Browse Articles

Proton-activated chloride channel 1 is essential for innate host defense against bacterial sepsis

Bacterial sepsis remains a devastating clinical problem. Here, we describe a protective role for the recently discovered acid-sensitive, proton-activated chloride channel, PACC1 (PAC/ASOR/TMEM206), during sepsis. Initially, we found PACC1 was enriched in healthy human and mouse mononuclear phagocytes, particularly macrophages, and differentially regulated by inflammatory stimuli, suggesting PACC1 involvement in innate immunity. To further investigate, we generated de novo Pacc1 knockout ( −/− ) mice, which presented without major immunologic abnormalities at baseline. Compared to wild-type (WT), Pacc1 −/− myeloid cells showed normal phagocytic uptake of acid-insensitive Escherichia coli BioParticles , but impaired development of the acidifying phagolysosome using acid-sensitive E. coli BioParticles. Transcriptomic profiling of Pacc1 −/− macrophages revealed dysregulated phagolysosomal and cytokine networks (e.g., interferons). Because phagolysosomal bacterial clearance is essential to resolve infection, we challenged Pacc1 −/− mice with intraperitoneal gram-negative E. coli sepsis. Pacc1 −/− mice displayed increased bacterial burden, immune cell infiltration, inflammation, and lethality. In contrast, phagocytosis-independent E. coli lipopolysaccharide (LPS)-induced endotoxemia yielded comparable WT and Pacc1 −/− survival, as well as similar inflammatory responses. Finally, we engineered Pacc1 -floxed ( fl/fl ) mice crossed with a myeloid lineage Cre-deleter strain to interrogate myeloid cell–intrinsic PACC1 in vivo. Consistent with a predominate role for PACC1 during phagocytosis and bacterial clearance in these cells, LysM-Cre/Pacc1 fl/fl mice exhibited impaired E. coli sepsis survival but indifferent endotoxemia phenotypes. In conclusion, PACC1 links sterilizing phagolysosomal activity with immune networks in sepsis pathobiology.

Asthma prevalence and risk factors in early-onset atopic dermatitis using Korean National Health Insurance Service data

Abstract Early-onset atopic dermatitis (AD) is a common pediatric allergic disease and a potential precursor of asthma. However, population-based evidence on long-term asthma risk following early AD is scarce. This study assessed age-specific asthma prevalence and risk factors in children diagnosed with AD before age 2 using Korean National Health Insurance Service data. In this retrospective cohort, children with AD diagnoses (ICD-10: L20) at least twice before age 2 between 2008 and 2017 were included. Asthma was defined by diagnosis (ICD-10: J45, J46) and concurrent prescription of asthma medication. Patients were followed until December 2022. Standardized prevalence ratios (SPRs) were calculated relative to the general population, and multivariate logistic regression identified risk factors. Of 1,647,199 children with early-onset AD, 1,161,172 were analyzed. Asthma prevalence peaked at age 3 (29.0%) and declined to 0.5% by age 15, remaining significantly higher than in the general population. Increased risk factors included male sex, preterm birth, diagnosis before 2010, persistent AD, food allergy, and early rhinovirus or RSV infection. Diagnosis after age 1 and higher socioeconomic status were linked to lower risk. Early-onset AD is strongly associated with later asthma, highlighting the need for early identification and targeted prevention.

Cosmic ray–driven electron-induced reaction theory does not quantify spatiotemporal variations in lower-stratospheric ozone and temperature

Integrated approaches for pathogen monitoring and shotgun metagenomic analysis in Atlantic salmon farming

Abstract Specific tools for detecting waterborne pathogens are essential for limiting disease spread in aquaculture. We evaluated a field-deployable workflow combining filtration of eDNA/eRNA with targeted (RT-)qPCR and complementary shotgun metagenomics to monitor pathogens and microbial community dynamics in a single-farm study following one Atlantic salmon production cohort from hatchery to slaughter. The primary aim was to assess workflow feasibility and performance under real farm conditions, while secondarily examining whether metagenomic profiles could contextualise microbial shifts associated with pathogen presence. ISAV was consistently detected in hatchery water at ~ 4 × 10 3 –9 × 10 3 copies/L, whereas PRV1 was detected only inside sea pens from August onward (~ 4 × 10 2 –1.5 × 10 4 copies/L) and increased by more than two orders of magnitude after wellboat delousing. Shotgun metagenomics yielded a median of ~ 1.5 × 10 5 reads per sample (mean read length ~ 2.5 kb; N50 > 2 kb), enabling broad taxonomic screening. PRV1-positive seawater samples showed modest decreases in richness and shifts in viral taxa, though patterns were subtle and should be interpreted cautiously given low pathogen loads. The workflow was practical for trained farm personnel, and this integrated approach offers a scalable system for routine pathogen surveillance and supports earlier, evidence-based biosecurity actions, providing broader microbial information than qPCR alone.

The influence of electrical charge on plasmodesma conductivity

Most plant tissues are symplasms in which cells are connected by plasmodesmata, membrane-lined cytosplasmic bridges that enable diffusive and/or advective cell-to-cell movements of components of the cytosol. Current models assume that hydrodynamic radius alone governs the mobility of molecules through plasmodesmata. In contrast, physical theory predicts that nm-sized pores with electrically charged walls are selective for counterions. Narrow plasmodesmal pores lined by membranes―which carry negative surface charges―therefore should be permselective for cations. Quantifying cell-to-cell movements of fluorophores varying in molecular mass and electrical charge in cell types with differently sized plasmodesmata, we confirmed the applicability of physical theory to plasmodesmata. Surprisingly, narrow plasmodesmata were permselective for anions rather than cations, suggesting a major flaw in our current understanding of plasmodesma structure. We hypothesize that structural proteins known to exist in plasmodesmata may establish the cationic electrostatic environment required to explain our findings.

Slope displacement forecasting with limited field data using time series model

Reply to Mazzaferro et al. and Niebaum: The limits of alignment: Grounding executive functions without assuming special contexts

Development and characterization of gelatin–platelet-rich plasma hydrogels for enhanced spinal cord injury repair

Abstract Spinal cord injury (SCI) remains a major clinical challenge due to the limited regenerative capacity of the central nervous system. This study presents the development and characterization of a gelatin–platelet-rich plasma (PRP) hydrogel as a therapeutic strategy for SCI repair. A composite gelatin–PRP scaffold was fabricated by incorporating PRP into a gelatin matrix to enhance tissue regeneration and functional recovery. In vitro analyses demonstrated excellent biocompatibility, with neuronal cell viability increasing from 75% on Day 1 to 96% on Day 7 ( p  < 0.05). The release of growth factors including transforming growth factor β1 (TGF-β1), platelet-derived growth factor BB (PDGF-BB), and insulin-like growth factor 1 (IGF-1) followed a biphasic pattern, with approximately 85–88% released within 96 h ( p  < 0.05). In vivo, the PRP + Hydrogel group exhibited significantly improved locomotor recovery on the Basso–Beattie–Bresnahan (BBB) scale, along with reduced cavity formation, improved tissue preservation, and decreased scar-like tissue appearance compared with other treatments (n = 6 per group, p  < 0.05). These findings indicate that gelatin–PRP hydrogels support growth factor delivery, promote tissue repair, and improve functional recovery, highlighting their potential as a biomaterial platform for spinal cord repair.

Phage display–mediated immuno-PCR to detect low-abundance secreted proteins in <i>Drosophila</i>

Circulating hormones, that mediate communications across organs to maintain physiological balance, are commonly detected and quantified using enzyme-linked immunosorbent assays (ELISAs). However, while ELISA is well suited for organisms where sample blood can be readily obtained, its application is considerably more challenging in smaller organisms, particularly Drosophila , which has gained widespread use in recent years for physiological studies. Here, we present sensitive phage display–mediated immuno-PCR (PD-iPCR) to detect Drosophila hemolymph proteins via two approaches: 1) by identifying high-affinity nanobodies through phage display library screening and subsequent affinity maturation and 2) by generating a knock-in fly line producing secreted proteins tagged with tandem NanoTags composed of VHH05 and 127D01. Using these approaches, we successfully established PD-iPCR to detect insulin-binding ImpL2 protein in fly hemolymph. Notably, the tandem NanoTag-based sandwich PD-iPCR enabled highly sensitive detection of tagged antigens, allowing us to quantify elevated ImpL2 levels in the hemolymph of starved flies and those bearing Yki -induced gut tumors. Collectively, our results demonstrate that PD-iPCR enables detection of endogenous, low-abundance circulating hormones in Drosophila , providing a powerful tool for studying interorgan communication.

Machine learning-driven time series analysis for SOH prediction of lithium-ion batteries

Reconsideration of Secure Communities rollout reveals preemptive local-federal cooperation in immigration enforcement

Qualitative studies on local police collaborations with federal immigration enforcement authorities reveal risks to the well-being of noncitizens, particularly the undocumented, and their families and communities. Yet statistical evidence of these policies’ effects is mixed. We propose that quantitative studies may misidentify the timing of when these policies begin disrupting immigrant communities by relying on a policy’s formal enactment date to indicate its activation. We test this proposal in the context of Secure Communities, a federal program with a staggered rollout that asked local police to detain noncitizens they arrested for possible transfer into Immigration and Customs Enforcement (ICE) custody and deportation. Individual states signed a Memorandum of Agreement (MOA) with the federal government as a framework for their county-by-county activation of Secure Communities. Counties were not required to activate immediately; their formal enactment frequently occurred later when prompted by ICE. We find that the date when a state signed an MOA consistently predicts a county’s increased probability of receiving ICE requests to hold noncitizens in detention, transferring detained noncitizens into ICE custody, and removing noncitizens from the country. This relationship operates most strongly in counties with preexisting enforcement infrastructure between local police and federal immigration authorities. By contrast, while we find that enactment dates are associated with increases in each outcome, pretreatment trends render these relationships statistically indeterminate. Our results highlight how multilayered relationships between local and federal authorities allow for policing to be used as a tool for facilitating the preemptive implementation of immigration enforcement across the country at the expense of noncitizens and their families and communities.

Integrated network pharmacology, molecular docking, and experimental validation reveal the antifungal and anti-inflammatory mechanisms of Camellia oleifera seed extracts against oral thrush

Extracellular matrix chemistry tunes bacterial biofilm metabolism and optimizes fitness

Chemically complex extracellular matrices define cellular microenvironments and shape cell behavior across all domains of life. But how has evolution optimized these materials to ensure the success of multicellular communities? Inspired by the well-established composition–properties–function relationships in engineered materials, we hypothesized that analogous relationships exist in extracellular matrices, where the composition and interactions among various matrix components govern material properties and cellular physiology. Here, we examine Pseudomonas aeruginosa biofilms—representative of ubiquitous multicellular microbial assemblies in nature and disease. We show that electrostatic interactions between the cationic polysaccharide Pel and extracellular DNA (eDNA) compete with eDNA binding to pyocyanin (PYO), a diffusible redox-active metabolite that supports anaerobic metabolism via extracellular electron transfer (EET). From a materials perspective, biofilm-mimetic hydrogels and natural biofilms revealed that altering Pel’s charge via pH adjustment or chemical acetylation, or tuning the Pel:eDNA ratio, directly and predictably modulates PYO retention and EET efficiency. Biologically, a lower Pel:eDNA ratio enhances biofilm metabolism under oxygen limitation, whereas a higher ratio promotes survival under antibiotic stress. Notably, these perturbations (pH, Pel structure, and abundance) can be achieved directly or indirectly through biological activities. Together, these findings highlight how biologically regulated matrix chemistry encodes tunable material properties that, in turn, affect cellular responses that confer biofilm fitness advantages. They further suggest cells might actively fine-tune the surrounding matrix chemistry to maximize survival across diverse environments. More broadly, our work establishes a materials-based framework for a mechanistic understanding of the biological functions of extracellular matrix components in multicellular communities.

The intermediate station trigonometric leveling method for replacing second-order leveling in complex terrain

Timing the decline: Cellular circadian rhythms and Alzheimer’s disease

Artificial intelligence-driven virtual reality eye-tracking for the objective measurement of MRD1 and MRD2 in blepharoptosis

Abstract Accurate measurement of eyelid position is essential for diagnosis and surgical planning in blepharoptosis, but traditional manual assessment using pen torch and ruler is subject to inter-observer variability and lack of standardisation. We evaluated an artificial intelligence-enabled virtual reality eye-tracking system to provide an objective alternative to current manual methods. In 101 patients with suspected blepharoptosis, the BulbiCAM device employed high-speed infrared video-oculography with convolutional neural network algorithms to automatically detect the pupil centre, corneal glint, and eyelid margins. When benchmarked against standard clinical assessment to establish validity, automated measurements showed high agreement, with mean differences of + 0.29 mm for upper eyelid position and + 0.01 mm for lower eyelid position. Critically, the device demonstrated high precision, with test-retest repeatability in 36 patients showing mean differences of − 0.03 mm and + 0.27 mm between visits. Successful acquisition was achieved in all participants with a median of one attempt, and 98% reported the device as comfortable and easy to use. This study demonstrates that AI-enabled VR eye-tracking matches the clinical accuracy of current standards while offering the repeatability and objectivity required to overcome the limitations of manual assessment.

Structural innovation and flexibility in plant chemical defenses

Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer’s and wild-type mice

A rare glycoalkaloid biosynthetic pathway from wild potato unlocks genetic routes to Colorado potato beetle resistance

Plants in the family Solanaceae produce steroidal glycoalkaloids (SGAs), specialized metabolites that are toxic to consumers while providing protection against herbivores. The Colorado potato beetle (CPB) is a major foliar pest of potatoes, and the wild species Solanum chacoense PI458310 displays resistance through the accumulation of the specific SGAs leptine I/II, the C-23-acetoxylated derivatives of α-chaconine/α-solanine. Although these leptines and their presumed C-23-hydroxylated precursors, leptinine I/II, have been recognized for decades, their biosynthetic routes have remained unresolved. In this study, we show that leptinines and leptines do not originate from direct modificfation of α-chaconine/α-solanine, but instead arise from earlier transformations of spirosolane-type precursors. We identified Sc23DOX , a spirosolane C-23 hydroxylase, and Sc23ACT , a 23- O -acetyltransferase, and demonstrated in vitro that these enzymes convert α/β-solamarine into 23-hydroxy and 23- O -acetyl intermediates, which are subsequently processed into leptinines and leptines by the ring-rearrangement enzymes Dioxygenase for Potato Solanidane synthesis (DPS), Reductase for Potato Glycoalkaloid biosynthesis 1 (RPG1), and RPG2. Notably, these C-23 hydroxylation and O-acetylation reactions parallel the initial steps of α-tomatine detoxification during fruit ripening in tomato ( Solanum lycopersicum ). Moreover, when Sc23DOX and Sc23ACT were expressed heterologously in cultivated potato, the plants produced leptinines and leptines de novo. Genomic and transcriptomic analyses further revealed that many cultivated potatoes ( Solanum tuberosum ) retain apparently functional 23DOX and 23ACT orthologues, and that expression of 23DOX alone can restore leptine biosynthesis in certain cultivars. Collectively, these findings clarify the leptinine/leptine biosynthetic pathway, illustrate the co-option of a detoxification-related module into a defense system, and provide a genetic basis for breeding or engineering CPB-resistant potatoes.

A bayesian approach to robust modeling of skewed biomedical data