/genetics Sequence Alignment10aBase Sequence Escherichia coli/classification/genetics Genes *Genomics History1 aHuerta-Cepas, J.1 aBueno, A.1 aDopazo, J.1 aGabaldón, T. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1796229702130nas a2200301 4500008004100000022001400041245007500055210006900130260001300199300001100212490000700223520123800230653001801468653002101486653001001507653001301517653002101530653001101551653001401562653001301576653002901589653002301618100002401641700001801665700002001683700002001703856010501723 2008 eng d a1362-496200aPhylomeDB: a database for genome-wide collections of gene phylogenies.0 aPhylomeDB a database for genomewide collections of gene phylogen c2008 Jan aD491-60 v363 aThe complete collection of evolutionary histories of all genes in a genome, also known as phylome, constitutes a valuable source of information. The reconstruction of phylomes has been previously prevented by large demands of time and computer power, but is now feasible thanks to recent developments in computers and algorithms. To provide a publicly available repository of complete phylomes that allows researchers to access and store large-scale phylogenomic analyses, we have developed PhylomeDB. PhylomeDB is a database of complete phylomes derived for different genomes within a specific taxonomic range. All phylomes in the database are built using a high-quality phylogenetic pipeline that includes evolutionary model testing and alignment trimming phases. For each genome, PhylomeDB provides the alignments, phylogentic trees and tree-based orthology predictions for every single encoded protein. The current version of PhylomeDB includes the phylomes of Human, the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli, comprising a total of 32 289 seed sequences with their corresponding alignments and 172 324 phylogenetic trees. PhylomeDB can be publicly accessed at http://phylomedb.bioinfo.cipf.es.
10aBase Sequence10aEscherichia coli10aGenes10aGenomics10aHistory, Ancient10aHumans10aPhylogeny10aProteins10aSaccharomyces cerevisiae10aSequence Alignment1 aHuerta-Cepas, Jaime1 aBueno, Anibal1 aDopazo, Joaquin1 aGabaldón, Toni uhttps://www.clinbioinfosspa.es/content/phylomedb-database-genome-wide-collections-gene-phylogenies-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=1850556202580nas a2200253 4500008004100000245009100041210006900132300001200201490000700213520154400220653002301764653025501787100001702042700001702059700002502076700001802101700002102119700002002140700001302160700002002173700001302193700001402206856010602220 2007 eng d00aPeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease0 aPeroxisomeDB a database for the peroxisomal proteome functional aD815-220 v353 aPeroxisomes are essential organelles of eukaryotic origin, ubiquitously distributed in cells and organisms, playing key roles in lipid and antioxidant metabolism. Loss or malfunction of peroxisomes causes more than 20 fatal inherited conditions. We have created a peroxisomal database (http://www.peroxisomeDB.org) that includes the complete peroxisomal proteome of Homo sapiens and Saccharomyces cerevisiae, by gathering, updating and integrating the available genetic and functional information on peroxisomal genes. PeroxisomeDB is structured in interrelated sections ’Genes’, ’Functions’, ’Metabolic pathways’ and ’Diseases’, that include hyperlinks to selected features of NCBI, ENSEMBL and UCSC databases. We have designed graphical depictions of the main peroxisomal metabolic routes and have included updated flow charts for diagnosis. Precomputed BLAST, PSI-BLAST, multiple sequence alignment (MUSCLE) and phylogenetic trees are provided to assist in direct multispecies comparison to study evolutionary conserved functions and pathways. Highlights of the PeroxisomeDB include new tools developed for facilitating (i) identification of novel peroxisomal proteins, by means of identifying proteins carrying peroxisome targeting signal (PTS) motifs, (ii) detection of peroxisomes in silico, particularly useful for screening the deluge of newly sequenced genomes. PeroxisomeDB should contribute to the systematic characterization of the peroxisomal proteome and facilitate system biology approaches on the organelle.10aAnimals *Databases10aProtein Genomics Humans Internet Mice Peroxisomal Disorders/*genetics Peroxisomes/*metabolism Protein Sorting Signals Proteome/chemistry/*genetics/*physiology Rats Saccharomyces cerevisiae Proteins/genetics/physiology Software User-Computer Interface1 aSchluter, A.1 aFourcade, S.1 aDomenech-Estevez, E.1 aGabaldón, T.1 aHuerta-Cepas, J.1 aBerthommier, G.1 aRipp, R.1 aWanders, R., J.1 aPoch, O.1 aPujol, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1713519002437nas 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=1788404202542nas a2200181 4500008004100000245010000041210006900141300000800210490000600218520184100224653001502065653004302080653008602123100001502209700001502224700001502239856010602254 2006 eng d00aPositive selection, relaxation, and acceleration in the evolution of the human and chimp genome0 aPositive selection relaxation and acceleration in the evolution ae380 v23 aFor years evolutionary biologists have been interested in searching for the genetic bases underlying humanness. Recent efforts at a large or a complete genomic scale have been conducted to search for positively selected genes in human and in chimp. However, recently developed methods allowing for a more sensitive and controlled approach in the detection of positive selection can be employed. Here, using 13,198 genes, we have deduced the sets of genes involved in rate acceleration, positive selection, and relaxation of selective constraints in human, in chimp, and in their ancestral lineage since the divergence from murids. Significant deviations from the strict molecular clock were observed in 469 human and in 651 chimp genes. The more stringent branch-site test of positive selection detected 108 human and 577 chimp positively selected genes. An important proportion of the positively selected genes did not show a significant acceleration in rates, and similarly, many of the accelerated genes did not show significant signals of positive selection. Functional differentiation of genes under rate acceleration, positive selection, and relaxation was not statistically significant between human and chimp with the exception of terms related to G-protein coupled receptors and sensory perception. Both of these were over-represented under relaxation in human in relation to chimp. Comparing differences between derived and ancestral lineages, a more conspicuous change in trends seems to have favored positive selection in the human lineage. Since most of the positively selected genes are different under the same functional categories between these species, we suggest that the individual roles of the alternative positively selected genes may be an important factor underlying biological differences between these species.10aAdaptation10aBiological/genetics Animals *Evolution10aMolecular Genome/*genetics Humans Pan troglodytes/*genetics *Selection (Genetics)1 aArbiza, L.1 aDopazo, J.1 aDopazo, H. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1668301901783nas a2200253 4500008004100000245010200041210006900143300001100212490000700223520089100230653004301121653008001164653002701244653005601271100001401327700002301341700001501364700001501379700001601394700001701410700002001427700001501447856006701462 2006 eng d00aPupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes0 aPupaSuite finding functional single nucleotide polymorphisms for aW621-50 v343 aWe have developed a web tool, PupaSuite, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect, specifically oriented to help in the design of large-scale genotyping projects. PupaSuite uses a collection of data on SNPs from heterogeneous sources and a large number of pre-calculated predictions to offer a flexible and intuitive interface for selecting an optimal set of SNPs. It improves the functionality of PupaSNP and PupasView programs and implements new facilities such as the analysis of user’s data to derive haplotypes with functional information. A new estimator of putative effect of polymorphisms has been included that uses evolutionary information. Also SNPeffect database predictions have been included. The PupaSuite web interface is accessible through http://pupasuite.bioinfo.cipf.es and through http://www.pupasnp.org.
10aAlgorithms Computer Graphics Databases10aMolecular Genotype Haplotypes Internet Linkage Disequilibrium *Polymorphism10aNucleic Acid Evolution10aSingle Nucleotide *Software User-Computer Interface1 aConde, L.1 aVaquerizas, J., M.1 aDopazo, H.1 aArbiza, L.1 aReumers, J.1 aRousseau, F.1 aSchymkowitz, J.1 aDopazo, J. uhttp://nar.oxfordjournals.org/cgi/content/full/34/suppl_2/W62102968nas a2200337 4500008004100000245012900041210006900170300000900239490000700248520175600255653010902011653003502120653001702155653006002172653007102232100001702303700001602320700001502336700001602351700001502367700001602382700001802398700002102416700001302437700001502450700001402465700001502479700001402494700001602508856010602524 2005 eng d00aPhenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers0 aPhenotypic characterization of BRCA1 and BRCA2 tumors based in a a5-140 v903 aFamilial breast cancers that are associated with BRCA1 or BRCA2 germline mutations differ in both their morphological and immunohistochemical characteristics. To further characterize the molecular difference between genotypes, the authors evaluated the expression of 37 immunohistochemical markers in a tissue microarray (TMA) containing cores from 20 BRCA1, 14 BRCA2, and 59 sporadic age-matched breast carcinomas. Markers analyzed included, amog others, common markers in breast cancer, such as hormone receptors, p53 and HER2, along with 15 molecules involved in cell cycle regulation, such as cyclins, cyclin dependent kinases (CDK) and CDK inhibitors (CDKI), apoptosis markers, such as BCL2 and active caspase 3, and two basal/myoepithelial markers (CK 5/6 and P-cadherin). In addition, we analyzed the amplification of CCND1, CCNE, HER2 and MYC by FISH.Unsupervised cluster data analysis of both hereditary and sporadic cases using the complete set of immunohistochemical markers demonstrated that most BRCA1-associated carcinomas grouped in a branch of ER-, HER2-negative tumors that expressed basal cell markers and/or p53 and had higher expression of activated caspase 3. The cell cycle proteins associated with these tumors were E2F6, cyclins A, B1 and E, SKP2 and Topo IIalpha. In contrast, most BRCA2-associated carcinomas grouped in a branch composed by ER/PR/BCL2-positive tumors with a higher expression of the cell cycle proteins cyclin D1, cyclin D3, p27, p16, p21, CDK4, CDK2 and CDK1. In conclusion, our study in hereditary breast cancer tumors analyzing 37 immunohistochemical markers, define the molecular differences between BRCA1 and BRCA2 tumors with respect to hormonal receptors, cell cycle, apoptosis and basal cell markers.10aAdult Apoptosis Breast Neoplasms/*genetics/*pathology Cell Cycle Proteins Cluster Analysis Female *Genes10aBiological/genetics/metabolism10aBRCA1 *Genes10aBRCA2 Humans Immunohistochemistry In Situ Hybridization10aFluorescence Phenotype Spain *Tissue Array Analysis *Tumor Markers1 aPalacios, J.1 aHonrado, E.1 aOsorio, A.1 aCazorla, A.1 aSarrio, D.1 aBarroso, A.1 aRodriguez, S.1 aCigudosa, J., C.1 aDiez, O.1 aAlonso, C.1 aLerma, E.1 aDopazo, J.1 aRivas, C.1 aBenitez, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1577052102881nas 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=1570918202075nas a2200205 4500008004100000245012600041210006900167300001100236490000700247520124100254653010501495653005601600100001401656700002301670700002101693700001901714700001501733700001501748856010601763 2005 eng d00aPupasView: a visual tool for selecting suitable SNPs, with putative pathological effect in genes, for genotyping purposes0 aPupasView a visual tool for selecting suitable SNPs with putativ aW501-50 v333 aWe have developed a web tool, PupasView, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupasView constitutes an interactive environment in which functional information and population frequency data can be used as sequential filters over linkage disequilibrium parameters to obtain a final list of SNPs optimal for genotyping purposes. PupasView is the first resource that integrates phenotypic effects caused by SNPs at both the translational and the transcriptional level. PupasView retrieves SNPs that could affect conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites and changes in amino acids in the proteins for which a putative pathological effect is calculated. The program uses the mapping of SNPs in the genome provided by Ensembl. PupasView will be of much help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of the identification of the genes responsible for the disease. The PupasView web interface is accessible through http://pupasview.ochoa.fib.es and through http://www.pupasnp.org.10aComputer Graphics Genes *Genetic Predisposition to Disease Genotype Internet Phenotype *Polymorphism10aSingle Nucleotide *Software User-Computer Interface1 aConde, L.1 aVaquerizas, J., M.1 aFerrer-Costa, C.1 ade la Cruz, X.1 aOrozco, M.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1598052200480nas 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=1557792001756nas a2200145 4500008004100000245011900041210006900160300001200229490001500241520120200256100001501458700001601473700001501489856010601504 2004 eng d00aPhylogenomics and the number of characters required for obtaining an accurate phylogeny of eukaryote model species0 aPhylogenomics and the number of characters required for obtainin ai116-210 v20 Suppl 13 aMOTIVATION: Through the most extensive phylogenomic analysis carried out to date, complete genomes of 11 eukaryotic species have been examined in order to find the homologous of more than 25,000 amino acid sequences. These sequences correspond to the exons of more than 3000 genes and were used as presence/absence characters to test one of the most controversial hypotheses concerning animal evolution, namely the Ecdysozoa hypothesis. Distance, maximum parsimony and Bayesian methods of phylogenetic reconstruction were used to test the hypothesis. RESULTS: The reliability of the ecdysozoa, grouping arthropods and nematodes in a single clade was unequivocally rejected in all the consensus trees. The Coelomata clade, grouping arthropods and chordates, was supported by the highest statistical confidence in all the reconstructions. The study of the dependence of the genomes’ tree accuracy on the number of exons used, demonstrated that an unexpectedly larger number of characters are necessary to obtain robust phylogenies. Previous studies supporting ecdysozoa, could not guarantee an accurate phylogeny because the number of characters used was clearly below the minimum required.
1 aDopazo, H.1 aSantoyo, J.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1526278902058nas a2200169 4500008004100000245006600041210006600107300001100173490000700184520119200191653019701383653012101580653004401701100001801745700001901763856010601782 2004 eng d00aPrediction of protein function and pathways in the genome era0 aPrediction of protein function and pathways in the genome era a930-440 v613 aThe growing number of completely sequenced genomes adds new dimensions to the use of sequence analysis to predict protein function. Compared with the classical knowledge transfer from one protein to a similar sequence (homology-based function prediction), knowledge about the corresponding genes in other genomes (orthology-based function prediction) provides more specific information about the protein’s function, while the analysis of the sequence in its genomic context (context-based function prediction) provides information about its functional context. Whereas homology-based methods predict the molecular function of a protein, genomic context methods predict the biological process in which it plays a role. These complementary approaches can be combined to elucidate complete functional networks and biochemical pathways from the genome sequence of an organism. Here we review recent advances in the field of genomic-context based methods of protein function prediction. Techniques are highlighted with examples, including an analysis that combines information from genomic-context with homology to predict a role of the RNase L inhibitor in the maturation of ribosomal RNA.10aATP-Binding Cassette Transporters/genetics/metabolism Amino Acid Sequence Animals Artificial Gene Fusion Base Sequence Chaperonins/genetics/metabolism Chromosomes/genetics/metabolism Evolution10aMolecular *Genome Genomics Humans Molecular Sequence Data Phylogeny *Proteins/classification/genetics/metabolism RNA10aRibosomal/metabolism Sequence Alignment1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1509501302164nas a2200229 4500008004100000245009400041210006900135300001100204490000700215520128900222653008201511653001201593653009301605100001401698700002301712700001601735700002401751700002201775700001601797700001501813856010601828 2004 eng d00aPupaSNP Finder: a web tool for finding SNPs with putative effect at transcriptional level0 aPupaSNP Finder a web tool for finding SNPs with putative effect aW242-80 v323 aWe have developed a web tool, PupaSNP Finder (PupaSNP for short), for high-throughput searching for single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupaSNP takes as its input lists of genes (or generates them from chromosomal coordinates) and retrieves SNPs that could affect the conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites (TFBS) and changes in amino acids in the proteins. The program uses the mapping of SNPs in the genome provided by Ensembl. Additionally, user-defined SNPs (not yet mapped in the genome) can be easily provided to the program. Also, additional functional information from Gene Ontology, OMIM and homologies in other model organisms is provided. In contrast to other programs already available, which focus only on SNPs with possible effect in the protein, PupaSNP includes SNPs with possible transcriptional effect. PupaSNP will be of significant help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of identification of the genes responsible for the disease. The PupaSNP web interface is accessible through http://pupasnp.bioinfo.cnio.es.10aAmino Acid Substitution Binding Sites Humans Internet Phenotype *Polymorphism10aGenetic10aSingle Nucleotide RNA Splicing *Software Transcription Factors/metabolism *Transcription1 aConde, L.1 aVaquerizas, J., M.1 aSantoyo, J.1 aAl-Shahrour, Fatima1 aRuiz-Llorente, S.1 aRobledo, M.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1521538801950nas 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