03351nas a2200265 4500008004100000022001400041245012500055210006900180260001600249300000800265490000600273520241900279100001802698700001902716700003602735700002902771700002702800700002002827700001802847700002002865700002002885700003102905700001902936856013002955 2023 eng d a2058-771600aRapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.0 aRapid degeneration of iPSCderived motor neurons lacking Gdap1 en c2023 Jul 01 a2170 v93 a
Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1 motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1 iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.
1 aLeón, Marian1 aPrieto, Javier1 aMolina-Navarro, María, Micaela1 aGarcia-Garcia, Francisco1 aBarneo-Muñoz, Manuela1 aPonsoda, Xavier1 aSáez, Rosana1 aPalau, Francesc1 aDopazo, Joaquin1 aBelmonte, Juan, Carlos Izp1 aTorres, Josema uhttp://clinbioinfosspa.es/content/rapid-degeneration-ipsc-derived-motor-neurons-lacking-gdap1-engages-mitochondrial-sustained02334nas a2200229 4500008004100000022001400041245013100055210006900186260001600255300000800271490000700279520147800286100002001764700002101784700002701805700002301832700003101855700002101886700002401907700002001931856015301951 2023 eng d a1743-422X00aReal-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments.0 aRealworld evidence with a retrospective cohort of 15968 COVID19 c2023 Oct 06 a2260 v203 aPURPOSE: Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19.
METHODS: Using data from a central registry of electronic health records (the Andalusian Population Health Database), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient outcomes, including survival and lymphocyte progression, was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020.
RESULTS: Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality.
CONCLUSIONS: In this study we have taken advantage of the availability of a regional clinical database to study the effect of drugs, which patients were taking for other indications, on their survival. The large size of the database allowed us to control covariates effectively.
1 aLoucera, Carlos1 aCarmona, Rosario1 aEsteban-Medina, Marina1 aBostelmann, Gerrit1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/real-world-evidence-retrospective-cohort-15968-covid-19-hospitalized-patients-suggests-21-new-effective-treatments02756nas a2200385 4500008004100000022001400041245015900055210006900214260001500283300001000298490000700308520150900315653001601824653001301840653001101853653001101864653002601875653000901901653002601910653001001936653002201946653001401968100002001982700002402002700002702026700003102053700002102084700002602105700002902131700001802160700002002178700002002198700002802218856012402246 2021 eng d a2045-232200aReal world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients.0 aReal world evidence of calcifediol or vitamin D prescription and c2021 12 03 a233800 v113 aCOVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.
10aCalcifediol10aCOVID-1910aFemale10aHumans10aKaplan-Meier Estimate10aMale10aRetrospective Studies10aSpain10aSurvival Analysis10aVitamin D1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aLópez-Miranda, José1 aRodríguez-Baño, Jesús1 aTúnez, Isaac1 aBouillon, Roger1 aDopazo, Joaquin1 aGomez, Jose, Manuel Que uhttp://clinbioinfosspa.es/content/real-world-evidence-calcifediol-or-vitamin-d-prescription-and-mortality-rate-covid-1905404nas a2201477 4500008004100000022001400041245007800055210006900133260001200202300001400214490000700228520122900235653002601464653001401490653001101504653001501515653003501530653002001565653003801585100001901623700001901642700001801661700002301679700002401702700002301726700002101749700002801770700001801798700002501816700002401841700002701865700001801892700002301910700002001933700001501953700002201968700002001990700002702010700002102037700002202058700001802080700001902098700002702117700002002144700001902164700002002183700002102203700001702224700002102241700002302262700002002285700002202305700002002327700001802347700002302365700001802388700002102406700002602427700001902453700001702472700001802489700002402507700001902531700001602550700001702566700001602583700002102599700002102620700002102641700002102662700002202683700002202705700002102727700001602748700001702764700001502781700002102796700001702817700002402834700002202858700002002880700002402900700001802924700001602942700002302958700002102981700002403002700001703026700002603043700002403069700002503093700002403118700002203142700002103164700001703185700001903202700001803221700001803239700001303257700001703270700001603287700001903303700002703322700002003349700001703369700002203386700001903408700001903427700002603446700001903472700002903491700002103520700001603541700002203557700001603579700002003595700002403615700001903639700002403658700002203682700002003704700001803724710003303742710004903775856010203824 2021 eng d a1546-170X00aReporting guidelines for human microbiome research: the STORMS checklist.0 aReporting guidelines for human microbiome research the STORMS ch c2021 11 a1885-18920 v273 aThe particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.
10aComputational Biology10aDysbiosis10aHumans10aMicrobiota10aObservational Studies as Topic10aResearch Design10aTranslational Science, Biomedical1 aMirzayi, Chloe1 aRenson, Audrey1 aZohra, Fatima1 aElsafoury, Shaimaa1 aGeistlinger, Ludwig1 aKasselman, Lora, J1 aEckenrode, Kelly1 avan de Wijgert, Janneke1 aLoughman, Amy1 aMarques, Francine, Z1 aMacIntyre, David, A1 aArumugam, Manimozhiyan1 aAzhar, Rimsha1 aBeghini, Francesco1 aBergstrom, Kirk1 aBhatt, Ami1 aBisanz, Jordan, E1 aBraun, Jonathan1 aBravo, Hector, Corrada1 aBuck, Gregory, A1 aBushman, Frederic1 aCasero, David1 aClarke, Gerard1 aCollado, Maria, Carmen1 aCotter, Paul, D1 aCryan, John, F1 aDemmer, Ryan, T1 aDevkota, Suzanne1 aElinav, Eran1 aEscobar, Juan, S1 aFettweis, Jennifer1 aFinn, Robert, D1 aFodor, Anthony, A1 aForslund, Sofia1 aFranke, Andre1 aFurlanello, Cesare1 aGilbert, Jack1 aGrice, Elizabeth1 aHaibe-Kains, Benjamin1 aHandley, Scott1 aHerd, Pamela1 aHolmes, Susan1 aJacobs, Jonathan, P1 aKarstens, Lisa1 aKnight, Rob1 aKnights, Dan1 aKoren, Omry1 aKwon, Douglas, S1 aLangille, Morgan1 aLindsay, Brianna1 aMcGovern, Dermot1 aMcHardy, Alice, C1 aMcWeeney, Shannon1 aMueller, Noel, T1 aNezi, Luigi1 aOlm, Matthew1 aPalm, Noah1 aPasolli, Edoardo1 aRaes, Jeroen1 aRedinbo, Matthew, R1 aRühlemann, Malte1 aSartor, Balfour1 aSchloss, Patrick, D1 aSchriml, Lynn1 aSegal, Eran1 aShardell, Michelle1 aSharpton, Thomas1 aSmirnova, Ekaterina1 aSokol, Harry1 aSonnenburg, Justin, L1 aSrinivasan, Sujatha1 aThingholm, Louise, B1 aTurnbaugh, Peter, J1 aUpadhyay, Vaibhav1 aWalls, Ramona, L1 aWilmes, Paul1 aYamada, Takuji1 aZeller, Georg1 aZhang, Mingyu1 aZhao, Ni1 aZhao, Liping1 aBao, Wenjun1 aCulhane, Aedin1 aDevanarayan, Viswanath1 aDopazo, Joaquin1 aFan, Xiaohui1 aFischer, Matthias1 aJones, Wendell1 aKusko, Rebecca1 aMason, Christopher, E1 aMercer, Tim, R1 aSansone, Susanna-Assunta1 aScherer, Andreas1 aShi, Leming1 aThakkar, Shraddha1 aTong, Weida1 aWolfinger, Russ1 aHunter, Christopher1 aSegata, Nicola1 aHuttenhower, Curtis1 aDowd, Jennifer, B1 aJones, Heidi, E1 aWaldron, Levi1 aGenomic Standards Consortium1 aMassive Analysis and Quality Control Society uhttp://clinbioinfosspa.es/content/reporting-guidelines-human-microbiome-research-storms-checklist02685nas a2200349 4500008004100000022001400041245011500055210006900170260001600239300001400255490000700269520162000276653001201896653002201908653001101930653001301941653001301954653001101967653002401978653002002002653003102022653001302053100003102066700001902097700002002116700002202136700001802158700001802176700002802194700002002222856009302242 2017 eng d a1367-481100aReference genome assessment from a population scale perspective: an accurate profile of variability and noise.0 aReference genome assessment from a population scale perspective c2017 Nov 15 a3511-35170 v333 aMotivation: Current plant and animal genomic studies are often based on newly assembled genomes that have not been properly consolidated. In this scenario, misassembled regions can easily lead to false-positive findings. Despite quality control scores are included within genotyping protocols, they are usually employed to evaluate individual sample quality rather than reference sequence reliability. We propose a statistical model that combines quality control scores across samples in order to detect incongruent patterns at every genomic region. Our model is inherently robust since common artifact signals are expected to be shared between independent samples over misassembled regions of the genome.
Results: The reliability of our protocol has been extensively tested through different experiments and organisms with accurate results, improving state-of-the-art methods. Our analysis demonstrates synergistic relations between quality control scores and allelic variability estimators, that improve the detection of misassembled regions, and is able to find strong artifact signals even within the human reference assembly. Furthermore, we demonstrated how our model can be trained to properly rank the confidence of a set of candidate variants obtained from new independent samples.
Availability and implementation: This tool is freely available at http://gitlab.com/carbonell/ces.
Contact: jcarbonell.cipf@gmail.com or joaquin.dopazo@juntadeandalucia.es.
Supplementary information: Supplementary data are available at Bioinformatics online.
10aAnimals10aGenetic Variation10aGenome10aGenomics10aGenotype10aHumans10aModels, Statistical10aQuality Control10aReproducibility of Results10aSoftware1 aCarbonell-Caballero, José1 aAmadoz, Alicia1 aAlonso, Roberto1 aHidalgo, Marta, R1 aCubuk, Cankut1 aConesa, David1 aLópez-Quílez, Antonio1 aDopazo, Joaquin uhttps://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btx48202531nas a2200361 4500008004100000022001400041245008000055210006900135260001300204300001300217490000800230520137100238653001801609653004901627653003401676653001701710653001101727653002801738653002301766653001301789653002501802653002701827653001001854100003301864700002301897700002801920700003301948700002201981700002002003700001902023700002502042856010202067 2015 eng d a1552-483300aRe-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.0 aReevaluation casts doubt on the pathogenicity of homozygous USH2 c2015 Jul a1597-6000 v1673 aMutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.
10aBase Sequence10aCyclic Nucleotide Phosphodiesterases, Type 610aExtracellular Matrix Proteins10aGene Library10aHumans10aMolecular Sequence Data10aMutation, Missense10aPedigree10aRetinitis pigmentosa10aSequence Analysis, DNA10aSpain1 aDel Pozo, María, González-1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aMontero-de-Espinosa, Ignacio1 aMillán, José, M1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/re-evaluation-casts-doubt-pathogenicity-homozygous-ush2a-pc759f02932nas a2200397 4500008004100000022001400041245010000055210006900155260001600224300000800240490000700248520172500255653001201980653001001992653001702002653002202019653002502041653001802066653001302084653001102097653002002108653001302128653001402141653002502155653002902180653002702209653001102236100002402247700002902271700003102300700002202331700002702353700002502380700002002405856010902425 2014 eng d a1744-429200aThe role of the interactome in the maintenance of deleterious variability in human populations.0 arole of the interactome in the maintenance of deleterious variab c2014 Sep 26 a7520 v103 aRecent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins.
10aAlleles10aExome10aGene Library10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aModels, Genetic10amutation10aPhenotype10aProtein Conformation10aProtein Interaction Maps10aSequence Analysis, DNA10aWhites1 aGarcía-Alonso, Luz1 aJiménez-Almazán, Jorge1 aCarbonell-Caballero, José1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aAntiňolo, Guillermo1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/role-interactome-maintenance-deleterious-variability-human-populations02722nas a2200505 4500008004100000022001400041245018900055210006900244260001300313300001000326490000700336520107200343653002801415653001001443653000901453653002201462653001101484653003801495653001101533653003001544653004401574653004301618653001601661653001101677653001701688653005001705653001401755653000901769653001601778653002001794653001401814653003201828653002801860653000901888653001901897653002101916100003001937700001901967700002001986700002002006700002902026700002002055700001702075856012402092 2013 eng d a1600-062500aRole of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.0 aRole of CPI17 in restoring skin homoeostasis in cutaneous field c2013 Jul a494-60 v223 aCutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P = 0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P = 0.012) and IL-1B (P = 0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.
10aAdministration, Topical10aAdult10aAged10aAged, 80 and over10aBiopsy10aDeoxyribodipyrimidine Photo-Lyase10aFemale10aGene Expression Profiling10aGene Expression Regulation, Enzymologic10aGene Expression Regulation, Neoplastic10aHomeostasis10aHumans10aInflammation10aIntracellular Signaling Peptides and Proteins10aLiposomes10aMale10aMiddle Aged10aMuscle Proteins10aPhenotype10aPhosphoprotein Phosphatases10aReactive Oxygen Species10aSkin10aSkin Neoplasms10aUltraviolet Rays1 aPuig-Butille, Joan, Anton1 aMalvehy, Josep1 aPotrony, Miriam1 aTrullas, Carles1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aPuig, Susana uhttp://clinbioinfosspa.es/content/role-cpi-17-restoring-skin-homoeostasis-cutaneous-field-cancerization-effects-topical01456nas a2200253 4500008004100000245009300041210006900134260000900203300000700212490000700219520063100226100002300857700001500880700001900895700002300914700002800937700001500965700001700980700002100997700002401018700002001042700002001062856012001082 2011 eng d00aRecent human evolution has shaped geographical differences in susceptibility to disease.0 aRecent human evolution has shaped geographical differences in su c2011 a550 v123 aSearching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.
1 aMarigorta, Urko, M1 aLao, Oscar1 aCasals, Ferran1 aCalafell, Francesc1 aMorcillo-Suarez, Carlos1 aFaria, Rui1 aBosch, Elena1 aSerra, François1 aBertranpetit, Jaume1 aDopazo, Hernán1 aNavarro, Arcadi uhttp://clinbioinfosspa.es/content/recent-human-evolution-has-shaped-geographical-differences-susceptibility-disease02322nas a2200241 4500008004100000245007500041210006900116260001300185300001100198490000700209520154000216100002401756700003301780700002101813700001901834700003501853700002001888700001801908700002701926700002001953700001701973856009001990 2011 eng d00aRole of tomato BRANCHED1-like genes in the control of shoot branching.0 aRole of tomato BRANCHED1like genes in the control of shoot branc c2011 Aug a701-140 v673 aIn angiosperms, shoot branching greatly determines overall plant architecture and affects fundamental aspects of plant life. Branching patterns are determined by genetic pathways conserved widely across angiosperms. In Arabidopsis thaliana (Brassicaceae, Rosidae) BRANCHED1 (BRC1) plays a central role in this process, acting locally to arrest axillary bud growth. In tomato (Solanum lycopersicum, Solanaceae, Asteridae) we have identified two BRC1-like paralogues, SlBRC1a and SlBRC1b. These genes are expressed in arrested axillary buds and both are down-regulated upon bud activation, although SlBRC1a is transcribed at much lower levels than SlBRC1b. Alternative splicing of SlBRC1a renders two transcripts that encode two BRC1-like proteins with different C-t domains due to a 3’-terminal frameshift. The phenotype of loss-of-function lines suggests that SlBRC1b has retained the ancestral role of BRC1 in shoot branch suppression. We have isolated the BRC1a and BRC1b genes of other Solanum species and have studied their evolution rates across the lineages. These studies indicate that, after duplication of an ancestral BRC1-like gene, BRC1b genes continued to evolve under a strong purifying selection that was consistent with the conserved function of SlBRC1b in shoot branching control. In contrast, the coding sequences of Solanum BRC1a genes have evolved at a higher evolution rate. Branch-site tests indicate that this difference does not reflect relaxation but rather positive selective pressure for adaptation.
1 aMartín-Trillo, Mar1 aGrandío, Eduardo, González1 aSerra, François1 aMarcel, Fabien1 aRodríguez-Buey, María, Luisa1 aSchmitz, Gregor1 aTheres, Klaus1 aBendahmane, Abdelhafid1 aDopazo, Hernán1 aCubas, Pilar uhttp://clinbioinfosspa.es/content/role-tomato-branched1-genes-control-shoot-branching02322nas a2200181 4500008004100000245005400041210005300095300001100148490000700159520158000166653005701746653002101803653014101824653002701965100001801992700002402010856010602034 2008 eng d00aRNA structure alignment by a unit-vector approach0 aRNA structure alignment by a unitvector approach ai112-80 v243 aMOTIVATION: The recent discovery of tiny RNA molecules such as microRNAs and small interfering RNA are transforming the view of RNA as a simple information transfer molecule. Similar to proteins, the native three-dimensional structure of RNA determines its biological activity. Therefore, classifying the current structural space is paramount for functionally annotating RNA molecules. The increasing numbers of RNA structures deposited in the PDB requires more accurate, automatic and benchmarked methods for RNA structure comparison. In this article, we introduce a new algorithm for RNA structure alignment based on a unit-vector approach. The algorithm has been implemented in the SARA program, which results in RNA structure pairwise alignments and their statistical significance. RESULTS: The SARA program has been implemented to be of general applicability even when no secondary structure can be calculated from the RNA structures. A benchmark against the ARTS program using a set of 1275 non-redundant pairwise structure alignments results in inverted approximately 6% extra alignments with at least 50% structurally superposed nucleotides and base pairs. A first attempt to perform RNA automatic functional annotation based on structure alignments indicates that SARA can correctly assign the deepest SCOR classification to >60% of the query structures. AVAILABILITY: The SARA program is freely available through a World Wide Web server http://sgu.bioinfo.cipf.es/services/SARA/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.10aAlgorithms Base Sequence Computer Simulation *Models10aChemical *Models10aMolecular Molecular Sequence Data Nucleic Acid Conformation RNA/*chemistry/*ultrastructure Sequence Alignment/*methods Sequence Analysis10aRNA/*methods *Software1 aCapriotti, E.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1868981100409nas a2200109 4500008004100000245004200041210004200083260002400125100001800149700001900167856011300186 2007 eng d00aReconstruction of ancestral proteomes0 aReconstruction of ancestral proteomes aOxfordbD. Liberles1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.us.oup.com/us/catalog/general/subject/LifeSciences/EvolutionaryBiology/?view=usa&ci=978019929918802791nas a2200193 4500008004100000245009800041210006900139300001200208490000800220520199800228653005602226653012802282100001302410700001802423700002402441700001302465700001302478856010602491 2006 eng d00aRefinement of protein structures by iterative comparative modeling and CryoEM density fitting0 aRefinement of protein structures by iterative comparative modeli a1655-680 v3573 aWe developed a method for structure characterization of assembly components by iterative comparative protein structure modeling and fitting into cryo-electron microscopy (cryoEM) density maps. Specifically, we calculate a comparative model of a given component by considering many alternative alignments between the target sequence and a related template structure while optimizing the fit of a model into the corresponding density map. The method relies on the previously developed Moulder protocol that iterates over alignment, model building, and model assessment. The protocol was benchmarked using 20 varied target-template pairs of known structures with less than 30% sequence identity and corresponding simulated density maps at resolutions from 5A to 25A. Relative to the models based on the best existing sequence profile alignment methods, the percentage of C(alpha) atoms that are within 5A of the corresponding C(alpha) atoms in the superposed native structure increases on average from 52% to 66%, which is half-way between the starting models and the models from the best possible alignments (82%). The test also reveals that despite the improvements in the accuracy of the fitness function, this function is still the bottleneck in reducing the remaining errors. To demonstrate the usefulness of the protocol, we applied it to the upper domain of the P8 capsid protein of rice dwarf virus that has been studied by cryoEM at 6.8A. The C(alpha) root-mean-square deviation of the model based on the remotely related template, bluetongue virus VP7, improved from 8.7A to 6.0A, while the best possible model has a C(alpha) RMSD value of 5.3A. Moreover, the resulting model fits better into the cryoEM density map than the initial template structure. The method is being implemented in our program MODELLER for protein structure modeling by satisfaction of spatial restraints and will be applicable to the rapidly increasing number of cryoEM density maps of macromolecular assemblies.10aAmino Acid Sequence Cryoelectron Microscopy *Models10aMolecular Molecular Sequence Data Plant Viruses/chemistry *Protein Conformation Software Viral Proteins/*chemistry/genetics1 aTopf, M.1 aBaker, M., L.1 aMarti-Renom, M., A.1 aChiu, W.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1649020700503nas a2200133 4500008004100000022001600041245010000057210006900157260003700226100001900263700001300282700001700295856005700312 2006 eng d a0-387-3452700aReliable and specific protein function prediction by combining homology with genomic(s) context0 aReliable and specific protein function prediction by combining h bF. Eisenhaber, Landes Bioscience1 aHuynen, M., A.1 aSnel, B.1 aT, Gabaldón uhttp://www.landesbioscience.com/iu/output.php?id=47900772nas a2200145 4500008004100000245005700041210005600098300000800154490000800162653016300170653015000333100001800483700001900501856010600520 2003 eng d00aReconstruction of the proto-mitochondrial metabolism0 aReconstruction of the protomitochondrial metabolism a6090 v30110aAerobiosis Algorithms Alphaproteobacteria/chemistry/genetics/*metabolism Amino Acids/metabolism Animals Bacterial Proteins/chemistry/*metabolism Genome Genome10aBacterial Glycerol/metabolism Humans Lipid Metabolism Mitochondria/chemistry/genetics/*metabolism Phylogeny *Proteome Symbiosis Yeasts/metabolism1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1289393401632nas a2200193 4500008004100000245007000041210006900111300001100180490000700191520092300198653004001121653008301161100002401244700002401268700001401292700001301306700001301319856010601332 2002 eng d00aReliability of assessment of protein structure prediction methods0 aReliability of assessment of protein structure prediction method a435-400 v103 aThe reliability of ranking of protein structure modeling methods is assessed. The assessment is based on the parametric Student’s t test and the nonparametric Wilcox signed rank test of statistical significance of the difference between paired samples. The approach is applied to the ranking of the comparative modeling methods tested at the fourth meeting on Critical Assessment of Techniques for Protein Structure Prediction (CASP). It is shown that the 14 CASP4 test sequences may not be sufficient to reliably distinguish between the top eight methods, given the model quality differences and their standard deviations. We suggest that CASP needs to be supplemented by an assessment of protein structure prediction methods that is automated, continuous in time, based on several criteria applied to a large number of models, and with quantitative statistical reliability assigned to each characterization.
10a*Computer Simulation Humans *Models10aMolecular *Protein Conformation Proteins/*chemistry Reproducibility of Results1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aFiser, A.1 aRost, B.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12005441