NK cells are important for the anti-tumour immune response for their potential to kill MHC class I-deficient tumor cells, but they often become dysfunctional in the immune-hostile tumour microenvironment. Here, using single-cell RNA sequencing, we identify an NK cell subpopulation that is specific to triple-negative breast cancers (TNBC) subtype, characterised by the expression of the long non-coding RNA UGDH-AS1. In these NK cells, UGDH-AS1 encodes the micropeptide, NKSM, which renders these NK cells dysfunctional due to the loss of their activation program, which leads to cancer progression. Conditional NKSM knock-in into NK cells of mice results in NK cell deactivation and increased growth of transplanted tumours. Targeted NKSM therapy effectively reduces tumor growth in TNBC mouse models. We find that UGDH-AS1+ NK cells are shaped by the tumor microenvironment (TME). Following upregulation by the TGF-β signaling pathway, NKSM binds to Myc, inhibiting its ERK1/2-mediated phosphoryla

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A common misconception that prevails within some research communities postulates that research results ‘speak for themselves’ and are thus sufficient to influence policy. Yet, high-fidelity uptake of research is rarely a passive process; more often, researchers need to actively engage with policymakers. This process of policy engagement strives towards producing robust science that contributes to the betterment of our societies—but it is a process for which many researchers are not adequately trained. If publicly funded research fails to influence policy, many would regard it as falling short of fulfilling its potential value to society. Herein, we provide a framework for research–policymaker engagement, framed around the questions of why, on what, with whom, when, where and how clinical and public-health researchers can and should undertake engagement with policymakers. The views presented in this Perspective are a synthesis of the diverse, collective experience of the authors across

Most Epstein–Barr virus-associated gastric carcinoma (EBVaGC) harbor non-silent mutations that activate phosphoinositide 3 kinase (PI3K) to drive downstream metabolic signaling. To gain insights into PI3K/mTOR pathway dysregulation in this context, we perform a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib. Multiple subunits of carboxy terminal to LisH (CTLH) E3 ligase, including the catalytic MAEA subunit, are among top screen hits. CTLH negatively regulates gluconeogenesis in yeast, but not in higher organisms. The CTLH substrates MKLN1 and ZMYND19, which highly accumulated upon MAEA knockout, associate with one another and with lysosome outer membranes to inhibit mTORC1. Rather than perturbing mTORC1 lysosomal recruitment, ZMYND19 and MKLN1 block the interaction between mTORC1 and Rheb and also with mTORC1 substrates S6 and 4E-BP1. Thus, CTLH enables cells to rapidly tune mTORC1 activity at

Bidirectional, multilevel communication between the heart and the brain is pivotal for the beat-to-beat regulation of cardiac function and the close titration of cardiac output to meet metabolic demand. Given this bidirectional communication, it is perhaps not surprising that cardiac pathologies lead to changes in the central and peripheral autonomic nervous system, which in turn lead to further progression of cardiovascular disease. Within the CNS, structural and functional changes have been reported in the setting of hypertension and heart failure in multiple autonomic regions and nuclei, including the spinal cord, brainstem, hypothalamus and higher centres, such as the amygdala and thalamus. These alterations enhance the excitability of sympathetic neuronal populations and diminish the excitability of neurons within the parasympathetic nuclei, resulting in sympathovagal imbalance. The primary drivers of these structural and functional changes appea

Obesity’s metabolic heterogeneity is not fully captured by body mass index (BMI). Here we show that deep multi-omics phenotyping of 1,408 individuals defines a metabolome-informed obesity metric (metBMI) that captures adipose tissue-related dysfunction across organ systems. In an external cohort (n = 466), metBMI explained 52% of BMI variance and more accurately reflected adiposity than other omics models. Individuals with higher-than-expected metBMI had 2–5-fold higher odds of fatty liver disease, diabetes, severe visceral fat accumulation and attenuation, insulin resistance, hyperinsulinemia and inflammation and, in bariatric surgery (n = 75), achieved 30% less weight loss. This obesogenic signature aligned with reduced microbiome richness, altered ecology and functional potential. A 66-metabolite panel retained 38.6% explanatory power, with 90% covarying with the microbiome. Mediation analysis revealed a bidirectional, metabolite-centered host–microbiome axis, mediated by lipids, am

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Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer1,2. Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division3–6 and persist over many generations. It has been more than 40 years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear3,7. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions tha

Brain function requires exquisitely adapted plasticity at multiple scales, from synapses to whole-brain networks. Evidence for large-scale plasticity in functional brain networks comes from neuroimaging data across a variety of species, particularly during development and following injury. However, how large-scale network remodelling is achieved at the microscopic level is unknown as the growth of entirely new long-distance axons is unlikely to occur. Recent insights from electron microscopic connectome studies and single-cell projectomes of neurons in the brains of multiple model organisms have provided new evidence for the incredible structural complexity of axons and their branches that traverse the brain. This evidence shows highly arborized axonal projections, differentially myelinated branches of the same axon, and axonal regions devoid of synaptic contacts but with the potential to form synaptic connections in new or additional areas. Recent electron microscopic data s

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Many electrochemical biosensors operate based on a threshold-sensing (TS) method, which indicates the presence of a disease when the concentration of a biomarker exceeds a predetermined, disease-specific threshold. The TS in biosensor systems is often implemented using power-hungry signal processing (SP) modules or computers, which increases energy consumption and system complexity. Here, we propose a memristor-based bio-to-electrical transducer with built-in TS functionality, allowing TS to be performed directly within the transducer instead of relying on SP modules and computers. Fabricated resistive random-access memory-based TaOX/Ta2O5 memristors meet the transducer requirements, such as a high on/off ratio greater than 30 while maintaining a long unit pulse width exceeding 10 μs. The intended operation of the proposed transducer was experimentally confirmed by the immediate change in resistance of the memristor (RM) from high resistance state to low resistance state. Using this pr

Plasmids play significant roles in microbial adaptation to ecosystems, yet their dynamics remain poorly understood due to identification challenges. We present the Global Soil Plasmidome Resource (GSPR), a comprehensive dataset of 98,728 plasmid sequences amassed from 6860 terrestrial microbial communities and isolates. We explore this resource through various computational approaches, including phylogenetic diversity analysis, host prediction, and extensive functional annotation, to understand the contribution of plasmids to the genetic and functional diversity in soil, correlating these findings with sample type, as well as the soil habitat they were retrieved from. Our analysis reveals insights into plasmid-encoded functions such as effector modules, quorum sensing, and stress resistance, which may contribute to their persistence and microbial adaptation in soil. Furthermore, CRISPR analysis suggests a prevalent role of these elements related to intra-plasmid competition. By co

Homo sapiens evolved hundreds of thousands of years ago in Africa, later spreading across the globe1, but the early evolutionary process is debated2–6. Here we present whole-genome sequencing data for 28 ancient southern African individuals, including six individuals with 25× to 7.2× genome coverage, dated to between 10,200 and 150 calibrated years before present (cal. bp). All ancient southern Africans dated to more than 1,400 cal. bp show a genetic make-up that is outside the range of genetic variation in modern-day humans (including southern African Khoe-San people, although some retain up to 80% ancient southern African ancestry), manifesting in a large fraction of Homo sapiens-specific variants that are unique to ancient southern Africans. Homo sapiens-specific variants at amino acid-altering sites fixed for all humans—which are likely to have evolved rapidly on the Homo sapiens branch—were enriched for genes associated with kidney function. Some Homo&nbsp

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Nuclear pore complexes (NPCs) mediate selective exchange of macromolecules between the nucleus and cytoplasm, but the organization of their transport barrier has been a matter of debate. Here we used high-speed atomic force microscopy, complemented with orthogonal in vitro and in vivo approaches, to probe the dynamic behaviour of the NPC central channel at millisecond resolution. We found that nuclear transport factors dynamically remodel intrinsically disordered phenylalanine-glycine (FG) domains tethered within the NPC channel, partitioning the barrier into two zones: a rapidly fluctuating annular region and a highly mobile central plug. Increased FG-repeat density in mutant NPCs dampened barrier dynamics and impaired transport. Notably, NPC-like behaviour was recapitulated in DNA origami nanopores bearing transport factors and correctly tethered FG domains but not in in vitro FG hydrogels. Thus, the rotationally symmetric architecture of NPCs supports a nanoscopic barrier organizati

Breastfeeding is inversely associated with cardiometabolic disease incidence in prospective studies; however, the metabolic pathways underlying these associations remain largely unknown. Here, we derive a plasma metabolomic score of lifetime total duration of breastfeeding using elastic net regularized regression in Nurses’ Health Studies (n = 4349) and replicate in the Women’s Health Initiative (n = 2088). Data include 181 untargeted plasma metabolites profiled by liquid chromatography mass spectrometry using blood samples collected in mid-life, and self-reported lifetime total duration of breastfeeding. We then examine the associations between the metabolite-based breastfeeding score and risk of T2D and CVD using multivariable Cox regression models and replicated in two external cohorts. The metabolite-based breastfeeding score comprised of 5 metabolites (i.e., C54:2 triglyceride, C56:2 triglyceride, C56:3 triglyceride, cotinine, indole-3-propionate), which show a modest but statisti

Over the past several decades, the pharmaceutical industry has progressed from identifying small-molecule natural products with favourable pharmacological properties mediated by unknown molecular mechanisms, to deliberate engineering of chemical compounds and macro-molecules that alter the activities of prespecified targets in predefined ways. The past quarter century has seen the emergence of an entirely new drug category: multispecific molecular drugs that are prospectively designed to engage two or more entities to exert their pharmacological effect. This design elicits emergent properties that endow the drugs with capabilities that are inaccessible to monospecific therapies. Furthermore, these properties enable multispecific drugs to circumvent biological barriers to pharmacology, including rapid clearance, functional redundancy, on-target/off-tissue toxicity, and lack of druggable features. Here, I describe how a new wave of approved multispecific drugs is recalibrating expectatio

Lung development generates a complex tree-like architecture through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs governing embryonic lung development remain poorly understood. Here, we present a comprehensive single-cell multi-omics atlas of mouse embryonic lungs, integrating gene expression and chromatin accessibility profiles. Through systematic analysis, we identify 13 distinct cell types and map cis-regulatory elements, peak-to-gene linkages, and transcription factors underlying lung development. Leveraging this multi-modal dataset, we uncover lineage-determining transcription factors driving cell differentiation, including the Activated Protein-1 complex. We further delineate gene regulatory networks involving diverse transcription regulators, including CCCTC-binding factor (CTCF). Using the Ctcf conditional knockout mouse, coupled with histological and multi-omics analyses, we demonstrate that CTCF orchestrates lung progenitor main

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