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In this work, the authors reveal that three non-ribosomal peptides targeting a common protein quality system differentially alter the Mycobacterium tuberculosis proteome, providing new insight into the molecular mechanisms behind their antimycobacterial activity.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Lipopeptides are used to combat drug-resistant infections, but drawbacks limit their application. Here, Lim et al. contrast the mechanisms of lipopeptides that are superficially similar yet disrupt membranes in distinctly different ways.

This work demonstrates the first miniature RF filter combining ultrawide tunability (4–18 GHz) and high nonreciprocity, achieving low loss, zero static power, and compact size (1 cc).

Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

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

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

How the brain supports speaking and listening during conversation of its natural form remains poorly understood. Here, by combining intracranial EEG recordings with Natural Language Processing, the authors show broadly distributed frontotemporal neural signals that encode context-dependent linguistic information during both speaking and listening..

SpbK protects Bacillus subtilis from phage infection by depleting NAD⁺. In this study, the authors uncover the molecular mechanisms underlying SpbK’s self association-dependent NADase activity and its activation by the SPβ phage portal protein YonE.

Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

New genome-wide data sheds light on the complex demographic histories of isolation, expansion, and contact among Mainland Southeast Asian Austroasiatic speakers, and also illuminate historical gene flow from East and South Asia into Mainland Southeast Asia.

In this phase 1 trial, treatment of patients with fibrolamellar hepatocellular carcinoma with a therapeutic peptide vaccine targeting the fusion kinase DNAJB1–PRKACA, which is the driver of the disease, together with nivolumab and ipilimumab, was safe and led to encouraging preliminary clinical responses, and translational analysis showed activation of immune responses.

Fire hydrants can create stagnant zones in drinking water systems that degrade water quality. This study shows that stagnant water has much higher metal and microbial levels than flowing water, revealing distinct chemical and microbial shifts that may pose health risks.

Man-made ammonia emissions have harmful effects on human health and ecosystems, yet global mitigation strategies remain underexploited. A study now finds that emissions could be halved cost-effectively by 2050 through targeted and prioritized measures, with benefits far outweighing costs.

Unprotected β-fluoroamines are important motifs in synthetic chemistry, offering versatility for the development of β-fluorinated nitrogen-containing compounds. Here, the authors disclose an iron-catalyzed three-component aminofluorination of alkenes using a hydroxylamine reagent and Et3N · 3HF, offering a direct entry to unprotected β-fluoroamines.

Inhibition of the histone methyltransferase NSD2 and the androgen receptor in preclinical models can reverse lineage plasticity to suppress tumour growth and promote cell death in multiple subtypes of castration-resistant prostate cancer.

The authors report the synthesis of (La_0.9Y_0.1)H₁₀ superhydrides and their characterization using synchrotron-based, spatially resolved x-ray diffraction and electrical transport imaging. They reveal μm-scale structural inhomogeneity with coexisting cubic and hexagonal clathrate phases exhibiting distinct superconducting transition temperatures.

Termites, the largest lineage of non-hymenopteran social insects, are important decomposers of plant organic matter in the tropics. Here, the authors sequence the genomes of 45 termites and two cockroach outgroups and investigate the influence of diet on the evolution of termite genomes.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Measles vaccination was interrupted globally during the COVID-19 pandemic. Here, the authors use data on measles antibody levels from Hunan province, China, to quantify the immunity gap and model the potential impact of supplementary immunisation activities.

Wildfire observations reveal that 21% of black carbon aerosols contain multiple cores, and accounting for this morphology increases global absorption by 19%, highlighting a missing source of radiative forcing in current models.

This study shows that TE, an inferotemporal (IT) cortex subregion, displays stronger neural plasticity than TEO, another IT subregion, during learning of a challenging visual categorization task in primates, to which both areas contribute.

Specific pain-sensing nociceptors and chemosensory tuft cells form a circuit to promote type 2 immune responses in the intestine.

Pilcher et al. present a single-cell transcriptomics-based immune atlas of participants with newly diagnosed multiple myeloma, reporting on the association of cell types, gene expression and intercellular interactions with disease progression phenotypes.

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.

Differentiating DCs express ALDH1A2, which produces retinoic acid and suppresses DC activity. Blocking this pathway with a new inhibitor, KyA33, enhances immune responses and boosts the effectiveness of DC cancer vaccines in mouse models.

Cancer cells can squeeze through confined spaces and undergo nuclear deformation, leading to changes in chromatin organisation. Here, the authors show that mechanical constriction in microcapillaries reprograms melanoma cells to a tumorigenic stem cell-like state through the mechanosensor PIEZO1.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

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.

The neurophysiology of excessive daytime sleepiness in Parkinson’s disease (PD) remains unclear. Here, the authors found that beta oscillatory activity, a pathophysiological signature of PD motor signs, is also associated with daytime vigilance in parkinsonism

This study introduces P3T-Net, a pseudo-3D deep learning model that enables accurate and efficient cross-domain transfer of large 3D material images, improving image quality and ensuring image consistency across diverse imaging conditions.

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.

The forelimbs of two Late Cretaceous theropod dinosaurs show the presence of the pisiform bone, previously thought to have been lost early in theropod evolution and regained in birds during the evolution of flight, indicating that a birdlike pisiform appeared prior to the evolution of flight.

Experimental evidence demonstrates long-distance remote epitaxial interactions of thin films even through thick amorphous carbon buffer layers and shows that these can be induced through dislocations in the substrate.

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.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Over 20 species of geographically and phylogenetically diverse bird species produce convergent whining vocalizations towards their respective brood parasites. Model presentation and playback experiments across multiple continents suggest that these learned calls provoke an innate response even among allopatric species.

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.

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.

Standard first line therapy in patients with non-small cell lung cancer is immunotherapy but responses vary and consistent predictive biomarkers are lacking. Here, using RNA-sequencing data from a large clinical trial in NSCLC patients, the authors define four molecular subsets with distinct tumour-intrinsic and -extrinsic features with differing outcomes to immunotherapy combinations.

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.

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.

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.

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.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.