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Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

Fragment-based drug design is an efficient yet challenging approach for developing therapeutics. Here, the authors employ structure-based docking screens of vast fragment libraries to identify inhibitors of 8-oxoguanine DNA glycosylase, a difficult drug target implicated in cancer and inflammation.

Klose and colleagues show that the neuropeptide vasoactive intestinal peptide (VIP) acts on LGR5⁺ epithelial stem cells in the gut to restrain their proliferation and differentiation to secretory cell types. This VIP–VIPR1 interaction acts to limit type 2 immune responses.

The authors show that regenerating liver requires de novo pyrimidine synthesis and it uses ammonia as precursors differentially as it traverses the liver zones. Tracing studies and spatial metabolomics reveal that assimilation periportally is via the urea cycle, and pericentrally through conversion into glutamine.

The authors quantify the changes in heat stress exposure at the district level in India from 1981-2023 using high resolution spatiotemporal data. Findings also highlight caste-based inequality in outdoor occupational heat stress exposure.

Systematic analysis from the Global Burden of Disease study reported that, despite global improvements from 1990 to 2021, dietary iron deficiency-associated disease burden remains high in women, children and residents in low socio-demographic index countries.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Analyses of mitochondrial genomes from populations in southern Africa provide evidence of a southern African origin of anatomically modern humans and a sustained occupation of the homeland before the first migrations of people appear to be driven by regional climate shifts.

The soils of urban greenspaces are strikingly rich. This study finds that the variety of microbial life there is linked to acidic conditions and that this diversity is more homogenous than found in farmland soils.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Here the authors engineer a bispecific antibody (Ab) for HIV-1 by combining a gp41 N-heptad repeat targeting Ab with a CD4 binding Ab. Prepositioning via CD4 binding results in high neutralization breadth and potency, and experiments in HIV infected humanized male mice show reduction of viral load.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

A 50 microRNA-based dynamic risk score for stratifying individuals with and without type 1 diabetes was developed using samples obtained from multicenter and multiethnic cohorts.

Variations in microbial composition, phage induction, antimicrobial resistance genes and bile acid profiles are identified by using an ingestible device for site-specific sampling along the intestines.

The efficacy of CAR-T cells against solid tumors is still limited by immunosuppressive factors. Here, the authors show that engineering of CAR T cells with A1R enhances their efficacy against solid tumors in vitro and in vivo.

This study shows how including different ancestry groups in a genome-wide association study for prostate-specific antigen levels can improve prostate cancer risk prediction, with implications for population screening.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Using multiplexed spatially resolved transcriptomic approaches, the authors generate a topographic atlas of the healthy adult lung with location-related gene expression variability or neighbourhood changes as exemplified by COPD patient sample analysis.

Several researchers share tales around the development of their widely used methods.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Single molecular layers of TiSe₂are promising for advanced electronic applications, and it is therefore important to characterize their phases. Here, the authors use ARPES to detect a charge density wave transition without Fermi surface nesting and that takes place at a temperature higher than in bulk.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Liver regeneration often fails during chronic liver disease. Here, the authors conduct multiomic profiling of human livers to demonstrate that RNA splicing is dysregulated in alcohol-associated liver disease, interfering with liver regeneration.

Uterine leiomyomata (UL) or fibroids are neoplasms of the uterine smooth muscle associated with heavy menstrual bleeding and other female reproductive tract morbidity. Here, the authors identify eight previously undescribed genetic loci for UL and further look into genetic overlap with heavy menstrual bleeding and endometriosis.

A rare variant burden analytical framework for Mendelian diseases was developed and applied to data from the 100,000 Genomes Project, identifying 69 probable new disease–gene associations.

Candida albicans infection exacerbates intestinal inflammation through IL-1β dependent mechanisms. Here the authors characterise the function of a hyphae protein Als3 and show that Als3 promotes ASC oligomerization so that innate cells sense infection and promote IL-1β mediated effector mechanisms.

Analysis of large-scale CRISPR screening data, combined with experiments in patient-derived tumour organoid models, identifies PELO as a potential therapeutic target in chromosomal 9p21.3-deleted cancers and microsatellite-unstable cancers harbouring specific mutations.

Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.

Polypropionates can be grown — one carbon atom at a time — using the iterative homologation of boronic esters. This assembly line strategy was enabled through the use of enantioenriched lithiated α-chlorosilanes as masked carbinol units. Polypropionates were obtained in a fully stereocontrolled manner, including the stereochemically challenging anti–anti isomers.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Photocaged molecules have advantages in terms of temporal and spatial control compared to conventional pharmacological compounds. The authors present a synthetic saxitoxin derivative affixed to a photocleavable group for precise modulation of Na channels.

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

The interaction of nanoparticles with target tissues is important in the design of nanoparticle-based therapies. Here, the authors develop a microfluidic chip to assess the interaction of nanoparticles with tumour tissues and demonstrate its capacity to predict in vivonanoparticle behaviour.

Anti-cancer fluoropyrimidine drugs have antibacterial effects on the gut microbiome, and these drugs can be metabolized by gut bacteria via conserved pathways also found in mammalian hosts.