12 research outputs found
Resource profile and user guide of the Polygenic Index Repository
Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIsâ prediction accuracies, we constructed them using genome-wide association studies â some not previously published â from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the âadditive SNP factorâ. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available
The impact of single and pairwise Toll-like receptor activation on neuroinflammation and neurodegeneration
Background Toll-like receptors (TLRs) enable innate immune cells to respond to
pathogen- and host-derived molecules. The central nervous system (CNS)
exhibits most of the TLRs identified with predominant expression in microglia,
the major immune cells of the brain. Although individual TLRs have been shown
to contribute to CNS disorders, the consequences of multiple activated TLRs on
the brain are unclear. We therefore systematically investigated and compared
the impact of sole and pairwise TLR activation on CNS inflammation and injury.
Methods Selected TLRs expressed in microglia and neurons were stimulated with
their specific TLR ligands in varying combinations. Cell cultures were then
analyzed by immunocytochemistry, FlowCytomix, and ELISA. To determine neuronal
injury and neuroinflammation in vivo, C57BL/6J mice were injected
intrathecally with TLR agonists. Subsequently, brain sections were analyzed by
quantitative real-time PCR and immunohistochemistry. Results Simultaneous
stimulation of TLR4 plus TLR2, TLR4 plus TLR9, and TLR2 plus TLR9 in microglia
by their respective specific ligands results in an increased inflammatory
response compared to activation of the respective single TLR in vitro. In
contrast, additional activation of TLR7 suppresses the inflammatory response
mediated by the respective ligands for TLR2, TLR4, or TLR9 up to 24 h,
indicating that specific combinations of activated TLRs individually modulate
the inflammatory response. Accordingly, the composition of the inflammatory
response pattern generated by microglia varies depending on the identity and
combination of the activated TLRs engaged. Likewise, neuronal injury occurs in
response to activation of only selected TLRs and TLR combinations in vitro.
Activation of TLR2, TLR4, TLR7, and TLR9 in the brain by intrathecal injection
of the respective TLR ligand into C57BL/6J mice leads to specific expression
patterns of distinct TLR mRNAs in the brain and causes influx of leukocytes
and inflammatory mediators into the cerebrospinal fluid to a variable extent.
Also, the intensity of the inflammatory response and neurodegenerative effects
differs according to the respective activated TLR and TLR combinations used in
vivo. Conclusions Sole and pairwise activation of TLRs modifies the pattern
and extent of inflammation and neurodegeneration in the CNS, thereby enabling
innate immunity to take account of the CNS diseasesâ diversity
Expression and function of G-protein-coupled receptorsin the male reproductive tract
This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.Esta revisĂŁo enfatiza a expressĂŁo e a função dos receptores muscarĂnicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressĂŁo dos receptores muscarĂnicos e adrenoceptores α1 em compartimentos especĂficos de dĂșctulos eferentes, epidĂdimo, ductos deferentes, vesĂcula seminal e prĂłstata de vĂĄrias espĂ©cies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do mĂșsculo liso, incluindo efeitos na fertilidade masculina. AlĂ©m disso, a ativação dos receptores muscarĂnicos leva Ă transativação do receptor para o fator crescimento epidermal e proliferação das cĂ©lulas de Sertoli. Os receptores para relaxina estĂŁo presentes no testĂculo, RXFP1 nas espermĂĄtides alongadas e cĂ©lulas de Sertoli de rato e RXFP2 nas cĂ©lulas de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogĂȘnico. A localização de ambos os receptores na porção apical das cĂ©lulas epiteliais e no mĂșsculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.Fundação de Amparo Ă Pesquisa do Estado de SĂŁo Paulo (FAPESP)Conselho Nacional de Desenvolvimento CientĂfico e TecnolĂłgico (CNPq)Universidade Federal de SĂŁo Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL
Newborn Cerebrovascular Responses after First Trimester Moderate Maternal Ethanol Exposure in Sheep
Non-targeted metabolomics of Brg1/Brm double-mutant cardiomyocytes reveals a novel role for SWI/SNF complexes in metabolic homeostasis
Mammalian SWI/SNF chromatin-remodeling complexes utilize either BRG1 or Brm as alternative catalytic subunits to alter the position of nucleosomes and regulate gene expression. Genetic studies have demonstrated that SWI/SNF complexes are required during cardiac development and also protect against cardiovascular disease and cancer. However, Brm constitutive null mutants do not exhibit a cardiomyocyte phenotype and inducible Brg1 conditional mutations in cardiomyocyte do not demonstrate differences until stressed with transverse aortic constriction, where they exhibit a reduction in cardiac hypertrophy. We recently demonstrated the overlapping functions of Brm and Brg1 in vascular endothelial cells and sought here to test if this overlapping function occurred in cardiomyocytes. Brg1/Brm double mutants died within 21 days of severe cardiac dysfunction associated with glycogen accumulation and mitochondrial defects based on histological and ultrastructural analyses. To determine the underlying defects, we performed nontargeted metabolomics analysis of cardiac tissue by GC/MS from a line of Brg1/Brm double-mutant mice, which lack both Brg1 and Brm in cardiomyocytes in an inducible manner, and two groups of controls. Metabolites contributing most significantly to the differences between Brg1/Brm double-mutant and control-group hearts were then determined using the variable importance in projection analysis. Increased cardiac linoleic acid and oleic acid suggest alterations in fatty acid utilization or intake are perturbed in Brg1/Brm double mutants. Conversely, decreased glucose-6-phosphate, fructose-6-phosphate, and myoinositol suggest that glycolysis and glycogen formation are impaired. These novel metabolomics findings provide insight into SWI/SNF-regulated metabolic pathways and will guide mechanistic studies evaluating the role of SWI/SNF complexes in homeostasis and cardiovascular disease prevention