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Exposome analyses across 34 countries showed that social exposures were associated with faster functional brain aging and physical exposures with faster structural brain aging.

While the benefits of crop diversity are known, doubts remain as to whether replacing cereals in rotations reduces nutrient production. A comparison of 16 long-term field experiments across Europe shows no trade-off between functionally rich rotations and food productivity.

The role of disorder in high-entropy oxides in electrocatalysis and zinc–air batteries remain unclear. Here, the authors induce controlled multilevel structural, electronic and atomic disorder to create new active sites, enabling robust, balanced oxygen catalysis and efficient zinc–air batteries.

The zebra finch robust nucleus of the arcopallium (RA) directs singing by providing descending projections to brainstem motor neurons. The authors show that electrophysiological characteristics of RA neurons rely on resurgent Na+ currents that emerge early during song development only in males.

A martensitic alloy with a tensile strength exceeding 3 GPa and a fracture elongation of 5.13% is developed. These mechanical properties arise from interface complexes interacting with dense dislocation networks, which is a mechanism shown to be applicable to other compositions.

Fine-scale field analysis and modelling of the spatial dynamics of infection of Darwin’s frogs with Batrachochytrium dendrobatidis fungus identifies highly localized transmission dynamics that generate clustered epidemics and can drive collapse of local subpopulations.

It has been previously shown theoretically that the average path length of random walks inside a closed domain is invariant. Here the authors demonstrate that this invariance property can be used to predict the mean residence time of swimming bacteria exploring structured micro-environments.

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.

Electrical excitability in neuroendocrine SCLC cells promotes tumour progression through action potential firing, increasing ATP demand and oxidative phosphorylation dependency, whereas non-neuroendocrine cells provide metabolic support, driving a tumour-autonomous cycle that enhances tumorigenesis and metastasis.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

Nicastro, Brohée et al. find that the fatty acid synthesis intermediate malonyl-CoA inhibits mTORC1, showing mTORC1 senses the capacity of a cell to synthesise fatty acids and linking fatty acid generation with the overall biosynthetic output through mTORC1.

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.

BamA carries out the essential process of folding outer membrane β-barrels in Gram-negative bacteria and is a potential antibiotic target. Here, the authors discover macrocyclic peptide inhibitors that trap BamA in distinct structural conformations.

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.

Kaiser et al. characterize the disordered extracellular N-terminus of a peptide-activated G protein-coupled receptor. They combine biophysical, biochemical, and computational methods to uncover its role in the activation of G protein and arrestin pathways.

We show that cytosolic inner mitochondrial membrane vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state and directly herniate into lysosomes through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane, thereby allowing their selective removal.

Myocardial infarction accelerates atherosclerosis through activation of the sympathetic nervous system, and the consequent release of haematopoietic stem and progenitor cells.

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.

Structural and functional studies of the sodium leak channel, non-selective (NALCN) in complex with a distinct auxiliary subunit reveal the structural basis of the channel function and pharmacology and the functional impact of mutations that cause NALCN channelopathies.

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.

Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.

Endothelial cells undergo rearrangements during angiogenic sprouting. Gerhardt and colleagues show that the flux in Notch signalling levels in individual cells of sprouting vessels results in differential dynamics of VE-cadherin at junctions to drive functional endothelial cell rearrangements during sprouting. They also find that differential VE-cadherin dynamics are affected in retinopathy and tumour vessels.

A metalloenzyme capable of oxidatively cleaving cellulose, found in a microbial community specialized in lignocellulose degradation, could enable sustainable biofuel production.

How the brain controls pain perception remains elusive. Here, authors show that layers 5 and 6 of the somatosensory cortex suppress or enhance nociception through cell-type-specific cortical and corticothalamic interactions.

This study characterised the landscapes and changes of RNA m6A in brains of individuals with or without Alzheimer’s disease, and revealed roles of a promoter antisense RNA next to MAPT in neuronal gene regulation that promote neuronal survival.

Discovery of macrocyclic ligands to the 19S regulatory particle protein PSMD2 enables the synthesis of heterobifunctional molecules that demonstrate proof-of-concept, targeted degradation of BRD4 through direct engagement of the 26S proteasome.

Clear experimental signatures of fractional statistics in topologically ordered phases have been lacking. Here, the authors predict detectable signatures of non-trivial mutual statistics of fractionalized excitations in gapped topological quantum spin liquids at finite temperature.

MatterGen is a model that generates stable, diverse inorganic materials across the periodic table and can further be fine-tuned to steer the generation towards a broad range of property constraints.

Ambroziak, Nencini, Pohle and colleagues identify a slowly emerging plasticity mechanism in a discrete set of hypothalamic preoptic neurons that is triggered by long-term heat exposure and that drives thermal acclimation to promote heat tolerance in mice.

During senescence, minority mitochondrial outer membrane permeabilization leads to the release of mtDNA into the cytosol through BAX and BAK macropores, in turn activating the cGAS–STING pathway, a major regulator of the senescence-associated secretory phenotype.

Analysing camera-trap data of 163 mammal species before and after the onset of COVID-19 lockdowns, the authors show that responses to human activity are dependent on the degree to which the landscape is modified by humans, with carnivores being especially sensitive.

Adipogenesis is important for white adipose tissue function. Here the authors identify the transcription factor PATZ1 as a regulator of adipogenesis and adipocyte maintenance, and report that adipose-tissue specific loss of PATZ1 leads to reduced fat mass and larger adipocytes in mice.

Albinism is a rare disorder often caused by high-effect rare variants in the TYR gene. Here, the authors study a large albinism cohort and find that a common variant in the TYR promoter contributes to albinism by modifying the penetrance of other common variants, demonstrating a complex genetic architecture.

This study presents real-time observation of plasmon-driven hot carrier creation. Auger heating is operative in enhancing carrier energy beyond single-photon excitation. These findings open new avenues in plasmonic energy conversion and photocatalysis.

Grune et al. show that hypokalemic mice develop spontaneous ventricular tachycardia after myocardial infarction, and they use this model to dissect the role of immune cells in arrhythmia: neutrophils increase ventricular tachycardia, partly by promoting reactive oxygen species production, whereas efferocytic macrophages play a protective role.

Rouge waves have been observed in a number of complex systems, but not in biological structures. Here, the authors report the observation of optical rouge waves manifesting in tumor-cell spheroids when illuminated by randomly modulated laser beams.

Mutations in the RRAGD gene are causative of an autosomal dominant disorder characterized by kidney tubulopathy and cardiomyopathy. Here, the authors identify a new RRAGD P88L mutation, demonstrating that all the identified RRAGD mutations inhibit the nuclear translocation of MiT/TFE transcription factors, resulting in defective responses to lysosomal or mitochondrial damage.

Supervised deep learning models hold promise for the interpretation of histology images, but are limited by cost and quality of training datasets. Here, the authors develop a self-supervised deep learning method that can automatically discover features in cancer histology images that are associated with diagnosis, survival, and molecular phenotypes.

Contractile forces are key to sorting the embryonic inner cell mass from the extraembryonic trophectoderm. Here they show that Lamin-A links changes in mechanical forces to cell fate specification, enabling Yap-Cdx2 signaling in outer, but not inner cells.

A structure of the MRAS–SHOC2–PP1C complex supports a RAS-driven and multi-molecular model for RAF activation in which individual RAS–GTP molecules recruit RAF–14-3-3 and SHOC2–PP1C to activate the downstream pathway.

Here the authors show a mechanism by which mitochondrial electron transport and ROS contribute to the differentiation and function of regulatory B cells in the context of systemic lupus erythematosus.

Genome-wide association analyses identify 30 risk loci for IgA nephropathy. Functional annotations of putative causal genes converge on inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets.