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1.
Nucleic Acids Res ; 47(20): 10597-10611, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31544924

RESUMO

Identifying functional variants underlying disease risk and adoption of personalized medicine are currently limited by the challenge of interpreting the functional consequences of genetic variants. Predicting the functional effects of disease-associated protein-coding variants is increasingly routine. Yet, the vast majority of risk variants are non-coding, and predicting the functional consequence and prioritizing variants for functional validation remains a major challenge. Here, we develop a deep learning model to accurately predict locus-specific signals from four epigenetic assays using only DNA sequence as input. Given the predicted epigenetic signal from DNA sequence for the reference and alternative alleles at a given locus, we generate a score of the predicted epigenetic consequences for 438 million variants observed in previous sequencing projects. These impact scores are assay-specific, are predictive of allele-specific transcription factor binding and are enriched for variants associated with gene expression and disease risk. Nucleotide-level functional consequence scores for non-coding variants can refine the mechanism of known functional variants, identify novel risk variants and prioritize downstream experiments.

2.
Sci Data ; 6(1): 180, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551426

RESUMO

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org .

4.
Nat Genet ; 51(4): 659-674, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30911161

RESUMO

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.


Assuntos
Encéfalo/fisiopatologia , Expressão Gênica/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Risco , Transcriptoma/genética
5.
Science ; 362(6420)2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30545857

RESUMO

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica , Transtornos Mentais/genética , Conjuntos de Dados como Assunto , Aprendizado Profundo , Elementos Facilitadores Genéticos , Epigênese Genética , Epigenômica , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas , Análise de Célula Única , Transcriptoma
6.
Nat Neurosci ; 21(8): 1126-1136, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30038276

RESUMO

Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas. Thousands of significant histone quantitative trait loci were identified in neuronal and neuron-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly over-represented in neuronal H3K4me3 and H3K27ac landscapes. Our Resource, sponsored by PsychENCODE and CommonMind, highlights the critical role of cell-type-specific signatures at regulatory and disease-associated noncoding sequences in the human frontal lobe.

8.
Am J Hum Genet ; 102(6): 1169-1184, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29805045

RESUMO

Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (n = 467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context-specific (e.g., tissue-, cell type-, or developmental time point-specific) regulation of gene expression. Integrating the 2014 Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC primary and conditional eQTL data reveals 40 loci with strong evidence for co-localization (posterior probability > 0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes, identify novel genes associated with schizophrenia risk, and provide specific hypotheses for their functional follow-up.

9.
Indian J Anaesth ; 61(5): 381-386, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28584346

RESUMO

BACKGROUND AND AIMS: Modified radical mastectomy (MRM) may be associated with severe post-operative pain, leading to chronic pain syndrome. We compared the post-operative analgesic profile of two ultrasound-guided nerve blocks: Paravertebral block (PVB) and serratus plane block (SPB). METHODS: This double-blind, randomised study was conducted on fifty adult females, scheduled for MRM with axillary dissection. After inducing general anaesthesia with intravenous midazolam 1 mg, fentanyl 1.5 mcg/kg, propofol 1-2 mg/kg and vecuronium 0.1 mg/kg, patients were administered either ultrasound-guided thoracic PVB at T4 (n = 25) or SPB at 5th rib (n = 25) with 20 ml of 0.5% bupivacaine, both as a single level injection. Time to first rescue analgesia and morphine consumption in 4, 6, 24, 48 and 72 h by PCA pump, visual analogue scale score and any adverse effects were recorded. Quantitative variables were compared using the unpaired t-test or the Mann-Whitney U test between the two groups. Qualitative variables were compared using the Chi-square test or Fisher's exact test. RESULTS: The duration of analgesia (mean ± Standard deviation [SD]) was significantly longer in the PVB group compared to SPB group (346 ± 57 min vs. 245.6 ± 58 min, P < 0.001). The post-operative 24 h morphine consumption (mean ± SD) was significantly higher in the SPB group (9.7 ± 2.1 mg) compared to PVB group (6.5 ± 1.5 mg) (P < 0.001). CONCLUSION: Ultrasound-guided SPB is an alternative analgesic technique to thoracic PVB for MRM although PVB provides a longer duration of analgesia.

10.
PLoS One ; 10(7): e0128668, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26132396

RESUMO

How simple is the underlying control mechanism for the complex locomotion of vertebrates? We explore this question for the swimming behavior of zebrafish larvae. A parameter-independent method, similar to that used in studies of worms and flies, is applied to analyze swimming movies of fish. The motion itself yields a natural set of fish "eigenshapes" as coordinates, rather than the experimenter imposing a choice of coordinates. Three eigenshape coordinates are sufficient to construct a quantitative "postural space" that captures >96% of the observed zebrafish locomotion. Viewed in postural space, swim bouts are manifested as trajectories consisting of cycles of shapes repeated in succession. To classify behavioral patterns quantitatively and to understand behavioral variations among an ensemble of fish, we construct a "behavioral space" using multi-dimensional scaling (MDS). This method turns each cycle of a trajectory into a single point in behavioral space, and clusters points based on behavioral similarity. Clustering analysis reveals three known behavioral patterns-scoots, turns, rests-but shows that these do not represent discrete states, but rather extremes of a continuum. The behavioral space not only classifies fish by their behavior but also distinguishes fish by age. With the insight into fish behavior from postural space and behavioral space, we construct a two-channel neural network model for fish locomotion, which produces strikingly similar postural space and behavioral space dynamics compared to real zebrafish.


Assuntos
Comportamento Animal , Locomoção , Redes Neurais (Computação) , Peixe-Zebra/fisiologia , Animais , Larva , Natação
12.
Indian J Anaesth ; 56(4): 353-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23087457

RESUMO

BACKGROUND: The flexible fibreoptic bronchoscope and bonfils rigid intubation endoscope are being widely used for difficult intubations. METHODS: The haemodynamic response to intubation under general anaesthesia was studied in 60 adult female patients who were intubated using either flexible fibreoptic bronchoscope or bonfils rigid intubation endoscope (30 in each group). Non-invasive blood pressure and heart rate (HR) was recorded before induction of anaesthesia, immediately after induction, at the time of intubation and, thereafter, every minute for the next 5 min. The product of HR and systolic blood pressure (rate pressure product) at every point of time was also calculated. STATISTICAL ANALYSES: Graph pad prism, 5.0 statistical software, independent t test and repeated measure ANOVA test were used. RESULTS: Both bonfils rigid intubation endoscope and flexible fibreoptic bronchoscope required a similar time (less than 1 min) for orotracheal intubation. After intubation, there was a significant increase in HR, blood pressure and rate pressure product (P<0.001) in both the groups compared with the baseline and post-induction values. There was no significant difference in HR, blood pressure and rate pressure product at any of the measuring points or in their maximum values during observation between the two groups. The time required for recovery of systolic blood pressure and HR to post-induction value (±10%) was not significantly different between the two groups (more than 2 min). CONCLUSION: In female adults under general anaesthesia, bonfils rigid intubation endoscope and flexible fibreoptic bronchoscope require a similar time for successful orotracheal intubation and cause a similar magnitude of haemodynamic response.

13.
J Chem Phys ; 135(1): 015102, 2011 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-21744920

RESUMO

Protein stability is measured by denaturation: When solvent conditions are changed (e.g., temperature, denaturant concentration, or pH) the protein population switches between thermodynamic states. The resulting denaturation curves have baselines. If the baselines are steep, nonlinear, or incomplete, it becomes difficult to characterize protein denaturation. Baselines arise because the chromophore probing denaturation is sensitive to solvent conditions, or because the thermodynamic states evolve structurally when solvent conditions are changed, or because the barriers are very low (downhill folding). Kinetics can largely eliminate such baselines: Relaxation of chromophores, or within thermodynamic states, is much faster than the transition over activation barriers separating states. This separation of time scales disentangles population switching between states (desired signal) from chromophore or population relaxation within states (baselines). We derive simple formulas to extract unfolding thermodynamics from kinetics. The formulas are tested with model data and with a difficult experimental test case: the apparent two-state folder PI3K SH3 domain. Its melting temperature T(m) can be extracted reliably by our "thermodynamics from kinetics approach," even when conventional fitting is unreliable.


Assuntos
Fosfatidilinositol 3-Quinases/química , Desnaturação Proteica , Termodinâmica , Sequência de Aminoácidos , Cinética , Dados de Sequência Molecular , Fosfatidilinositol 3-Quinases/genética , Engenharia de Proteínas , Estabilidade Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Domínios de Homologia de src
14.
J Anesth ; 25(4): 585-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21626261

RESUMO

Congenital diaphragmatic eventration is uncommon in adults and is caused by paralysis, aplasia or atrophy of the muscular fibers of the diaphragm. It may cause severe dyspnea, orthopnea and hypoxia in adult patients. Most symptomatic patients may be managed efficiently without the need for surgical correction, although any event that leads to an increase in intra-abdominal pressure puts them at the risk of spontaneous diaphragmatic rupture. This case report presents the successful anesthetic management of an adult female with congenital diaphragmatic eventration undergoing diagnostic laparoscopy and hysteroscopy using a total intravenous anesthesia technique. Essential steps to prevent any rise in intrathoracic and intra-abdominal pressures along with care to minimize intragastric volume were taken.


Assuntos
Anestesia Intravenosa/métodos , Diafragma/cirurgia , Eventração Diafragmática/diagnóstico , Eventração Diafragmática/cirurgia , Feminino , Humanos , Histeroscopia/métodos , Laparoscopia/métodos , Adulto Jovem
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