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Here, Wulczynski et al. find fewer small-intestinal fiber-degrading bacteria in CeD patients, independent of the gluten-free diet, while inulin-supplemented diet in gluten-sensitized mice facilitates microbial saccharolytic function and SCFAs, accelerating mucosal healing in the small intestine.

Analysis of nuclear and mitochondrial genomes from archaeological canid remains found across Europe and Anatolia shows that a genetically homogeneous dog population was already widely distributed across the region by 15,000 years ago.

Pouget et al. identified distinct CA1 neuron ensembles active during specific moments of fear learning and uncovered the core engram essential for memory formation.

Robustness checks and reproduction of analyses with existing and updated data based on 110 articles in economics and political science journals with data and code-sharing requirements found high levels of robustness and reproducibility and determined that robustness was not dependent on author characteristics or data availability.

In mice, a circuit between the spinal cord and various regions of the brain, centring on spinal-cord-projecting neurons in the rostral ventromedial medulla, has a key role in driving chronic pain.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Meningiomas are common brain tumors with variable behavior. This study reveals high STING expression across multiple cell types in the meningioma microenvironment. STING agonism triggers tumor cell death via programmed necrosis and pyroptosis, enhancing survival in preclinical models.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

The mitochondrial pathway of apoptosis requires coordinated protein–lipid signals. Here, Gelles et al. show that a BAX lipid-binding cavity for 2-trans-hexadecenal cooperates with BIM to allosterically activate BAX prior to membrane insertion.

Longitudinal metatranscriptomics in a prospective cohort of 1,164 adults hospitalized for COVID-19 reveals that azithromycin offered no apparent anti-inflammatory benefit but enriched the respiratory microbiome with potential pathogens and antimicrobial resistance genes.

It remains unclear why some BRCA-deficient high-grade serous carcinomas (HGSC) do not respond to platinum-based therapy. Here, multi-omic analysis of BRCA1- and BRCA2-deficient HGSC attributes co-occurring mutations, DNA repair deficiency and tumor microenvironment features to short survival in these patients.

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.

Genomic analysis of 118 cervical tumors from Ugandan individuals identifies HPV-clade-specific differences in tumor DNA methylation, regulatory-region-associated histone marks, gene expression and pathway dysregulation.

The substantia nigra and all Parkinson’s disease deep-brain stimulation targets are selectively connected to the somato-cognitive action network rather than to effector-specific motor regions.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Erlich et al. show that soluble LTα and membrane-bound LTα1β2 lymphotoxins expressed by B cells play distinct roles to attenuate the pathology observed in ileitis.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Glioblastoma is characterised by high levels of intratumoural heterogeneity and plasticity, hindering treatment. Here, the authors develop an analytical framework, scFOCAL, to predict the sensitivity of glioblastoma cell subpopulations to therapies based on reversal of disease transcriptional signatures to identify synergistic therapeutic combinations.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

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).

Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity drives proliferation of small lung cell cancer via paracrine interactions and through synapses formed with tumour cells.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

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.

The gut microbiome-kidney crosstalk has been previously linked with metabolic and kidney diseases. Here, the authors show that microbial amino acid metabolism interacts with host kidney function to influence cardiorenal physiology in the early stages, with potential implications for long-term risk of cardiovascular disease in human populations.

Stem cell repair of injured monkey spinal cords restores hand function in 53% of trials.

Sosa et al. find that hippocampal neural activity in mice encodes both environmental location and experience relative to rewards, spanning distances far from reward, through parallel and flexible population-level codes.

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.

How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

Targeting neurons that regulate energy balance may offer new approaches for obesity treatment. Here, authors show that chemogenetic and pharmacological manipulation of GABAergic neurons in the DRN/vlPAG increases adaptive thermogenesis and reduces weight gain in mice fed a highfat diet.

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.

In the brain of fruit flies, the mushroom body achieves flexible learning by using interconnected short- and long-term memory units for dopamine-mediated integration of innate valences with learnt valences obtained through experience.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

In a previous clinical trial, the authors reported that SCFA-yielding biotherapy in adults with type 1 diabetes remodels the gut proteome and metabolome. Here, the show that colonization of the post-therapy microbiome into mice delayed diabetes and increased aryl-hydrocarbon receptor ligand and IgA production in the gut.

Our knowledge of life in the Carboniferous Period is largely restricted to low-lying wetlands dated to 315–310 million years ago. Here, the authors present an older Lagerstätte on an alluvial fan 320–318 million years ago, preserving a diverse ecosystem of vertebrates, invertebrates, plants, and plant-insect interactions.

Soil fauna is an important but often neglected component of terrestrial food webs. Here the authors use a large dataset of stable isotope observations to analyse how soil animal trophic diversity varies across climates and land-use types and identify potential biotic mechanisms.

Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

Rubio-Navarro et al. identify a subset of pancreatic beta cells marked by high CD63 levels with enhanced glucose-stimulated insulin secretion. CD63-high beta cells are diminished in mouse models of and in humans with type 2 diabetes.

Caffeine may reduce cardiovascular disease risk, but the underlying mechanisms for these effects are incompletely understood. Here the authors report that caffeine inhibits the activation of the transcription factor SREBP2 to promote LDLc clearance through the PCSK9-LDLR axis.

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.