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In this single-arm phase 2 trial in patients with HR⁺HER2⁻ advanced breast cancer, treatment with the HER3-targeting antibody–drug conjugate paritumab deruxtecan led to encouraging objective response rates, and comprehensive exploratory analyses indicate potential biomarkers of response.

A blood test has achieved 96% accuracy in diagnosing the condition in a small study of individuals. What does the test detect, and is it a biomarker of the condition?

The quark structure of the f₀(980) hadron is still unknown after 50 years of its discovery. Here, the CMS Collaboration reports a measurement of the elliptic flow of the f₀(980) state in proton-lead collisions at a nucleon-nucleon centre-of-mass energy of 8.16 TeV, providing strong evidence that the state is an ordinary meson.

Lowering the levels of coagulation factor XII may prevent thrombosis without increasing the risk of bleeding. Here, Haj et al. use a large human dataset to show that this is the case for people carrying mutations that lower the levels of factor XII.

The synthesis of crystalline 2D polymers typically relies on reversible dynamic covalent reactions, but achieving 2D polymers through irreversible carbon-carbon coupling reactions remains a formidable challenge. Here, the authors present an on-liquid surface synthesis method for constructing diyne-linked 2D polymers.

Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT_2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.

The enzyme ABHD18 is shown to have a key role in cardiolipin metabolism in mitochondria, offering a potential route for a small-molecule treatment of the rare genetic disease Barth syndrome.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Flores et al. show that brain-penetrant eIF2B agonists suppress ISR activation in cellular and mouse models of ALS and reduce ISR biomarkers in humans, enabling further clinical studies of ISR inhibition in individuals with neurological diseases

Two phase 2 trials, along with translational analysis of prospective cohorts and experimental analysis, indicate that immunosenescence as a mechanism of resistance to immunotherapy can be overcome with the senolytics dasatinib and quercetin in patients with head and neck squamous cell carcinoma.

DNA2 suppresses recombination-restarted replication and checkpoint activation at stalled forks, and its loss triggers recombination-dependent synthesis, checkpoint signalling and cell-cycle exit, highlighting its essential role in proliferation and growth failure in primordial dwarfism.

Antibiotic resistance poses a critical global health threat. Here, the authors identify a carbapenem resistant clone of uropathogenic Escherichia coli with atypical virulence features as an increasing cause of urinary tract infection

Aging is a risk factor for neurodegenerative diseases associated with protein aggregation. Here the authors identify age-related hyperactivation of EPS8/RAC signaling in C. elegans as a driver of pathological protein aggregation, highlighting EPS8 and its regulators as potential therapeutic targets.

Iridoids are terpenoid metabolites found in thousands of plants. Using single-cell transcriptomics, the authors discovered an unexpected enzyme that has been neofunctionalized to catalyse the cyclization required to form the iridoid scaffold.

Half a century ago, two theoretical papers were published that together sparked major new directions — conceptual, mathematical and practically applicable — in several previously disparate fields of science. In this Comment, the authors of one of those papers expose key aspects of the thinking behind them, their implementations and implications, along with sketches of several subsequent and consequential developments.

Here, the authors present fossilized neural traits from the lower Cambrian euarthropod Jianfengia multisegmentalis, including structured eyestalks and compound eyes, that resolve multiple phylogenetic relationships within Euarthropoda.

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.

In strongly correlated systems, how magnetic excitations are renormalized by charge carriers remains an open question. An experiment now reports the observation of magnon-polarons—magnons dressed by doped holes—in a Fermi–Hubbard quantum simulator.

An analysis of data from the Sherlock-Lung study provides insight into the mutational processes that contribute to lung cancer in never smokers, and looks at the possible role of factors such as air pollution and passive smoking.

The cortex fuels essential physiological processes with glucose-derived carbon, while gliomas fuel their aggressiveness by rerouting glucose carbon pathways and scavenging alternative carbon sources such as environmental amino acids, providing a potential therapeutic target.

PROTAC development has surged in popularity, however our ability to characterize PROTAC specificity in living cells has lagged behind. Here, the authors develop ProtacID, a flexible proximity-dependent biotinylation (BioID)-based approach to identify PROTAC-protein interactions in living cells.

Circulating tumor cell (CTC) clusters are much more likely to produce viable metastasis than single CTCs. Here the authors find that the transmembrane protein Plexin-B2 (PLXNB2) mediates homotypic and heterotypic CTC cluster formation, driving lung metastasis in breast cancer mouse models.

Here, the authors find that BMAL1, best known for controlling the body clock, partners with TRIM28 in naïve pluripotent stem cells to repress retrotransposons.

The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.

Brown adipose tissue (BAT) is key for metabolic balance. Here, the authors show that RAP250 deficiency enhances BAT activity. Under these conditions, BAT-derived neuritin-1 regulates thermogenesis and fat metabolism, showing therapeutic promise for obesity and metabolic disorders.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Natural killer T (NKT) cell defects have been implicated in several diseases such as autoimmunity, asthma and cancer, but will targeting them really be of clinical benefit? Here, the authors investigate this question and conclude that more careful studies are needed before the true clinical potential of NKT cell-targeted therapies can be determined.

A greater diversity of crops at the national level increases the temporal stability of total national harvest, reflecting markedly lower frequencies of years with sharp harvest losses.

Here authors reveal a method to predict key information on phenotypes - their direction. This is achievable even for phenotypes with incomplete genotype-to-phenotype mapping, and applicable for individuals from the same family or population, as well as between species.

CRISPR-Cas9-based screens have allowed the study of gene-drug interactions. Here, the authors develop CRISPR-Cas9 knock-out, activation and repression screens in human gastric 3D organoids, also integrating single-cell CRISPR screens, to identify genes involved in the response to cisplatin in gastric cancer.

An algorithm for proteoform identification with top-down mass spectra is proposed, and a pipeline is developed for generating simulated top-down spectra on the basis of input protein sequences with modifications.

This large meta-analysis of 11 GWAS identified 7 genetic loci associated with strabismus, esotropia and exotropia. Mendelian randomisation provided genetic evidence of the causal link between maternal smoking to increased strabismus risk in offspring.

This study introduces the Cattle Cell Atlas, a single-cell expression resource including 1,793,854 cells from 59 tissues. Integrative analyses leveraging this atlas provide insights into the biology underlying bovine monogenic and complex traits.

Designer box H/ACA RNA-guided pseudouridylation can target both mRNA and tRNA. Modifying the first U of a stop codon and U36 of the matching anticodon forms one Ψ–Ψ and two Watson–Crick pairs, enabling efficient and specific stop codon readthrough.

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.

Species’ traits and environmental conditions determine the abundance of tree species across the globe. Here, the authors find that dominant tree species are taller and have softer wood compared to rare species and that these trait differences are more strongly associated with temperature than water availability.

Nitrogen and phosphorus limitations are both key to spatial patterns and temporal trends in primary production. This global analysis indicates that phosphorus limitation on terrestrial primary productivity has become stronger and is increasing more rapidly than nitrogen limitation.

The authors develop and characterise a selective Greatwall inhibitor, C-604, and show that its cytotoxicity stems from PP2A-B55α hyperactivation. They identify B55α and Greatwall levels as biomarkers of responses to Greatwall-targeted therapy.

Li et al. characterize overlapping and divergent metabolic requirements of human and murine NK cells in response to activation, with a focus on serine metabolism

Here Yan et al. assess the community dynamics that are driving biodiversity-ecosystem function relationships across the world’s reef fishes. While reef fish abundances and species richness have similar impacts on productivity in temperate regions, productivity in the tropics is driven by abundances.

The glucagon-like peptide 1 receptor agonist (GLP-1RA) class of medicines has emerged as transformative for the treatment of diabetes, obesity and other diseases. On the twentieth anniversary of the approval of exenatide (Byetta), three former employees of Amylin Pharmaceuticals acknowledge the contributions of some of the individuals and the innovation responsible for delivering the first approved GLP-1RA — the forerunner to the modern blockbuster drugs.

Specific functions of viral helicases in genome replication of RNA viruses are widely unknown. This study suggests that hepatitis C virus NS3 helicase unwinds stem loop structures at the 3’end of the genome, thereby facilitating (−) strand synthesis.

An interferometer design allows systematic investigation of the anyonic statistics of bulk fractional quantum Hall states.

Depletion of a transcriptional factor ZBTB11 using molecular glue degraders can overcome oxidative-phosphorylation-mediated KRAS inhibitor resistance in pancreatic ductal adenocarcinoma with low acute neurotoxicity.

Using historical aerial photographs and new bed topography data, accelerating changes on Kennicott and Root Glaciers, Alaska since 1938 are documented. These observations inform projections showing 38–63% mass loss by 2100, depending on future climate.

Glucocorticoid (GC) induced osteoporosis (GIOP) remains a significant clinical problem. Here, the authors find that GCs disrupt skeletal stem cell–endothelial crosstalk via Basigin that can be targeted as a potential therapy for GIOP.

Arboviruses are climate sensitive, and their global distributions are changing. Here, the authors describe results of a One Health study programme to investigate the occurrence of Usutu and West Nile Virus in the Netherlands, a previously non-endemic area.

Gonzalez-Hurtado, Leveau and colleagues characterize adipose resident tissue macrophages across lifespan in mice, finding that nerve-associated macrophages, which mitigate inflammation and control lipolysis and catecholamine resistance, are lost during aging.