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KRAS is an oncogene that switches between a GDP-bound inactive state and a GTP-bound active state. Recently developed KRAS G12C inhibitors are specific to the GDP-bound inactive state. Here, the authors develop a class of covalent KRAS G12C inhibitors capable of targeting both states for the treatment of KRAS-driven cancer.

T cell activation requires major metabolic adaptation. Here authors find that in mice and humans, expression of the NAD/H-synthesis enzyme nicotinamide riboside kinase 1 (NRK1) increases in CD4+ T cells upon activation, particularly within the cytoplasm, which impacts NADP/H and reactive oxygen species signalling, restraining activation and cytokine production while promoting CD4 + T cell survival during viral and fungal infections.

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.

Navigational affordances describe our ability to identify routes of egress within scenes. Here, the authors show that this process likely occurs in early dorsal visual cortex and that such navigational affordances can emerge following brief presentation times.

Nudt21-mediated 3′UTR regulation orchestrates tissue regeneration through dose-dependent control of stem cell differentiation and multiprotein complex assembly, revealing alternative polyadenylation as essential for organismal survival.

Metabolomic profiling of 581 mother–child pairs revealed patterns associated with neurodevelopmental disorders (NDD). Maternal metabolomic profiles at gestational week 24 showed the strongest predictive value, with quinolinate consistently associated with NDD across time points and linking maternal inflammation to NDD risk.

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

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

Urban soils are exposed to numerous human-driven stressors that can interact in unpredictable ways. This study concludes that the impact of adding one factor does not correspond to the impact of removing it from a set of interacting stressors.

CDK4/6 inhibitors are promising treatments for ER+ breast cancer, however resistance remains a challenge. Here, the authors analyse the NeoPalANA cohort and indicate that a 33 gene signature was predictive of response to neoadjuvant anastrozole and palbociclib.

The xylosyltransferase isoenzymes XT1 and XT2 catalyze the first glycosylation step in the biosynthesis of proteoglycans. Now, bump-and-hole engineering of XT1 and XT2 enables substrate profiling and modification of proteins as designer proteoglycans to modulate cellular behavior.

In vitro propagation of the pathogenic bacterium Coxiella burnetii, the causative agent of Q fever, leads to attenuated virulence and lipopolysaccharide (LPS) truncation. Here, Long et al. show that a strain considered to be avirulent (NMII) can be recovered from infected animals, and these isolates display increased virulence and an elongated LPS due to reversion of a 3-bp mutation in a gene.

Bayesian psychophysical modelling of cardiac and respiratory interoception (N=241) showed no cross-domain associations in sensitivity, precision, or metacognition, indicating that interoceptive performance is organ-specific.

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).

Using a non-human primate model, the authors identified the tissue sites of initial viral rebound after discontinuation of antiretroviral therapy, demonstrating that such rebound preferentially occurs in the gastrointestinal tract-associated lymphoid tissues.

Radiation reaction (RR) on particles in strong fields is the subject of intense experimental research, but previous efforts lacked statistical significance due to the extreme regimes required. Here, the authors report a 5σ observation of RR and obtain strong, quantitative evidence favouring quantum models over classical, using an all-optical setup where electrons are accelerated by a laser in a gas jet before colliding with a second, intense pulse.

A platform using matched patient-derived lung tumouroids and healthy lung organoids enables accurate examination of patient responses to CAR T therapy and offers a faithful framework for improved CAR T design.

A national classification system of wetland hydrologic connectivity to streams, which could be applied globally, demonstrates and advances current understanding of how wetland connectivity affects surface water quality.

Krisai et al. compare brain structure and cognitive function in elderly patients with and without atrial fibrillation using brain MRI and cognitive testing. They find that atrial fibrillation is associated with more brain lesions and lower cognitive function, but the cognitive impairment occurs primarily through direct effects of the arrhythmia rather than through brain damage.

Multi-layer film packaging revolutionized food preservation by combining diverse material layers to optimize barrier properties, mechanical strength, and shelf-life but they pose significant recycling challenges due to their structural complexity. This perspective examines key structure-property relationships governing barrier performance and highlights innovations in material design.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

Natural products inspire the development of pseudo-natural products through combinations of fragments of compound classes that are chemically and biologically distinct. Here, the authors report a library of 244 pseudo-natural products, evaluate them in the cell painting essays and identify the phenotypic role of individual fragments.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

How landscapes are arranged affects soil pathogenic fungi worldwide. The authors reveal the global pattern and pronounced scale-dependency of landscape complexity and land-cover quantity on soil pathogenic fungal diversity.

Walmsley and colleagues report that systemic hypoxia induces persistent loss of histone H3K4me3 marks and epigenetic reprogramming in neutrophil progenitors, resulting in long-term impairment of subsequent neutrophil effector functions.

An implementation trial conducted across 60 schools in Rwanda found that CyberRwanda, a digital, school-based intervention, did not affect the primary outcomes of modern contraceptive use, childbearing and HIV testing among adolescents but was associated with higher contraceptive use among sexually active participants.

Long COVID has heterogeneous presentation and clinical trajectories are not well defined. Here, the authors define trajectories using data from a prospective cohort study in the United States involving symptom questionnaires from acute infection up to 15 months.

Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.

This study associates p53 loss and brain metastasis in breast cancer. Mechanistically, p53-null tumors recruit astrocytes that provide substrates for enhanced fatty acid synthesis via upregulated SCD1 expression, representing a targetable axis in the disease.

Blocking peptidoglycan synthesis kills bacteria. The authors show that the E. faecium PBP5 peptidoglycan binding site is distal to the active site, which could be the focus of antibiotic strategies that hinder substrate recruitment.

Xenotransplantation of a genetically edited pig kidney with a thymic autograft into a brain-dead human for 61 days with immunosuppression resulted in stable kidney function without proteinuria, and xenograft rejection was treated and reversed by the end of the study.

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.

Merlino et al. demonstrate that the cytokine Interleukin-27 contributes to innate antiviral immunity in the placenta and is an important defense against congenital Zika virus infection.

The authors optimize an in vitro human epiblast model, which they utilize to show that early TGFβ family inhibition prevents epithelial identity, whereas it is dispensable after epithelium formation. These phenomena are conserved in mice.

cAMP export by ABCC4 is critical for localized signaling. Here, the authors revealed that PKA activation drives ABCC4 to the plasma membrane and organizes a PDZ-dependent protein network with actin cytoskeleton and scaffolds, like SCRIB, that stabilize the transporter and optimize cAMP efflux. Furthermore, the authors show that the potent ABCC4 inhibitor Ceefourin 2 disrupts this network, revealing a non-canonical mechanism of ABCC4 inhibition.

Translation initiation and elongation factors can be targets for cancer treatment. Here, the authors show that inhibiting translation elongation through eIF5A impairs mitochondrial function, slowing the proliferation of tumour cells.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

Heritz et al. use an orthogonal approach to identify a selective inhibitor for HIF2α that disrupts its interaction with the molecular chaperone Hsp70. This inhibitor utilizes an alternative mechanism of action to previous HIF2α antagonists, providing a promising approach in addressing kidney cancer drug resistance.

The metastatic potential of patients following breast cancer neoadjuvant therapy is highly variable. Here, the authors demonstrated the predictive and prognostic value of ctDNA in 723 patients with high-risk early-stage breast cancer using serial analysis.

Demand for agricultural water resources under climate change may come into conflict with achieving positive environmental outcomes. In Australia’s Macquarie basin, environmentally minded management can ensure agricultural needs are met without sacrificing environmental outcomes.

Methods used to date a network of marine sediment cores reveal that rapid retreat of the Ross Ice Shelf was contemporaneous with the lowering of nearby outlet glaciers, implicating warm ocean waters as a driver of Antarctic deglaciation.

Transfer RNA-derived small RNAs (tsRNAs) emerge as crucial players in biological processes but their disease relevance is unknow. Here, the authors show that tsRNA-Glu-CTC is the most abundant hepatic tsRNA that plays a key role in regulating cholesterol homeostasis and atherosclerosis development.

Here, the authors generated and analyzed run-on sequencing data to observe transcription in species across the tree of life to uncover the origins of the promoter-proximal pause.

The predicted increase in frequency of droughts and rising temperatures in Europe will lead core populations of a temperate plant to an evolutionary dead-end unless they acquire genetic alleles that are present only in extreme edge Mediterranean, Scandinavian, or Siberian populations.

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.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

H5N1 avian influenza viruses caused an outbreak in dairy cattle. We show that the potential for avian viruses to replicate in cow cells varies across H5N1 evolution, suggesting that the risk of spillover into mammals differs between variants.

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.