TFEC contributes to heart failure hypertrophy simply by curbing AMPKmTOR signaling

An automated platform for cytogenetic biodosimetry, the "Rapid Automated Biodosimetry Tool II (RABiT-II)," adapts the dicentric chromosome assay (DCA) for high-throughput mass-screening of the population after a large-scale radiological event. To validate this test, the U.S. Federal Drug Administration (FDA) recommends demonstrating that the high-throughput biodosimetric assay in question correctly reports the dose in an in vivo model. Here we describe the use of rhesus macaques (Macaca mulatta) to augment human studies and validate the accuracy of the high-throughput version of the DCA. To perform analysis, we developed the 17/22-mer peptide nucleic acid (PNA) probes that bind to the rhesus macaque's centromeres. To our knowledge, these are the first custom PNA probes with high specificity that can be used for chromosome analysis in M. mulatta. The accuracy of fully-automated chromosome analysis was improved by optimizing a low-temperature telomere PNA FISH staining in multiwell plates and adding the telomere detection feature to our custom chromosome detection software, FluorQuantDic V4. The dicentric frequencies estimated from in vitro irradiated rhesus macaque samples were compared to human blood samples of individuals subjected to the same ex vivo irradiation conditions. The results of the RABiT-II DCA analysis suggest that, in the lymphocyte system, the dose responses to gamma radiation in the rhesus macaques were similar to those in humans, with small but statistically significant differences between these two model systems.Identification of partial sweeps, which include both hard and soft sweeps that have not currently reached fixation, provides crucial information about ongoing evolutionary responses. To this end, we introduce partialS/HIC, a deep learning method to discover selective sweeps from population genomic data. partialS/HIC uses a convolutional neural network for image processing, which is trained with a large suite of summary statistics derived from coalescent simulations incorporating population-specific history, to distinguish between completed versus partial sweeps, hard versus soft sweeps, and regions directly affected by selection versus those merely linked to nearby selective sweeps. We perform several simulation experiments under various demographic scenarios to demonstrate partialS/HIC's performance, which exhibits excellent resolution for detecting partial sweeps. We also apply our classifier to whole genomes from eight mosquito populations sampled across sub-Saharan Africa by the Anopheles gambiae 1000 Genomes Consortium, elucidating both continent-wide patterns as well as sweeps unique to specific geographic regions. These populations have experienced intense insecticide exposure over the past two decades, and we observe a strong overrepresentation of sweeps at insecticide resistance loci. Our analysis thus provides a list of candidate adaptive loci that may be relevant to mosquito control efforts. More broadly, our supervised machine learning approach introduces a method to distinguish between completed and partial sweeps, as well as between hard and soft sweeps, under a variety of demographic scenarios. As whole-genome data rapidly accumulate for a greater diversity of organisms, partialS/HIC addresses an increasing demand for useful selection scan tools that can track in-progress evolutionary dynamics.North Borneo (NB) is home to more than 40 native populations. These natives are believed to have undergone local adaptation in response to environmental challenges such as the mosquito-abundant tropical rainforest. We attempted to trace the footprints of natural selection from the genomic data of NB native populations using a panel of ∼2.2 million genome-wide single nucleotide polymorphisms. #link# As a result, an ∼13-kb haplotype in the Major Histocompatibility Complex Class II region encompassing candidate genes TSBP1-BTNL2-HLA-DRA was identified to be undergoing natural selection. This putative signature of positive selection is shared among the five NB populations and is estimated to have arisen ∼5.5 thousand years (∼220 generations) ago, which coincides with the period of Austronesian expansion. Owing to the long history of endemic malaria in NB, the putative signature of positive selection is postulated to be driven by Plasmodium parasite infection. The findings of this study imply that despite high levels of genetic differentiation, the NB populations might have experienced similar local genetic adaptation resulting from stresses of the shared environment.
Crohn's disease (CD) is a chronic, relapsing and incurable inflammatory disorder. MiRNAs, which modulate gene expression by binding to mRNAs, may make significant contributions to understanding the complex pathobiology and etiology of CD. this website aimed to investigate the therapeutic role and mechanism of miR-130a-3p in CD.
Differentially expressed miRNAs in colon tissues of CD patients and normal controls (NCs) were screened using a miRNA microarray and then validated by quantitative reverse transcriptase-PCR (qRT-PCR). The functional role of miR-130a-3p in the pathogenesis of CD was then demonstrated by in vitro and in vivo studies. The target genes of miR-130a-3p and the associated signaling pathways were identified using bioinformatics analysis and experimental verification of the interactions between the target predicted by the algorithms and dysregulated mRNAs. The therapeutic role of miR-130a-3p in trinitro-benzene-sulfonic acid (TNBS)-induced colitis models was further investigated.
Our data demonstrated that miR-130a-3p is the most significantly upregulated miRNA and that miR-130a KO significantly protects mice against TNBS-induced colitis. Gain- and loss-of-function studies indicated that miR-130a-3p promotes CD development by targetingATG16L1via the NF-κB pathway. Furthermore, a miR-130a-3p inhibitor significantly suppressed NLRP3 inflammasome activity by inducing autophagy in a mouse macrophage cell line (RAW264.7). Therapeutically, a miR-130a-3p inhibitor effectively ameliorated the severity of TNBS-induced colitis.
Our study reveals that miR-130a-3p promotes CD progression via the ATG16L1/NF-κB pathway and serves as a potential preclinical therapeutic target in CD.
Our study reveals that miR-130a-3p promotes CD progression via the ATG16L1/NF-κB pathway and serves as a potential preclinical therapeutic target in CD.