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Direct evidence and quantification of homologous recognition between DNA duplexes
Stretches of double-stranded DNA sharing the same sequence can recognize each other in cells. This phenomenon, known as homologous recognition, is essential for DNA recombination and repair. Yet, its mechanism remains debated, with purely physical interactions proposed as a contributing factor. Here, we use a minimal DNA nanosensor to quantify homologous pairwise interactions with exquisite precision. We find that homology enhances the duplex–duplex affinity induced by physiological divalent cations and measure the homology-driven recognition free energy as ∼ − 0.01 kcal / mol per base pair. This affinity substantially enhances coalignment of homologous DNA in the confined geometry of the nanosensor, which mimics physical effects of concentrated biological environments. We introduce a quantitative electrostatic framework that attributes this emergent behavior to coherent charge distributions unique to homologous DNA. Our findings provide compelling evidence in support of purely physical sequence-specific interactions between intact double-stranded DNA, which may bear biological relevance for homologous recombination.
Etiology of severe acute respiratory infections among adults in northern Thailand using multiplex PCR: A post-COVID-19 surveillance study (2023–2024)
Introduction The COVID-19 pandemic disrupted the circulation patterns of respiratory viruses. In tropical regions like Thailand, ongoing surveillance is essential to understand the etiology of severe acute respiratory infections (SARIs) in the post-pandemic era. We investigated the etiology of SARI among hospitalized adults in the post-pandemic era. Methods We conducted a retrospective analysis of respiratory samples collected from adult patients (≥18 years) who were hospitalized at a regional hospital in Chiang Mai, Thailand, between November 2023 and April 2024 due to symptoms of SARI (fever of ≥38°C, cough, and onset within 10 days). Sputum and/or nasopharyngeal swab were collected at admission and tested using a multiplex real-time PCR assay targeting 22 respiratory viruses and Mycoplasma pneumoniae (Siemens Healthineers Fast Track Diagnostics and Tellgen SARS-CoV-2 Nucleic Acid Detection Kit). Demographic, clinical, treatment, and comorbidity data were extracted from hospital records, and descriptive statistics were used to summarize patient characteristics and pathogen distribution. Results Among 101 hospitalized SARI patients (median age 62 years (interquartile range 43–71); 57 males), 47 (47%) tested positive for at least one respiratory pathogen. The most frequently detected viruses were adenovirus (17/101, 17%) and rhinovirus (13/101, 13%). Co-infections occurred in 9% (9/101) of cases. Seasonal trends showed peaks of influenza A and rhinovirus in January, while adenovirus and enterovirus circulated consistently throughout the study period. Conclusions Nearly half of adult SARI cases were associated with viral pathogens. Other SARI etiologies could be due to bacterial or fungal infections not tested in our study. The high rate of empiric antibiotic use highlights the need for broader and rapid molecular diagnostics. Enhanced pathogen-specific surveillance is essential to guide evidence-based clinical management in the post-pandemic context.
Eisosomal proteins are essential for plant–fungal interaction of Neurospora crassa and the sweetgrass Brachypodium distachyon
Abstract Plant fungal associations encompass a continuum from pathogenic to mutualistic interactions that have profoundly shaped terrestrial ecosystems. The ability of fungi to colonize living plant tissues typically depends on tightly coordinated signaling and membrane organizations processes. Recently, we described a previously unrecognized endophytic interaction between the filamentous model fungus Neurospora crassa and the sweetgrass Brachypodium distachyon . Contrary to its long-standing classification as a strictly saprotrophic species, N. crassa was observed to invade root epidermal and cortical cells and to colonize the vascular bundles without inducing disease symptoms, indicating a stable nonpathogenic association. To identify functional elements in this interaction, we systematically screened N. crassa mutants lacking key signaling and membrane-associated components. Disruption of certain signaling pathways including MAP kinase and NADPH oxidase mutants did not impair plant colonization. However, deletion of ncw -6 or div -23, two proteins associated with and localized to eisosomes, completely disrupted plant root colonization of N. crassa . Eisosomes are plasma membrane microdomains in fungi that contain transporters and integral membrane proteins. These findings suggest an integral function of eisosomes in plant–fungal interaction of N. crassa and possibly other fungi as well.
Assessing probe reliability: Functional group–specific biases revealed by interactome-wide docking of general anesthetics
General anesthetics are widely used to induce reversible unconsciousness, yet their molecular mechanisms remain incompletely understood. Despite their low binding affinities and broad protein-binding promiscuity, general anesthetics still interact with neuronal proteins in a structurally selective manner. Experimentally, chemically modified probes have been used to map their protein targets. However, the biases introduced by the structural modifications of these remain unknown, raising the key question of how reliable such experiments are in capturing true anesthetic–protein interactions. In this study, we present an interactome-scale computational approach to characterize anesthetic – protein interactions using high-throughput molecular docking. We screened two families of anesthetic ligands—propofol and etomidate, as well as chemically modified analogs of each—against a set of 2,388 experimentally determined mouse neuronal protein structures. By comparing parent and modified ligands, we reveal how functional group–specific biases, introduced by chemical modifications, altering ligands engage protein environments across the interactome. Docking poses and energies identify recurrent binding-site features and quantify how small modifications reshape interaction profiles. Using 3D spatial distribution functions, we summarize local amino acid environments surrounding each ligand, providing intuitive visualizations of interaction hotspots. This analysis exposes conserved and variable elements of anesthetic recognition and clarifies how probe modifications shape observed patterns. Our results offer a statistical and structural description of anesthetic binding across an interactome, providing mechanistic insight into affinity-based protein profiling mapping biases and guiding improved probe and drug design.
Replicative and stress-induced premature senescence distinctively affect the endothelial anticoagulation capacity
Aging is strongly associated with an increased risk of morbidity and mortality from multiple diseases, including thromboembolic disorders. Endothelial dysfunction is considered a key contributor to age-related thrombus formation, although its underlying mechanisms remain incompletely understood. Cellular senescence is a fundamental driver of aging; however, the distinct functional roles of replicative (RS) and stress-induced premature senescence (SIPS) in cellular functions remain unclear. This study, investigated the effects of endothelial cell (EC) senescence on blood coagulation, and demonstrated that RS and SIPS differentially regulate endothelial anticoagulation capacity. Plasma coagulation capacity, assessed using calibrated automated thrombogram, was unexpectedly reduced in the presence of RS-ECs compared with that in the presence of young control cells, whereas SIPS-EC showed no such effect. RNA sequencing analysis revealed distinct global transcriptional and coagulation pathway-related alterations between RS- and SIPS-ECs. Despite enhanced anticoagulation capacity in RS-ECs in vitro , thrombus formation was exacerbated in naturally aged mice in vivo . The contribution of SIPS-ECs to thrombus formation was further evaluated in vivo using EC-specific SIPS mouse models. EC-specific SIPS mice exhibited aggravated venous thrombus formation, with thrombus histological features resembling those observed in naturally aged mice. Gene expression profiles related to blood coagulation were also largely similar between ECs isolated from naturally aged and EC-specific SIPS mice. These findings demonstrate distinct contributions of endothelial RS and SIPS to blood coagulation and suggest that SIPS, rather than RS, may represent the predominant form of endothelial senescence during in vivo aging with respect to age-related dysregulation of blood coagulation.
Assessing future invasion risk by Solanum viarum Dunal in Northwestern Himalaya to inform early detection and management
Cytoplasmic region of beta-dystroglycan is essential for postsynaptic maturation and neuromuscular function in mice
The dystrophin–glycoprotein complex (DGC) provides structural integrity to the sarcolemma, and disruption of the DGC leads to muscular dystrophy. A core member of the DGC is dystroglycan (DG), which binds to extracellular ligands via α-DG and intracellular cytoskeleton via β-DG. Mutations in DAG1 or genes involved in the posttranslational processing of DG lead to a subset of neuromuscular diseases referred to as dystroglycanopathies. The importance of the α-DG extracellular interactions is well established; however, little is known about the significance of the β-DG intracellular interactions. Here, we investigate the importance of intracellular β-DG in neuromuscular health. Using a mouse that lacks a large intracellular region of β-DG (residues 777 to 893), we show that the deletion of cytoplasmic β-DG leads to skeletal muscle pathology accompanied by postsynaptic disruption. Our data show that within the specialized neuromuscular junction (NMJ), cytoplasmic β-DG is necessary for the localization of utrophin and rapsyn, and clustering of acetylcholine receptors. Moreover, we provide evidence that the postsynaptic abnormalities contribute to neuromuscular dysfunction in mice lacking the cytoplasmic region of β-DG. Further, using a mouse model that only lacks the C-terminal tail (residues 879 to 893) of β-DG, we demonstrate that skeletal muscle and NMJ health rely on β-DG residues 777 to 878. Together, our mouse models suggest that deletion of the cytodomain of β-DG surprisingly results in very severe neuromuscular pathophysiology in mice. Our results identify β-DG as a critical player in shaping and maintaining neuromuscular synapse architecture in vivo, thus further defining the molecular mechanisms underlying neuromuscular health.
Embodied intelligence-driven adaptive collaboration in supply chains: A four-dimensional synergy framework and mechanism analysis
Existing research focuses on data-driven algorithm optimization but overlooks the embodied nature of supply chains as physical and digital integrated systems, leading to a disconnect between AI and physical collaboration. This study introduces embodied intelligence into supply chain management, transcending the traditional paradigm to propose an adaptive collaboration framework through embodied perception, contextual reasoning, and physical execution. It deconstructs the core of supply chain embodied intelligence, revealing issues such as fragmented perception and delayed feedback. Based on embodied cognition and complex adaptive systems theory, a four-layer architecture with embodied perception, contextual reasoning, physical execution, and closed-loop feedback is constructed, clarifying its mechanisms. Future directions in theory, technology, and practice are outlined. This work deepens the integration of embodied intelligence with supply chains, bridges the digital and physical divide, and advances supply chain management toward an embodied adaptive paradigm for next-generation intelligent systems.
Research on aerodynamic characteristics prediction of folding-wing aircraft based on improved PointNet++
Partial reconstitution of the prophenoloxidase activation system in <i>Anopheles gambiae</i>
Melanization is a central insect immune response to wounding and microbial invasion. It is mediated by a system of serine proteases and their homologs, mostly members of the CLIP subfamily, and leads to prophenoloxidase (proPO) activation and PO-mediated production of cytotoxic compounds and melanin polymers that kill and sequester invading pathogens. In mosquitoes, melanotic encapsulation provides an effective defense against malaria parasites, yet the composition and organization of the underlying serine protease system remain largely unclear. Guided by gene orthology and protein abundance, we expressed SP217, four CLIPCs, and 12 CLIPBs from Anopheles gambiae and reconstructed a five-step branched cascade using purified zymogens. SP217, an ortholog of Drosophila ModSP, initiates the cascade by activating proCLIPC1. CLIPC1 activates proCLIPB13 and proCLIPB47, two of the 10 orthologs of Drosophila Grass and Manduca HP5. CLIPB13 activates proCLIPC4, proCLIPC6, and proCLIPB10 whereas CLIPB47 activates proCLIPC6 only. In the next step, CLIPC6 activates proCLIPB4 and proCLIPB9. CLIPB9 and CLIPB10 function as proPO-activating proteases (PAPs), cleaving proPO2 to generate highly active PO2 in the presence of a cofactor. Together, these results have revealed a framework of the mosquito serine protease system that drives melanization. Our findings highlight both strong evolutionary conservation of the system among holometabolous insects and species-specific differences in its organization, providing a foundation for future analysis through combinational genetic perturbation.
Association between ICU-level variation in arterial blood gas utilization and in-hospital mortality: A retrospective cohort study using the Japanese Intensive care PAtient Database registry
Background The role of arterial blood gas (ABG) testing in the intensive care unit (ICU) remains debated within the “less is more” paradigm. While unnecessary testing may pose risks without benefit, timely ABGs provide critical information in unstable patients. Institutional variation in early ABG utilization and its association with outcomes remains unclear. Methods We conducted a multicenter retrospective cohort study using the Japanese Intensive Care PAtient Database (JIPAD) between April 2015 and March 2023. Adult ICU patients with a stay ≥24 h and arterial line placement were included. The standardized number of ABGs (SNABGs) within the first 24 h was calculated as the ratio of observed to expected values, where expectations were derived from a multivariable model adjusting for patient covariates. ICUs were categorized into tertiles according to SNABG utilization. The primary outcome was in-hospital mortality, analyzed using multilevel logistic regression with ICU-level random intercepts. Restricted cubic splines were used to explore non-linear associations. Results Among 117,546 patients from 87 ICUs, the mean number of ABGs varied widely. After standardization, SNABGs ranged from 0.73–0.90 in the low tertile to 1.09–1.15 in the high tertile. In the multilevel model, SNABG was not significantly associated with in-hospital mortality (adjusted OR 0.942 [95% CI 0.807–1.100] for tertile 2; 0.874 [95% CI 0.751–1.017] for tertile 3). Flexible modeling suggested a non-linear trend toward better outcomes with higher utilization, but confidence intervals included unity. Conclusion Early ABG utilization varied across ICUs, yet was not significantly associated with mortality. Sensitivity analysis suggested a non-linear relationship, with a tendency toward better outcomes at higher utilization. These findings warrant further investigation to clarify the role of early ABG utilization in critical care.
A biophysical model linking cortical scalar potentials and polarization waves to slow traveling activity in vision
Abstract Recent experimental studies indicate that visual cognition is accompanied by slowly propagating biophysical traveling waves in cortical tissue. Here, we propose that polarization waves within the visual cortex provide the biophysical basis for the observed slowly propagating traveling waves. For this, we first compute the propagation speed of scalar potential fields generated by impressed ionic currents in primary visual cortex using a theoretically derived telegraph-type model equation. On the basis of the linear convolution framework, we then show that the scalar potential field $$\varvec{\phi\:}(\varvec{x},\varvec{t})$$ and the polarization wave $$\varvec{P}(\varvec{x},\varvec{t})$$ , arising from slowly oscillating neuronal dipoles, propagate with the same velocity. Remarkably, the predicted speed is consistent with the independently estimated propagation speed of an effective cortical modulation wave (~ 1.5 cm/s). Since each parallel retinal/LGN/geniculocortical pathway gathers signals from more than a hundred photoreceptors, the resulting response is likely to cover a range of effective cortical wave numbers. In this multi- $$\varvec{k}$$ regime, we show that dispersive spreading naturally emerges over time, which may reduce cross-channel interference and help stabilize perceptual processing.
Mutational analyses of an instability domain reveal its conserved role in the regulation of class-B ARF levels in <i>Arabidopsis</i>
The plant hormone auxin is a central regulator of plant growth and development. The canonical nuclear auxin signaling pathway acts through the regulation of gene transcription, and the protein levels of core component AUXIN RESPONSE FACTORS (ARFs) are key to this regulation. Here, we investigate the physiological role of a conserved instability (INS) domain in two class-B ARFs, ARF2 and ARF3, in Arabidopsis thaliana . Using native-promoter transgenic lines expressing different ARF2 variants, we show that T298N, T298D, and T298E mutant versions of the INS domain cause pronounced auxin-related phenotypes, including male sterility and defective root hair development. Notably, the T298D and T298E ARF2 variants, which exhibit increased protein stability, persist in epidermal nuclei within the root differentiation zone and are associated with shorter, branched root hairs, whereas wild-type ARF2 levels decline in this region coincident with root hair elongation. These lines also display auxin-resistant primary root elongation and lateral root promotion, along with reduced DR5:Luciferase responses, correlating with impaired ubiquitylation and enhanced ARF2 stability. Similarly, stabilized ARF3 variants (S293E and S293N) exhibit auxin resistance and severe developmental defects, indicating a shared regulatory mechanism among class-B ARFs. Our findings highlight critical physiological roles for class-B ARFs and verified the conserved function of the instability domain in controlling protein stability in Arabidopsis . We also reveal that INS domain-mediated turnover of ARF2 restricts their spatial accumulation and is essential for root hair elongation, providing insight into how signaling specificity is achieved through posttranslational control of ARF activity.
Early mortality risk stratification in childhood bacterial meningitis using cerebrospinal fluid glucose and protein levels and their combinations: A multicontinental cohort study
Background Bacterial meningitis remains a major cause of death and neurological disability in children worldwide, particularly in low-resource settings where access to intensive care is limited. Cerebrospinal fluid (CSF) glucose, protein, and leukocyte concentrations are routinely measured at hospital presentation, yet their potential for early risk stratification – individually or in combination – has not been clearly defined. Because mortality risk is often difficult to assess at admission, identifying simple CSF-based thresholds that help clinicians recognize high-risk patients could improve triage and management globally. Methods and findings We evaluated CSF glucose, protein and leukocyte levels in 1598 children with bacteriologically confirmed bacterial meningitis across six countries in Latin America, Angola, and Finland to determine their individual and combined associations with mortality and neurological outcome. CSF glucose, protein, and leukocyte counts were measured at admission and examined in relation to in-hospital mortality and neurological outcome at discharge, as assessed by the Glasgow Outcome Scale. CSF glucose and protein concentrations were categorized into five clinically interpretable groups. Mortality increased progressively with decreasing CSF glucose (from 8% to 29%) and with increasing protein concentrations (from 5% to 23%). Children with both low CSF glucose (<10 mg/dL) and high CSF protein (≥200 mg/dL) had a mortality rate of 27% compared with 1% among those with normal CSF glucose and protein. A CSF leukocyte count <500/µL was also associated with increased mortality. Lower CSF glucose (ρ = 0.24; P < .001) and higher protein (ρ = 0.15; P < .001) were both associated with poorer neurological outcomes. Conclusions Routine CSF markers available at the time of hospital admission provide prognostic information that supports risk stratification in pediatric bacterial meningitis. Simple CSF-based thresholds—particularly when CSF glucose and protein are interpreted in combination—may help identify high-risk children early and guide clinical prioritization in settings with limited critical care capacity.
Efficient uncertainty aware human activity recognition on microcontrollers using hyperdimensional computing and conformal prediction
Reconstructing EBV reactivation and DNA damage response kinetics in morphologic pseudotime
Epstein–Barr virus (EBV) lytic infection contributes to oncogenesis and autoimmunity and depends on subversion of host DNA damage responses (DDR). We used high-content screening (HCS) to systematically capture single-cell morphologic profiles and pseudotemporal dynamics of EBV reactivation and DDR across common B cell models and lytic induction treatments. We generated an atlas (>850,000 cells) of spatiotemporally distinct phenotypes of immediate-early and late lytic proteins, viral and cellular DNA replication, and double-stranded break (DSB) DDR factors. Cell segmentation, feature quantification, and clustering identified treatment- and model-dependent cell responses and lytic induction. Lytic and latent cells showed distinct genotoxin-induced DDR profiles, and lytic protein localization varied by pharmacologic and physiologic stimuli. Pseudotime trajectories revealed viral replication compartment (VRC) nucleation and expansion alongside concomitant DDR localization. The early DDR marker γH2AX was depleted from VRCs but widespread across host chromatin throughout reactivation. Surprisingly, the lytic-essential late DDR protein 53BP1 was present prior to viral genome replication but subsequently undetected in VRCs and host chromatin, indicating spatial and kinetic DDR dysregulation during EBV reactivation. These data support a model wherein EBV transiently employs host DSB DDR mediators to initiate genome replication while host-targeted DDR is initiated but impaired. We further show biological generalizability and utility of our method across microscope systems. HCS paired with morphologic pseudotime analysis thus provides a powerful approach to recover single-cell host–virus dynamics from snapshot samples.