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Continuously tunable multistability in DNA replication networks
No full textAbstract Multistable systems, ideally, could stabilize at any desired, switchable state within a continuous spectrum. However, conventional systems, constrained by signal-mediated mutual activation or inhibition, are limited to a finite set of discrete steady states. Here, we propose a rational framework for achieving continuously tunable multistability through reversible displacement reaction-mediated competition between positive autoregulatory DNA polymerization/nicking modules. This framework harnesses the chemical energy of dNTP hydrolysis to suppress spontaneous interconversion between modules for stabilizing at any target state along a continuous compositional gradient. With unparalleled tunability, the framework enables continuous, orthogonal state transitions and concentration-adaptive molecular memory in response to transient stimuli. Moreover, the single-stranded DNAs generated by polymerization/nicking reactions can be customized with predefined structures and functions, enabling continuously multistable control over downstream processes, e.g., biocatalysis and RNA transcription, while maintaining multistability. This framework establishes a versatile and robust platform for developing chemical and material systems with continuously tunable multistability
PTRAMP, CSS and Ripr form a conserved complex required for merozoite invasion of Plasmodium species into erythrocytes
No full textAbstract Invasion of erythrocytes by members of the Plasmodium genus is an essential step of the parasite lifecycle, orchestrated by numerous host-parasite interactions. In P. falciparum Rh5, with PfCyRPA, PfRipr, PfCSS, and PfPTRAMP, forms the essential PCRCR complex which binds basigin on the erythrocyte surface. Rh5 is restricted to P. falciparum and its close relatives; however, PTRAMP, CSS and Ripr orthologs are present across the Plasmodium genus. We investigated PTRAMP, CSS and Ripr orthologs from three species to elucidate common features of the complex. Like P. falciparum, PTRAMP and CSS form a disulfide-linked heterodimer in both P. vivax and P. knowlesi with all three species forming a complex with Ripr by binding its C-terminal region, termed the PTRAMP-CSS-Ripr (PCR) complex. Cross-reactive antibodies targeting the PCR complex differentially inhibit merozoite invasion. The crystal structure of a cross-reactive antibody reveals an inhibitory epitope on the C-terminal tail of PvRipr. Cryo-EM visualization of the P. knowlesi PCR complex confirms predicted models and demonstrates a core invasion scaffold in Plasmodium spp. with implications for vaccines targeting multiple species of malaria-causing parasites
Phosphorothioate DNA modification by BREX type 4 systems in the human gut microbiome
No full textAbstract Among dozens of microbial DNA modifications regulating gene expression and host defense, phosphorothioation (PT) is the only known backbone modification, with sulfur inserted at a non-bridging oxygen by dnd and ssp gene families. Here we explored the distribution of PT genes in 13,663 human gut microbiome genomes, finding that 6.3% possessed dnd or ssp genes predominantly in Bacillota, Bacteroidota, and Pseudomonadota. This analysis revealed several previously undescribed PT synthesis systems, including type 4 Bacteriophage Exclusion (BREX) type 4 brx genes, which we genetically validated in Bacteroides salyersiae. Mass spectrometric analysis of DNA from 226 gut microbiome isolates possessing dnd, ssp, and brx genes revealed 8 PT dinucleotide settings confirmed in 10 consensus sequences by PT-specific DNA sequencing. Genomic analysis showed PT enrichment in rRNA genes and depletion at gene boundaries. These results illustrate the power of the microbiome for discovering prokaryotic epigenetics and the widespread distribution of oxidation-sensitive PTs in gut microbes
Adipocytic sclerostin loop3-LRP4 interaction required by sclerostin to impair whole-body lipid and glucose metabolism
No full textAbstract Sclerostin, which has three loops, inhibits bone formation and impairs whole-body lipid and glucose metabolism. The marketed therapeutic sclerostin antibody for postmenopausal osteoporosis (POP) mainly targeting loop2 promotes bone formation and improves whole-body lipid and glucose metabolism. However, FDA/EMA warns of its cardiovascular risk. We previously demonstrate that sclerostin loop3 contributes to the inhibitory effect of sclerostin on bone formation but not its cardioprotective effect. Here we find elevated serum sclerostin levels in both POP-T2DM patients and newly-diagnosed T2DM patients and further demonstrate that sclerostin loop3 participates in the impairment effect of sclerostin on whole-body lipid and glucose metabolism in vivo. Mechanistically, specific blockade of adipocytic sclerostin loop3-LRP4 interaction attenuates the impairment effect of sclerostin on lipid and glucose metabolism in vitro and in vivo. This study provides an innovative strategy, blocking adipocytic sclerostin loop3-LRP4 interaction, to normalize lipid and glucose metabolism in POP-T2DM patients, in cardiovascular safety
Atomic-scale mechanism unlocks thermal-stable high-κ performance in HfO2 via coherent interfaces
No full textAbstract Complementary-metal-oxide-semiconductor-compatible HfO2-based high-κ dielectrics are pivotal for next-generation electronics in the post-Moore’s Law era. However, establishing coherent interfaces via morphotropic phase boundaries across the tetragonal and orthorhombic (ferroelectric or antiferroelectric) phases—a key strategy for enhancing dielectric properties—remains challenging due to unclear atomic-scale mechanisms and inherent thermal instability, which compromises long-term stability and reliability. To address this, we leverage metallurgical quenching principles to stabilize tetragonal/orthorhombic-antiferroelectric morphotropic phase boundaries in HfO2-based (Lu:Hf0.6Zr0.4O2) bulk crystals. Through precise composition tuning and growth optimization, we stabilize these metastable morphotropic phase boundaries at the tetragonal/orthorhombic-antiferroelectric interface at room temperature, achieving a comparable κ-value (57) to actively studied tetragonal/orthorhombic-ferroelectric counterparts. Microstructural characterization reveals how tensile strain within the t-phase drives dielectric enhancement through softening of the low-frequency E u phonon mode. Critically, the tetragonal/orthorhombic-antiferroelectric morphotropic phase boundary demonstrates a ~58% reduction in κ variation rate over 30–200 °C relative to tetragonal/orthorhombic-ferroelectric counterparts, signifying superior thermal stability. Our study establishes a generalizable design paradigm for developing high-κ dielectrics in fluorite-structured materials, advancing next-generation complementary-metal-oxide-semiconductor-compatible-integrated functional devices for data storage, energy harvesting, sensing, and integrated photonics
Functional variants at 1p36.23 confer risk of schizophrenia through modulating RERE
No full textAbstract Genome-wide association studies have identified 1p36.23 as a schizophrenia risk locus. However, the functional variants and genes driving the association remain unknown. Here, we identified two functional variants (i.e., rs159961 and rs301792) at the 1p36.23 risk locus. Both variants reside introns of RERE and exhibit allele-specific enhancer activity. Risk alleles of rs159961 and rs301792 increase enhancer activity by altering REST and POLR2A binding, leading to RERE upregulation. Consistently, RERE was significantly elevated in brains of schizophrenia cases. Functionally, RERE-overexpression impaired neurogenesis, altered dendritic spine density and dendritic complexity, and altered genes related to dendrite development and glutamatergic synapses. Through interacting with RARB and RXRA at the Grin2a promoter, RERE regulates the well-known schizophrenia risk gene Grin2a (encodes an NMDAR subunit), and RERE-overexpression impairs excitatory synaptic transmission. Our study indicates that functional variants rs159961 and rs301792 confer schizophrenia risk by upregulating RERE, which affects neuronal development and synaptic function
Membrane-free CO2 hydrogenation electrolyzer for salt precipitation management in acidic electrochemical CO2 reduction
No full textAbstract Electrochemical CO2 reduction (ECR) in acidic electrolytes minimizes CO2 loss and carbonate formation issues, allowing for high CO2 utilization efficiency and showing good potential for practical CO2 upgrading applications. However, in the membrane-based electrolyzer, the proton transfer efficiency across the membrane from the anolyte to the catholyte is crucial for the stability of the catholyte pH in acidic ECR, especially at high current density and during long-term electrolysis. Here, we investigate the effects of proton transfer efficiency and salt precipitation in different acidic ECR electrolyzer and propose a membrane-free CO2 hydrogenation electrolyzer, which couple CO2 reduction and hydrogen oxidation. This electrolyzer design effectively maintains a stable electrolyte pH during long-term electrolysis, and simultaneously achieves high Faradaic efficiency for HCOOH production, high single-pass carbon utilization efficiency, and a lower cell voltage. At a current density of 100 mA cm−2, the system requires only 1.7 V to achieve a 90% HCOOH Faradaic efficiency and demonstrates stable operation for 208 hours
Ultrafast scintillating metal-organic framework films
No full textAbstract Compositionally engineered metal-organic frameworks are designed and used to fabricate ultrafast scintillating films. The inclusion of hafnium ions in the nodes of the metal-organic framework enhances the interaction with ionizing radiation, partially compensating for the low density of the porous material and increasing the scintillation yield. The high diffusivity of molecular excitons within the framed conjugated ligands allows bimolecular annihilation processes that partially quench the system luminescence, resulting in fast scintillation pulses in the hundreds of picoseconds time scale. Despite the quenching, the gain in scintillation yield achieved is large enough to maintain the film light yield above 104 ph MeV-1 under soft X-rays. These high efficiencies and fast emission kinetics are obtained at room temperature in a technologically attractive solid-state configuration, placing the metal-organic framework platform in a prominent position for the realization of the next generation of fast scintillation counters for high-energy physics studies and medical imaging applications
Machine learning-predicted insulin resistance is a risk factor for 12 types of cancer
No full textAbstract Insulin resistance is suggested to be a risk factor for cancer; however, large-scale epidemiological evidence linking insulin resistance to cancer remains limited. Here we apply a machine learning-based prediction model of insulin resistance with nine clinical parameters, termed artificial intelligence–derived insulin resistance (AI-IR), to the UK Biobank and demonstrated that AI-IR exhibits the highest predictive performance for diabetes incidence compared to body mass index (BMI), metabolic syndrome (MetS), triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio, and triglyceride-glucose (TyG) index. Moreover, AI-IR is significantly associated with an increased risk of six cancers (uterine, kidney, esophagus, pancreas, colon, and breast) and showed nominal associations with six additional cancers (renal pelvis, small intestine, stomach, liver and gallbladder, leukemia, and bronchial and lung). When we define composite cancers by merging cancer types whose risks increase with AI-IR, age- and sex-adjusted hazard ratio is 1.25 (95% confidence interval, 1.20-1.31; P < 1 ×10-11). AI-IR is a better predictor of the composite cancers compared to BMI and TyG index, while its capability is comparable to that of MetS and TG/HDL ratio. We conclude that AI-IR is a robust metric for predicting both diabetes and the composite cancer incidence and could be utilized for identification of high-risk individuals and focused screening
Robust and interpretable prediction of gene markers and cell types from spatial transcriptomics data
No full textAbstract Spatial transcriptomics (ST) links tissue morphology with gene expression values, opening new avenues for digital pathology. Deep learning models are used to predict gene expression or classify cell types directly from images, offering significant clinical potential but still requiring improvements in interpretability and robustness. We present STimage as a comprehensive suite of models to predict spatial gene expression and classify cell types directly from standard H&E images. STimage enhances robustness by estimating gene expression distributions and quantifying both data-driven (aleatoric) and model-based (epistemic) uncertainty using an ensemble approach with foundation models. Interpretability is achieved through attribution analysis at single-cell resolution integrated with histopathological annotations, functional genes, and latent representations. We validated STimage across diverse datasets, demonstrating its performance across various platforms. STimage-predicted gene expression can stratify patient survival and predict drug response. By enabling molecular and cellular prediction from routine histology, STimage offers a powerful tool to advance digital pathology
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