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In a prospective study enrolling 1,222 patients from 22 emergency departments, a device using a machine-learning-based signature of blood mRNAs demonstrated clinically acceptable performance to diagnose bacterial and viral infections and to predict the all-cause need for critical care interventions within 7 days, with benchmark to established biomarkers and risk scores.

A significant challenge in modern drug development is the comprehensive profiling of covalent inhibitors. Here, the authors develop COOKIE-Pro, an unbiased method for quantifying the binding kinetics of irreversible covalent inhibitors on a proteome-wide scale.

The authors describe the isolation and characterization of broadly cross-neutralizing monoclonal antibodies (mAbs) against diverse H5Nx viruses from individuals who received a monovalent H5N1 vaccine 15 years ago. They identify five mAbs that potently neutralized the majority of H5 clades and protected against lethal 2.3.4.4b H5N1 infection in mice.

PetaKit5D offers versatile processing workflows for light sheet microscopy data including performant image input/output, geometric transformations, deconvolution and stitching. The software is efficient and scalable to petabyte-size datasets.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

This Consensus Statement presents the standards for technical reporting in environmental and host-associated microbiome studies (STREAMS) guidelines.

An RNA aptamer and a ribozyme are both observed to retain a surprising degree of activity despite backbone heterogeneity caused by the presence of non-natural 2′–5′ phosphodiester linkages. These results suggest that absolute regioselectivity of non-enzymatic replication may not have been required for the emergence of RNA as the first biopolymer.

Sunshine et al. use Perturb-seq to study host dependencies of SARS-CoV-2 by inactivating host factors genetically and monitoring the course of infection by single-cell sequencing, characterizing global host phenotypes. They identified NFKBIA, EIF4E2 and EIF4H as strong host dependency factors.

The authors report a co-occurrence of the U2AF1 S34F splicing factor mutation and ROS1 translocations in lung adenocarcinomas and profile effects of S34F on transcriptome-wide RNA binding. They further show that U2AF1 S34F enhances invasive potential and alters splicing of ROS1 fusion transcripts

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

Characterization of clinical isolates of the cryptic fungal pathogen Aspergillus latus revealed traits that distinguish it from other species. Steenwyck et al show that A. latus originated via allodiploid hybridization with both parental subgenomes actively expressed.

N⁶-methyladenosine (m⁶A) modification of mRNA regulates gene expression in eukaryotes. Here, Zeng et al. show that m⁶A modification of mRNAs contributes to protection against the pathogen Helicobacter pylori by downregulating a host protein that acts as receptor for the pathogen.

Dysregulated protein degradation drives diseases like cancer. Here, authors use protein language models to design target-binding peptides, which are subsequently attached to the catalytic domain of the OTUB1 deubiquitinase, generating “deubiquibodies” (duAbs). duAbs restore tumor suppressors and fusion oncoproteins, offering a programmable strategy for protein stabilization.

Vignali and colleagues show that a full complement of ITAMs is required in the TCR-CD3 complex for TCR-driven T cell proliferation, whereas a low number of functional ITAMs is sufficient for cytokine secretion.

Cooperative species of extrachromosomal DNAs are coordinately inherited through mitotic co-segregation.

Social disconnection across socioeconomic lines is explained by both differences in exposure to people with high socioeconomic status and friending bias—the tendency for people to befriend peers with similar socioeconomic status even conditional on exposure.

Depression is correlated with many brain-related traits. Here, Shen et al. perform phenome-wide association studies of a depression polygenic risk score (PRS) and find associations with 51 behavioural and 26 neuroimaging traits which are further followed up on using Mendelian randomization and mediation analyses.

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

In transgenic mice with temporally and spatially restricted neurodegeneration, fear memories formed before induction of neuronal loss can be restored by environmental enrichment, even though the degeneration does not recover. Histone deacetylase inhibitors mimic the effects of environmental enrichment .

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Here, using Citrobacter rodentium colonization of mice as a model, the authors characterize the impact of pathogen dose on the number of bacteria that initiate infection in the mouse gut, providing a framework for quantifying the host bottlenecks that eliminate pathogens to protect from infection.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Systematic phenotyping of 58,101 mutants of the model eukaryotic alga Chlamydomonas reinhardtii under 121 environmental and chemical stress conditions provides a large resource for characterizing gene function.

Comprehensive analyses of 178 lung squamous cell carcinomas by The Cancer Genome Atlas project show that the tumour type is characterized by complex genomic alterations, with statistically recurrent mutations in 11 genes, including TP53 in nearly all samples; a potential therapeutic target is identified in most of the samples studied.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

The authors in this work introduce RosettaVS, an AI-accelerated open-source drug discovery platform. They apply this tool to multi-billion compound libraries, where it was able to identify compounds that bind important targets KLHDC2 and Na_V1.7.

Breast cancer cells interact with neighbouring adipocytes, but the mechanisms are not fully understood. Here, the authors show that triple-negative breast cancer (TNBC) cells transfer cAMP through gap junctions, activating lipolysis in tumour-associated adipocytes to promote TNBC growth.

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal degradation.

Using sequencing and haplotype-resolved assembly of 65 diverse human genomes, complex regions including the major histocompatibility complex and centromeres are analysed.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

Genome-wide sequencing of 180 ancient individuals shows a continuous gradient of ancestry in Early-to-Mid-Holocene hunter-gatherers from the Baltic to the Transbaikal region and distinct contemporaneous groups in Northeast Siberia, and provides insights into the origins of modern Uralic and Yeniseian speakers.

The accumulation of senescent cells drives age-related diseases. In this study, the authors show that senolytic CAR T cells can rejuvenate metabolic function and fitness in old mice and that a single dose is sufficient to lead to long-term preventive effects.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

The Vertebrate Genome Project has used an optimized pipeline to generate high-quality genome assemblies for sixteen species (representing all major vertebrate classes), which have led to new biological insights.

Huntington disease (HD) has been linked via biochemical uptake assays to impaired glutamate clearance and resultant excitotoxicity. Here, utilizing a fluorescent reporter, the authors measure real-time glutamate dynamics in mouse model HD brain slices and find normal or even accelerated glutamate clearance.

Ancient DNA reveals how the explosive expansion of Yamnaya steppe pastoralists began with a small community north of the Black Sea speaking ancestral Indo-European, and detects genetic links with Anatolian speakers, stemming from a common Indo-Anatolian homeland in the North Caucasus–lower Volga region.