Bacterial viruses can send and receive signals to inform critical decisions. In this issue of Cell, Manley et al. and Gallego-del-Sol et al. independently identify crosstalk between bacterial viruses, leading us to wonde...Bacterial viruses can send and receive signals to inform critical decisions. In this issue of Cell, Manley et al. and Gallego-del-Sol et al. independently identify crosstalk between bacterial viruses, leading us to wonder what the information warfare landscape between them looks like.
In this issue of Cell, Gongwer et al. and Johnson et al. identify the plasticity of intratelencephalic (IT) neuronal projections to anterior insula as a central substrate mediating the antidepressant effects of accelerat...In this issue of Cell, Gongwer et al. and Johnson et al. identify the plasticity of intratelencephalic (IT) neuronal projections to anterior insula as a central substrate mediating the antidepressant effects of accelerated intermittent theta burst stimulation. These studies suggest a revolutionary future in which brain stimulation can enable circuit-specific plasticity.
Wang S, Su Y, Xu Y
… +19 more, Wang Z, Yao L, Wu Y, Hu Y, Liu H, Kou J, Li P, Wang X, Li Y, Zhang L, Deng J, Wang L, Huang Y, Wei J, Zhou J, You X, Zhou M, He H, Wang W
Circadian rhythms are mainly generated by a gene regulatory network (GRN) constituted by transcription factors (TFs). Comparisons between plant and mammalian circadian clock GRNs suggest conservation of the network archi...Circadian rhythms are mainly generated by a gene regulatory network (GRN) constituted by transcription factors (TFs). Comparisons between plant and mammalian circadian clock GRNs suggest conservation of the network architecture rather than its components. Therefore, a rhythm-generating capacity is not restricted to canonical circadian clock GRNs. Here, we showed that although the circadian clock GRN was arrhythmic, circadian rhythms were maintained in refrigerated postharvest strawberries. Through systematic dual-luciferase assays and network analysis, we discovered a noncanonical GRN pillared by five uncharacterized TFs. We developed a heterologous reconstitution system and demonstrated the rhythm-generating ability of this GRN. Subsequent systematic evolution of ligands by exponential enrichment followed by high-throughput sequencing (SELEX-seq), electrophoretic mobility shift assay (EMSA), and DNA affinity purification (DAP)-qPCR analyses suggested that this GRN was responsible for the circadian rhythms of downstream genes. Fruit-specific perturbation of this GRN led to enhanced susceptibility to Botrytis cinerea. Collectively, our study identified a noncanonical quasi-circadian GRN, realized the heterologous reconstitution of eukaryotic circadian GRNs, and demonstrated its function in immune regulation.
Genetic variants produce complex phenotypic effects that confound current assays and predictive models. We developed variant in situ sequencing (VIS-seq), a pooled, image-based method measuring variant effects on molecul...Genetic variants produce complex phenotypic effects that confound current assays and predictive models. We developed variant in situ sequencing (VIS-seq), a pooled, image-based method measuring variant effects on molecular and cellular phenotypes in diverse cell types. Applying VIS-seq to ∼3,000 LMNA and PTEN variants yielded high-dimensional morphological profiles capturing changes in protein abundance, localization, activity, and cell architecture. VIS-seq identified a subset of linker-subdomain LMNA variants that increase nuclear circularity, in contrast to aggregating or low-abundance rod-subdomain variants that decrease circularity. VIS-seq also identified autism-associated PTEN variants that mislocalize and accurately distinguished autism-linked from tumor syndrome-linked and gnomAD control variants. Most variants impacted a multidimensional phenotypic continuum not recapitulated by any single functional readout. By linking variants to cell images at scale, VIS-seq illuminates how variant effects cascade from molecules to subcellular structures to cells, providing a framework for resolving the complexity of variant function.
Jiang J, Chen S, Tsou T
… +12 more, McGinnis CS, Khazaei T, Zhu Q, Park JH, Strazhnik IM, Vielmetter J, Gong Y, Hanna J, Chow ED, Sivak DA, Gartner ZJ, Thomson M
Gene regulatory networks modulate the expression of the genome in response to signals and environmental conditions. Reconstructions of such networks can reveal the control principles cells use to maintain homeostasis and...Gene regulatory networks modulate the expression of the genome in response to signals and environmental conditions. Reconstructions of such networks can reveal the control principles cells use to maintain homeostasis and execute cell-state transitions. Here, we introduce a computational framework, dimension-scalable single-cell perturbation integration network (D-SPIN), that infers mechanistically interpretable and generative models of gene regulatory networks from single-cell mRNA-seq datasets collected across thousands of perturbation conditions. The models explain how perturbations modulate cell-state proportions by reconfiguring underlying regulatory interactions. Using large Perturb-seq and drug response datasets, D-SPIN models reveal key regulators of cell fate decisions and the coordination of distant cellular pathways in response to gene knockdowns and drug treatments, elucidate how combinations of immunomodulatory drugs induce combinatorial cell states through additive recruitment of gene expression programs, and simulate shifts in immune cell population structures across unobserved drug dosage combinations. D-SPIN provides a computational framework for revealing principles of cellular information processing and physiological control.
Directed migration of immune and epithelial cells is critical for rapid responses to tissue injury or infection. Endogenous electric fields, generated by disruption of the transepithelial potential across the skin, are t...Directed migration of immune and epithelial cells is critical for rapid responses to tissue injury or infection. Endogenous electric fields, generated by disruption of the transepithelial potential across the skin, are thought to guide cells to wound sites. However, how single cells detect these electrical cues remains unclear. We identified Galvanin (TMEM154), a poorly characterized single-pass transmembrane protein, as required for electric-field-guided migration of rapidly moving cells. Expression of Galvanin is sufficient to confer electric-field-guided migration on otherwise non-responsive epithelial cells. Upon electric-field exposure, Galvanin rapidly relocalizes to the anodal side of cells, and in human neutrophils, relocalization is immediately followed by changes in spatial patterns of cellular protrusion and retraction. These data suggest Galvanin acts as a direct sensor of the electric field, transducing spatial information about a cell's electrical environment to the intracellular migratory apparatus to support directed cell migration.
Cell fate transitions are driven by regulatory circuitry, yet RNA velocity models cellular dynamics without explicitly accounting for gene regulatory interactions, limiting mechanistic insight. Conversely, gene regulator...Cell fate transitions are driven by regulatory circuitry, yet RNA velocity models cellular dynamics without explicitly accounting for gene regulatory interactions, limiting mechanistic insight. Conversely, gene regulatory network (GRN) inference methods largely neglect the dynamic nature of biological systems. To overcome this conceptual disconnect, we present RegVelo, a bottom-up, actionable, and interpretable deep learning framework that jointly models splicing kinetics and gene regulatory interactions. Across diverse biological systems, RegVelo provides reliable predictive power for terminal states, gene interactions, and perturbation simulations. By applying RegVelo to zebrafish neural crest development using full-length Smart-seq3 and shared gene expression and chromatin accessibility measurements, we delineate regulatory programs underlying fate specification. Guided by in silico perturbations and validated by CRISPR-Cas9 knockout and single-cell Perturb-seq, we establish tfec as an early driver and elf1 as a regulator of pigment cell fate. RegVelo establishes a quantitative framework for bridging gene regulation and cell fate decisions.
Shulman ED, Campagnolo EM, Lodha R
… +31 more, Chung Y, Stemmer A, Cantore T, Ru B, Chang TG, Biswas S, Dhruba SR, Patiyal S, Patkar S, Wang A, Barman RK, Wang C, Paul R, Kalisetty SC, Hu T, Nasrallah MP, Patrick E, Yang J, Yuan Y, Sargsyan K, Plotkin A, Rajagopal PS, Sammut SJ, Lipkowitz S, Jiang P, Caldas C, Knott SRV, Aldape K, Lee JS, Hoang DT, Ruppin E
Spatial transcriptomics (ST) assays are transforming our understanding of tumor heterogeneity, but their high cost limits their application in large-scale biomarker discovery. Here, we present "Path2Space," a deep-learni...Spatial transcriptomics (ST) assays are transforming our understanding of tumor heterogeneity, but their high cost limits their application in large-scale biomarker discovery. Here, we present "Path2Space," a deep-learning model that predicts spatial gene expression directly from histopathology slides. Trained on extensive breast cancer ST data, Path2Space robustly predicts the spatial expression of thousands of genes, outperforming 21 established methods. Charting the tumor microenvironment (TME) of 976 breast cancer TCGA (The Cancer Genome Atlas) tumors, it accurately infers cell-type abundances and identifies three spatially defined breast cancer subgroups with distinct survival outcomes. Notably, the derived low-cost spatial TME landscapes enable more accurate predictions of patient response to chemotherapy and trastuzumab compared with costly conventional bulk-sequencing-based biomarkers. Path2Space thus offers a scalable, fast, and cost-effective alternative to molecular assays. It opens avenues for large cohort treatment biomarker discovery and translationally relevant insights into tumor biology, with potential applicability across many cancer indications.
Ischemia-reperfusion injury (IRI) is a major clinical challenge in transplantation, vascular surgeries, myocardial infarction, and stroke. Disruption of energy and redox homeostasis triggers ferroptosis, a regulated, iro...Ischemia-reperfusion injury (IRI) is a major clinical challenge in transplantation, vascular surgeries, myocardial infarction, and stroke. Disruption of energy and redox homeostasis triggers ferroptosis, a regulated, iron-dependent form of cell death, leading to organ dysfunction. We identify an early and transient increase of lipid peroxidation in human liver transplants and validate it as a therapeutic target. FXT-001, a ferroptosis inhibitor with dual radical and iron-trapping activity, provides robust protection in preclinical models, including ex situ perfusion of porcine liver and lung grafts. In a split ex vivo machine perfusion setting using declined human donors, FXT-001 treatment preserves graft viability, whereas untreated lungs deteriorate. We also develop FXT-002 and FXT-003 with enhanced pharmacokinetic and safety profiles. These findings support the use of ferroptosis inhibitors as a therapeutic strategy in transplantation and other IRI-associated conditions.
Wang Z, Han L, Gao L
… +21 more, Zhang L, Xie Y, Liu H, Fan J, Wu M, Yue N, Wang Y, Han M, Sun T, Ding Q, Zheng X, Cao J, Shen X, Wang H, Aizitili T, Wu C, Wu X, Liu Z, Hong Y, Lei X, Liu Y
Phytoalexins are core components of plant chemical defense against pathogens. However, the genetic basis and regulatory mechanisms governing their biosynthesis remain preliminary. Debneyol is a well-defined, broad-spectr...Phytoalexins are core components of plant chemical defense against pathogens. However, the genetic basis and regulatory mechanisms governing their biosynthesis remain preliminary. Debneyol is a well-defined, broad-spectrum fungicidal phytoalexin. Here, we elucidate its biosynthetic pathway, key regulators, and activity against multiple pathogens. We show that debneyol is synthesized from farnesyl pyrophosphate (FPP) through three steps catalyzed by 5-epi-aristolochene synthase (EAS), 5-epi-aristolochene epoxidase (EAE), and epoxide hydrolase-1 (EH1). MCD1 (miR1919-targeted cell death-factor-1) interacts with EAS and EAE, enhancing their association and EAE activity and promoting debneyol biosynthesis. Increased MCD1 expression confers plant resistance not only against fungal but also viral and bacterial pathogens. Our work reveals a complete plant phytoalexin-based chemical defense machinery, opening avenues for engineering broad-spectrum plant resistance and industrial-scale debneyol production via synthetic biology.
Fitzpatrick CR, Allen Smith R, Hige J
… +18 more, Law TF, Russ D, Ajayi OE, Eida AA, Jacob P, Jowers M, Kumar N, Lai CTU, Anguita-Maeso M, Peterson SB, Saha C, Skelly T, Zhao Q, Zhou W, Grant SR, Mougous JD, Jones CD, Dangl JL
Drought reshapes the plant root microbiota, yet the mechanistic drivers and consequences of this observation remain unclear. We discovered that suppression of host immunity and iron homeostasis is required for Streptomyc...Drought reshapes the plant root microbiota, yet the mechanistic drivers and consequences of this observation remain unclear. We discovered that suppression of host immunity and iron homeostasis is required for Streptomyces enrichment in roots during drought across diverse soils. Genetic and physiological manipulation of these host pathways confirmed their requirement in modulating Streptomyces root enrichment. Drought-induced suppression of iron uptake was conserved across the ∼160 mya monocot-eudicot divergence. Some Streptomyces strains enhanced plant growth and rescued iron uptake under drought. These benefits were uncoupled from Streptomyces root enrichment. They were instead shaped by intra-Streptomyces antagonism. We propose a two-step model: drought-driven downregulation of host iron and immune pathways enriches Streptomyces, while intra-genus dynamics fine-tune strain-level assembly and functional outcomes. Our data refine the idea that Streptomyces are enriched in roots during drought in response to a plant "cry for help" and consequently contribute to the alleviation of this abiotic stress.
Polyploidy, or whole-genome duplication (WGD), serves as both a significant evolutionary force and a potential evolutionary dead end, particularly among angiosperms. Despite the prevalence of polyploid organisms, instanc...Polyploidy, or whole-genome duplication (WGD), serves as both a significant evolutionary force and a potential evolutionary dead end, particularly among angiosperms. Despite the prevalence of polyploid organisms, instances of ancient polyploidy are surprisingly rare, presenting a paradox that remains poorly understood. In this study, we constructed a comprehensive genomic dataset of 470 angiosperm species and dated 132 ancient WGD events that are non-randomly distributed, revealing a clustering around pivotal periods of environmental upheaval and extinction. Notably, our findings highlight a strong correlation between waves of paleopolyploidization and significant events such as the Middle Miocene Disruption, the Eocene-Oligocene Transition (EOT), the Paleocene-Eocene Thermal Maximum (PETM), the Cretaceous-Paleogene (K-Pg) extinction, and different oceanic anoxic events (OAEs). We propose that polyploid organisms have an increased chance of survival during times of great environmental turmoil, a conclusion with important implications in the context of contemporary climate change and rapid global warming.
Li J, Jiang B, Zhang W
… +109 more, Hao J, Liu Z, Ji Q, Zheng Y, Lu X, Zheng Z, Ma S, Fan Y, Gao DD, Hou XW, Li J, Tang J, Jing Y, Geng L, Wu R, Zhang B, Sun S, Cai Y, Yan K, Xiong M, Dong C, Ma X, Xu G, Ji Z, Yan H, Zheng Q, Huang H, Zhang L, Li J, Jiang M, Xu LJ, Chen Y, Qu G, Lei W, Wang H, Ping J, Zhou J, Yi M, Jiang M, Jing Y, Ye WD, Zhang X, Chu X, He Y, Zhao Q, Wu Q, He M, Ma L, Liu P, Zhao L, Zhai QC, Qin J, Lu J, Yang X, Zhang S, Xiong Y, Ren H, Yang W, Huang Z, Zhang J, Zhang M, Chen P, Dong J, Zhang Y, Yan T, Ye JL, Huang P, Qi Z, Liu Y, Shuai J, Chen CS, Li P, Li D, Xu X, Song X, Li J, Ping J, Hu J, Sun X, Ai J, Wang Z, Zhang Y, Yang P, Ning T, Yu Y, He Z, Zhang H, Zhang T, Yang Y, Wang Q, Lin F, Jin X, Chen X, Ren J, Song M, Wang S, Yang J, Li J, Song W, He F, Yang YG, Pei G, Qu J, Zhang W, Pu J, Zhang F, Zhao G, Zhang W, Liu GH
Human aging is characterized by complex structural and functional decline, but quantifying its heterogeneity and assessing biological age remain challenges. We present the mCAS (multicentric Chinese aging standardized co...Human aging is characterized by complex structural and functional decline, but quantifying its heterogeneity and assessing biological age remain challenges. We present the mCAS (multicentric Chinese aging standardized cohort) developed from 2,019 Chinese individuals aged 18-91 years. Integrating high-dimensional clinical, physiological, and molecular-level data, we constructed a three-tiered aging framework: the core capacity clock (CC-clock) to quantify clinical physiological decline, the multimodal clock (MM-clock) with extensive parameter coverage and enhanced predictive precision, and organ-associated aging clocks. Cross-layer analysis demonstrates that plasma protein clocks not only capture chronological age but also serve as efficient proxies for systemic physiological capacity. Leveraging this framework for discovery, we identified the age-dependent accumulation of coagulation factors as a driver of multi-organ senescence and systemic inflammatory activation. This study provides a foundational framework that bridges molecular signatures with functional decline, identifies new biomarkers for aging assessment, and reveals a novel translational driver of aging.
Transcranial magnetic stimulation (TMS) is a widely used neuromodulation treatment for depression, but its mechanisms are poorly understood. Indirect clinical evidence suggests that TMS enhances plasticity within the pre...Transcranial magnetic stimulation (TMS) is a widely used neuromodulation treatment for depression, but its mechanisms are poorly understood. Indirect clinical evidence suggests that TMS enhances plasticity within the prefrontal cortical target site and engages downstream networks. However, establishing causal mechanisms to help optimize the large stimulation parameter space has been challenging. Using an optogenetic model of accelerated intermittent theta burst stimulation (prelimbic [PL]-aiTBS) that drives rapid antidepressant-like effects, we examined cell type-specific effects on synapse-related gene expression, increased spine density, and increased excitatory currents in prefrontal intratelencephalic projection neurons. Whole-brain c-Fos immunolabeling, fiber photometry, chemogenetic, and projection-specific optogenetic manipulations revealed that PL-aiTBS activates a fronto-insular network that is necessary and sufficient for its antidepressant-like behavioral effects. Finally, we validate a key role for fronto-insular connectivity and TMS-evoked responses in the human insula using intracortical stereo-electroencephalogram (EEG) and resting-state fMRI. These results establish a fronto-insular circuit as a critical mediator of the antidepressant effects of aiTBS.
Wang Y, Zhong A, Wang B
… +29 more, Zhai X, Lei C, Liang Z, Deng X, Zhong J, Xiao C, Zheng J, Wu B, Zhang L, Wang Y, Luo X, Wang J, Zhang M, Liu H, Wan X, Dai S, Yang Y, Zhang S, Wang W, Yang S, Xue J, Zhao C, Tammela T, Li Z, Zhang Y, Na F, Wang M, Liu Y, Chen C
Small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, exhibits poor response to immunotherapy, and the underlying mechanisms remain unclear. Here, we identify a blood-brain barrier-like vascular g...Small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, exhibits poor response to immunotherapy, and the underlying mechanisms remain unclear. Here, we identify a blood-brain barrier-like vascular gate (BVG) in SCLC, distinct from non-SCLC (NSCLC) and other cancers, composed of tightly connected endothelial cells, a thickened basement membrane, and dense pericyte coverage. Functionally, this blood-brain barrier-like vascular gate restricts immune cell infiltration, contributing to SCLC's immunotherapy resistance. Mechanistically, achaete-scute family basic-helix-loop-helix (bHLH) transcription factor 1 (ASCL1), the master transcription factor of SCLC, is essential for BVG formation by regulating insulin-like growth factor-binding protein 5 (IGFBP5), which activates the IGF1 signaling in endothelial cells. IGFBP5 knockout or treatment with the IGF1R inhibitor OSI-906 enhances CD8 T cell infiltration and synergizes with anti-PD1 therapy. Furthermore, this ASCL1-IGFBP5-IGF1R axis and the BVG are conserved across multiple neuroendocrine cancers (NECs). Our findings reveal a previously unrecognized vascular gate in NECs and propose novel therapeutic strategies to enhance immunotherapy efficacy in these recalcitrant cancers.
Gongwer MW, Qi A, Enos AS
… +15 more, Rueda Mora SA, Solakoğlu ST, Ahmed RN, Klune CB, Shari M, Kashay AQ, Williams OH, Hacking A, Riley JP, Wilke GA, Yang Y, Lu H, Leuchter AF, DeNardo LA, Wilke SA
Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism is poorly understood. We developed a mouse model of rTMS with superior clinical face validit...Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism is poorly understood. We developed a mouse model of rTMS with superior clinical face validity and investigated the neural mechanism by which accelerated intermittent theta burst stimulation (aiTBS), the first rapid-acting rTMS antidepressant protocol, reversed chronic stress-induced behavioral deficits. Using fiber photometry, we showed that aiTBS drives distinct patterns of neural activity in intratelencephalic (IT) and pyramidal tract (PT) projection neurons in dorsomedial prefrontal cortex (dmPFC). However, only IT neurons exhibited persistently increased activity during both aiTBS and subsequent depression-related behaviors. aiTBS reversed stress-related loss of dendritic spines on IT, but not PT neurons, further demonstrating cell type-specific effects of stimulation. Chemogenetically inhibiting dmPFC IT, but not PT neurons, during rTMS blocked the antidepressant-like behavioral effects of aiTBS. Thus, we demonstrate a prefrontal mechanism linking rapid aiTBS-driven therapeutic effects to cell type-specific circuit plasticity.
Wacharapluesadee S, Saikruang W, Lytras S
… +44 more, Matsumoto K, Uriu K, Hinay A, Guo Z, Rattanatumhi K, Supataragul A, Ninwattana S, Thippamom N, Srisuk T, Maneeorn P, Noradechanon K, Duengkae P, Sirichan N, Kosugi Y, Fujita S, Yo MS, Matsunaga R, Hu B, Du L, Wang L, Tsuda M, Oda Y, Nasser H, Kimura KT, Akasaka H, Asakura H, Nagashima M, Sadamasu K, Yoshimura K, Yamamoto Y, Nagamoto T, Asakura T, Shihoya W, Hashiguchi T, Ikeda T, Tanaka S, Chu H, Tsumoto K, Nureki O, Genotype to Phenotype Japan (G2P-Japan) Consortium, Genotype to Phenotype Asia (G2P-Asia) Consortium, Plianchaisuk A, Putcharoen O, Sato K
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 exp...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.
Fournier M, Vanderkerken M, Dorgham K
… +57 more, Bastard P, Ahouzi O, Duquerroy S, Nguyen NK, Broutin M, Charlet M, Vandenberghe A, Van Endert P, Bizien L, Da Mata-Jardin O, Ferriño-Iriarte A, Haouz A, Belmondo T, Hüe S, Borghesi A, Rodríguez-Gallego C, Vinh DC, Andreakos E, Haerynck F, Halwani R, Pan-Hammarström Q, Björkström NK, Strunz B, Mogensen TH, COVID Human Genetic Effort, Piralla A, Varchetta S, Freixinet J, Roussel L, Trouillet Assant S, Neven B, Levy R, le Voyer T, Delmonte OM, O'Farrelly C, Rivière J, Amador Borrero B, Servettaz A, Kouyos RD, Kaufmann DE, Crickx E, Michel M, Puel A, Abel L, Luyt CE, Mathian A, Kisand K, Duffy D, Quintana-Murci L, Amoura Z, Hale BG, Weill JC, Casanova JL, Rey FA, Gorochov G, Chappert P, Mahévas M
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-1...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), i...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.
Sang B, Ye LF, Fu Z
… +21 more, Pourfarjam Y, Cuevas-Navarro A, Fan S, Hu F, Washington A, Rodriguez DJ, Vides A, Kar S, Ahler E, Lin KK, Hegde A, Smith JAM, Wolpin BM, Punekar SR, Spira AI, Garrido-Laguna I, Hong DS, Dar AC, Yaeger R, Arbour KC, Lito P
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. Althou...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.