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The cellular nucleotide pool is a major focal point of the host immune response to viral infection. Immune effector proteins that disrupt the nucleotide pool enable animal and bacterial cells to broadly restrict diverse viruses, but reduced nucleotide availability induces cellular toxicity and can limit host fitness^1-5. Here we identify Clover, a bacterial anti-phage defence system that overcomes this trade-off by encoding a deoxynucleoside triphosphohydrolase enzyme (CloA) that dynamically responds to both an activating phage cue and an inhibitory nucleotide immune signal produced by a partnering regulatory enzyme (CloB). Analysis of phage restriction by Clover in cells and reconstitution of enzymatic function in vitro demonstrate that CloA is a dGTPase that responds to viral enzymes that increase cellular levels of dTTP. To restrain CloA activation in the absence of infection, we show that CloB synthesizes a dTTP-related inhibitory nucleotide signal, p3diT (5'-triphosphothymidyl-3'5'-thymidine), that binds to CloA and suppresses activation. Cryo-electron microscopy structures of CloA in activated and suppressed states reveal how dTTP and p3diT control distinct allosteric sites and regulate effector function. Our results define how nucleotide signals coordinate both activation and inhibition of antiviral immunity and explain how cells balance defence and immune-mediated toxicity.

Rare diseases affect more than 300 million people worldwide^1-3, yet timely and accurate diagnosis remains an urgent challenge^1,3-5. Patients often endure a prolonged 'diagnostic odyssey' exceeding 5 years, marked by repeated referrals, misdiagnoses and unnecessary interventions, leading to delayed treatment and substantial emotional and economic burden^4,5. Here we present DeepRare-a multi-agent system for rare disease differential diagnosis decision support^6-8 powered by large language models, integrating more than 40 specialized tools and up-to-date knowledge sources. DeepRare processes heterogeneous clinical inputs, including free-text descriptions, structured human phenotype ontology terms and genetic testing results to generate ranked diagnostic hypotheses with transparent reasoning linked to verifiable medical evidence. Evaluated across nine datasets from literature, case reports and clinical centres across Asia, North America and Europe spanning 14 medical specialties, DeepRare demonstrates exceptional performance on 2,919 diseases. In human-phenotype-ontology-based tasks, it achieves an average Recall@1 of 57.18%, outperforming the next best method by 23.79%; in multi-modal tests, it reaches 69.1% compared with Exomiser's 55.9% on 168 cases. Expert review achieved 95.4% agreement on its reasoning chains, confirming their validity and traceability. Our work not only advances rare disease diagnosis but also demonstrates how the latest powerful large-language-model-driven agentic systems can reshape current clinical workflows.

Cytopathology, often abbreviated as cytology, has a central role in the early detection of cancer, such as cervical, lung and bladder cancers, owing to its speed, simplicity and minimally invasive nature^1-9. However, its effectiveness is limited by variability in diagnostic accuracy stemming from subjective visual interpretation^10-21. Although many artificial intelligence (AI)-powered systems have been proposed to improve consistency^22-26, none have achieved fully autonomous, clinical-grade performance. Existing approaches serve as assistive tools and still rely on human oversight for interpretation and decision-making^22-26. Here we present a clinical-grade autonomous cytopathology pipeline that combines high-resolution, real-time optical whole-slide tomography with edge computing to deliver end-to-end automation. The system achieves practical performance in imaging speed, quality and data volume, with localized data compression enabling streamlined storage and accelerated AI-driven analysis. In addition to supporting cell-level classification, the platform enables flow cytometry-like, population-wide morphological profiling for comprehensive interpretation of cellular distributions and patterns. A vision transformer achieved area under the receiver operating characteristic (ROC) curve (AUC) values exceeding 0.99 at the single-cell level for detecting low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs) and adenocarcinoma. In a multicentre evaluation of 1,124 cervical liquid-based cytology samples across four centres, the AI model achieved slide-level AUC values of 0.86-0.91 for LSIL⁺ and 0.89-0.97 for HSIL⁺, with LSIL counts correlating strongly with human papillomavirus positivity and HSIL counts scaling with diagnostic severity. The system enables autonomous triage cytology, offering a foundation for routine, scalable and objective diagnostics.

The central nervous system is surrounded by three interconnected membranes referred to as the meninges, which host a diverse immune network^1-3. Within the skull-interfacing dura mater are venous sinuses, large veins that are traditionally viewed as passive blood drains for the brain and skull^4,5. However, these structures also constitute an important neuroimmune interface^6-8. Here we used intravital microscopy to gain mechanistic insight into this interface and reveal that dural sinuses and their endothelial cells form a highly dynamic surface that continually restructures to regulate blood flow, fluid movement and immune surveillance. We show that sinuses are not passive conduits, but instead undergo RAMP1-dependent constriction and dilation mediated by smooth muscle, resembling arterial behaviour. Moreover, the superior sagittal sinus in mice is bifurcated into upper and lower chambers that contribute to intracranial pressure regulation. Both chambers are lined by specialized, highly fenestrated sinus endothelial cells (SECs) that permit movement of fluids, macromolecules and microorganisms between the sinus lumen and leukocyte-rich perisinus space. To safeguard this permeable interface, SECs dynamically open and close intercellular boundaries in a RAMP2-dependent manner. Transcranial RAMP2 antagonism impaired SEC boundary dynamics and reduced immune cell trafficking along the sinus wall during homeostasis and systemic viral infection. Disruption of SEC dynamics during infection compromised local antiviral immunity and promoted pathogen entry into the meninges. Together, these findings establish dural sinuses as dynamic venous structures that regulate fluid exchange and support immune surveillance and antiviral defence.

HIV-1 integrase (IN) promotes encapsulation of viral genomic RNA into mature viral cores, and this function is a target for ongoing antiretroviral drug development efforts^1-3. Here we determined the cryogenic electron microscopy (cryo-EM) structure of a primate lentiviral IN in a complex with RNA, revealing a linear filament made of IN octamer repeat units, each comprising a pair of asymmetric homotetramers. The assembly is stabilized through IN-RNA interactions involving mainly the IN C-terminal domains and RNA backbone. The spacing and orientation of the IN filament repeat units closely matched those of consecutive capsid (CA) hexamers within the mature CA lattice. Using cryo-EM images of native purified HIV-1 cores, we refined the structure of the IN filament as it propagates along the luminal side of the CA lattice. Each IN tetramer within the filament nestled in a CA hexamer, engaging closely with the major homology regions. Substitutions of residues involved in IN-CA contacts yielded eccentric virions with RNA nucleoids located outside of the cores. Collectively, our results establish the structural basis for the HIV-1 IN-RNA interaction and reveal that IN forms an RNA-binding module on the luminal side of the mature CA lattice.