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1.
Gene ; 764: 145105, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32882333

RESUMO

Sarcoma (SARC) represents a group of highly histological and molecular heterogeneous rare malignant tumors with poor prognosis. There are few proposed classifiers for predicting patient's outcome. The Cancer Proteome Atlas (TPCA) and The Cancer Genome Atlas (TCGA) databases provide multi-omics datasets that enable a comprehensive investigation for this disease. The proteomic expression profile of SARC patients along with the clinical information was downloaded. 55 proteins were found to be associated with overall survival (OS) of patients using univariate Cox regression analysis. We developed a prognostic risk signature that comprises seven proteins (AMPKALPHA, CHK1, S6, ARID1A, RBM15, ACETYLATUBULINLYS40, and MSH6) with robust predictive performance using multivariate Cox stepwise regression analysis. Additionally, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters. Patients in high-risk group also have worse progression free intervals (PFI) than that of patients in low-risk group, but not for disease free intervals (DFI). The signature was validated using transcriptomic profile of SARC patients from TCGA. Potential mechanisms between high- and low-risk groups were identified using differentially expressed genes (DEGs) analysis. These DEGs were primarily enriched in RAS and MPAK signaling pathways. The signature protein molecules are candidate biomarkers for SARC, and the analysis of computational biology in tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinctly immune landscapes of high- and low-risk patients. Together, we constructed a prognostic signature for predicting outcomes for SARC integrating proteomic and transcriptomic profiles, this might have value in guiding clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Testes Genéticos/métodos , Sarcoma/mortalidade , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Mapeamento de Interação de Proteínas , Proteômica , Curva ROC , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/imunologia , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
2.
Gene ; 764: 145106, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889059

RESUMO

BACKGROUND: Circular RNAs (circRNAs) are a new class of non-coding RNA with a stable structure formed by special loop splicing. Research increasingly suggests that circRNAs play a vital role in the pathogenesis and progression of various diseases. However, the roles of circRNAs in osteoblast differentiation under microgravity remain largely unknown. Here, we investigated the roles and mechanobiological response of circRNAs in osteoblasts under simulated microgravity. METHODS: Differential circRNA and mRNA expression profiles of MC3T3-E1 cells during exposure to microgravity were screened by RNA transcriptome sequencing technology (RNA-seq). The selected RNAs were validated using quantitative real-time polymerase chain reaction (qRT-PCR). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied for gene function analyses. RESULTS: A total of 427 circRNAs and 1912 mRNAs were differentially expressed along with osteogenic differentiation in the simulated microgravity group (SMG) compared to the control group (CON). Of these, 232 circRNAs and 991 mRNAs were upregulated, whereas 95 circRNAs and 921 mRNAs were downregulated (fold change ≥ 2, p < 0.05). The results showed that the parental genes of circRNAs and mRNAs were mainly enriched in anatomical structure morphogenesis, anchoring junction and protein binding. KEGG analysis results showed that the differentially expressed mRNAs were enriched in the regulation of the actin cytoskeleton, focal adhesion, and Ras signalling pathway. Subsequently, 9 core regulatory genes, including 6 mRNAs and 3 circRNAs, were identified based on their possible function in osteoblast differentiation. Based on this analysis, circ_014154 was selected as the target circRNA, which likely plays important roles in osteogenic differentiation processes under microgravity. The circRNA-miRNA-mRNA network showed that circRNAs might act as miRNA sponges to regulate osteoblast differentiation. CONCLUSION: By presenting a better understanding of the molecular mechanisms of genes and circRNAs in simulated microgravity, the present study will provide a novel view of circRNAs in the regulation of osteogenic differentiation and bone formation.


Assuntos
Diferenciação Celular/genética , Osteoblastos/fisiologia , Osteogênese/genética , RNA Circular/metabolismo , Simulação de Ausência de Peso/efeitos adversos , Animais , Linhagem Celular , Biologia Computacional , Conjuntos de Dados como Assunto , Redes Reguladoras de Genes/fisiologia , Camundongos , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo
3.
J Toxicol Sci ; 45(11): 695-700, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132243

RESUMO

Coumarin is a dietary-derived substance that is extensively metabolized by human liver to excretable 7-hydroxycoumarin. Although coumarin under daily dietary consumption is generally regarded as nontoxic, the substance is of toxicological and clinical interest because of its potential association with hepatotoxicity, which is especially evident in rats. In this study, the pharmacokinetics of coumarin were modeled after virtual oral administration in humans. The adjusted monitoring equivalents of coumarin, along with the biotransformation of coumarin to o-hydroxyphenylacetic acid (via 3,4-epoxidation) based on reported plasma concentrations from rat studies, were scaled to human coumarin equivalents using known species allometric scaling factors. Using rat and human liver preparations, data on the rapid in vitro metabolic clearance for humans (~50-fold faster than in rats) were obtained for in vitro-in vivo extrapolation. For human physiologically based pharmacokinetic (PBPK) modeling, the metabolic ratios to o-hydroxyphenylacetic acid and 7-hydroxycoumarin were set at minor (0.1) and major (0.9) levels for the total disappearance of coumarin. The resulting modeled plasma concentration curves in humans generated by simple PBPK models were consistent with reported simulated coumarin maximum concentrations. These results provide basic information to simulate plasma levels of coumarin and its primary metabolite 7-hydroxycoumarin or its secondary activated metabolite o-hydroxyphenylacetic acid (via 3,4-epoxidation) resulting from dietary foodstuff consumption. Under the current assumptions, little toxicological impact of coumarin was evident in humans, thereby indicating the usefulness of forward dosimetry using PBPK modeling for human risk assessment.


Assuntos
Cumarínicos/sangue , Cumarínicos/toxicidade , Animais , Simulação por Computador , Cumarínicos/metabolismo , Cumarínicos/farmacocinética , Conjuntos de Dados como Assunto , Humanos , Técnicas In Vitro , Fígado/metabolismo , Masculino , Modelos Biológicos , Fenilacetatos/sangue , Ratos Sprague-Dawley , Medição de Risco , Umbeliferonas/sangue
4.
Nat Commun ; 11(1): 5511, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139731

RESUMO

Parallel molecular evolution and adaptation are important phenomena commonly observed in viruses. Here, we exploit parallel molecular evolution to understand virulence evolution in avian influenza viruses (AIV). Highly-pathogenic AIVs evolve independently from low-pathogenic ancestors via acquisition of polybasic cleavage sites. Why some AIV lineages but not others evolve in this way is unknown. We hypothesise that the parallel emergence of highly-pathogenic AIV may be facilitated by permissive or compensatory mutations occurring across the viral genome. We combine phylogenetic, statistical and structural approaches to discover parallel mutations in AIV genomes associated with the highly-pathogenic phenotype. Parallel mutations were screened using a statistical test of mutation-phenotype association and further evaluated in the contexts of positive selection and protein structure. Our resulting mutational panel may help to reveal new links between virulence evolution and other traits, and raises the possibility of predicting aspects of AIV evolution.


Assuntos
Evolução Molecular , Vírus da Influenza A/patogenicidade , Influenza Aviária/virologia , Influenza Humana/virologia , Virulência/genética , Animais , Sequência de Bases/genética , Aves/virologia , Conjuntos de Dados como Assunto , Genoma Viral/genética , Humanos , Vírus da Influenza A/genética , Influenza Aviária/transmissão , Influenza Humana/transmissão , Mutação , Filogenia , Estabilidade Proteica , Seleção Genética , Alinhamento de Sequência , Proteínas Virais/genética
5.
Medicine (Baltimore) ; 99(45): e22985, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157942

RESUMO

This study aimed to identify significantly altered long non-coding RNAs (lncRNAs), microRNAs (miRNAs), mRNAs, pathways in preeclampsia (PE), and to investigate their targeted relationships and biological functions.GSE96985 from Gene Expression Omnibus database was extracted, involving 3 PE and 4 normal tissues. After the differential expression analysis of miRNAs, lncRNAs, and mRNAs using the limma package, protein-protein interaction (PPI) network and module analyses were performed for differentially expressed mRNAs (dif-mRNAs). Combined with the miRanda and miRWalk tools, a regulatory relationship between dif-miRNAs and dif-mRNAs/lncRNAs (dif-mRNAs/dif-lncRNAs) was predicted. Finally, mRNA-miRNA-lncRNA regulatory network construction was performed using Cytoscape software.A total of 511 dif-mRNAs were screened in PE. The top 5 nodes in the PPI networks included up-regulated complement component 3 (C3), C-X-C motif chemokine ligand 8 (CXCL8), and fibronectin 1 (FN1). Three significant network modules were identified for dif-mRNAs. C3 and CXCL8 were identified in module A, and FN1 was identified in module C. A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6) was down-regulated by the miR-210-3p. Therefore, lnc-CTD-2383M3.1 functions as a competing endogenous RNA in ADAMTS6 expression regulation by competitively binding to miR-210-3p during the regulation process of PE.C3, CXCL8, FN1, and ADAMTS6 might be involved in the development of PE. The lnc-CTD-2383M3.1-miR-210-3p-ADAMTS6 axis might be a potential regulatory mechanism in PE.


Assuntos
Redes Reguladoras de Genes , MicroRNAs/metabolismo , Pré-Eclâmpsia/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Proteínas ADAMTS/genética , Biomarcadores/metabolismo , Complemento C3/genética , Conjuntos de Dados como Assunto , Regulação para Baixo , Feminino , Fibronectinas/genética , Perfilação da Expressão Gênica , Humanos , Interleucina-8/genética , Gravidez , Regulação para Cima
6.
Science ; 370(6513): 208-214, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33033216

RESUMO

Linking genomic variation to phenotypical traits remains a major challenge in evolutionary genetics. In this study, we use phylogenomic strategies to investigate a distinctive trait among mammals: the development of masculinizing ovotestes in female moles. By combining a chromosome-scale genome assembly of the Iberian mole, Talpa occidentalis, with transcriptomic, epigenetic, and chromatin interaction datasets, we identify rearrangements altering the regulatory landscape of genes with distinct gonadal expression patterns. These include a tandem triplication involving CYP17A1, a gene controlling androgen synthesis, and an intrachromosomal inversion involving the pro-testicular growth factor gene FGF9, which is heterochronically expressed in mole ovotestes. Transgenic mice with a knock-in mole CYP17A1 enhancer or overexpressing FGF9 showed phenotypes recapitulating mole sexual features. Our results highlight how integrative genomic approaches can reveal the phenotypic impact of noncoding sequence changes.


Assuntos
Adaptação Fisiológica/genética , Fator 9 de Crescimento de Fibroblastos/genética , Toupeiras/genética , Elementos Reguladores de Transcrição , Diferenciação Sexual/genética , Esteroide 17-alfa-Hidroxilase/genética , Animais , Inversão Cromossômica , Conjuntos de Dados como Assunto , Feminino , Regulação da Expressão Gênica , Genoma , Camundongos , Camundongos Transgênicos , Sequências de Repetição em Tandem , Testosterona/sangue , Testosterona/genética
7.
Science ; 370(6513): 220-222, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33033218

RESUMO

Environmental change is transforming ecological assemblages into new configurations, resulting in novel communities. We developed a robust methodology to detect novel communities, examine patterns of emergence, and quantify probabilities of local demographic turnover in transitions to and from novel communities. Using a global dataset of Cenozoic marine plankton communities, we found that the probability of local extinction, origination, and emigration during transitions to a novel community increased two to four times that of background community changes. Although rare, novel communities were five times more likely than chance to shift into another novel state. For marine plankton communities at a 100,000-year time grain, novel communities were sensitive to further extinctions and substantial community change.


Assuntos
Biodiversidade , Extinção Biológica , Plâncton , Conjuntos de Dados como Assunto , Especiação Genética , Espécies Introduzidas , Probabilidade
8.
J Card Surg ; 35(11): 2995-3003, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33111448

RESUMO

BACKGROUND: Preoperative dental screening before cardiac valve surgery is widely accepted but its required scope remains unclear. This study evaluates two preoperative dental screening (PDS) approaches, a focused approach (FocA) and a comprehensive approach (CompA), to compare postsurgical 90-day mortality. METHODS: Retrospective cohort analysis was performed on all patients who underwent valve surgery at Brigham and Women's Hospital with FocA and Massachusetts General Hospital with CompA of PDS approach from January 2009 to December 2016. Patients with intravenous drug abuse and systemic infections were excluded. Univariate, multivariable, and subgroup analysis was performed. RESULTS: A total of 1835 patients were included in the study. With FocA 96% of patients (1097/1143) received dental clearance in a single encounter with 3.3% receiving radiographs and undergoing dental extractions. With CompA 35.5% of patients (245/692) received dental clearance in a single encounter, 94.2% received radiographs, and 21.8% underwent dental extractions. There was no significant difference in 90-day mortality when comparing both PDS approach (10% vs 8.4%, P = .257). This remained unchanged in a multivariable model after adjusting for risk factors (odds ratio:1.32 [95%CI:0.91-1.93] [P = .14]). Reoperation due to infection was less in FocA (0.5%) vs CompA (2.6) (P < .001) and postoperative septicemia was increased in the FocA (1.7%) cohort when compared to the CompA (0.7%) (P < .001) patients. CONCLUSIONS: There was no difference in post valve surgery 90-day mortality between patients who underwent a FocA vs CompA of PDS.


Assuntos
Procedimentos Cirúrgicos Cardíacos/mortalidade , Doenças das Valvas Cardíacas/mortalidade , Doenças das Valvas Cardíacas/cirurgia , Valvas Cardíacas/cirurgia , Resultados Negativos , Higiene Bucal , Cuidados Pré-Operatórios/métodos , Doenças Estomatognáticas/diagnóstico , Doenças Estomatognáticas/terapia , Infecção da Ferida Cirúrgica/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Cardíacos/métodos , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
9.
Nat Commun ; 11(1): 5183, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33056981

RESUMO

Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome and/or transcriptome data from 702 neuroblastoma samples. Forty percent of samples harbor at least one recurrent driver gene alteration and most aberrations, including MYCN, ATRX, and TERT alterations, differ in frequency by age. MYCN alterations occur at median 2.3 years of age, TERT at 3.8 years, and ATRX at 5.6 years. COSMIC mutational signature 18, previously associated with reactive oxygen species, is the most common cause of driver point mutations in neuroblastoma, including most ALK and Ras-activating variants. Signature 18 appears early and is continuous throughout disease evolution. Signature 18 is enriched in neuroblastomas with MYCN amplification, 17q gain, and increased expression of mitochondrial ribosome and electron transport-associated genes. Recurrent FGFR1 variants in six patients, and ALK N-terminal structural alterations in five samples, identify additional patients potentially amenable to precision therapy.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neuroblastoma/genética , Adolescente , Adulto , Fatores Etários , Quinase do Linfoma Anaplásico/genética , Criança , Pré-Escolar , Estudos de Coortes , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Transporte de Elétrons/genética , Exoma/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Ribossomos Mitocondriais , Mutação , Neuroblastoma/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Ribossômicas/genética , Transcriptoma/genética , Sequenciamento Completo do Genoma , Adulto Jovem
10.
Nucleic Acids Res ; 48(19): e114, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33035301

RESUMO

The ability to characterize repetitive regions of the human genome is limited by the read lengths of short-read sequencing technologies. Although long-read sequencing technologies such as Pacific Biosciences (PacBio) and Oxford Nanopore Technologies can potentially overcome this limitation, long segmental duplications with high sequence identity pose challenges for long-read mapping. We describe a probabilistic method, DuploMap, designed to improve the accuracy of long-read mapping in segmental duplications. It analyzes reads mapped to segmental duplications using existing long-read aligners and leverages paralogous sequence variants (PSVs)-sequence differences between paralogous sequences-to distinguish between multiple alignment locations. On simulated datasets, DuploMap increased the percentage of correctly mapped reads with high confidence for multiple long-read aligners including Minimap2 (74.3-90.6%) and BLASR (82.9-90.7%) while maintaining high precision. Across multiple whole-genome long-read datasets, DuploMap aligned an additional 8-21% of the reads in segmental duplications with high confidence relative to Minimap2. Using DuploMap-aligned PacBio circular consensus sequencing reads, an additional 8.9 Mb of DNA sequence was mappable, variant calling achieved a higher F1 score and 14 713 additional variants supported by linked-read data were identified. Finally, we demonstrate that a significant fraction of PSVs in segmental duplications overlaps with variants and adversely impacts short-read variant calling.


Assuntos
Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Duplicações Segmentares Genômicas , Análise de Sequência de DNA/métodos , Software , Algoritmos , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Humanos
11.
Nat Commun ; 11(1): 5038, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028830

RESUMO

Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.


Assuntos
Epilepsia Resistente a Medicamentos/genética , Epilepsia do Lobo Temporal/genética , Neurônios/patologia , Lobo Temporal/patologia , Transcriptoma/genética , Adolescente , Adulto , Biópsia , Estudos de Casos e Controles , Núcleo Celular/genética , Núcleo Celular/metabolismo , Conjuntos de Dados como Assunto , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/patologia , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Ácido Glutâmico/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Microdissecção , Pessoa de Meia-Idade , Modelos Genéticos , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neurônios/citologia , Neurônios/metabolismo , RNA-Seq , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Transdução de Sinais/genética , Análise de Célula Única , Lobo Temporal/citologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/cirurgia , Transcrição Genética , Regulação para Cima , Adulto Jovem
12.
J Med Internet Res ; 22(11): e23361, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33035176

RESUMO

BACKGROUND: Despite electronic health records being in existence for over 50 years, our ability to exchange health data remains frustratingly limited. Commonly used clinical content standards, and the information models that underpin them, are primarily related to health data exchange, and so are usually document- or message-focused. In contrast, over the past 12 years, the Clinical Models program at openEHR International has gradually established a governed, coordinated, and coherent ecosystem of clinical information models, known as openEHR archetypes. Each archetype is designed as a maximal data set for a universal use-case, intended for reuse across various health data sets, known as openEHR templates. To date, only anecdotal evidence has been available to indicate if the hypothesis of archetype reuse across templates is feasible and scalable. As a response to the COVID-19 pandemic, between February and July 2020, 7 openEHR templates were independently created to represent COVID-19-related data sets for symptom screening, confirmed infection reporting, clinical decision support, and research. Each of the templates prioritized reuse of existing use-case agnostic archetypes found in openEHR International's online Clinical Knowledge Manager tool as much as possible. This study is the first opportunity to investigate archetype reuse within a range of diverse, multilingual openEHR templates. OBJECTIVE: This study aims to investigate the use and reuse of openEHR archetypes across the 7 openEHR templates as an initial investigation about the reuse of information models across data sets used for a variety of clinical purposes. METHODS: Analysis of both the number of occurrences of archetypes and patterns of occurrence within 7 discrete templates was carried out at the archetype or clinical concept level. RESULTS: Across all 7 templates collectively, 203 instances of 58 unique archetypes were used. The most frequently used archetype occurred 24 times across 4 of the 7 templates. Total data points per template ranged from 40 to 179. Archetype instances per template ranged from 10 to 62. Unique archetype occurrences ranged from 10 to 28. Existing archetype reuse of use-case agnostic archetypes ranged from 40% to 90%. Total reuse of use-case agnostic archetypes ranged from 40% to 100%. CONCLUSIONS: Investigation of the amount of archetype reuse across the 7 openEHR templates in this initial study has demonstrated significant reuse of archetypes, even across unanticipated, novel modeling challenges and multilingual deployments. While the trigger for the development of each of these templates was the COVID-19 pandemic, the templates represented a variety of types of data sets: symptom screening, infection report, clinical decision support for diagnosis and treatment, and secondary use or research. The findings support the openEHR hypothesis that it is possible to create a shared, public library of standards-based, vendor-neutral clinical information models that can be reused across a diverse range of health data sets.


Assuntos
Conjuntos de Dados como Assunto , Registros Eletrônicos de Saúde , Multilinguismo , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Sistemas de Apoio a Decisões Clínicas , Utilização de Instalações e Serviços , Humanos , Pandemias , Pneumonia Viral/epidemiologia
13.
Nat Commun ; 11(1): 5057, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028812

RESUMO

Engineered RNA elements are programmable tools capable of detecting small molecules, proteins, and nucleic acids. Predicting the behavior of these synthetic biology components remains a challenge, a situation that could be addressed through enhanced pattern recognition from deep learning. Here, we investigate Deep Neural Networks (DNN) to predict toehold switch function as a canonical riboswitch model in synthetic biology. To facilitate DNN training, we synthesize and characterize in vivo a dataset of 91,534 toehold switches spanning 23 viral genomes and 906 human transcription factors. DNNs trained on nucleotide sequences outperform (R2 = 0.43-0.70) previous state-of-the-art thermodynamic and kinetic models (R2 = 0.04-0.15) and allow for human-understandable attention-visualizations (VIS4Map) to identify success and failure modes. This work shows that deep learning approaches can be used for functionality predictions and insight generation in RNA synthetic biology.


Assuntos
Aprendizado Profundo , Engenharia Genética/métodos , Riboswitch/genética , Biologia Sintética/métodos , Conjuntos de Dados como Assunto , Genoma Viral/genética , Humanos , Cinética , Termodinâmica , Fatores de Transcrição/genética
14.
Nat Commun ; 11(1): 5046, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028816

RESUMO

Signal loss in blood oxygen level-dependent (BOLD) functional neuroimaging is common and can lead to misinterpretation of findings. Here, we reconstructed compromised fMRI signal using deep machine learning. We trained a model to learn principles governing BOLD activity in one dataset and reconstruct artificially compromised regions in an independent dataset, frame by frame. Intriguingly, BOLD time series extracted from reconstructed frames are correlated with the original time series, even though the frames do not independently carry any temporal information. Moreover, reconstructed functional connectivity maps exhibit good correspondence with the original connectivity maps, indicating that the model recovers functional relationships among brain regions. We replicated this result in two healthy datasets and in patients whose scans suffered signal loss due to intracortical electrodes. Critically, the reconstructions capture individual-specific information. Deep machine learning thus presents a unique opportunity to reconstruct compromised BOLD signal while capturing features of an individual's own functional brain organization.


Assuntos
Mapeamento Encefálico/métodos , Córtex Cerebral/diagnóstico por imagem , Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Adolescente , Adulto , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/fisiologia , Conjuntos de Dados como Assunto , Estimulação Encefálica Profunda , Feminino , Voluntários Saudáveis , Humanos , Masculino , Modelos Neurológicos , Oxigênio/sangue , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Adulto Jovem
15.
Nat Commun ; 11(1): 5058, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028819

RESUMO

While synthetic biology has revolutionized our approaches to medicine, agriculture, and energy, the design of completely novel biological circuit components beyond naturally-derived templates remains challenging due to poorly understood design rules. Toehold switches, which are programmable nucleic acid sensors, face an analogous design bottleneck; our limited understanding of how sequence impacts functionality often necessitates expensive, time-consuming screens to identify effective switches. Here, we introduce Sequence-based Toehold Optimization and Redesign Model (STORM) and Nucleic-Acid Speech (NuSpeak), two orthogonal and synergistic deep learning architectures to characterize and optimize toeholds. Applying techniques from computer vision and natural language processing, we 'un-box' our models using convolutional filters, attention maps, and in silico mutagenesis. Through transfer-learning, we redesign sub-optimal toehold sensors, even with sparse training data, experimentally validating their improved performance. This work provides sequence-to-function deep learning frameworks for toehold selection and design, augmenting our ability to construct potent biological circuit components and precision diagnostics.


Assuntos
Biotecnologia/métodos , Aprendizado Profundo , Engenharia Genética/métodos , Riboswitch/genética , Biologia Sintética/métodos , Sequência de Bases/genética , Simulação por Computador , Conjuntos de Dados como Assunto , Genoma Humano/genética , Genoma Viral/genética , Humanos , Modelos Genéticos , Mutagênese , Processamento de Linguagem Natural , Relação Estrutura-Atividade
16.
Nat Commun ; 11(1): 4930, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004804

RESUMO

Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.


Assuntos
LDL-Colesterol/sangue , Regulação da Expressão Gênica , Predisposição Genética para Doença , Modelos Genéticos , Locos de Características Quantitativas , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , LDL-Colesterol/metabolismo , Simulação por Computador , Conjuntos de Dados como Assunto , Pleiotropia Genética , Humanos , Desequilíbrio de Ligação , Metabolismo dos Lipídeos/genética , Análise da Randomização Mendeliana , Redes e Vias Metabólicas/genética , Herança Multifatorial , Nectinas/genética , Nectinas/metabolismo , Países Baixos , Proteômica , RNA-Seq
17.
Hum Genomics ; 14(1): 36, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33036646

RESUMO

INTRODUCTION: The course of COVID-19 varies from asymptomatic to severe in patients. The basis for this range in symptoms is unknown. One possibility is that genetic variation is partly responsible for the highly variable response. We evaluated how well a genetic risk score based on chromosomal-scale length variation and machine learning classification algorithms could predict severity of response to SARS-CoV-2 infection. METHODS: We compared 981 patients from the UK Biobank dataset who had a severe reaction to SARS-CoV-2 infection before 27 April 2020 to a similar number of age-matched patients drawn for the general UK Biobank population. For each patient, we built a profile of 88 numbers characterizing the chromosomal-scale length variability of their germ line DNA. Each number represented one quarter of the 22 autosomes. We used the machine learning algorithm XGBoost to build a classifier that could predict whether a person would have a severe reaction to COVID-19 based only on their 88-number classification. RESULTS: We found that the XGBoost classifier could differentiate between the two classes at a significant level (p = 2 · 10-11) as measured against a randomized control and (p = 3 · 10-14) as measured against the expected value of a random guessing algorithm (AUC = 0.5). However, we found that the AUC of the classifier was only 0.51, too low for a clinically useful test. CONCLUSION: Genetics play a role in the severity of COVID-19, but we cannot yet develop a useful genetic test to predict severity.


Assuntos
Algoritmos , Betacoronavirus/isolamento & purificação , Aberrações Cromossômicas , Cromossomos Humanos/genética , Infecções por Coronavirus/diagnóstico , Aprendizado de Máquina , Pneumonia Viral/diagnóstico , Índice de Gravidade de Doença , Betacoronavirus/genética , Estudos de Casos e Controles , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Conjuntos de Dados como Assunto , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/virologia , Fatores de Risco
18.
Sci Data ; 7(1): 329, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33057040

RESUMO

The COVID-19 pandemic has ignited interest in age-specific manifestations of infection but surprisingly little is known about relative severity of infectious disease between the extremes of age. In a systematic analysis we identified 142 datasets with information on severity of disease by age for 32 different infectious diseases, 19 viral and 13 bacterial. For almost all infections, school-age children have the least severe disease, and severity starts to rise long before old age. Indeed, for many infections even young adults have more severe disease than children, and dengue was the only infection that was most severe in school-age children. Together with data on vaccine response in children and young adults, the findings suggest peak immune function is reached around 5-14 years of age. Relative immune senescence may begin much earlier than assumed, before accelerating in older age groups. This has major implications for understanding resilience to infection, optimal vaccine scheduling, and appropriate health protection policies across the life course.


Assuntos
Fatores Etários , Doenças Transmissíveis/imunologia , Adolescente , Adulto , Betacoronavirus , Criança , Pré-Escolar , Doenças Transmissíveis/mortalidade , Infecções por Coronavirus , Conjuntos de Dados como Assunto , Humanos , Imunossenescência , Pandemias , Pneumonia Viral , Índice de Gravidade de Doença , Adulto Jovem
19.
PLoS One ; 15(10): e0241170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33112895

RESUMO

Estimating the percentages of undiagnosed and asymptomatic patients is essential for controlling the outbreak of SARS-CoV-2, and for assessing any strategy for controlling the disease. In this paper, we propose a novel analysis based on the birth-death process with recursive full tracing. We estimated the numbers of undiagnosed symptomatic patients and the lower bound of the number of total infected individuals per diagnosed patient before and after the declaration of the state of emergency in Hokkaido, Japan. The median of the estimated number of undiagnosed symptomatic patients per diagnosed patient decreased from 1.7 to 0.77 after the declaration, and the median of the estimated lower bound of the number of total infected individuals per diagnosed patient decreased from 4.2 to 2.4. We will discuss the limitations and possible expansions of the model.


Assuntos
Infecções Assintomáticas/epidemiologia , Betacoronavirus , Busca de Comunicante/estatística & dados numéricos , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Técnicas de Laboratório Clínico , Análise por Conglomerados , Simulação por Computador , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Conjuntos de Dados como Assunto , Humanos , Ilhas , Japão/epidemiologia , Modelos Teóricos , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão , Quarentena , Processos Estocásticos
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