By sampling horseshoe bats-the reservoir hosts of SARS-CoV-2-related coronaviruses (SC2r-CoVs)-in Thailand, we present two clades of SC2r-CoVs co-circulating in the same bat population. Through a comprehensive set of experimental approaches, including cryo-electron microscopy (cryo-EM), pseudovirus and live virus assays, and hamster experiments, we characterize the virological properties of these new viruses. We show that one of the two clades discovered in this study is able to bind the human angiotensin converting enzyme 2 (ACE2) receptor; however, it exhibits reduced fusogenicity and replication in vitro and lower pathogenicity and transmissibility compared with SARS-CoV-2. Phylogeography and recombination analyses reveal a complex evolutionary history for these viruses characterized by extensive, recent geographic movement and recombination with co-circulating virus lineages. Our findings provide new insights into the diversity of SC2r-CoVs dynamically co-circulating in Southeast Asia as well as the virological characteristics of these viruses relative to SARS-CoV-2.

Autoantibodies neutralizing type-I interferons (AAN-I-IFNs) emerge as global, common, and strong determinants of a growing number of severe viral diseases. We report that AAN-I-IFNs+ patients with life-threatening COVID-19 pneumonia harbor circulating type-I IFN-specific B cells indistinguishable from patients bearing T cell tolerance defects of genetic origin. This autoimmune response mobilizes a highly diverse and stable circulating B cell response that is detected prior to severe viral infection and acquires high affinity and neutralization potential to type-I IFNs through extended somatic hypermutation. X-ray crystallography and AlphaFold3 structural analysis of hundreds of patient-derived monoclonal antibodies reveals the extended breadth of this response, targeting three major B cell epitopes covering all facets of type-I IFNs. These findings support a model in which a germinal-center-derived memory B cell response directed against type-I IFNs is established before severe viral infection, providing a core mechanism linking T cell tolerance defect to pathogenic AAN-I-IFNs underlying severe viral diseases.

Understanding the genetic regulation of circulating protein levels can provide new insights into disease mechanisms. Here, we present the largest proteogenomic study to date (n = 78,664 participants across 38 studies), identifying >24,000 protein quantitative trait loci (QTLs) associated with 1,116 proteins, acting near to (n = 5,040) or distant (n = 19,698) from the cognate gene. Using machine learning-guided effector gene assignment, we provide genetic evidence for pathways, cell types, and tissues that modulate circulating protein levels, highlighting N-linked glycosylation as an important regulatory pathway. We demonstrate that genetic instruments of protein production/function ("cis") versus modulation ("trans") reveal distinct phenotypic insights. We identify proteins as candidates for drug targets and engagement (e.g., plasma furin and cardiovascular diseases) by comparing cis-based genetic evidence with protein-disease associations. Systematic triangulation of trans-protein QTLs (pQTLs) with genetic and protein associations across many diseases highlights potential drug repurposing opportunities, e.g., tyrosine kinase 2 (TYK2) inhibitors for rheumatoid arthritis. Our multi-cohort meta-analyses generate proteogenomic insights into disease mechanisms and new treatment opportunities.

Tri-complex inhibitors (TCIs) are molecular glues that bind the active, guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA) to form a synthetic complex that blocks oncogenic signaling. Although these agents have shown clinical activity in RAS mutant cancers, resistance mechanisms remain poorly defined. Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases. Structural and functional analyses revealed that acquired mutations confer resistance by disrupting interactions essential for daraxonrasib binding to RAS, including RAS Y64 mutations, or by enhancing the RAS-RAF interaction, thereby favoring native RAS-RAF signaling, including RAS Y71 or kinase-dead/hypoactive BRAF mutations. We then identified a TCI that targets RAS Y64 mutants and combination therapies to target resistance driven by kinase-dead BRAF. These findings uncover convergent resistance mechanisms that undermine the molecular glue function and offer a mechanistic blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.

Microorganisms represent an important component of the tumor microenvironment, but conflicting reports have left the extent of microbial prevalence across cancer types unclear, necessitating more robust methods for characterizing tumor-associated microbiomes. We built and benchmarked a host-subtraction and classification pipeline to identify microbiota in whole-genome sequencing data and applied it to 16,369 high-depth tumor whole genomes from the UK 100,000 Genomes Project. After decontamination, microbial signatures were indistinguishable from the background in most cancer types. However, in orodigestive tumors, we detected multi-kingdom polymicrobial communities, including bacteria, fungi, viruses, archaea, and, in some cases, Trichomonas, a protozoan parasite. These communities varied by tumor site and subtype, with increased microbial colonization of microsatellite-instable and polymerase ε (POLE)/polymerase δ (POLD1)-mutated tumors, supported by a correlation between microbial load and tumor mutation burden observed across orodigestive cancers. This analysis helps to resolve pan-cancer microbial structure and links the tumor microbiome to host phenotype and tumor genomic context.

The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We found that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we named HOXA opposite-strand transcript, stem-cell regulator, antisense mid-cluster between loci (HOTSCRAMBL). The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.

To colonize their host and cause disease, enteric pathogens must deploy their virulence factors to establish distinct nutrient niches. How anaerobic pathogens construct nutrient niches in the densely populated large intestine remains poorly understood. Enterotoxigenic Bacteroides fragilis (ETBF) is a classically anaerobic bacterium implicated in inflammation-associated diseases, including colitis and colorectal cancer. Here, we show that ETBF uses its virulence factor, Bacteroides fragilis toxin (BFT), to generate and adapt to a localized oxidative niche that supports gut colonization. BFT manipulates colonic epithelial signaling and the bile acid recycling pathway, inducing a metabolic shift in the epithelium from oxidative phosphorylation to glycolysis. This shift increases local concentrations of lactate and oxygen, nutrients that support oxidative metabolism in ETBF. These findings reveal an unexpected strategy by which a classically anaerobic pathogen leverages host metabolic remodeling to generate and exploit an oxidative niche in the inflamed gut.

Donor-derived CD19-CAR T cells offer a therapeutic option for B cell malignancies relapsing after allogeneic hematopoietic stem cell transplantation but are often constrained by poor engraftment, expansion, and persistence. In a first-in-human study (NCT01087294), we found that CAR-modified stem-cell memory T (TSCM) cells exhibited greater expansion and persistence than standard CAR T cells, enabling complete responses at low doses in the absence of lymphodepletion. CAR TSCM cells induced mild cytokine-release syndrome, dominated by IFN-γ. Both products differentiated into effectors; however, only CAR TSCM cells robustly reconstituted the stem-like compartment over time. CAR TSCM cells were sustained through clonal succession, whereas persisting standard CAR T cells resulted from maintenance or contraction of early-expanded clones. While poor expansion limited standard CAR T cell activity, resistance to CAR TSCM cells was driven primarily by tumor- and host-related factors. These findings establish CAR TSCM cells as a promising platform for next-generation CAR T cell therapies.

Land plants underpin civilization and planetary health, yet their genomic diversity remains largely uncharted. Current resources are unstandardized and scarce, lacking reference genomes for 95% of genera, 70% of families, and 51% of orders, impeding evolutionary and functional insight. We thus propose the PLANeT initiative, an international effort to generate high-quality, standardized genomes across the plant tree of life. Integrating artificial intelligence (AI) with genomics, we will decode conserved principles to advance fundamental plant biology, biodiversity conservation, crop improvement, and natural product discovery. Engaging around 100 labs to train 1,000 scientists, we will tackle pivotal questions for a sustainable future.

Hu et al identify ROCK2 in liver sinusoidal endothelial cells as a key factor in liver fibrosis. Through single-cell analysis, knockout models, protein studies, and early clinical research, the authors show that ROCK2-driven endothelial cytoskeletal changes trigger angiocrine signals that activate hepatic stellate cells-highlighting a potential therapeutic target.

Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation into an "exhausted" state. Tissue-resident memory T cells (TRM) maintain protection from infection for years in healthy tissues, and patient tumors that contain TIL with TRM features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing TRM and progenitor-exhausted TIL from terminally exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins despite functional proteasome activity. Enforced expression of these ligases in T cells preserved stem-like TCF1+ populations and improved function in tumors and chronic infection, whereas deficiency impaired TIL and altered T cell differentiation during acute infection. Sustained ligase expression rescued the accumulation of unfolded proteins in TIL and improved immunotherapy outcomes in preclinical models, underscoring the critical role of proteostasis in TIL function and highlighting a promising avenue for advancing cancer immunotherapy.

ERDRP-0519 is a non-nucleoside polymerase inhibitor developed against measles virus (MeV) of the Morbillivirus genus. Here, we show that ERDRP-0519 also cross-inhibits Nipah virus (NiV) of the Henipavirus genus with reduced potency. ERDRP-0519 binds to a shared pocket within the RNA-dependent RNA polymerase (RdRp) palm domains of MeV, peste des petits ruminants virus (PPRV), and NiV polymerases. ERDRP-0519 forms more extensive interactions with Morbillivirus polymerases, whereas binding to NiV polymerase requires substantial RdRp motif rearrangements, likely incurring an energetic cost and resulting in reduced affinity. ERDRP-0519 binding impedes RNA synthesis by sterically blocking RNA and nucleotide binding. Guided by these insights, we designed GL22 and G671, ERDRP-0519 derivatives with extended moieties that engage additional cross-domain RdRp contacts in the NiV polymerase. These derivatives exert more extensive steric hindrance to RNA and nucleotide binding, enhancing biochemical inhibition potency. These findings elucidate the molecular mechanism of ERDRP-0519 action and guide structure-based inhibitor design.

The detection of olfactory cues is essential to signal food, predators, and social encounters. To determine how the sensory detection of physiologically relevant odors is systematically mapped into the mouse primary olfactory system, we used multiplexed error-robust fluorescent in situ hybridization (MERFISH) to construct a molecular atlas of olfactory receptor (OR) expression in the main olfactory epithelium (MOE) and olfactory bulb (OB). We comprehensively quantified the expression of the mouse OR repertoire and uncovered stereotypical gradients of sensory neuron distribution in the MOE along two axes, central-to-peripheral and apical-to-basal. Projections of sensory neurons mirror these two MOE gradients along the dorsal-ventral and anterior-posterior axes of the OB, respectively. Integration with sequencing data revealed candidate signaling molecules underlying this spatial organization. Co-imaging OR and activity marker expression identified distinct spatial domains of sensory responses in the MOE and OB, providing a topographical basis for olfactory responses to ethologically relevant odors.

Metastatic cancer cell fate is shaped by the local microenvironment niches. To unbiasedly define the cellular and molecular features of metastatic niches, we developed sortase A-based microenvironment niche tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastasis. Applying SAMENT across multiple cancer models and target organs revealed shared niche features, including macrophage enrichment and T cell depletion, alongside marked organ-specific phenotype heterogeneity in niche macrophages. In bone, metastatic niches are enriched for macrophages expressing estrogen receptor alpha (ERα) with active ERα signaling. Conditional deletion of Esr1 in macrophages significantly impaired bone colonization by enabling T cell infiltration. ERα⁺ macrophages were also identified in human bone metastases across multiple cancer types. Together, these findings define a distinct ERα⁺ macrophage niche and establish macrophage ERα signaling as a key driver of T cell exclusion during metastatic colonization.

Endoplasmic reticulum (ER) redox homeostasis is critical for ER functionality and is implicated in various human diseases, yet its physiological significance in plants remains largely elusive. Ethylene, a key phytohormone, is perceived and transduced at the ER, suggesting an underexplored connection between the ER and ethylene signaling. Here, we show that ethylene receptors sense the ER redox state via lumen-localized intermolecular disulfide bonds. ER reductive stress, rather than ethylene, disrupts the disulfide-linked dimers of the receptors, repressing their function and thereby activating downstream ethylene signaling. Moreover, modulating disulfide bond formation in the receptor ETHYLENE RESPONSE 1 (ETR1) through ER redox shifts supports plant resilience under hypoxia and during photomorphogenesis. Finally, our findings suggest that sensing ER redox may be an ancestral receptor function, predating the substantial emergence of ethylene biosynthesis. This study illuminates a deeper nexus between organelle homeostasis and hormone signaling.

Dimerization is crucial for the activation of ErbB family receptors, yet the real-time dynamics and effects of oncogenic mutations remain unclear. Here, we performed long-term, multicolor single-particle tracking (SPT) of EGFR, HER2, and HER3 in living cells using upconverting nanoparticles (UCNPs), which do not photobleach. Our technique enables continuous observation of receptor interactions, revealing details of their dimerization dynamics. Oncogenic EGFR mutations promote stable, ligand-independent dimerization. Unexpectedly, both HER2 and HER3 exhibit constitutive homodimerization, prompting a revised model for their activation mechanisms. HER2 mutations modestly enhance homodimer stability compared with EGFR mutations, while HER3 mutations destabilize homodimers, suggesting that HER3 homodimerization sequesters HER3 and limits heterodimerization with other receptors. We also identified stable, ligand-independent heterodimers among all three receptors, further stabilized by ligand stimulation. These insights offer a comprehensive ErbB interaction network, elucidating diverse dimerization mechanisms and implications for oncogenic signaling.

Although topographical maps organize many peripheral sensory systems, mouse olfactory sensory neurons (OSNs) are thought to randomly choose which one of ∼1,100 possible olfactory receptors (ORs) to express, with spatial organization in the olfactory epithelium limited to a handful of broad anatomical "zones" that modestly restrict OR choice. Here, we reveal that each OR is instead expressed at a unique mean dorsoventral position, thereby instantiating a stereotyped receptor map in the olfactory epithelium. OSN dorsoventral identities are encoded by a coherent gene expression program, which includes key transcription factors and axon guidance molecules; use of this program reflects a dorsoventral gradient in retinoic acid signaling, translates each physical location into a spatially appropriate distribution of potential OR choices, and aligns receptor maps in the nose and brain. Spatial order in the olfactory system, therefore, arises from a continuously varying transcriptional code that precisely organizes the many discrete channels responsible for smell.

Deciphering how genes interact within human cells is essential for understanding their functional wiring and for developing targeted therapeutic strategies. In this study, we present a genome-scale map of genetic interactions in the human haploid cell line HAP1, based on CRISPR-based perturbation of ∼4 million gene pairs. The resulting network comprises ∼89,000 high-confidence gene-gene interactions, organizing genes into hierarchical modules corresponding to protein complexes and pathways, biological processes, and cellular compartments, mirroring principles observed in yeast and highlighting the functional architecture of a human cell. This large-scale genetic network complements the DepMap gene co-essentiality network by capturing unique functional information, uncovering roles of previously uncharacterized genes, and identifying molecular determinants of cancer-cell-line-specific genetic dependencies. This study presents a general data-driven strategy for systematically exploring the roles of genes and their functional connections in human cell lines.

Ferroptosis is an iron-dependent form of regulated cell death. However, the critical regulators that restrain iron overload to suppress ferroptosis remain undefined. Utilizing multi-omics, we identify the E3 ubiquitin ligase membrane-associated RING-CH 7 (MARCH7) as a non-redundant, dual suppressor of ferroptosis via direct regulation of intracellular iron homeostasis. Mechanistically, MARCH7 ubiquitylates nuclear receptor coactivator 4 (NCOA4) at residue Lys42 by K48-linked ubiquitination, promoting NCOA4 proteasomal degradation and reducing the labile iron pool. Concomitantly, MARCH7 modifies transferrin receptor 1 (TFR1) at residue Lys53 by K63 ubiquitination, restricting its plasma membrane translocation and thereby inhibiting cellular iron uptake. Through high-content screening, we further identify emodinanthrone (EmodAn) as a specific MARCH7 stabilizer with a strong cardioprotective effect in rodent models by blocking ferroptosis. In conclusion, our findings define an iron homeostasis regulatory hub for ferroptosis and suggest that stabilizing MARCH7 is a promising therapeutic strategy to protect against ferroptosis- or iron-overload-induced diseases.

The gut-liver-brain axis is central to metabolic and neurological homeostasis and is mediated by host- and microbiota-derived metabolites. Disruptions in this axis contribute to complex disorders, underscoring the need for targeted, multi-metabolite interventions. Here, we engineered commensal Lactobacillus plantarum WCFS1 strains to specifically modulate metabolites dysregulated in hepatic encephalopathy (HE), a disorder driven by hyperammonemia and amino acid imbalance. One strain couples ammonia assimilation with branched-chain amino acid (BCAA) biosynthesis, whereas the other enhances L-glutamine utilization to suppress ammonia generation. In two preclinical HE models, these strains reduced systemic ammonia by up to 10-fold, restored BCAA and L-glutamine balance, and improved anxiety-like and cognitive behaviors. Notably, they outperformed rifaximin, a clinically used HE therapy, while preserving gut microbiota diversity. These findings establish engineered commensals as a modular, responsive platform for multi-metabolite modulation of host-microbiota metabolism, offering a programmable strategy to restore metabolic homeostasis in disorders of the gut-liver-brain axis.