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Hepatitis C virus remains a health burden due to the lack of an effective vaccine, hindered by difficulties in replicating the native E1E2 antigen structure. Here, the authors engineer a stabilized E1E2 heterodimer using cryo-EM-guided modifications, enhancing immunogenicity and paving the way for future HCV vaccine development.

Most patients with B-cell leukemia respond to chimeric antigen receptor T cell (CAR T) therapy, yet many relapse due to loss of CAR T function. Here, the authors show that the metabolism of CAR T from short- and long-term responders is different, which may explain why CAR T lose functionality.

Riboswitches are RNA elements that regulate gene expression through dynamic changes in secondary structure. Here, the authors reveal how the glycine tandem riboswitch integrates sequential signals via stepwise folding and binding of ligands to orchestrate gene regulation during transcription.

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.

Mass spectrometry (MS)-based proteomics is increasingly central to systems biology. Here, the authors present a high-throughput, multi-organ workflow that profiles 11,472 proteins in 507 mouse samples, enabling rapid, system-level evaluation of drug efficacy and toxicity.

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.

While therapies targeting type I BRAF mutations have been developed, there are limited options for those with type II and III mutations. Here, the authors identify a subset of BRAF-mutant non-small cell lung cancer patients and characterise the pan-RAF inhibitor exarafenib, demonstrating efficacy in preclinical models and investigating subsequent resistance mechanisms.

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.

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.

Papaya is a trioecious species with XX females, XY males, and XY^h hermaphrodites, and the combination of Y and Y^h chromosomes is lethal. Here, the authors identify the degeneration of the YY lethality gene on the Y chromosome as the causal balancing lethal factor that reenforces dioecy and stabilizes balanced sex ratios.

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.

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.

Analysis combining multiple global tree databases reveals that whether a location is invaded by non-native tree species depends on anthropogenic factors, but the severity of the invasion depends on the native species diversity.

This research identifies two neural factors linked to externalizing and internalizing symptoms through a longitudinal imaging-genetic cohort. Distinct neural configurations and cognitive-behavioral relevance highlight the need for tailored therapeutic strategies addressing psychiatric comorbidity across developmental stages.

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

Female mosquitoes inject saliva into vertebrate hosts during blood feeding, transmitting mosquito-borne pathogens. Here, cryo-EM of mosquito salivary gland extract uncovers the native SGS1 structure and domains relevant to pathogen transmission.

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

Here, the authors find that time-varying brain network analysis better captures cognitive processing than static methods and reveals network measurement linked to task performance and psychopathology that offer precise neural markers for mental health risks.

Although photocatalysis research has evolved towards increasingly sophisticated structural regulation and material design, the synergistic enhancement of photocatalysis by multi-component semiconductors and biochar remains underexplored. Here, the authors present a biochar-based g-C₃N₄/Bi₂WO₆/Ag₃PO₄ nanocomposite and apply it to the efficient removal of tetracycline, showing that it forms a double Z-scheme heterojunction that significantly reduces photogenerated carrier recombination.

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.

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.

Yakut communities, with Trans-Baikal admixture during the Mongol expansion, preserved genomic diversity and oral microbiomes despite the Russian conquest, which introduced cereals, pathogens and Christianity, whereas marital practices preserved low consanguinity except in one late case of traditional shamanism.

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.

Spiking neural networks are generally used for sequential information and event data processing but still lack high performance. Through algorithm and hardware co-design, Zhang et al. report a State Space Model based approach to implement on compute-in memory hardware, enabling asynchronous and real-time processing capability with high energy efficiency for event sequences.

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.

Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

Recent work has revealed that dendritic cells (DCs) are more heterogeneous than previously thought, yet the functional roles of these newly described DC subsets remain unclear. Here, Li et al. find that in mice, TSLP from keratinocytes activates transitional DC-derived DC2 to promote GATA3⁺ regulatory T cells and mediate immunosuppression during inflammation and cancer.

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.

Several recent publications have attempted to detect novel unannotated microproteins using mass spectrometry proteomics. Here, the authors reassess these claimed microprotein detections, finding that many are poorly supported, while a subset represents likely genuine discoveries of novel proteins.

Here the authors report that some aspects of clinical heterogeneity in type 2 diabetes vary across populations. Using a deep-learning–based tree model built from over 32,000 patients, they document disease patterns and risks specific for the Chinese population, potentially enabling more precise prediction and personalized care.

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.

2D p-type transistors are essential for the realization of complementary circuits for post-silicon electronics. Here, the authors report a chloroform doping strategy to fabricate p-type monolayer WSe₂ transistors with high performance and long-term stability.

Twisted bilayer (tb) MoTe₂ is an ideal platform for investigating the fractional quantum anomalous Hall effect but issues related to air sensitivity make the study of its electronic structure experimentally challenging. As a solution, the authors prepare hBN encapsulated tb-MoTe₂ and using micro-angle resolved photoemission spectroscopy determine the band structure. Furthermore, through in-situ alkali metal deposition, they obtain evidence indicating a direct band gap.

Researchers studied the blood-based metabolome of over 23,000 people from ten ethnically diverse cohorts. They identified 235 metabolites associated with future risk of type 2 diabetes (T2D). By integrating genetic and modifiable lifestyle factors, their findings provide insights into T2D mechanisms and could improve risk prediction and inform precision prevention.

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.

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.

Kinematic measurements of the Perseus galaxy cluster reveal two drivers of gas motions: a small-scale driver in the inner core associated with black-hole feedback and a large-scale driver in the outer core powered by mergers.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

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.

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.

The vasopressin V2 receptor (V2R) is a key regulator of water balance, and its antagonists are promising therapeutics for hyponatremia. Here, the authors offer structural insights into antagonist recognition and antagonism of V2R.

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.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

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.

Specific pain-sensing nociceptors and chemosensory tuft cells form a circuit to promote type 2 immune responses in the intestine.

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.