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1.
Gigascience ; 112022 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-36409836

RESUMO

The Common Fund Data Ecosystem (CFDE) has created a flexible system of data federation that enables researchers to discover datasets from across the US National Institutes of Health Common Fund without requiring that data owners move, reformat, or rehost those data. This system is centered on a catalog that integrates detailed descriptions of biomedical datasets from individual Common Fund Programs' Data Coordination Centers (DCCs) into a uniform metadata model that can then be indexed and searched from a centralized portal. This Crosscut Metadata Model (C2M2) supports the wide variety of data types and metadata terms used by individual DCCs and can readily describe nearly all forms of biomedical research data. We detail its use to ingest and index data from 11 DCCs.


Assuntos
Ecossistema , Administração Financeira , Metadados
2.
Genome Med ; 13(1): 141, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470669

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer's disease (AD), but the genes responsible for these associations remain largely unknown. METHODS: We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures) prediction models of ten brain tissues that are potentially related to AD to discover novel AD genetic loci and putative target genes in 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry. RESULTS: We identified 53 genes with predicted expression associations with AD risk at Bonferroni correction threshold (P value < 3.38 × 10-6). Based on fine-mapping analyses, 21 genes at nine loci showed strong support for being causal. CONCLUSIONS: Our study provides new insights into the etiology and underlying genetic architecture of AD.


Assuntos
Alelos , Doença de Alzheimer/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Transcriptoma , Doença de Alzheimer/metabolismo , Mapeamento Cromossômico , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Modelos Biológicos , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Resorcinóis , Transdução de Sinais
3.
Neurobiol Dis ; 152: 105277, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33516874

RESUMO

The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are associated with disease-induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how alterations in tau expression impact the retina, we analyzed the retinas of transgenic mice overexpressing mutant 3R tau (m3R tau-Tg), a model known to exhibit Pick's Disease pathology in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy that were uniquely altered in m3R tau-Tg retina. The upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. In adult m3R tau-Tg, the dorsal peripheral retina of the adult m3R tau-Tg exhibited decreased cell density in the ganglion cell layer (GCL) and reduced thickness of the inner plexiform layer (IPL) compared to the ventral peripheral retina. Together, these data indicate that mutant 3R tau may mediate toxicity in retinal ganglion cells (RGC) by promoting caspase-2 expression which results in RGC degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test novel therapeutics for degenerative diseases such as glaucoma.


Assuntos
Caspase 2/metabolismo , Doenças Retinianas/patologia , Células Ganglionares da Retina/patologia , Tauopatias/patologia , Proteínas tau/metabolismo , Animais , Morte Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Isoformas de Proteínas , Doenças Retinianas/metabolismo , Células Ganglionares da Retina/metabolismo , Proteínas tau/genética
4.
J Neuroinflammation ; 17(1): 112, 2020 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-32276639

RESUMO

BACKGROUND: HIV-associated neurocognitive disorders (HAND) persist in the era of combined antiretroviral therapy (ART) despite reductions in viral load (VL) and overall disease severity. The mechanisms underlying HAND in the ART era are not well understood but are likely multifactorial, involving alterations in common pathways such as inflammation, autophagy, neurogenesis, and mitochondrial function. Newly developed omics approaches hold potential to identify mechanisms driving neuropathogenesis of HIV in the ART era. METHODS: In this study, using 33 postmortem frontal cortex (FC) tissues, neuropathological, molecular, and biochemical analyses were used to determine cellular localization and validate expression levels of the prolific transcription factor (TF), CCAAT enhancer binding protein (C/EBP) ß, in brain tissues from HIV+ cognitively normal and HAND cases. RNA sequencing (seq) and transcriptomic analyses were performed on FC tissues including 24 specimens from well-characterized people with HIV that had undergone neurocognitive assessments. In vitro models for brain cells were used to investigate the role of C/EBPß in mediating gene expression. RESULTS: The most robust signal for TF dysregulation was observed in cases diagnosed with minor neurocognitive disorder (MND) compared to cognitive normal (CN) cases. Of particular interest, due to its role in inflammation, autophagy and neurogenesis, C/EBPß was significantly upregulated in MND compared to CN brains. C/EBPß was increased at the protein level in HAND brains. C/EBPß levels were significantly reduced in neurons and increased in astroglia in HAND brains compared to CN. Transfection of human astroglial cells with a plasmid expressing C/EBPß induced expression of multiple targets identified in the transcriptomic analysis of HAND brains, including dynamin-1-like protein (DNM1L) and interleukin-1 receptor-associated kinase 1. Recombinant HIV-Tat reduced and increased C/EBPß levels in neuronal and astroglial cells, respectively. CONCLUSIONS: These findings are the first to present RNAseq-based transcriptomic analyses of HIV+ brain tissues, providing further evidence of altered neuroinflammation, neurogenesis, mitochondrial function, and autophagy in HAND. Interestingly, these studies confirm a role for CEBPß in regulating inflammation, metabolism, and autophagy in astroglia. Therapeutic strategies aimed at transcriptional regulation of astroglia or downstream pathways may provide relief to HIV+ patients at risk for HAND and other neurological disorders.


Assuntos
Complexo AIDS Demência/metabolismo , Encéfalo/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Adulto , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino
5.
Cell Rep ; 28(4): 1103-1116.e4, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340147

RESUMO

Asymptomatic and symptomatic Alzheimer's disease (AD) subjects may present with equivalent neuropathological burdens but have significantly different antemortem cognitive decline rates. Using the transcriptome as a proxy for functional state, we selected 414 expression profiles of symptomatic AD subjects and age-matched non-demented controls from a community-based neuropathological study. By combining brain tissue-specific protein interactomes with gene networks, we identified functionally distinct composite clusters of genes that reveal extensive changes in expression levels in AD. Global expression for clusters broadly corresponding to synaptic transmission, metabolism, cell cycle, survival, and immune response were downregulated, while the upregulated cluster included largely uncharacterized processes. We propose that loss of EGR3 regulation mediates synaptic deficits by targeting the synaptic vesicle cycle. Our results highlight the utility of integrating protein interactions with gene perturbations to generate a comprehensive framework for characterizing alterations in the molecular network as applied to AD.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Demência/patologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Proteoma/análise , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Biomarcadores/análise , Encéfalo/metabolismo , Estudos de Casos e Controles , Demência/genética , Demência/metabolismo , Feminino , Seguimentos , Humanos , Masculino
6.
Ann Biomed Eng ; 46(1): 186-196, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29086223

RESUMO

Mortality during follow-up after acute Type B aortic dissection is substantial with aortic expansion observed in over 59% of the patients. Lumen pressure differential is considered a prime contributing factor for aortic dilation after propagation. The objective of the study was to evaluate the relationship between changes in vessel geometry with and without lumen pressure differential post propagation in an ex vivo porcine model with comparison with patient clinical data. A pulse duplicator system was utilized to propagate the dissection within descending thoracic porcine aortic vessels for set proximal (%circumference of the entry tear: 40%, axial length: 2 cm) and re-entry (50% of distal vessel circumference) tear geometry. Measurements of lumen pressure differential were made along with quantification of vessel geometry (n = 16). The magnitude of mean lumen pressure difference measured after propagation was low (~ 5 mmHg) with higher pressures measured in false lumen and as anticipated the pressure difference approached zero after the creation of distal re-entry tear. False lumen Dissection Ratio (FDR) defined as arc length of dissected wall divided by arc length of dissection flap, had mean value of 1.59 ± 0.01 at pressure of 120/80 mmHg post propagation with increasing values with increase in pulse pressure that was not rescued with the creation of distal re-entry tear (p < 0.01). An average FDR of 1.87 ± 0.27 was measured in patients with acute Type B dissection. Higher FDR value (FDR = 1 implies zero dissection) in the presence of distal re-entry tear demonstrates an acute change in vessel morphology in response to the dissection independent of local pressure changes challenges the re-apposition of the aortic wall.


Assuntos
Aneurisma da Aorta Torácica/fisiopatologia , Dissecção Aórtica/fisiopatologia , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Suínos
7.
J Mech Behav Biomed Mater ; 74: 261-273, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28645069

RESUMO

Multiscale damage due to cavitation is considered as a potential mechanism of traumatic brain injury (TBI) associated with explosion. In this study, we employed a TBI relevant hippocampal ex vivo slice model to induce bubble cavitation. Placement of single reproducible seed bubbles allowed control of size, number, and tissue location to visualize and measure deformation parameters. Maximum strain value was measured at 45 µs after bubble collapse, presented with a distinct contour and coincided temporally and spatially with the liquid jet. Composite injury maps combined this maximum strain value with maximum measured bubble size and location along with histological injury patterns. This facilitated the correlation of bubble location and subsequent jet direction to the corresponding regions of high strain which overlapped with regions of observed injury. A dynamic threshold strain range for tearing of cerebral cortex was estimated to be between 0.5 and 0.6. For a seed bubble placed underneath the hippocampus, cavitation induced damage was observed in hippocampus (local), proximal cerebral cortex (marginal) and the midbrain/forebrain (remote) upon histological evaluation. Within this test model, zone of cavitation injury was greater than the maximum radius of the bubble. Separation of apposed structures, tissue tearing, and disruption of cellular layers defined early injury patterns that were not detected in the blast-exposed half of the brain slice. Ultrastructural pathology of the neurons exposed to cavitation was characterized by disintegration of plasma membrane along with loss of cellular content. The developed test system provided a controlled experimental platform to study cavitation induced high strain deformations on brain tissue slice. The goal of the future studies will be to lower underpressure magnitude and cavitation bubble size for more sensitive evaluation of injury.


Assuntos
Traumatismos por Explosões/patologia , Lesões Encefálicas/patologia , Animais , Encéfalo/patologia , Membrana Celular/patologia , Masculino , Ratos Sprague-Dawley , Sonicação
8.
PLoS One ; 12(4): e0175396, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28403239

RESUMO

Exposure to explosive blasts can produce functional debilitation in the absence of brain pathology detectable at the scale of current diagnostic imaging. Transient (ms) overpressure components of the primary blast wave are considered to be potentially damaging to the brain. Astrocytes participate in neuronal metabolic maintenance, blood-brain barrier, regulation of homeostatic environment, and tissue remodeling. Damage to astrocytes via direct physical forces has the potential to disrupt local and global functioning of neuronal tissue. Using an ex vivo brain slice model, we tested the hypothesis that viable astrocytes within the slice could be injured simply by transit of a single blast wave consisting of overpressure alone. A polymer split Hopkinson pressure bar (PSHPB) system was adapted to impart a single positive pressure transient with a comparable magnitude to those that might be present inside the head. A custom built test chamber housing the brain tissue slice incorporated revised design elements to reduce fluid space and promote transit of a uniform planar waveform. Confocal microscopy, stereology, and morphometry of glial fibrillary acidic protein (GFAP) immunoreactivity revealed that two distinct astrocyte injury profiles were identified across a 4 hr post-test survival interval: (a) presumed conventional astrogliosis characterized by enhanced GFAP immunofluorescence intensity without significant change in tissue area fraction and (b) a process comparable to clasmatodendrosis, an autophagic degradation of distal processes that has not been previously associated with blast induced neurotrauma. Analysis of astrocyte branching revealed early, sustained, and progressive differences distinct from the effects of slice incubation absent overpressure testing. Astrocyte vulnerability to overpressure transients indicates a potential for significant involvement in brain blast pathology and emergent dysfunction. The testing platform can isolate overpressure injury phenomena to provide novel insight on physical and biological mechanisms.


Assuntos
Astrócitos/patologia , Traumatismos por Explosões/patologia , Lesões Encefálicas/patologia , Encéfalo/patologia , Animais , Modelos Animais de Doenças , Explosões , Proteína Glial Fibrilar Ácida/análise , Masculino , Pressão/efeitos adversos , Ratos Sprague-Dawley
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