07193nas a2202077 4500008004100000022001400041245010000055210006900155260001200224300001100236490000700247520130900254653002101563653002601584653002201610653001301632653001401645653001601659653002301675653003101698653003201729653001101761653002301772653002201795653002101817653001601838653003601854653001801890653003201908653001501940653002401955653001301979653002601992653001902018100002302037700001902060700002202079700002102101700001802122700002702140700001902167700002602186700002602212700001802238700001902256700001702275700002202292700002102314700001902335700002902354700001802383700001602401700002902417700001802446700002302464700002202487700002002509700002002529700002702549700002102576700001702597700001802614700002402632700002102656700001602677700002102693700001902714700002302733700002302756700002002779700001702799700001902816700002402835700002102859700002402880700001702904700002302921700002402944700001902968700002002987700001903007700001903026700002903045700002303074700002003097700001703117700001803134700002403152700003303176700002003209700002003229700001603249700001503265700001803280700001903298700002603317700002703343700002003370700002403390700001803414700002403432700002203456700002203478700001903500700002003519700002103539700001803560700001503578700002203593700002303615700001703638700001903655700002403674700001703698700001803715700001703733700002303750700001803773700001803791700002303809700002103832700001703853700002203870700002003892700001803912700001803930700002303948700002103971700002503992700001804017700002004035700001704055700001904072700001704091700002104108700002504129700002704154700002404181700001604205700002104221700002504242700001704267700002004284700001804304700002504322700002404347700002304371700002104394700001904415700002204434700001804456700001604474700002204490700002004512700001804532700002504550700001904575700002204594700002404616700002304640700002004663700002304683700002204706700002304728700002304751700002604774700002004800700002204820700002004842700002304862700002104885700001804906700002404924710003504948856013204983 2021 eng d a1744-429200aCOVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.0 aCOVID19 Disease Map a computational knowledge repository of viru c2021 10 ae103870 v173 a
We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.
10aAntiviral Agents10aComputational Biology10aComputer Graphics10aCOVID-1910aCytokines10aData Mining10aDatabases, Factual10aGene Expression Regulation10aHost Microbial Interactions10aHumans10aImmunity, Cellular10aImmunity, Humoral10aImmunity, Innate10aLymphocytes10aMetabolic Networks and Pathways10aMyeloid Cells10aProtein Interaction Mapping10aSARS-CoV-210aSignal Transduction10aSoftware10aTranscription Factors10aViral Proteins1 aOstaszewski, Marek1 aNiarakis, Anna1 aMazein, Alexander1 aKuperstein, Inna1 aPhair, Robert1 aOrta-Resendiz, Aurelio1 aSingh, Vidisha1 aAghamiri, Sara, Sadat1 aAcencio, Marcio, Luis1 aGlaab, Enrico1 aRuepp, Andreas1 aFobo, Gisela1 aMontrone, Corinna1 aBrauner, Barbara1 aFrishman, Goar1 aGómez, Luis, Cristóbal1 aSomers, Julia1 aHoch, Matti1 aGupta, Shailendra, Kumar1 aScheel, Julia1 aBorlinghaus, Hanna1 aCzauderna, Tobias1 aSchreiber, Falk1 aMontagud, Arnau1 ade Leon, Miguel, Ponce1 aFunahashi, Akira1 aHiki, Yusuke1 aHiroi, Noriko1 aYamada, Takahiro, G1 aDräger, Andreas1 aRenz, Alina1 aNaveez, Muhammad1 aBocskei, Zsolt1 aMessina, Francesco1 aBörnigen, Daniela1 aFergusson, Liam1 aConti, Marta1 aRameil, Marius1 aNakonecnij, Vanessa1 aVanhoefer, Jakob1 aSchmiester, Leonard1 aWang, Muying1 aAckerman, Emily, E1 aShoemaker, Jason, E1 aZucker, Jeremy1 aOxford, Kristie1 aTeuton, Jeremy1 aKocakaya, Ebru1 aSummak, Gökçe, Yağmur1 aHanspers, Kristina1 aKutmon, Martina1 aCoort, Susan1 aEijssen, Lars1 aEhrhart, Friederike1 aRex, Devasahayam, Arokia Bal1 aSlenter, Denise1 aMartens, Marvin1 aPham, Nhung1 aHaw, Robin1 aJassal, Bijay1 aMatthews, Lisa1 aOrlic-Milacic, Marija1 aRibeiro, Andrea, Senff1 aRothfels, Karen1 aShamovsky, Veronica1 aStephan, Ralf1 aSevilla, Cristoffer1 aVarusai, Thawfeek1 aRavel, Jean-Marie1 aFraser, Rupsha1 aOrtseifen, Vera1 aMarchesi, Silvia1 aGawron, Piotr1 aSmula, Ewa1 aHeirendt, Laurent1 aSatagopam, Venkata1 aWu, Guanming1 aRiutta, Anders1 aGolebiewski, Martin1 aOwen, Stuart1 aGoble, Carole1 aHu, Xiaoming1 aOverall, Rupert, W1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aVega, Carlos1 aGrouès, Valentin1 aVazquez, Miguel1 aPorras, Pablo1 aLicata, Luana1 aIannuccelli, Marta1 aSacco, Francesca1 aNesterova, Anastasia1 aYuryev, Anton1 ade Waard, Anita1 aTurei, Denes1 aLuna, Augustin1 aBabur, Ozgun1 aSoliman, Sylvain1 aValdeolivas, Alberto1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aHelikar, Tomáš1 aPuniya, Bhanwar, Lal1 aModos, Dezso1 aTreveil, Agatha1 aOlbei, Marton1 aDe Meulder, Bertrand1 aBallereau, Stephane1 aDugourd, Aurélien1 aNaldi, Aurélien1 aNoël, Vincent1 aCalzone, Laurence1 aSander, Chris1 aDemir, Emek1 aKorcsmaros, Tamas1 aFreeman, Tom, C1 aAugé, Franck1 aBeckmann, Jacques, S1 aHasenauer, Jan1 aWolkenhauer, Olaf1 aWilighagen, Egon, L1 aPico, Alexander, R1 aEvelo, Chris, T1 aGillespie, Marc, E1 aStein, Lincoln, D1 aHermjakob, Henning1 aD'Eustachio, Peter1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aValencia, Alfonso1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community uhttps://www.clinbioinfosspa.es/content/covid19-disease-map-computational-knowledge-repository-virus-host-interaction-mechanisms03233nas a2200613 4500008004100000022001400041245014900055210006900204260001200273300001200285490000800297520129600305653002101601653002601622653001301648653001001661653003101671653003201702653001101734653000901745653003301754653002101787653001901808653002201827653001301849653002601862653003401888653002701922100003001949700002701979700002802006700001702034700001902051700001902070700002102089700002902110700002202139700001902161700002402180700002202204700002102226700001902247700002102266700002202287700001702309700001902326700002002345700002602365700003002391700001902421700002602440700001902466856013402485 2021 eng d a1552-483300aDe novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.0 aDe novo small deletion affecting transcription start site of sho c2021 03 a877-8830 v1853 aDisruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.
10aChild, Preschool10aCytoskeletal Proteins10aDwarfism10aExons10aGene Expression Regulation10aGenetic Association Studies10aHumans10aMale10aNeurodevelopmental Disorders10aProtein Isoforms10aRNA, Messenger10aSequence Deletion10aSyndrome10aTranscription Factors10aTranscription Initiation Site10aTranscription, Genetic1 aMartinez-Delgado, Beatriz1 aLopez-Martin, Estrella1 aLara-Herguedas, Julián1 aMonzon, Sara1 aCuesta, Isabel1 aJuliá, Miguel1 aAquino, Virginia1 aRodriguez-Martin, Carlos1 aDamian, Alejandra1 aGonzalo, Irene1 aGomez-Mariano, Gema1 aBaladron, Beatriz1 aCazorla, Rosario1 aIglesias, Gema1 aRoman, Enriqueta1 aRos, Purificacion1 aTutor, Pablo1 aMellor, Susana1 aJimenez, Carlos1 aCabrejas, Maria, Jose1 aGonzalez-Vioque, Emiliano1 aAlonso, Javier1 aBermejo-Sánchez, Eva1 aPosada, Manuel uhttps://www.clinbioinfosspa.es/content/de-novo-small-deletion-affecting-transcription-start-site-short-isoform-auts2-gene-patient03115nas a2200493 4500008004100000022001400041245014400055210006900199260001500268490000700283520148700290653001201777653003601789653003001825653003101855653001801886653001101904653003601915653000901951653001501960653002401975653003401999653003302033653002402066653000902090653002502099653001502124653001702139653002302156653001802179653003402197653001802231100001802249700002902267700001702296700002402313700002102337700003102358700002002389700002102409700002602430700003402456856013102490 2020 eng d a2073-442500aTranscriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.0 aTranscriptomic Analysis of a Diabetic SkinHumanized Mouse Model c2020 12 310 v123 aDefective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.
10aAnimals10aDiabetes Mellitus, Experimental10aGene Expression Profiling10aGene Expression Regulation10aGene ontology10aHumans10aMetabolic Networks and Pathways10aMice10aMice, Nude10aMicroarray Analysis10aMolecular Sequence Annotation10aPrincipal Component Analysis10aSignal Transduction10aSkin10aSkin Transplantation10aSkin Ulcer10aStreptozocin10aTissue Engineering10aTranscriptome10aTransplantation, Heterologous10aWound Healing1 aLeón, Carlos1 aGarcia-Garcia, Francisco1 aLlames, Sara1 aGarcía-Pérez, Eva1 aCarretero, Marta1 aArriba, María, Del Carmen1 aDopazo, Joaquin1 aDel Rio, Marcela1 aEscamez, Maria, José1 aMartínez-Santamaría, Lucía uhttps://www.clinbioinfosspa.es/content/transcriptomic-analysis-diabetic-skin-humanized-mouse-model-dissects-molecular-pathways05146nas a2200745 4500008004100000022001400041245013000055210006900185260001200254300001200266490000800278520304400286653001503330653001003345653001103355653001203366653002503378653002003403653001003423653002103433653002603454653003803480653002503518653003403543653001103577653001603588653001303604653003103617653002303648653001103671653001103682653002003693653000903713653001603722653001303738653002503751653003103776653002503807653001203832653000903844653002603853653001603879100002203895700001303917700001303930700002303943700001503966700001903981700002404000700001604024700001604040700002904056700001404085700001504099700002704114700002404141700001404165700001204179700001604191700001504207700001504222700001404237700001504251856013404266 2019 eng d a1365-213300aFibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.0 aFibroblast activation and abnormal extracellular matrix remodell c2019 09 a512-5220 v1813 aBACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.
OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.
METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.
RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.
CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.
10aAdolescent10aAdult10aBiopsy10aBlister10aCase-Control Studies10aCells, Cultured10aChild10aChild, Preschool10aEpidermolysis Bullosa10aEpidermolysis Bullosa Dystrophica10aExtracellular Matrix10aExtracellular Matrix Proteins10aFemale10aFibroblasts10aFibrosis10aGene Expression Regulation10aHealthy Volunteers10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10amutation10aPeriodontal Diseases10aPhotosensitivity Disorders10aPrimary Cell Culture10aRNA-seq10aSkin10aXeroderma Pigmentosum10aYoung Adult1 aChacón-Solano, E1 aLeón, C1 aDíaz, F1 aGarcía-García, F1 aGarcía, M1 aEscámez, M, J1 aGuerrero-Aspizua, S1 aConti, C, J1 aMencía, Á1 aMartínez-Santamaría, L1 aLlames, S1 aPévida, M1 aCarbonell-Caballero, J1 aPuig-Butillé, J, A1 aMaseda, R1 aPuig, S1 ade Lucas, R1 aBaselga, E1 aLarcher, F1 aDopazo, J1 aDel Rio, M uhttps://www.clinbioinfosspa.es/content/fibroblast-activation-and-abnormal-extracellular-matrix-remodelling-common-hallmarks-three03417nas a2200793 4500008004100000022001400041245009300055210006900148260001500217300000900232490000600241520096600247653001201213653001401225653002301239653001801262653003601280653003001316653001101346653003101357653001101388653002401399653002101423653001201444653002801456653002501484653004101509653001601550653000901566653000901575653002301584653001501607653003901622653001701661653003001678653003401708100002801742700002201770700003201792700002901824700002601853700002601879700003101905700003301936700002201969700003101991700001902022700002002041700002002061700002202081700002002103700002302123700001602146700002302162700002302185700002302208700001902231700002502250700002902275700002102304700002502325700003202350700001602382700001802398700003802416700001702454700002402471856012802495 2018 eng d a2041-172300aLRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.0 aLRH1 agonism favours an immuneislet dialogue which protects agai c2018 04 16 a14880 v93 aType 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.
10aAnimals10aApoptosis10aCell Communication10aCell Survival10aDiabetes Mellitus, Experimental10aDiabetes Mellitus, Type 210aFemale10aGene Expression Regulation10aHumans10aHypoglycemic Agents10aImmunity, Innate10ainsulin10aInsulin-Secreting Cells10aIslets of Langerhans10aIslets of Langerhans Transplantation10aMacrophages10aMale10aMice10aMice, Inbred C57BL10aPhenalenes10aReceptors, Cytoplasmic and Nuclear10aStreptozocin10aT-Lymphocytes, Regulatory10aTransplantation, Heterologous1 aCobo-Vuilleumier, Nadia1 aLorenzo, Petra, I1 aRodríguez, Noelia, García1 aGómez, Irene, de Gracia1 aFuente-Martin, Esther1 aLópez-Noriega, Livia1 aMellado-Gil, José, Manuel1 aRomero-Zerbo, Silvana-Yanina1 aBaquié, Mathurin1 aLachaud, Christian, Claude1 aStifter, Katja1 aPerdomo, German1 aBugliani, Marco1 aDe Tata, Vincenzo1 aBosco, Domenico1 aParnaud, Geraldine1 aPozo, David1 aHmadcha, Abdelkrim1 aFlorido, Javier, P1 aToscano, Miguel, G1 ade Haan, Peter1 aSchoonjans, Kristina1 aPalazón, Luis, Sánchez1 aMarchetti, Piero1 aSchirmbeck, Reinhold1 aMartín-Montalvo, Alejandro1 aMeda, Paolo1 aSoria, Bernat1 aBermúdez-Silva, Francisco-Javier1 aSt-Onge, Luc1 aGauthier, Benoit, R uhttps://www.clinbioinfosspa.es/content/lrh-1-agonism-favours-immune-islet-dialogue-which-protects-against-diabetes-mellitus03226nas a2200697 4500008004100000022001400041245013600055210006900191260001500260300001000275490000600285520117300291653000901464653001201473653002601485653002001511653001901531653003801550653001801588653002801606653001001634653001701644653001101661653003101672653002101703653002501724653001501749653001101764653000901775653000901784653001601793653003601809653003201845653001101877653002401888653003601912653002501948653001001973653002101983653002602004100001402030700002402044700001602068700001602084700001702100700002402117700002702141700002402168700002102192700001302213700002302226700001402249700002702263700002002290700002302310700001402333700002402347700001402371700001302385856013002398 2016 eng d a2045-232200aIdentification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.0 aIdentification of the Photoreceptor Transcriptional CoRepressor c2016 10 13 a353700 v63 aRetinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.
10aAged10aAnimals10aCo-Repressor Proteins10aCodon, Nonsense10aCohort Studies10aComparative Genomic Hybridization10aConsanguinity10aDNA Mutational Analysis10aExome10aEye Proteins10aFemale10aGene Expression Regulation10aGenes, Recessive10aHomeodomain Proteins10aHomozygote10aHumans10aMale10aMice10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aRetina10aRetinal Dystrophies10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aSpain10aTrans-Activators10aTranscription Factors1 aCorton, M1 aAvila-Fernández, A1 aCampello, L1 aSánchez, M1 aBenavides, B1 aLópez-Molina, M, I1 aFernández-Sánchez, L1 aSánchez-Alcudia, R1 ada Silva, L, R J1 aReyes, N1 aMartín-Garrido, E1 aZurita, O1 aSan José, Fernández-1 aPérez-Carro, R1 aGarcía-García, F1 aDopazo, J1 aGarcía-Sandoval, B1 aCuenca, N1 aAyuso, C uhttps://www.clinbioinfosspa.es/content/identification-photoreceptor-transcriptional-co-repressor-samd11-novel-cause-autosomal02504nas a2200277 4500008004100000022001400041245005900055210005600114260001300170300001200183490000700195520165100202653001501853653002801868653003001896653003101926653001101957653002001968653004401988100002002032700003002052700002002082700002002102700001602122856008802138 2011 eng d a1549-546900aDifferential expression in RNA-seq: a matter of depth.0 aDifferential expression in RNAseq a matter of depth c2011 Dec a2213-230 v213 aNext-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and additional research is needed for understanding how these data respond to differential expression analysis. In this work, we set out to gain insights into the characteristics of RNA-seq data analysis by studying an important parameter of this technology: the sequencing depth. We have analyzed how sequencing depth affects the detection of transcripts and their identification as differentially expressed, looking at aspects such as transcript biotype, length, expression level, and fold-change. We have evaluated different algorithms available for the analysis of RNA-seq and proposed a novel approach--NOISeq--that differs from existing methods in that it is data-adaptive and nonparametric. Our results reveal that most existing methodologies suffer from a strong dependency on sequencing depth for their differential expression calls and that this results in a considerable number of false positives that increases as the number of reads grows. In contrast, our proposed method models the noise distribution from the actual data, can therefore better adapt to the size of the data set, and is more effective in controlling the rate of false discoveries. This work discusses the true potential of RNA-seq for studying regulation at low expression ranges, the noise within RNA-seq data, and the issue of replication.
10aAlgorithms10aExpressed Sequence Tags10aGene Expression Profiling10aGene Expression Regulation10aHumans10aModels, Genetic10aOligonucleotide Array Sequence Analysis1 aTarazona, Sonia1 aGarcía-Alcalde, Fernando1 aDopazo, Joaquin1 aFerrer, Alberto1 aConesa, Ana uhttps://www.clinbioinfosspa.es/content/differential-expression-rna-seq-matter-depth03520nas a2200493 4500008004100000022001400041245012700055210006900182260001600251300000700267490000600274520197600280653001202256653002302268653001802291653001602309653002002325653001102345653003102356653002902387653002302416653002802439653000902467653001202476653002402488653002002512653001502532653002402547653002702571653003602598100001802634700003002652700002302682700002902705700002102734700002002755700001902775700001602794700001602810700002002826700002402846700002302870856013302893 2011 eng d a1755-879400aEarly peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.0 aEarly peroxisome proliferatoractivated receptor gamma regulated c2011 Dec 30 a860 v43 aBACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion
RESULTS: Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.
CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.
10aAnimals10aCell Proliferation10aCell Survival10aCholesterol10aDown-Regulation10aFemale10aGene Expression Regulation10aGene Knockout Techniques10aInsulin Resistance10aInsulin-Secreting Cells10aMice10aobesity10aOxidation-Reduction10aPhosphorylation10aPPAR gamma10aSignal Transduction10aTranscription, Genetic10aTransforming Growth Factor beta1 aVivas, Yurena1 aMartinez-Garcia, Cristina1 aIzquierdo, Adriana1 aGarcia-Garcia, Francisco1 aCallejas, Sergio1 aVelasco, Ismael1 aCampbell, Mark1 aRos, Manuel1 aDopazo, Ana1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aMedina-Gomez, Gema uhttps://www.clinbioinfosspa.es/content/early-peroxisome-proliferator-activated-receptor-gamma-regulated-genes-involved-expansion01719nas a2200229 4500008004100000022001400041245009600055210006900151260001300220300001000233490000600243520095200249653003101201653002901232653001301261653002001274653001301294653002001307100001901327700002001346856012301366 2010 eng d a1744-838700aFunctional genomics and networks: new approaches in the extraction of complex gene modules.0 aFunctional genomics and networks new approaches in the extractio c2010 Feb a55-630 v73 aThe engine that makes the cell work is made of an intricate network of molecular interactions. Nowadays, the elements and relationships of this complex network can be studied with several types of high-throughput techniques. The dream of having a global picture of the cell from different perspectives that can jointly explain cell behavior is, at least technically, feasible. However, this task can only be accomplished by filling the gap between data and information. The availability of methods capable of accurately managing, integrating and analyzing the results from these experiments is crucial for this purpose. Here, we review the new challenges raised by the availability of different genomic data, as well as the new proposals presented to cope with the increasing data complexity. Special emphasis is given to approaches that explore the transcriptome trying to describe the modules of genes that account for the traits studied.
10aGene Expression Regulation10aGene Regulatory Networks10aGenomics10aProtein Binding10aProteins10aSystems biology1 aMinguez, Pablo1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/functional-genomics-and-networks-new-approaches-extraction-complex-gene-modules03322nas a2200613 4500008004100000022001400041245010400055210006900159260001600228300001100244490000700255520144400262653001901706653001201725653001501737653002801752653002501780653001701805653002501822653002001847653002001867653002501887653002201912653003001934653003101964653001101995653000902006653002602015653003602041653001102077653002702088653000902115653001502124653004102139100002302180700001602203700001902219700003002238700002702268700002102295700002002316700002002336700001702356700002002373700002702393700002202420700001802442700002902460700001802489700002002507700002202527700002302549856013602572 2010 eng d a1549-491800aHypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.0 aHypoxia promotes efficient differentiation of human embryonic st c2010 Mar 31 a407-180 v283 aEarly development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O(2)) as somatic cells. We hypothesized that O(2) levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O(2)) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O(2) levels; after 24 hours at 5% O(2), more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.
10aAngiopoietin-110aAnimals10abiomarkers10aCell Culture Techniques10aCell Differentiation10aCell Hypoxia10aCell Transplantation10aCells, Cultured10aDown-Regulation10aEmbryonic Stem Cells10aEndothelial Cells10aGene Expression Profiling10aGene Expression Regulation10aHumans10aMale10aMyocardial Infarction10aNeovascularization, Physiologic10aOxygen10aPluripotent Stem Cells10aRats10aRats, Nude10aVascular Endothelial Growth Factor A1 aPrado-Lopez, Sonia1 aConesa, Ana1 aArmiñán, Ana1 aMartínez-Losa, Magdalena1 aEscobedo-Lucea, Carmen1 aGandia, Carolina1 aTarazona, Sonia1 aMelguizo, Dario1 aBlesa, David1 aMontaner, David1 aSanz-González, Silvia1 aSepúlveda, Pilar1 aGötz, Stefan1 aO'Connor, José, Enrique1 aMoreno, Ruben1 aDopazo, Joaquin1 aBurks, Deborah, J1 aStojkovic, Miodrag uhttps://www.clinbioinfosspa.es/content/hypoxia-promotes-efficient-differentiation-human-embryonic-stem-cells-functional-endothelium