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A prehistoric East-Asian Yersinia pestis genome and a ~5.3 ka trans-Eurasian expansion of plague
Receptor allostery promotes context-specific Sonic Hedgehog signaling during embryonic development
Abstract Sonic Hedgehog (SHH) signaling functions in temporal- and context-dependent manners to pattern diverse tissues during embryogenesis. The signal transducer Smoothened (SMO) is induced by sterols, oxysterols, and arachidonic acid (AA) through binding pockets in its extracellular cysteine-rich domain (CRD) and 7-transmembrane (7TM) bundle. In vitro analyses suggest SMO signaling is allosterically enhanced by combinatorial ligand binding to these pockets, but in vivo evidence of SMO allostery is lacking. Herein, we map an AA binding pocket at the top of the 7TM bundle and show that its disruption attenuates SHH- and sterol-stimulated SMO induction. A knock-in mouse model of compromised AA binding reveals that homozygous mutant mice are cyanotic, exhibit perinatal lethality, and display congenital heart disease. Surviving mutants demonstrate pulmonary maldevelopment and fail to thrive. Neurodevelopment is unaltered in these mice, suggesting that context-specific allosteric regulation of SMO signaling allows for precise tuning of pathway activity during cardiopulmonary development.
Counteranion-mediated dynamic kinetic asymmetric fluorination to access sulfur-stereogenic center
Navigating optimal solar-wind trade-offs under climate change
A natural solution from caterpillar cuticles for flexible impact-resistant materials
Cost-effective abatement of industrial sources of nitrous oxide with methane for urgent climate mitigation
Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis
Abstract Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.
Dielectric stacking-engineered scalable reconfigurable transistor platform for adaptive logic circuits
Abstract Although reconfigurable van der Waals devices featuring flexible logic transformation offer a promising strategy toward adaptable architectures to accommodate diverse computational demands, reliable polarity control and scalable integration remain challenging. Here, we demonstrate a reconfigurable field-effect transistor based on the scalable dielectric oxide-van der Waals quasi-floating-gate configuration, enabling nonvolatile polarity switching and multi-state programmability. Charge trapping engineering in an atomic-layer Al 2 O 3 /HfO 2 /Al 2 O 3 dielectric stack achieves performance with nonvolatile conductance update (>6-bits for 1000 s), robust endurance (>3 × 10 5 cycles), and well-balanced electron/hole transport (current mismatch ratio ~ 1%). TCAD simulation and surface potential analysis reveal oxygen vacancies-dominated polarity switching dynamics. Using a silicon-compatible top-gate dielectric process and complementary design, diverse logic gates—including eight Boolean operations and seamless AND-OR-Invert/OR-AND-Invert transformations—are accommodated into compact reconfigurable logic-in-memory circuits. These transistors also simplify ternary content-addressable memory design, underscoring their potential for efficient logic-in-memory computing.
Nickel catalysis enables chemoselectivity in radiation chemistry
A benchmark study of vision and pathology foundation models for computational pathology
JN.1-adapted vaccination is associated with readjustment of ancestral memory B cells toward neutralization within the JN.1 antigenic space
Abstract The antigenic drift of SARS-CoV-2 toward the JN.1 lineage has prompted the development of variant-adapted COVID-19 booster vaccines. However, these boosters are thought to primarily recall pre-existing memory B cells (MBC), raising concerns about their ability to realign the immune response in highly pre-exposed populations. Here we analyze antibody and B cell responses in pre-exposed individuals ( n = 42; median 4.5 prior COVID-19 vaccinations; 90% with at least one prior SARS-CoV-2 infection) following vaccination with a JN.1-adapted mRNA vaccine. Vaccination is associated with increased IgG binding and enhanced neutralization of JN.1 and related descendant variants. Longitudinal profiling of antigen-specific MBC shows that Wu01-only and Wu01/JN.1 cross-reactive cells remain dominant, while JN.1-only cells modestly increase by day 21. Single-cell RNA-sequencing of antigen-specific MBC in a representative sub-cohort ( n = 7 ), combined with functional monoclonal antibody analyses, demonstrates that somatic hypermutation (SHM) drives intra-clonotype specialization toward improved JN.1 binding and neutralization. These findings indicate maturation of pre-existing, class-switched MBC rather than substantial de novo recruitment of naïve B cells. In conclusion, JN.1-adapted booster vaccination is associated with refinement of pre-existing MBC repertoires toward the JN.1 antigenic space and with enhanced neutralization of contemporary and antigenically proximate variants.
The BRCT domain enhances DNA binding and catalytic efficiency of fungal PARPs
Abstract Aspergillus fumigatus infections are a major yet often neglected global health challenge magnified by a growing at-risk population, limited treatment options, and the emergence of drug-resistant strains. Regulation of the DNA damage response (DDR) by ADP-ribosylation signalling has recently emerged as an important feature of fungal pathogenesis, but the underlying mechanisms remain largely elusive. Here we present a comprehensive phylogenetic and functional characterisation of Af -PARP1, the A. fumigatus PARP homologue. Our data reveal Af -PARP1 as a DNA-dependent poly(ADP-ribosyl)transferase with unique domain architecture, DNA damage selectivity, and activation dynamics distinct from its mammalian and plant homologues. We show that the fungal specific BRCT domain plays a crucial role in both damage recognition and ADP-ribosylation signal establishment. Collectively, our findings reveal a divergence in DDR-associated ADP-ribosylation specific to fungi, highlighting the potential of this signalling pathway as target for antifungal therapy.
CDC7 and APC/CCdh1 gate distinct routes to initiate DNA replication
Structural insights into ligand recognition and activation of the human oxoglutarate receptor OXGR1
Transcript-aware rare genetic variant association analyses of cardiopulmonary traits in participants from the All of Us Research Program
IFI208, an interferon-stimulated gene, promotes host antiviral responses through liquid-liquid phase separation of MDA5
Cryo-EM structures of biopsy-derived TTR fibrils in hereditary transthyretin amyloidosis
Abstract Hereditary transthyretin amyloidosis (ATTRv) is a fatal autosomal dominant disease characterized by systemic deposition of transthyretin (TTR) amyloid fibrils, leading to progressive neuropathy and cardiomyopathy. More than 130 pathogenic mutations in the TTR gene have been identified, but their roles in TTR fibril formation and disease pathogenesis remain unclear. Here, using cryo-electron microscopy (cryo-EM), we present nineteen high-resolution TTR fibril structures (1.9-3.4 Å) from gastrocnemius muscle biopsies and vitreous humor of ten living ATTRv patients carrying nine distinct heterozygous mutations. Deep-learning-based analysis of cryo-EM densities enables semi-quantitative assessment of mutant or wild-type dominance within fibrils. These compositional profiles, combined with their structures, suggest an association between disease onset and the TTR species (wild-type or mutant) that primarily initiates amyloid formation. This biopsy-based workflow broadens access to patient tissue for amyloid structural studies, enabling systematic investigation of heterogeneous hereditary amyloidoses and the role of mutations in amyloid formation.