Abstract
Traditional RNA sequencing (RNA-seq) allows the detection of gene expression variations between two or more cell populations through differentially expressed gene (DEG) analysis. However, ...genes that contribute to cell-to-cell differences are not discoverable with RNA-seq because RNA-seq samples are obtained from a mixture of cells. Single-cell RNA-seq (scRNA-seq) allows the detection of gene expression in each cell. With scRNA-seq, highly variable gene (HVG) discovery allows the detection of genes that contribute strongly to cell-to-cell variation within a homogeneous cell population, such as a population of embryonic stem cells. This analysis is implemented in many software packages. In this study, we compare seven HVG methods from six software packages, including BASiCS, Brennecke, scLVM, scran, scVEGs and Seurat. Our results demonstrate that reproducibility in HVG analysis requires a larger sample size than DEG analysis. Discrepancies between methods and potential issues in these tools are discussed and recommendations are made.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Over a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are ...selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions. To answer this question, we investigated how well the current archive of genetic evidence predicts drug mechanisms. We found that, among well-studied indications, the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas. We estimate that selecting genetically supported targets could double the success rate in clinical development. Therefore, using the growing wealth of human genetic data to select the best targets and indications should have a measurable impact on the successful development of new drugs.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Linnorm is a novel normalization and transformation method for the analysis of single cell RNA sequencing (scRNA-seq) data. Linnorm is developed to remove technical noises and simultaneously preserve ...biological variations in scRNA-seq data, such that existing statistical methods can be improved. Using real scRNA-seq data, we compared Linnorm with existing normalization methods, including NODES, SAMstrt, SCnorm, scran, DESeq and TMM. Linnorm shows advantages in speed, technical noise removal and preservation of cell heterogeneity, which can improve existing methods in the discovery of novel subtypes, pseudo-temporal ordering of cells, clustering analysis, etc. Linnorm also performs better than existing DEG analysis methods, including BASiCS, NODES, SAMstrt, Seurat and DESeq2, in false positive rate control and accuracy.
Abstract This study aimed to assess the current status and changing trends of the disease burden of stroke and its subtypes due to low dietary fiber intake in China from 1990 to 2019. In cases of ...stroke and its subtypes attributable to low dietary fiber, deaths, disability-adjusted life-years (DALYs), age-standardized mortality rates (ASMR), age-standardized DALYs rates (ASDR), and percentage change were used to assess disease burden. Data were obtained from the 2019 global burden of disease study. Trends were assessed using Joinpoint regression and age-period-cohort analysis. Between 1990 and 2019, there was a declining trend in stroke and its subtypes, ASDR and ASMR, as well as the corresponding number of deaths and DALYs, due to low dietary fiber intake in China. Subarachnoid hemorrhage (SH) showed the greatest decrease, followed by intracerebral hemorrhage (IH) and ischemic stroke (IS). Local drift curves showed a U-shaped distribution of stroke, IS, and IH DALYs across the whole group and sex-based groups. For mortality, the overall and male trends were similar to those for DALYs, whereas female stroke, IH, and IS showed an upward trend. The DALYs for stroke and IH showed a clear bimodal distribution, IS showed an increasing risk with age. For mortality, the SH subtype showed a decreasing trend, whereas other subtypes showed an increasing risk with age. Both the period and cohort rates of stroke DALYs and motality due to low dietary fiber have declined. Males had a higher risk of DALYs and mortality associated with low fiber levels. The burden of stroke and its subtypes associated with a low-fiber diet in China has been declining over the past 30 years, with different patterns of change for different stroke subtypes and a higher burden for males, highlighting the differential impact of fiber intake on stroke and its subtypes.
Inadequate vitamin D status has been linked to increased risk of type 2 diabetes and cardiovascular disease. Inducible cyclooxygenase (COX) isoform COX-2 has been involved in the pathogenesis of such ...chronic inflammatory diseases. We found that the active form of vitamin D, 1,25(OH)2D produces dose-dependent inhibition of COX-2 expression in murine macrophages under both basal and LPS-stimulated conditions and suppresses proinflammatory mediators induced by LPS. Administration of 1,25(OH)2D significantly alleviated local inflammation in a carrageenan-induced paw edema mouse model. Strikingly, the phosphorylation of both Akt and its downstream target IκBα in macrophages were markedly suppressed by 1,25(OH)2D in the presence and absence of LPS stimulation through up-regulation of THEM4 (thioesterase superfamily member 4), an Akt modulator protein. Knockdown of both vitamin D receptor and THEM4 attenuated the inhibitory effect of 1,25(OH)2D on COX-2 expression in macrophages. A functional vitamin D-responsive element in the THEM4 promoter was identified by chromatin immunoprecipitation and luciferase reporter assay. Our results indicate that vitamin D restrains macrophage-mediated inflammatory processes by suppressing the Akt/NF-κB/COX-2 pathway, suggesting that vitamin D supplementation might be utilized for adjunctive therapy for inflammatory disease.
Vitamin D insufficiency has been associated with chronic inflammatory diseases. However, the underlying mechanisms remain unclear.
Vitamin D inhibits COX-2-mediated inflammatory response by modulating the Akt/NF-κB signaling pathway via direct up-regulation of thioesterase superfamily member 4.
Vitamin D plays novel roles in anti-inflammation.
Supplemental vitamin D could protect against chronic inflammatory diseases by targeting THEM4/Akt/NF-κB signaling.
Owing to the small size of the defect pixel area and poor defect-background contrast issues in industrial images, noise and missed detection can easily occur. Therefore, automated defect detection is ...both necessary and challenging. To address these issues, with parallel attention mechanism (PAM) and dual-channel spatial pyramid pooling-fast block (DC_SPPF), a novel defect detection network, namely, PDDD-Net, is proposed in this paper. First, to make the detection network emphasize small defect areas better, the PAM block is proposed to be embedded into YOLOv5 to obtain more low-level visual features and improve the detection accuracy of microdefects. Meanwhile, by fusing multi-channel features, the DC_SPPF block is proposed to replace the raw spatial pyramid pooling-fast block to acquire richer discriminative features of the defect areas. Finally, The soft non-maximum suppression (Soft-NMS) module is used to undertake the feature candidate box filtering task in YOLOv5 to reduce missed detection. Two public datasets are adopted for the model evaluation: the Tianchi aluminum profile defects dataset (APDDD) and the power line insulator dataset (CPLID). The experimental results indicate that the proposed PDDD-Net network exhibits remarkable defect detection performance compared with other related detection methods.
Abstract
Genome-wide association studies have generated over thousands of susceptibility loci for many human complex traits, and yet for most of these associations the true causal variants remain ...unknown. Tissue/cell type-specific prediction and prioritization of non-coding regulatory variants will facilitate the identification of causal variants and underlying pathogenic mechanisms for particular complex diseases and traits. By leveraging recent large-scale functional genomics/epigenomics data, we develop an intuitive web server, GWAS4D (http://mulinlab.tmu.edu.cn/gwas4d or http://mulinlab.org/gwas4d), that systematically evaluates GWAS signals and identifies context-specific regulatory variants. The updated web server includes six major features: (i) updates the regulatory variant prioritization method with our new algorithm; (ii) incorporates 127 tissue/cell type-specific epigenomes data; (iii) integrates motifs of 1480 transcriptional regulators from 13 public resources; (iv) uniformly processes Hi-C data and generates significant interactions at 5 kb resolution across 60 tissues/cell types; (v) adds comprehensive non-coding variant functional annotations; (vi) equips a highly interactive visualization function for SNP-target interaction. Using a GWAS fine-mapped set for 161 coronary artery disease risk loci, we demonstrate that GWAS4D is able to efficiently prioritize disease-causal regulatory variants.
Interpreting the genetic variants located in the regulatory regions, such as enhancers and promoters, is an indispensable step to understand molecular mechanism of complex traits. Recent studies show ...that genetic variants detected by genome-wide association study (GWAS) are significantly enriched in the regulatory regions. Therefore, detecting, annotating and prioritizing of genetic variants affecting gene regulation are critical to our understanding of genotype-phenotype relationships. Here, we developed a web server GWAS3D to systematically analyze the genetic variants that could affect regulatory elements, by integrating annotations from cell type-specific chromatin states, epigenetic modifications, sequence motifs and cross-species conservation. The regulatory elements are inferred from the genome-wide chromosome interaction data, chromatin marks in 16 different cell types and 73 regulatory factors motifs from the Encyclopedia of DNA Element project. Furthermore, we used these function elements, as well as risk haplotype, binding affinity, conservation and P-values reported from the original GWAS to reprioritize the genetic variants. Using studies from low-density lipoprotein cholesterol, we demonstrated that our reprioritizing approach was effective and cell type specific. In conclusion, GWAS3D provides a comprehensive annotation and visualization tool to help users interpreting their results. The web server is freely available at http://jjwanglab.org/gwas3d.
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