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Computationally designing proteins with interfaces that bind small molecules has posed a long-standing challenge. Here, authors combine deep learning and physics-based approaches to design proteins that bind small molecules, and demonstrate their approach by designing a cortisol biosensor.

A large-scale study on the replicability of claims from social and behavioural science journals reports that about half of the results replicate in the same patterns as the original study.

Most advanced triple-negative breast cancers remain resistant to immunotherapy. Here, the authors discover that RIPK1-driven necroptosis in both tumor and stromal compartments is essential for effective immunogenic cell death-based therapy and immune checkpoint blockade.

Genetic analyses in more than 15,000 individuals from across the Americas, including individuals with autism and family members, define the genetic landscape of autism in Latin American populations and identify significant overlap with other ancestries.

Here, Wulczynski et al. find fewer small-intestinal fiber-degrading bacteria in CeD patients, independent of the gluten-free diet, while inulin-supplemented diet in gluten-sensitized mice facilitates microbial saccharolytic function and SCFAs, accelerating mucosal healing in the small intestine.

Manipulating chemical interactions is crucial in protein assembly. Here, the authors highlight the importance of accounting for solvent forces mediated by interfacial hydration structures when designing protein assemblies at liquid-crystal interfaces.

Polymer thin films that emit and absorb circularly polarised light are promising in achieving important technological advances, but the origin of the large chiroptical effects in such films has remained elusive. Here the authors demonstrate that in non-aligned polymer thin films, large chiroptical effects are caused by magneto-electric coupling, not structural chirality as previously assumed.

Long COVID is associated with challenges in energy management, with limited interventions available. In this study, a just-in-time app-based energy management intervention for long COVID did not reduce postexertional malaise compared to usual care, though both groups improved over time, showing the approach was safe but not effective.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Variant mapping of sorghum promoters identifies CRISPR-accessible mutations that upregulate gene expression.

A star in a primordial dwarf galaxy has preserved the elements produced by the first generation of stars. The star lacks heavy elements but exhibits an extreme amount of carbon, suggesting that low-energy explosions can seed the initial chemistry of early galaxies.

An ion pump that does not require redox reactions to drive aqueous ions against forces is demonstrated, and may find applications in selective ion separation and water desalination.

In this study, long-read RNA sequencing achieves accurate single-nucleotide polymorphism calling, haplotype phasing and allele-specific expression analysis.

Metal-organic frameworks (MOFs) offer tunable magnetic properties, but their ordering temperatures are often limited to cryogenic conditions due to weak exchange interactions. Here, the authors investigate a chromium-based MOF exhibiting robust ferromagnetism near ambient conditions, revealing mesoscopic magnetic clusters and suggesting MOFs as platforms for studying correlated electron phenomena.

From 2014–2017, marine heatwaves caused global mass coral bleaching, where the corals lose their symbiotic algae. The authors find, this event exceeded the severity of all prior global bleaching events in recorded history, with approximately half the world’s reefs bleaching and 15% experiencing substantial mortality.

A nine-year transit-timing campaign has measured the extremely low masses and densities of four large planets orbiting the young star V1298 Tau, which are now predicted to contract and form a typical compact super-Earth and sub-Neptune system.

A pangenome reference for the phenotypically diverse crop sorghum aims to help accelerate future efforts to breed crops that are better adapted to changing environments.

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.

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.

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.

Robust protein synthesis by the ribosome is required for rapid cancer growth. Here authors present interdictors, small molecule inhibitors of protein synthesis with context-dependent activity that inhibit MYC-driven cancer cell growth in a mouse model.

A hierarchical microstructure is important for the fatigue performance of titanium alloys, and is usually achieved by successive rounds of nucleation. Here, intermediate temperature deformation causes nucleation of nanoscale HCP precipitates between micron-thick plates, enhancing high-cycle fatigue strength.

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.

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.

TnpB endonucleases are engineered for improved genome editing.

Mass number measurements of the molecular species produced when ions of actinium (Ac) and nobelium (No) are exposed to trace amounts of H₂O and N₂ demonstrate direct species identification using an atom-at-a-time technique for heavy elements.

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

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

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.

A COVID vaccine developer, an Arctic voyager and a prime minister are some of the people behind the year’s big research stories.

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 characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Non-basaltic volcanism is rare on the Moon and has been found predominantly on the lunar nearside. Analysis of Lunar Reconnaissance Orbiter Camera images and spectral data reveal the presence of compositionally evolved, non-basaltic volcanism on the lunar farside.

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.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

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.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

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.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.