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The study finds that IPMK and InsP₆activate HDAC3 to preserve gut integrity. Loss of IPMK impairs this axis, causing leaky gut, while InsP₆ restores HDAC3 function, offering a potential therapy for inflammatory bowel disease.

KRAS is an oncogene that switches between a GDP-bound inactive state and a GTP-bound active state. Recently developed KRAS G12C inhibitors are specific to the GDP-bound inactive state. Here, the authors develop a class of covalent KRAS G12C inhibitors capable of targeting both states for the treatment of KRAS-driven cancer.

Early-life exposure to allergens triggers a distinct local mode of dendritic cell activation in neonatal skin without requiring migration to lymph nodes, which shapes responses to allergens in later life.

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.

Conventional type 1 dendritic cells (cDC1) can boost the precursor exhausted T cell population thought to be essential for efficacy of immune checkpoint therapy. Here the authors enhance this cellular network using Flt3L to expand cDC1s and then map the movement of T cells and DCs between tumors and lymph nodes.

Application of multiancestry and ensemble-based approaches yields improved polygenic risk prediction models for breast cancer and its subtypes among women of African ancestry.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

A soft robotic probe enables continuous in utero monitoring of fetal physiological parameters, including heart rate, blood oxygen saturation, temperature and electrocardiogram data, during open or fetoscopic surgery to provide real-time information on fetal condition and distress.

The deactivation of CO₂ reduction electrocatalyst in microbial media remains a key barrier for hybrid bio-electrochemical systems. Here, the authors present a bioadaptive nickel single atom catalyst that resists organic poisoning to enable high-rate CO-mediated isopropanol production from CO₂.

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.

Mellman and colleagues present a multiomic single-cell analysis of the effects of combined anti-TIGIT and anti-PD-1 blockade on T cell populations trafficking from the draining lymph node to the blood and tumor.

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.

Spin-polarized defects in 2D materials are attracting attention for future quantum technology applications, but their controlled fabrication is still challenging. Here, the authors report the creation and characterization of effective spin 1/2 defects via the atomically-precise generation of magnetic carbon radical ions in 2D WS₂.

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.

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.

Turley and colleagues find that Gremlin1-expressing lymph node fibroblastic reticular cells support dendritic cell homeostasis via provision of FLT3L.

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.

A multiscale photoproximity labeling proteomics workflow captures dynamic neighborhoods of extracellular and intracellular epidermal growth factor (EGF) receptor interactomes during early, middle and late signaling upon activation by EGF.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

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.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

Using data from the CoVPN 3008 study, the authors show that the neutralizing antibody correlate of risk holds in people living with HIV. However, the nAb correlate was weaker and shorter-lived in a vaccine-immunity versus hybrid-immunity population.

Hu et al. discovered that the truncated form of human epidermal growth factor receptor 2 (HER2), called p95HER2, drives tumor progression and resistance to the antibody–drug conjugate trastuzumab deruxtecan in HER2⁺ breast cancer. Blocking p95HER2 restores antitumor immunity.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

 A transcriptomic cell-type atlas of the whole adult mouse brain with ~5,300 clusters built from single-cell and spatial transcriptomic datasets with more than eight million cells reveals remarkable cell type diversity across the brain and unique cell type characteristics of different brain regions. 

The directed self-assembly (DSA) of block copolymers (BCPs) has shown great promise in fabricating customized two-dimensional (2D) geometries at the nano- and mesoscale. Here, the authors report the discovery of spontaneous symmetry breaking and superlattice formation in DSA of BCP.

BRCA1 and BRCA2 are well known breast cancer predisposition genes, however, many variants have not yet been classified for their pathogenicity. Here, the authors analyse a large combined cohort to provide evidence of variant pathogenicity.

Studies using human pluripotent stem cells and a mouse model of Down syndrome identify HMGN1 as a key contributor to congenital heart defects in individuals with Down syndrome.

Analyses focusing on protein-truncating variants from 106,973 women from in the UK Biobank identify variants in genes that reinforce the link between reproductive lifespan in women and cancer risk in both sexes.

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.

The role of vascular plasticity in brain function remains poorly understood. Here, the authors demonstrate that a significant portion of blood vessels in the adult brain periodically occlude and regress, a process that is associated with a reduction in neuronal activity.

The clinical benefit of anti-PD-1 antibody treatment is dependent on the extent to which exhausted CD8 T cells are reinvigorated in relation to the tumour burden of the patient.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

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.

IL-27 promotes tumour control by preventing dysfunction and enhancing cytotoxicity of tumour-specific CD8⁺ T cells.

The immune response to the spike protein of SARS-CoV-2 has been relatively well studied, but less is known about other viral proteins. Here, the authors identify immunopeptides from seven structural and non-structural SARS-CoV-2 proteins presented to the immune system by HLA molecules and confirm T-cell responses against some of them in convalescent individuals.

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.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

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.

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

Although ordered membrane nanodomains, also known as lipid rafts, have many proposed cellular functions, pharmacological tools to modulate protein affinity for rafts and to manipulate raft formation are currently lacking. Here, the authors screened 24,000 small molecules for compounds that impact the raft affinity of a known raft-preferring model protein, peripheral myelin protein 22 (PMP22), in giant plasma membrane vesicles, identifying three chemically distinct tools for modulating raft formation in a protein-independent manner by altering lipid–lipid interactions and membrane fluidity in biophysical experiments and in living cells.

A CRISPR knock-in strategy that uses endogenous gene regulatory mechanisms can engineer ‘armoured’ CAR T cells that secrete proinflammatory cytokines directly within a tumour without causing toxicity, leading to prolonged survival in mice.

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.

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.