Gene-regulatory networks (GRNs) offer a mechanistic framework for dissecting the complex molecular and genetic architecture of coronary artery disease and for identifying new therapeutic opportunities. Here, we present a GRN-driven drug-repurposing strategy that integrates transcriptional signatures induced by silencing key drivers of the human arterial wall foam cell regulator GRN 42 with drug-induced gene expression profiles from the NIH LINCS program. In vitro screening of top candidate compounds validates the computational predictions, identifying candidate foam cell modulators and showing that auranofin, an FDA-approved gold salt used to treat rheumatoid arthritis, effectively reduces foam cell formation. In vivo, auranofin attenuates atherosclerosis and inflammation in both male mice and rabbits. Clinically, auranofin was associated with reduced cardiovascular risk in a retrospective cohort of patients with rheumatoid arthritis. Together, these findings show that a GRN-based drug-repurposing framework, coupled with preclinical and clinical validation, can uncover new therapeutic applications for existing drugs, including auranofin, in coronary artery disease.

Antibody-producing plasmablasts (PB) and plasma cells (PC) are critical for humoral immunity, autoimmunity and vaccine responses. Despite the importance of environmental stressors in regulating humoral immune responses, the influence of pH on PB and PC differentiation remains elusive. Here, we identify SLC4A7/NBCn1, a Na+/HCO3- cotransporter, as a selective regulator of PB differentiation in vitro. SLC4A7 deletion also impairs the formation of antibody secreting cells (ASCs) and antibody responses in mice in vivo following immunization and influenza A virus infection. Mechanistically, SLC4A7 deletion results in intracellular acidification and lysosomal alkalinization, and is associated with impaired function of the mechanistic target of rapamycin complex 1 (mTORC1). Enforcing mTORC1 activation in SLC4A7-deficient B cells or B cells in which intracellular pH is acidified by blocking Na+/H+ exchanger (NHE) function restores PB differentiation in vitro. Moreover, ASC differentiation and antibody responses are impaired under conditions of extracellular acidosis in vitro and in a mouse model of metabolic acidosis. Altogether, we identify a critical relationship between intracellular pH regulation through SLC4A7 and mTORC1-dependent ASC differentiation and humoral immunity.

Antichiral states propagate in the same direction on opposite boundaries, defying the conventional constraint that boundary modes must cancel net chirality. Previously found antichiral states have been limited to first-order topological semimetals. However, antichiral hinge states-the antichiral counterpart of recently discovered higher-order chiral hinge states-remain elusive. Here, we report the observation of antichiral hinge states in a higher-order nodal-ring semimetal made of a three-dimensional gyromagnetic photonic crystal. Near-field scanning measurements reveal a pair of hinge states at two parallel one-dimensional boundaries propagating unidirectionally along the same direction, with robust transport against metallic scatterers. Their spatial positions can be reconfigured by adding or removing photonic layers. The additionally observed antichiral and drumhead surface states manifest a hierarchy of first- and second-order topological boundary states within a single photonic system. Our work extends antichiral states to higher-order topological semimetals and has potential applications in robust and reconfigurable photonic routing.

Perovskite quantum dot-based light-emitting diodes (QLEDs) have been regarded as promising emitters for lighting and displays. However, the operational stability still greatly hinders their practical applications. Here, we introduce ultrathin nano-layered boron nitride (BN) as buried interfacial layer to enhance device stability. As an effective blocking layer, BN not only interacts with perovskite to passivate interface defects and eliminate ion migration channel, but also directly suppresses ion migration. Meanwhile, BN makes exciton recombination behavior and electrical transport properties of perovskite QDs less sensitive to the heat. Resultantly, BN-optimized QLEDs achieved an average EQE of 30.05% and extrapolated operational lifetime T50 of 25,263 h at an initial luminance (L0) of 100 cd m-2, which is 1.7-fold and about 100-fold improvement compared to control devices, respectively. In this work, integrating 2D materials into perovskites through interface engineering provides a pragmatic tactic to enhance the performance of halide perovskite-based LEDs.

Solar photovoltaic power is essential for achieving carbon neutrality, yet its output is highly sensitive to changes in air quality under future emission pathways. We integrate energy-economy, coupled meteorology-chemistry, and photovoltaic performance models to quantify how alternative carbon-neutrality pathways influence solar power generation via air quality changes in China. Here we show that a pathway emphasizing renewable-energy deployment yields the greatest air-quality improvements, boosting annual photovoltaic power generation by 57,526 ± 10,314 gigawatt-hours (GWh) relative to business-as-usual, equivalent to economic gains of US$5.18 ± 0.93 billion by 2060. These gains are driven primarily by aerosol-cloud interactions rather than aerosol-radiation interactions. In contrast, pathways relying on biomass or carbon capture achieve only about one-third of these gains. The largest gains occur in eastern and southern China, where electricity demand is highest. These findings highlight the importance of co-optimizing decarbonization and air-pollution mitigation to maximize the renewable energy benefits of carbon-neutrality strategies.

Orthobunyaviruses are linked to a broad spectrum of neurological disorders. However, the molecular determinants governing bunyavirus neuropathogenesis remain poorly understood, precluding the identification of drugs able to alleviate virus-induced neuronal dysfunctions. Here, we show that the prevalent, yet neglected, orthobunyavirus Ťahyňa virus (TAHV) disrupts neuronal integrity and proteostasis in human cerebral organoids (hCO), significantly decreasing synaptic protein expression and density. Moreover, TAHV-induced synaptic remodeling is associated with perturbed local field potential in organotypic cultures of human post-mortem adult brain explants (OPAB) and higher expression of the metabotropic Glutamate receptor 1 (mGluR1) in mice in the absence of overt neurological disease or neuroinflammation. Using proteome-based network medicine, we identified gabapentin as a therapeutic candidate that restores neurotransmitter receptor levels back to baseline in mice, and prevents TAHV-induced hyperexcitability in OPAB. Together, our data highlights the underappreciated neuropathological potential of a neglected orthobunyavirus, that interferes with neural integrity and neurotransmission, while neuromodulatory interventions may help to preserve cerebral functions.

Transposable elements (TEs) are usually silenced by DNA methylation and H3K9me2, but in the absence of DNA methylation they can instead acquire the Polycomb-associated mark H3K27me3. Here, we initially set out to test whether DNA methylation and H3K27me3 compete during TE silencing establishment in Arabidopsis. Although we observe this competition at one newly inserted transgenic TE, we remarkably find that H3K27me3 deposition at another neo-inserted TE requires the de novo methyltransferase DRM2, revealing that DNA methylation can also promote Polycomb recruitment. Accordingly, genome-wide H3K27me3 profiling in different DNA methylation mutants shows that DNA methylation either antagonizes or promotes H3K27me3 in a locus-specific manner. Targeted DNA methylation experiments as well as the use of a drm2 catalytic mutant further demonstrate that DNA methylation directly influences Polycomb recruitment. Overall, our work reveals a previously unappreciated interplay between DNA methylation and Polycomb pathways that maintains genome and epigenome integrity in eukaryotes.

Despite significant advances in nanoengineering, developing a universal nanoparticle engineering strategy that enables tailored nanoparticle organ deposition post intravenous administration remains challenging. Here, we report a simple and modular strategy mediated by metal-organic network coatings composed of polyethylene glycol (PEG), proteins, phenolic ligands, and metal ions. The versatile binding affinity of phenolic ligands facilitates the formation of coatings on diverse nanoparticle platforms, including quantum dots, lipid, polymeric, inorganic, and metal-organic nanoparticles. The organ deposition selectivity of these coated nanoparticles is readily directed towards the kidney, lung, heart, and brain by varying the coating composition. Mechanistic studies reveal that the combined effect of PEG, phenolic ligands, and metal ions on the surface properties governs the overall biodistribution of the coated nanoparticles, while the protein component contributes to the coating integrity. This work provides a generalizable approach for developing an organ-targeting nanotechnology, with the potential to advance nanoparticle-mediated treatments and theranostics.

Minimal cells offer a platform to uncover the fundamental physicochemical principles of cellular life. While genomes, proteomes, and metabolic networks of cells have been elucidated, the lipidome, which determines the physicochemical identity of the membrane, remains only partially characterized. Yet, the membrane is a central determinant of cellular viability, regulating solute permeability, mechanical stability, and environmental cues. Here, we investigate membranes that recapitulate the lipid composition of the minimal cell JCVI-syn3A, which is distinguished by an unusually high cholesterol content and simple composition. Combining cryo-electron microscopy, Langmuir monolayer experiments, permeability assays, and coarse-grained molecular dynamics simulations, we demonstrate that cholesterol and sphingomyelin act as dominant condensing agents that stabilize the membrane while preserving an ordered yet fluid state. These lipids enhance lipid packing and acyl-chain order, whereas cardiolipin, POPC, and DOPG counterbalance condensation by promoting fluidity and compressibility. Cholesterol-sphingomyelin interactions emerge as a key thermodynamic driver that fine-tunes membrane order, fluidity, and permeability. Remarkably, membranes containing up to 60 mol% of cholesterol remain permeable to water and physiologically relevant osmolytes at rates compatible with growth of JCVI-syn3A. Together, our results define the physicochemical principles underlying minimal cell membranes and reveal how lipid composition enables passive permeation while maintaining membrane integrity.

Cyclopeptides have emerged as promising candidates for drug development. However, owing to the scarcity of efficient cyclization strategies for natural peptides, the development of diverse cyclopeptides remains a formidable challenge. In this study, a variety of macrocyclic peptides featuring (thio)urea bridges are developed through the site-selective lysine‑lysine crosslinking of native peptides, employing N, N'-carbonyldiimidazole or N, N'-thiocarbonyldiimidazole as  bridging reagents. In particular, dual thiourea-bridged macrocyclic peptides are further synthesized by using a one-pot two-step multicomponent macrocyclization. These strategies enable the chemoselective macrocyclization of peptides bearing diverse nucleophilic residues to afford (thio)urea-bridged macrocyclic analogs, as exemplified by the successful transformation of the targeted peptide RGD (Arg-Gly-Asp) and the antimicrobial peptide Anoplin analogue. Biological evaluation demonstrates that the cyclopeptides, particularly the thiourea- and bis-thiourea-bridged analogs, exhibit enhanced target binding affinity, potent antitumor activity, as well as improved membrane permeability and stability. Molecular docking elucidates the structural origin of the enhanced bioactivity, suggesting that the reinforced molecular interactions might be a potential underlying cause.

Large repetitive elements and complex chromosomal organization continue to challenge accurate assembly of eukaryotic genomes. Optical genome mapping (OGM) provides long-range genomic information by imaging individual DNA molecules. While most OGM protocols rely on sparse enzymatic labeling that restricts resolution in poorly labeled or structurally complex regions, dense labeling strategies generate continuous fluorescence intensity profiles that offer a complementary representation of genome structure. Here we extend our Dense Optical Genome Mapping Assembly (DOGMA) pipeline, previously used for bacterial genomes, to eukaryotic genomes, exemplified by the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, with compact, yet structurally rich genomes. We use a competitive binding (CB)-based dense OGM protocol that produces continuous intensity profiles, reflecting local AT/GC-content, along individual DNA molecules. By explicitly accounting for structural features inherent to eukaryotic genomes that complicate assembly, DOGMA reconstructs genome-wide optical maps while avoiding collapse of non-adjacent repetitive loci. The resulting chromosome-scale assemblies span the genomes of both yeasts and show local differences relative to the corresponding reference genomes, including expanded repetitive arrays ( > 500 kbp). These results establish a comprehensive framework for scalable dense OGM to increasingly complex genomes, including the human genome, where we foresee that it can be efficiently used for disease diagnosis.