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This prespecified updated survival and exploratory subgroup efficacy analysis of the phase 3 DESTINY-Breast04 trial shows that trastuzumab deruxtecan treatment in patients with HER2-low metastatic breast cancer leads to continuous survival benefit irrespective of estrogen receptor or hormone receptor status.

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.

Net-zero policies can put pressure on land use, which can conflict with preserving natural landscapes, cultural sites and agricultural areas. Now a study integrates national energy models with proactive and collaborative planning to design net-zero pathways that conserve natural capital and address diverse concerns.

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.

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.

BAG3 is found in the serum of pancreatic cancer patients and can be used as a marker of disease, but its role in cancer is unclear. Here, the authors show that BAG3 secreted from tumour cells binds to and activates macrophages, which in turn promotes cell growth, and an antibody blocking BAG3 binding reduces tumour formation in mice.

Marabelle et al. present updated data from the KEYNOTE-158 trial after ~4.5 years of follow-up, reporting an overall response rate of 34% and a median overall survival of 19.8 months in participants with MSI-H/MMR advanced noncolorectal solid tumors.

Trained on large and multicenter datasets with different imaging modalities, a foundation model is shown to have strong performance on the full spectrum of clinically relevant tasks and to increase user accuracy in diagnostic tasks.

This large integrated analysis of the KRAS^G12C inhibitor sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 trials shows that low expression of TTF-1 and high expression of NRF2 determine anti-tumor efficacy of sotorasib in non–small-cell lung cancer.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

Plasma turbulence is the main driver to deteriorate the performance of fusion power plants. This work presents an unprecedented comparison of plasma turbulence between experiment and simulation, proving that the gyrokinetic model GENE reached a high level of maturity to predict core turbulence.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

A method to label and visualize nascent RNA allows real-time study of transcriptional dynamics at single-cell resolution in vivo. The approach is used to study transcriptional repression of the SPX1 gene by phosphate in Arabidopsis roots.

Over time, paralogous genes accumulate changes in their sequences that do not affect their function, which is called cryptic variation. Using paralogous myosins, this study shows how cryptic variation modulates the functional effect of mutations and biases duplicates to distinct evolutionary fates.

An extreme Einstein ring ~10,000 times as bright as the Milky Way in the infrared is studied with VLT/ERIS and ALMA, and the authors find that the lensed galaxy is a starburst with a fast-rotating disk, rather than being driven by a major merger.

Evolutionary modelling and expert review are applied to integrate experimentally supported knowledge accumulated in the Gene Ontology knowledgebase to create a draft human gene ‘functionome’.

Exosomes are increasingly recognized as key intermediaries of intercellular communication, yet the mechanisms governing their biogenesis remain unclear. Zimmermann, David and colleagues report that interactions between the transmembrane protein syndecan, its associated protein syntenin and the ESCRT adaptor ALIX are necessary for exosome formation, supporting a role for the ESCRT machinery in this process.

This Review provides an overview of the main applications of single-port robotic surgery in urology, presenting emerging outcomes and discussing the transformative potential of this approach.

SMARCB1 inactivation is prevalent in human atypical teratoid/rhabdoid tumours but a mouse model that accurately phenocopies the human disease is lacking. Here, the authors show that inactivation of SMARCB1between E6 and E10 in mice results in tumours that better recapitulate the human phenotype, compared to previously reported models.

Stem cell plasticity is crucial for early embryo development and the differentiation of stem cells. Here, the authors show that the extracellular protein Cripto sustains mouse ESC self-renewal and maintains mouse EpiSC as well as human ESC pluripotency and controls the metabolic reprogramming in ESCs to EpiSC transition.

Gaining mechanistic insight into the microbiological and immunological factors that are associated with spontaneous preterm birth is important for the development of prevention strategies. Here authors show that the complement system in conjunction with specific vaginal microbial and associated immunological changes are contributing to this condition.

Whole-genome sequence data for 108 individuals representing 28 language groups across Australia and five language groups for Papua New Guinea suggests that Aboriginal Australians and Papuans diverged from Eurasian populations approximately 60–100 thousand years ago, following a single out-of-Africa dispersal and subsequent admixture with archaic populations.

An online approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups has been developed to help to improve current diagnostic standards.

Genomic analyses of large population-based cohorts uncover the genetic determinants of perivascular space burden, an MRI marker of cerebral small vessel disease, across the lifespan, and reveal potential pathways implicated in the etiology of stroke and dementia.

The syndecan binding protein syntenin promotes the budding of intraluminal vesicles from the endosomal membrane, resulting in increased exosome secretion. Ghossoub et al.show that syntenin activates a pathway including ADP-ribsoylation factor 6 and phospholipase D to stimulate budding.

Visualizing cellular Pi distribution is crucial for the understanding of Pi signalling and homeostasis in plants. Here Guo et al. developed a rapid colorimetric Pi imaging method to reveal the intracellular Pi distribution and related regulators.

In a phase 3 trial, selection of non-small cell lung cancer patients based on high blood-based tumor mutation burden did not improve clinical response to the checkpoint blockade inhibitor atezolizumab, as compared with standard of care platinum-based chemotherapy.

Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.

Sergey Nikolaev, Stylianos Antonarakis and colleagues analyze the genetic architecture of 293 basal cell carcinomas (BCCs) and characterize their mutational landscape. They observe UV signature mutations and identify new driver mutations in MYCN, PTPN14 and LATS1 in BCC.

Acne vulgarisis a common, inflammatory skin disorder. Here the authors carry out a genome-wide association study and identify three genetic variants that associate with an increased risk of developing acne, which together suggest a mechanistic role for the TGFβ cell signalling pathway in acne development and progression.

The core North American monsoon arises through topographic steering of the jet stream, and should be considered as convection-enhanced orographic rainfall produced by a mechanically forced stationary wave.

Although B cell-targeting therapies can provide clinical benefits to children with idiopathic nephrotic syndrome (INS), B lymphocyte subsets have not been extensively studied in this disease. Here, using single-cell RNA sequencing, the authors identify an extrafollicular B cell signature in children with INS.

ISG15 is a ubiquitin-like modifier that can be upregulated in response to bacterial infections. Here, the authors use proteomics to identify endogenous ISGylation substrates in the liver of Listeria monocytogenes infected mice and show that ISGylation alters basal and infection-induced autophagy.

This study on respiratory syncytial virus (RSV) reveals global genomic gaps. Using INFORM-RSV data, it uncovers selection’s impact on RSVA and RSVB diversity. Analysing full genomes, it highlights non-neutral epidemic processes. The research emphasises air travel’s influence on global spread, underscoring the need for comprehensive RSV genomic surveillance.