RESUMO
We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
Assuntos
Transtorno Autístico/genética , Córtex Cerebral/crescimento & desenvolvimento , Sequenciamento do Exoma/métodos , Regulação da Expressão Gênica no Desenvolvimento , Neurobiologia/métodos , Estudos de Casos e Controles , Linhagem da Célula , Estudos de Coortes , Exoma , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Mutação de Sentido Incorreto , Neurônios/metabolismo , Fenótipo , Fatores Sexuais , Análise de Célula Única/métodosRESUMO
Applications of machine learning in the biomedical sciences are growing rapidly. This growth has been spurred by diverse cross-institutional and interdisciplinary collaborations, public availability of large datasets, an increase in the accessibility of analytic routines, and the availability of powerful computing resources. With this increased access and exposure to machine learning comes a responsibility for education and a deeper understanding of its bases and bounds, borne equally by data scientists seeking to ply their analytic wares in medical research and by biomedical scientists seeking to harness such methods to glean knowledge from data. This article provides an accessible and critical review of machine learning for a biomedically informed audience, as well as its applications in psychiatry. The review covers definitions and expositions of commonly used machine learning methods, and historical trends of their use in psychiatry. We also provide a set of standards, namely Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN), for designing and reporting studies that use machine learning as a primary data-analysis approach. Lastly, we propose the establishment of the Machine Learning in Psychiatry (MLPsych) Consortium, enumerate its objectives, and identify areas of opportunity for future applications of machine learning in biological psychiatry. This review serves as a cautiously optimistic primer on machine learning for those on the precipice as they prepare to dive into the field, either as methodological practitioners or well-informed consumers.
Assuntos
Psiquiatria Biológica , Aprendizado de Máquina , Humanos , Psiquiatria Biológica/métodos , Psiquiatria/métodos , Pesquisa Biomédica/métodosRESUMO
Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.
Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Transtorno do Espectro Autista/patologia , Criança , Metilação de DNA/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epigênese Genética/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Transcriptoma/genéticaRESUMO
BACKGROUND: The pathophysiology of autism spectrum disorder (ASD) involves genetic and environmental factors. Mounting evidence demonstrates a role for the gut microbiome in ASD, with signaling via short-chain fatty acids (SCFA) as one mechanism. Here, we utilize mice carrying deletion to exons 4-22 of Shank3 (Shank3KO) to model gene by microbiome interactions in ASD. We identify SCFA acetate as a mediator of gut-brain interactions and show acetate supplementation reverses social deficits concomitant with alterations to medial prefrontal cortex (mPFC) transcriptional regulation independent of microbiome status. METHODS: Shank3KO and wild-type (Wt) littermates were divided into control, Antibiotic (Abx), Acetate and Abx + Acetate groups upon weaning. After six weeks, animals underwent behavioral testing. Molecular analysis including 16S and metagenomic sequencing, metabolomic and transcriptional profiling were conducted. Additionally, targeted serum metabolomic data from Phelan McDermid Syndrome (PMS) patients (who are heterozygous for the Shank3 gene) were leveraged to assess levels of SCFA's relative to ASD clinical measures. RESULTS: Shank3KO mice were found to display social deficits, dysregulated gut microbiome and decreased cecal levels of acetate - effects exacerbated by Abx treatment. RNA-sequencing of mPFC showed unique gene expression signature induced by microbiome depletion in the Shank3KO mice. Oral treatment with acetate reverses social deficits and results in marked changes in gene expression enriched for synaptic signaling, pathways among others, even in Abx treated mice. Clinical data showed sex specific correlations between levels of acetate and hyperactivity scores. CONCLUSION: These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.
Assuntos
Transtorno do Espectro Autista , Humanos , Masculino , Feminino , Camundongos , Animais , Transtorno do Espectro Autista/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal , Acetatos/farmacologia , Suplementos Nutricionais , Proteínas dos MicrofilamentosRESUMO
Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N = 525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n = 186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n = 174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N = 888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis-regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis-regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Veteranos , Encéfalo , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Polimorfismo de Nucleotídeo Único/genética , Proteoma/genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/psicologia , Transcriptoma , Veteranos/psicologiaRESUMO
Rock climbing has evolved from a method for alpine mountaineering into a popular recreational activity and competitive sport. Advances in safety equipment and the rapid growth of indoor climbing facilities has enabled climbers to focus on the physical and technical movements needed to elevate performance. Through improved training methods, climbers can now achieve ascents of extreme difficulty. A critical aspect to further improve performance is the ability to continuously measure body movement and physiologic responses while ascending the climbing wall. However, traditional measurement devices (e.g., dynamometer) limit data collection during climbing. Advances in wearable and non-invasive sensor technologies have enabled new applications for climbing. This paper presents an overview and critical analysis of the scientific literature on sensors used during climbing. We focus on the several highlighted sensors with the ability to provide continuous measurements during climbing. These selected sensors consist of five main types (body movement, respiration, heart activity, eye gazing, skeletal muscle characterization) that demonstrate their capabilities and potential climbing applications. This review will facilitate the selection of these types of sensors in support of climbing training and strategies.
Assuntos
Montanhismo , Esportes , Dispositivos Eletrônicos Vestíveis , Montanhismo/fisiologia , Músculo Esquelético/fisiologia , Coleta de DadosRESUMO
Competitive indoor climbing has increased in popularity at the youth, collegiate, and Olympic levels. A critical aspect for improving performance is characterizing the physiologic response to different climbing strategies (e.g., work/rest patterns, pacing) and techniques (e.g., body position and movement) relative to location on climbing wall with spatially varying characteristics (e.g., wall inclinations, position of foot/hand holds). However, this response is not well understood due to the limited capabilities of climbing-specific measurement and assessment tools. In this study, we developed a novel method to examine time-resolved sensor-based measurements of multiple personal biometrics at different microlocations (finely spaced positions; MLs) along a climbing route. For the ML-specific biometric system (MLBS), we integrated continuous data from wearable biometric sensors and smartphone-based video during climbing, with a customized visualization and analysis system to determine three physiologic parameters (heart rate, breathing rate, ventilation rate) and one body movement parameter (hip acceleration), which are automatically time-matched to the corresponding video frame to determine ML-specific biometrics. Key features include: (1) biometric sensors that are seamlessly embedded in the fabric of an athletic compression shirt, and do not interfere with climbing performance, (2) climbing video, and (3) an interactive graphical user interface to rapidly visualize and analyze the time-matched biometrics and climbing video, determine timing sequence between the biometrics at key events, and calculate summary statistics. To demonstrate the capabilities of MLBS, we examined the relationship between changes in ML-specific climbing characteristics and changes in the physiologic parameters. Our study demonstrates the ability of MLBS to determine multiple time-resolved biometrics at different MLs, in support of developing and assessing different climbing strategies and training methods to help improve performance.
Assuntos
Esportes , Dispositivos Eletrônicos Vestíveis , Adolescente , Biometria , Humanos , Movimento/fisiologia , Postura , Esportes/fisiologiaRESUMO
Personal exposure to volatile organic compounds (VOCs) from indoor sources including consumer products is an understudied public health concern. To develop and evaluate methods for monitoring personal VOC exposures, we performed a pilot study and examined time-resolved sensor-based measurements of geocoded total VOC (TVOC) exposures across individuals and microenvironments (MEs). We integrated continuous (1 min) data from a personal TVOC sensor and a global positioning system (GPS) logger, with a GPS-based ME classification model, to determine TVOC exposures in four MEs, including indoors at home (Home-In), indoors at other buildings (Other-In), inside vehicles (In-Vehicle), and outdoors (Out), across 45 participant-days for five participants. To help identify places with large emission sources, we identified high-exposure events (HEEs; TVOC > 500 ppb) using geocoded TVOC time-course data overlaid on Google Earth maps. Across the 45 participant-days, the MEs ranked from highest to lowest median TVOC were: Home-In (165 ppb), Other-In (86 ppb), In-Vehicle (52 ppb), and Out (46 ppb). For the two participants living in single-family houses with attached garages, the median exposures for Home-In were substantially higher (209, 416 ppb) than the three participant homes without attached garages: one living in a single-family house (129 ppb), and two living in apartments (38, 60 ppb). The daily average Home-In exposures exceeded the estimated Leadership in Energy and Environmental Design (LEED) building guideline of 108 ppb for 60% of the participant-days. We identified 94 HEEs across all participant-days, and 67% of the corresponding peak levels exceeded 1000 ppb. The MEs ranked from the highest to the lowest number of HEEs were: Home-In (60), Other-In (13), In-Vehicle (12), and Out (9). For Other-In and Out, most HEEs occurred indoors at fast food restaurants and retail stores, and outdoors in parking lots, respectively. For Home-In HEEs, the median TVOC emission and removal rates were 5.4 g h-1 and 1.1 h-1, respectively. Our study demonstrates the ability to determine individual sensor-based time-resolved TVOC exposures in different MEs, in support of identifying potential sources and exposure factors that can inform exposure mitigation strategies.
Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Compostos Orgânicos Voláteis , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Monitoramento Ambiental , Sistemas de Informação Geográfica , Humanos , Projetos Piloto , Compostos Orgânicos Voláteis/análiseRESUMO
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. It is a leading monogenic cause of autism spectrum disorder and inherited intellectual disability and is often comorbid with attention deficits. Most FXS cases are due to an expansion of CGG repeats leading to suppressed expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA metabolism. We found that the previously published Fmr1 knockout rat model of FXS expresses an Fmr1 transcript with an in-frame deletion of exon 8, which encodes for the K-homology (KH) RNA-binding domain, KH1. Notably, 3 pathogenic missense mutations associated with FXS lie in the KH domains. We observed that the deletion of exon 8 in rats leads to attention deficits and to alterations in transcriptional profiles within the medial prefrontal cortex (mPFC), which map to 2 weighted gene coexpression network modules. These modules are conserved in human frontal cortex and enriched for known FMRP targets. Hub genes in these modules represent potential therapeutic targets for FXS. Taken together, these findings indicate that attentional testing might be a reliable cross-species tool for investigating FXS and identify dysregulated conserved gene networks in a relevant brain region.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Regulação da Expressão Gênica , Córtex Pré-Frontal/metabolismo , Animais , Atenção/fisiologia , Modelos Animais de Doenças , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Redes Reguladoras de Genes , Masculino , Ratos Sprague-Dawley , Ratos TransgênicosRESUMO
The optimal duration of treatment with nucleos(t)ide analogues (NAs) for patients with HBeAg-negative chronic hepatitis B (CHB) is unknown. The aim of this study was to identify an immune signature associated with off-treatment remission to NA therapy. We performed microarray analysis of peripheral blood mononuclear cell (PBMCs) from six patients with chronic hepatitis B who stopped NA therapy (three with off-treatment remission, three with relapse) and five patients with chronic HBV infection (previously termed 'inactive carriers') served as controls. Results were validated using qRT-PCR on a second group of 21 individuals (17 patients who stopped treatment and four controls). PBMCs from 38 patients on long-term NA treatment were analysed for potential to stop treatment. Microarray analysis indicated that patients with off-treatment remission segregated as a distinct out-group. Twenty-one genes were selected for subsequent validation. Ten of these were expressed at significantly lower levels in the patients with off-treatment remission compared to the patients with relapse and predicted remission with AUC of 0.78-0.92. IFNγ, IL-8, FASLG and CCL4 were the most significant by logistic regression. Twelve (31.6%) of 38 patients on long-term NA therapy had expression levels of all these four genes below cut-off values and hence were candidates for stopping treatment. Our data suggest that patients with HBeAg-negative CHB who remain in off-treatment remission 3 years after NA cessation have a distinct immune signature and that PBMC RNA levels of IFNγ, IL-8, FASLG and CCL4 may serve as potential biomarkers for stopping NA therapy.
Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/imunologia , Nucleosídeos/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Expressão Gênica , Genoma Humano , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Indução de Remissão , Análise Serial de Tecidos , Carga ViralRESUMO
OBJECTIVE: Features of posttraumatic stress disorder (PTSD) typically include sleep disturbances, impaired declarative memory, and hyperarousal. This study evaluated whether these combined features may accurately delineate pathophysiological changes associated with PTSD. METHOD: We recruited a cohort of PTSD-diagnosed individuals (N = 20), trauma survivors without PTSD (TE; N = 20), and healthy controls (HC; N = 20). Analyses of between-group differences and support vector machine (SVM)-learning were applied to participant features. RESULTS: Analyses of between-group differences replicated previous findings, indicating that PTSD-diagnosed individuals self-reported poorer sleep quality, objectively demonstrated less sleep depth, and evidenced declarative memory deficits in comparison to HC. Integrative SVM-learning distinguished HC from trauma participants with 80% accuracy using a combination of five features, including subjective and objective sleep, neutral declarative memory, and metabolite variables. PTSD and TE participants could be distinguished with 70% accuracy using a combination of subjective and objective sleep variables but not by metabolite or declarative memory variables. CONCLUSION: From among a broad range of sleep, cognitive, and biochemical variables, sleep characteristics were the primary features that could differentiate those with PTSD from those without. Our exploratory SVM-learning analysis establishes a framework for future sleep- and memory-based PTSD investigations that could drive improvements in diagnostic accuracy and treatment.
Assuntos
Epinefrina/metabolismo , Aprendizado de Máquina , Memória/fisiologia , Norepinefrina/metabolismo , Sono/fisiologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Transtornos da Memória/diagnóstico , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/psicologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto JovemRESUMO
Prenatal exposure to maternal stress and depression has been identified as a risk factor for adverse behavioral and neurodevelopmental outcomes in early childhood. However, the molecular mechanisms through which maternal psychopathology shapes offspring development remain poorly understood. We applied transcriptome-wide screens to 149 umbilical cord blood samples from neonates born to mothers with posttraumatic stress disorder (PTSD; nâ¯=â¯20), depression (nâ¯=â¯31) and PTSD with comorbid depression (nâ¯=â¯13), compared to carefully matched trauma exposed controls (nâ¯=â¯23) and healthy mothers (nâ¯=â¯62). Analyses by maternal diagnoses revealed a clear pattern of gene expression signatures distinguishing neonates born to mothers with a history of psychopathology from those without. Co-expression network analysis identified distinct gene expression perturbations across maternal diagnoses, including two depression-related modules implicated in axon-guidance and mRNA stability, as well as two PTSD-related modules implicated in TNF signaling and cellular response to stress. Notably, these disease-related modules were enriched with brain-expressed genes and genetic risk loci for autism spectrum disorder and schizophrenia, which may imply a causal role for impaired developmental outcomes. These molecular alterations preceded changes in clinical measures at twenty-four months, including reductions in cognitive and socio-emotional outcomes in affected infants. Collectively, these findings indicate that prenatal exposure to maternal psychological distress induces neuronal, immunological and behavioral abnormalities in affected offspring and support the search for early biomarkers of exposures to adverse in utero environments and the classification of children at risk for impaired development.
Assuntos
Transtornos do Neurodesenvolvimento/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Estresse Psicológico/genética , Adulto , Transtorno do Espectro Autista/genética , Cordocentese/métodos , Depressão/fisiopatologia , Depressão/psicologia , Feminino , Sangue Fetal/metabolismo , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mães/psicologia , Transtornos do Neurodesenvolvimento/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fatores de Risco , Esquizofrenia/genética , África do Sul , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/fisiopatologia , Transcriptoma/genéticaRESUMO
The main forces directing long-term molecular evolution remain obscure. A sizable fraction of amino-acid substitutions seem to be fixed by positive selection, but it is unclear to what degree long-term protein evolution is constrained by epistasis, that is, instances when substitutions that are accepted in one genotype are deleterious in another. Here we obtain a quantitative estimate of the prevalence of epistasis in long-term protein evolution by relating data on amino-acid usage in 14 organelle proteins and 2 nuclear-encoded proteins to their rates of short-term evolution. We studied multiple alignments of at least 1,000 orthologues for each of these 16 proteins from species from a diverse phylogenetic background and found that an average site contained approximately eight different amino acids. Thus, without epistasis an average site should accept two-fifths of all possible amino acids, and the average rate of amino-acid substitutions should therefore be about three-fifths lower than the rate of neutral evolution. However, we found that the measured rate of amino-acid substitution in recent evolution is 20 times lower than the rate of neutral evolution and an order of magnitude lower than that expected in the absence of epistasis. These data indicate that epistasis is pervasive throughout protein evolution: about 90 per cent of all amino-acid substitutions have a neutral or beneficial impact only in the genetic backgrounds in which they occur, and must therefore be deleterious in a different background of other species. Our findings show that most amino-acid substitutions have different fitness effects in different species and that epistasis provides the primary conceptual framework to describe the tempo and mode of long-term protein evolution.
Assuntos
Epistasia Genética/genética , Evolução Molecular , Substituição de Aminoácidos/genética , Animais , Núcleo Celular/genética , Biologia Computacional , Aptidão Genética , Genótipo , Modelos Genéticos , Mutação , Organelas/genética , Filogenia , Proteínas/química , Proteínas/genética , Alinhamento de Sequência , Especificidade da EspécieRESUMO
In spite of advances in understanding the cross-talk between the peripheral immune system and the brain, the molecular mechanisms underlying the rapid adaptation of the immune system to an acute psychological stressor remain largely unknown. Conventional approaches to classify molecular factors mediating these responses have targeted relatively few biological measurements or explored cross-sectional study designs, and therefore have restricted characterization of stress-immune interactions. This exploratory study analyzed transcriptional profiles and flow cytometric data of peripheral blood leukocytes with physiological (endocrine, autonomic) measurements collected throughout the sequence of events leading up to, during, and after short-term exposure to physical danger in humans. Immediate immunomodulation to acute psychological stress was defined as a short-term selective up-regulation of natural killer (NK) cell-associated cytotoxic and IL-12 mediated signaling genes that correlated with increased cortisol, catecholamines and NK cells into the periphery. In parallel, we observed down-regulation of innate immune toll-like receptor genes and genes of the MyD88-dependent signaling pathway. Correcting gene expression for an influx of NK cells revealed a molecular signature specific to the adrenal cortex. Subsequently, focusing analyses on discrete groups of coordinately expressed genes (modules) throughout the time-series revealed immune stress responses in modules associated to immune/defense response, response to wounding, cytokine production, TCR signaling and NK cell cytotoxicity which differed between males and females. These results offer a spring-board for future research towards improved treatment of stress-related disease including the impact of stress on cardiovascular and autoimmune disorders, and identifies an immune mechanism by which vulnerabilities to these diseases may be gender-specific.
Assuntos
Estresse Psicológico/imunologia , Córtex Suprarrenal/metabolismo , Adulto , Catecolaminas/sangue , Estudos Transversais , Regulação para Baixo , Feminino , Expressão Gênica/genética , Humanos , Hidrocortisona/metabolismo , Imunomodulação , Interleucina-12/sangue , Interleucina-12/metabolismo , Células Matadoras Naturais/imunologia , Leucócitos/imunologia , Masculino , Fatores Sexuais , Transdução de Sinais/imunologia , Estresse Psicológico/metabolismo , Sudorese Gustativa , Receptores Toll-Like/sangue , Receptores Toll-Like/metabolismo , Transcriptoma/imunologia , Regulação para CimaRESUMO
INTRODUCTION: The utility of blood for genome-wide gene expression profiling and biomarker discovery has received much attention in patients diagnosed with major neuropsychiatric disorders. While numerous studies have been conducted, statistical rigor and clarity in terms of blood-based biomarker discovery, validation, and testing are needed. METHODS: We conducted a systematic review of the literature to investigate methodological approaches and to assess the value of blood transcriptome profiling in research on mental disorders. We were particularly interested in statistical considerations related to machine learning, gene network analyses, and convergence across different disorders. RESULTS: A total of 108 peripheral blood transcriptome studies across 15 disorders were surveyed: 25 studies used a variety of machine learning techniques to assess putative clinical viability of the candidate biomarkers; 11 leveraged a higher-order systems-level perspective to identify gene module-based biomarkers; and nine performed analyses across two or more neuropsychiatric phenotypes. Notably, ~50% of the surveyed studies included fewer than 50 samples (cases and controls), while ~75% included less than 100. CONCLUSIONS: Detailed consideration of statistical analysis in the early stages of experimental planning is critical to ensure blood-based biomarker discovery and validation. Statistical guidelines are presented to enhance implementation and reproducibility of machine learning and gene network analyses across independent studies. Future studies capitalizing on larger sample sizes and emerging next-generation technologies set the stage for moving the field forwards. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Doenças do Sistema Nervoso Central/genética , Regulação da Expressão Gênica , Transtornos Mentais/genética , Biomarcadores/sangue , Doenças do Sistema Nervoso Central/fisiopatologia , Perfilação da Expressão Gênica/métodos , Guias como Assunto , Humanos , Aprendizado de Máquina , Transtornos Mentais/fisiopatologia , Reprodutibilidade dos TestesRESUMO
Air pollution health studies of fine particulate matter (diameter ≤2.5 µm, PM2.5) often use outdoor concentrations as exposure surrogates. Failure to account for variability of indoor infiltration of ambient PM2.5 and time indoors can induce exposure errors. We developed and evaluated an exposure model for individuals (EMI), which predicts five tiers of individual-level exposure metrics for ambient PM2.5 using outdoor concentrations, questionnaires, weather, and time-location information. We linked a mechanistic air exchange rate (AER) model to a mass-balance PM2.5 infiltration model to predict residential AER (Tier 1), infiltration factors (Tier 2), indoor concentrations (Tier 3), personal exposure factors (Tier 4), and personal exposures (Tier 5) for ambient PM2.5. Using cross-validation, individual predictions were compared to 591 daily measurements from 31 homes (Tiers 1-3) and participants (Tiers 4-5) in central North Carolina. Median absolute differences were 39% (0.17 h(-1)) for Tier 1, 18% (0.10) for Tier 2, 20% (2.0 µg/m(3)) for Tier 3, 18% (0.10) for Tier 4, and 20% (1.8 µg/m(3)) for Tier 5. The capability of EMI could help reduce the uncertainty of ambient PM2.5 exposure metrics used in health studies.
Assuntos
Poluição do Ar em Ambientes Fechados/análise , Exposição Ambiental/análise , Modelos Teóricos , Adulto , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar em Ambientes Fechados/efeitos adversos , Monitoramento Ambiental/métodos , Feminino , Habitação , Humanos , Masculino , North Carolina , Material Particulado/efeitos adversos , Material Particulado/análise , Reprodutibilidade dos Testes , Inquéritos e Questionários , Fatores de Tempo , Tempo (Meteorologia)RESUMO
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.
Assuntos
Transtorno do Espectro Autista , Ketamina , Transcriptoma , Ketamina/farmacologia , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Humanos , Masculino , Transcriptoma/efeitos dos fármacos , Criança , Feminino , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/sangue , Pré-Escolar , Proteínas do Tecido Nervoso/genética , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/tratamento farmacológico , Perfilação da Expressão Gênica , Adolescente , Proteínas de HomeodomínioRESUMO
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating up-regulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.
RESUMO
Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.
Assuntos
Adenosina Desaminase , Adenosina , Autopsia , Encéfalo , Inosina , Edição de RNA , Proteínas de Ligação a RNA , Humanos , Adenosina/metabolismo , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Encéfalo/metabolismo , Inosina/metabolismo , Inosina/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Córtex Pré-Frontal/metabolismo , Mudanças Depois da Morte , MasculinoRESUMO
Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.