A highland-adaptation variant near MCUR1 reduces its transcription and attenuates erythrogenesis in Tibetans.

To identify genomic regions subject to positive selection that might contain genes involved in high-altitude adaptation (HAA), we performed a genome-wide scan by whole-genome sequencing of Tibetan highlanders and Han lowlanders. We revealed a collection of candidate genes located in 30 genomic loci under positive selection. Among them, MCUR1 at 6p23 was a novel pronounced candidate.

Aculeapyridones A-Q, Pyranopyridone Alkaloids with Protective Effects against Acetaminophen-Induced Acute Liver Injury Discovered from a Coculture of WHUF0198 and a sp.

In the search for novel natural products with hepatoprotective effects against acetaminophen-induced acute liver injury, the marine-derived fungus WHUF0198 was investigated. Seventeen undescribed pyranopyridone alkaloids, aculeapyridones A-Q (-), were isolated by bioactivity-guided fractionation of an extract obtained by coculture of the WHUF0198 with the mangrove-associated fungus sp. DM27.

Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant.

Macrophage Notch1 signaling modulates regulatory T cells via the TGFB axis in early MASLD.

Background & Aims: Hepatic immune imbalance is crucial for driving metabolic dysfunction-associated steatotic liver disease (MASLD) progression. However, the role of hepatic regulatory T cells (Tregs) in MASLD initiation and the mechanisms responsible for their change are not completely understood.

Methods: A mouse model subjected to a short-term high-fat diet (HFD) to mimic early steatosis, along with liver biopsy samples from patients with simple steatosis, and macrophage-specific Notch1-knockout mice (Notch1), were used to investigate the role of Tregs in early MASLD and the effect of hepatic macrophage Notch1 signaling on Treg frequency.

Enhancing disease risk gene discovery by integrating transcription factor-linked trans-variants into transcriptome-wide association analyses.

Transcriptome-wide association studies (TWAS) have been successful in identifying disease susceptibility genes by integrating cis-variants predicted gene expression with genome-wide association studies (GWAS) data. However, trans-variants for predicting gene expression remain largely unexplored. Here, we introduce transTF-TWAS, which incorporates transcription factor (TF)-linked trans-variants to enhance model building for TF downstream target genes.

A proteome-wide association study identifies putative causal proteins for breast cancer risk.

Background: Genome-wide association studies (GWAS) have identified more than 200 breast cancer risk-associated genetic loci, yet the causal genes and biological mechanisms for most loci remain elusive. Proteins, as final gene products, are pivotal in cellular function. In this study, we conducted a proteome-wide association study (PWAS) to identify proteins in breast tissue related to breast cancer risk.

Mesenchymal stem cells-derived exosomes alleviate liver fibrosis by targeting Hedgehog/SMO signaling.

Background & Aims: Despite increasing knowledge regarding the cellular and molecular mechanisms of liver fibrogenesis, there is currently no approved drug for the treatment of liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation. This study was designed to determine the protective effect and underlying mechanism of human umbilical cord-derived MSCs (UC-MSCs) on thioacetamide-induced liver fibrosis.

Integrating muti-omics data to identify tissue-specific DNA methylation biomarkers for cancer risk.

The relationship between tissue-specific DNA methylation and cancer risk remains inadequately elucidated. Leveraging resources from the Genotype-Tissue Expression consortium, here we develop genetic models to predict DNA methylation at CpG sites across the genome for seven tissues and apply these models to genome-wide association study data of corresponding cancers, namely breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancers. At Bonferroni-corrected P < 0.

Large-scale integration of omics and electronic health records to identify potential risk protein biomarkers and therapeutic drugs for cancer prevention and intervention.

Identifying risk protein targets and their therapeutic drugs is crucial for effective cancer prevention. Here, we conduct integrative and fine-mapping analyses of large genome-wide association studies data for breast, colorectal, lung, ovarian, pancreatic, and prostate cancers, and characterize 710 lead variants independently associated with cancer risk. Through mapping protein quantitative trait loci (pQTL) for these variants using plasma proteomics data from over 75,000 participants, we identify 365 proteins associated with cancer risk.

Association of ESR1 Germline Variants with TP53 Somatic Variants in Breast Tumors in a Genome-wide Study.

Unlabelled: In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors.

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium.

Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes.

Alternative polyadenylation (APA) modulates mRNA processing in the 3'-untranslated regions (3' UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls.

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV.

Drug-target Mendelian randomization revealed a significant association of genetically proxied metformin effects with increased prostate cancer risk.

The association between metformin use and risk of prostate cancer remains controversial, while data from randomized trials is lacking. We aim to evaluate the association of genetically proxied metformin effects with prostate cancer risk using a drug-target Mendelian randomization (MR) approach. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium (79,148 cases and 61,106 controls).

Association of germline variants with somatic variants in breast tumors in a genome-wide study.

Background: In breast tumors, somatic mutation frequencies in and vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of somatic mutations than other subtypes. mutations are more frequently observed in hormone receptor positive tumors.

Single-cell map of dynamic cellular microenvironment of radiation-induced intestinal injury.

Intestine is a highly radiation-sensitive organ that could be injured during the radiotherapy for pelvic, abdominal, and retroperitoneal tumors. However, the dynamic change of the intestinal microenvironment related to radiation-induced intestine injury (RIII) is still unclear. Using single-cell RNA sequencing, we pictured a dynamic landscape of the intestinal microenvironment during RIII and regeneration.

Large-scale alternative polyadenylation (APA)-wide association studies to identify putative susceptibility genes in human common cancers.

Alternative polyadenylation (APA) modulates mRNA processing in the 3' untranslated regions (3'UTR), which affect mRNA stability and translation efficiency. Here, we build genetic models to predict APA levels in multiple tissues using sequencing data of 1,337 samples from the Genotype-Tissue Expression, and apply these models to assess associations between genetically predicted APA levels and cancer risk with data from large genome-wide association studies of six common cancers, including breast, ovary, prostate, colorectum, lung, and pancreas among European-ancestry populations. At a Bonferroni-corrected □<□0.

A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis in mice via binding and relocating acetyl-coA carboxylase.

Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drugs targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, have been approved by the FDA. Whether cytosolic ACC1 can be regulated spatially remains to be explored.

Deep neural network based tissue deconvolution of circulating tumor cell RNA.

Prior research has shown that the deconvolution of cell-free RNA can uncover the tissue origin. The conventional deconvolution approaches rely on constructing a reference tissue-specific gene panel, which cannot capture the inherent variation present in actual data. To address this, we have developed a novel method that utilizes a neural network framework to leverage the entire training dataset.

A large-scale microRNA transcriptome-wide association study identifies two susceptibility microRNAs, miR-1307-5p and miR-192-3p, for colorectal cancer risk.

Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression.

Enhancing Disease Risk Gene Discovery by Integrating Transcription Factor-Linked Trans-located Variants into Transcriptome-Wide Association Analyses.

Transcriptome-wide association studies (TWAS) have been successful in identifying disease susceptibility genes by integrating cis-variants predicted gene expression with genome-wide association studies (GWAS) data. However, trans-located variants for predicting gene expression remain largely unexplored. Here, we introduce transTF-TWAS, which incorporates transcription factor (TF)-linked trans-located variants to enhance model building.