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In this work, the authors reveal that three non-ribosomal peptides targeting a common protein quality system differentially alter the Mycobacterium tuberculosis proteome, providing new insight into the molecular mechanisms behind their antimycobacterial activity.

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

Targeting neurons that regulate energy balance may offer new approaches for obesity treatment. Here, authors show that chemogenetic and pharmacological manipulation of GABAergic neurons in the DRN/vlPAG increases adaptive thermogenesis and reduces weight gain in mice fed a highfat diet.

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.

Large-scale computational and in vitro analyses identify commensal type III secretion systems and substrates in the human gut microbiome that can interact with human proteins to modulate immune pathways.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

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.

Climate change can alter when and how animals grow, breed, and migrate, but it is unclear whether this allows populations to persist. This global study shows that shifts in seasonal timing are key to helping vertebrate species maintain population growth under global warming.

High-resolution satellite data enables a unique verification of national methane emissions worldwide. Global estimates are 63 Tg a⁻¹ for oil-gas, 30% higher than the UNFCCC reports due to under-reporting by four largest emitters, and 33 Tg a⁻¹ for coal, consistent with previous estimates.

In mice, DHPS supports the maturation, maintenance and function of tissue-resident macrophages via the polyamine–hypusine axis, with implications for macrophage-targeting therapies.

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 4D Nucleome Project demonstrates the use of genomic assays and computational methods to measure genome folding and then predict genomic structure from DNA sequence, facilitating the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 histone ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the ubiquitination-dependent recruitment motif.

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.

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

Integrated single-cell and spatial data analysis, combined with bidirectional CRISPR screens, identify the transcription factor GLIS3 as a key driver of chronic inflammation and fibrosis and a potential marker of disease severity in patients with ulcerative colitis.

Instabilities in chiral plasmas can amplify electromagnetic waves, raising the question of whether chiral solids behave similarly. Now a magneto-chiral instability is demonstrated in tellurium, observed as growing terahertz emission after photoexcitation.

Using activity-based chemical probes, oncogenic IDH1-R132H but not the wild type was found to acquire a unique autopalmitoylation at C269. This mutant-specific modification is critical for the enzyme’s abnormal activity in cancer.

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.

Eukaryotic DNA can be methylated as 5-methylcytosine and N6-methyladenine, but whether other forms of DNA methylation occur has been controversial. Here the authors show that a bacterial DNA methyltransferase was acquired >60 Mya in bdelloid rotifers that catalyzes N4-methylcytosine addition and is involved in suppression of transposon proliferation.

Using pancreatic organoids, Lee et al. show that the balance between epithelial tissue permeability-driven lumenal pressure and cell proliferation affects ductal morphogenesis.

Wearable devices generate vast streams of health data, but making sense of these measurements requires complex numerical reasoning beyond the reach of conventional language models. This study introduces a large language model agent that interprets wearable data to deliver accurate, personalized health insights.

As Nature Aging celebrates its fifth anniversary, the journal asks some of the researchers who contributed to the journal early on to reflect on the past and the future of aging and age-related disease research, the impact of the field on human health now and in the future, and what challenges need to be addressed to ensure sustained progress.

Pulmonary type 2 inflammation is associated with type 2 innate lymphoid cells. Here the authors use the Collaborative Cross mouse panel to show that ILC2 abundance during type 2 lung inflammation is different across the panel and identify free-fatty acid receptor 3 (Ffar3) as a gene responsible and show cytokine and ILC2 functional changes.

Here, the authors examine the mechanisms behind cheatgrass’s successful invasion of North American ecosystems. Their genetic analyses and common garden experiments demonstrate that multiple introductions and migrations facilitated cheatgrass local adaptation.

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.

Replication fork plasticity upon genotoxic stress is modulated by nuclear architectural components by elusive mechanisms. Here the authors implicate Lamin A/C – best known for its structural support of nuclear periphery – in the control of replication fork restart throughout the nucleus, by supporting heterochromatin establishment and ADP ribosylation levels at replication factories.

A study examines the effects of mutations that occur naturally in T cell cancers, reporting that such mutations can potentially be exploited to increase the potency of T cell therapies.

Vaginal birth, exclusive breastfeeding and early contact with siblings promote colonization of the infant gut with bifidobacteria capable of producing aromatic lactates, a microbial and metabolite signal that is inversely related to the risk of allergen-specific sensitization and dermatitis later in life.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

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.

Kang, Lazo de la Vega et al. introduce iCatalog, a precision oncology reporting tool developed to address the needs of a large multi-institutional pediatric study. iCatalog combines a database for patient, sample, and genomic data to enable clinical interpretation of patient-level tumor profiling results.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

iGluSnFR4f and iGluSnFR4s are the latest generation of genetically encoded glutamate sensors. They are advantageous for detecting rapid dynamics and large population activity, respectively, as demonstrated in a variety of applications in the mouse brain.

Through next-generation spectral analysis, scientists have uncovered an evolutionary path for Wolf–Rayet stars in metal-poor environments. Characterized by hard ionizing radiation, these stars challenge current assumptions about massive star evolution.

Epstein–Barr virus (EBV) is a widespread herpesvirus linked to cancer and autoimmune disease. The authors in this work design and characterize a stabilized prefusion form of gB, an essential viral fusion protein, advancing EBV vaccine and therapeutic development.

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.

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.

Here the authors show that tissue-resident memory and exhausted T cells in tumors are distinct populations that are shaped by relative presence or absence of TCR signals, suggesting that a tailored therapeutic strategy is needed to target each subset.

Thirty years of forest demographic data, combined with recent ecophysiological measurements, reveal that intense Amazon droughts sharply increase tree mortality once soil moisture falls below a threshold, and that these hot droughts will become more frequent and intense as Earth warms towards hypertropical conditions.

A high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex from embryonic to postnatal development is presented, providing a real-time dynamic molecular map associated with individual cell types and specific developmental events.

The dorsomedial prefrontal cortex encodes the value, salience and valence of learned stimuli along distinct neural dimensions, and the geometry of these representations shapes motivated behaviours in mice.

The early postnatal roles of dendrite-targeting interneurons in primary visual cortex (V1) remain elusive. Here, the authors find that somatostatin interneurons in mouse V1 exhibit a uniquely delayed developmental trajectory for innervation and sensory responses, highlighting a window for the emergence of a key mechanism for normalization in cortical circuits.

Non-syndromic orofacial cleft is a relatively common congenital anomaly. Many non-coding genetic variants are associated with this disorder but only a subset is functional. Here the authors use reporter assays and stem cells to reveal members of this subset.

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.

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.