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The authors demonstrate that targeted protein degradation of the dengue virus capsid suppresses infection through capsid-dependent pathways rather than classical inhibition, revealing a new antiviral strategy effective against resistant viral variants.

Here the authors present scLong, a billion parameter foundation model trained on 48M single cells, using self attention across all 28k human genes and Gene Ontology knowledge. It captures long range gene context in single Cell transcriptomics.

Trimodal single-cell analysis reveals gene-regulatory architecture in complex tissues.

Post-transcriptional regulation of mRNA translation was explored using Ribo-STAMP and single-cell RNA sequencing to reveal cell-type-specific and isoform-specific translation patterns across hippocampal neuronal and non-neuronal cell types, highlighting functional differences between CA1 and CA3.

Cryo-electron microscopy structures of nucleotide excision repair complexes reveal the roles of the constituent proteins XPA, XPB, XPC, XPD, XPF, XPG and RPA in DNA bubble formation and excision of the lesion strand.

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.

Cryogenic electron microscopy structures of human Ostα/β uncover a unique transport pathway featuring two substrate-binding sites connected by an amphipathic helix-gated conduit, and electrophysiological studies demonstrate voltage-sensitive, bidirectional transport, showing its efflux role in vivo.

This study utilized a longitudinal cohort of adolescents to identify distinct brain signatures linked to ADHD symptom trajectories, revealing that specific cortical and subcortical changes correlate with symptom persistence, remission and emergence, enhancing predictive capabilities for ADHD outcomes.

Scanning nitrogen-vacancy microscopy unveils super-moiré spin textures emerging in twisted double-bilayer CrI₃ and provides real-space evidence of antiferromagnetic Néel-type skyrmions spanning multiple moiré cells.

The ZFTA–RELA fusion, an oncogene for ependymomas, promotes the production of itaconate, and its dependence on this metabolite represents a new therapeutic target for this cancer.

Phage therapy is an alternative treatment against biofilm-associated infections. In this case report, phage-antibiotic therapy was used to treat a vascular graft infection caused by a refractory fluoroquinolone non-susceptible Pseudomonas aeruginosa.

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

Zhang et al. examine associations between wildfire-specific PM_2.5 and emergency department visits for mental disorders in children across 845 communities in Australia, Brazil and Canada over a 15-year period.

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.

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.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

A general stereospecific glycosylation is developed that is applicable across a range of monosaccharides. A directing-group-on-leaving-group strategy allows mild donor activation and enables the complete inversion of anomeric configuration with excellent yields. This method can be applied in multistep oligosaccharide syntheses and automated glycan assembly.

Resistance to combination therapies has been reported in rhabdomyosarcoma (RMS). Here, the authors discover that PIK3CA/AKT pathway regulation of multidrug-resistant ABC transporters is involved in the resistance to therapies in RMS, and use of the PI3Kα inhibitor alpelisib re-sensitizes RMS to therapy.

Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.

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.

Laser shock experiments on an iron-water phase reveal its density, melting, and electronic changes under extreme pressures. The results suggest dense deep magma oceans and show that iron-water reactions can greatly shrink and densify super-Earths.

As the indications for T cell immunotherapies, particularly chimeric antigen receptor T cell therapy, continue to expand, a nuanced understanding of their potential adverse effects is required. In this Review, Raddatz and colleagues summarize the mechanisms, epidemiology and management of T cell therapy-associated cytokine release syndrome and subsequent cardiotoxicity.

Lung adenocarcinomas bearing the ID2 mutational signature display increased LINE-1 retrotransposon activity, which contributes to their fast evolutionary dynamics and aggressive phenotype.

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

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.

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.

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.

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.

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.

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.

Multi-ancestry genome-wide and transcriptome-wide association studies of aortic stenosis identify more than 200 independent risk loci and provide insights into its genetic architecture.

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.

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 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.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Here, as part of the Sherlock-Lung study, the authors profile the microbiomes of 940 lung cancers in never smokers finding no significant associations with demographic and clinical features, suggesting lung bacteria are unlikely to have a sizable role in lung cancer.

Steatotic liver diseases affect millions worldwide through alcohol and metabolic insults. This Review highlights steatotic liver disease genetic architecture, how it informs disease biology, drug discovery and risk stratification through polygenic risk scores and the need for improved clinical applications.

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.

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.

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.

Extracellular vesicles (EVs) have shown potential as a therapeutic delivery system for cancer treatment. In here the authors have established HEK293T cells engineered with α-HLA-G VHH antibody-chimeric CD63 protein to promote the production of EVs that can augment the targeting of HLA-G-positive tumor cells

Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

This study reveals that the protein AKAP11 plays a crucial role in regulating neuronal signaling and synaptic function by linking PKA activity to autophagy. Loss of AKAP11 distorts compartment-specific PKA and GSK3α/β activities and impairs neurotransmission, highlighting a shared molecular pathway between bipolar disorder and schizophrenia.