The prevalence of pre-frailty and frailty is increasing in Asia, resulting in substantial morbidity and mortality in older populations. Modelling frameworks are required to estimate the prevalence of frailty and potential impacts of ongoing population-level nutritional interventions. Using a microsimulation sociodemographic model of 3,353,032 individuals from 2011 to 2050, and published estimates from the Singapore Longitudinal Ageing Study 2 of 3270 participants, we developed a Bayesian multistate model of robust, pre-frail, and frail stages with estimated transition probabilities by age, ethnicity, gender, and body mass index category. We then explored four scenarios where weight management interventions are applied that modify the annual distribution of underweight, normal weight, overweight, obese I and obese II individuals. Here we show that, between 2011 and 2050, the projected overall prevalence of pre-frailty and frailty increases from 44.2% to 49.57% (95% credible interval: 47.60-51.00%), and from 3.2% to 11.97% (7.34-15.60%), respectively. Reductions range from 22,045 (18,430-23,487) to 3,599 (2554-4621) pre-frail individuals and from 62,847 (40,165-91,517) to 15,802 (13,238-17,133) frail individuals when 100% to 5% of both underweight individuals shift to normal weight and obese II individuals move to obese I, respectively. Total healthcare utilisation decreases by 7.1% (3.9-9.4%) to 0.3% (0.2-0.5%) under 100% to 5% intervention coverage. Frailty prevalence in Singapore is projected to substantially increase by 2050, while population-level weight management interventions could avert cases of both pre-frailty and frailty in older individuals, even at modest real-world effectiveness. As people live longer, more older adults are expected to experience pre-frailty or frailty, which can make everyday activities harder and increase the need for healthcare. Body weight is one factor linked to frailty risk, as both being underweight and having severe obesity can increase this risk. In this study, we used a population simulation model of Singapore residents to project changes in pre-frailty and frailty up to 2050. We also explored whether weight management interventions could reduce this future burden. Our results suggest that frailty is likely to rise substantially in Singapore, but helping older adults move towards healthier weight categories could prevent or delay some cases. These findings support early, population-wide interventions to promote healthy ageing and reduce future healthcare needs.
Food market accessibility is a critical yet underexplored dimension of food systems, particularly in low- and middle-income countries. In this paper, we present a continent-wide assessment of spatial food market accessibility in Africa, integrating open geospatial data from OpenStreetMap and the World Food Programme. We compare three complementary metrics: travel time to the nearest market, market availability within a 30-minute threshold, and an entropy-based measure of spatial distribution, to quantify accessibility across diverse settings. We find pronounced disparities in accessibility: rural and economically disadvantaged populations face substantially longer travel times and reduced market availability, with some areas requiring several hours of travel. These accessibility patterns align with socioeconomic stratification, as measured by the Relative Wealth Index, and moderately correlate with food insecurity levels, assessed using the Integrated Food Security Phase Classification. Overall, results suggest that access to food markets reflects broader geographic and economic inequalities and plays a relevant role in shaping food security outcomes. Despite limitations related to incomplete and spatially heterogeneous market data coverage, this framework provides a scalable, data-driven approach for identifying relative structural market accessibility gaps, supporting equitable infrastructure planning and spatially informed food security analyses across diverse African contexts.
Clear aligner therapy has expanded substantially in mixed dentition, yet the boundaries of clinical predictability across indications, movement types, and growth stages remain incompletely defined. The aim of this review was to synthesize evidence on clear aligner therapy in mixed dentition, describe indication-specific performance patterns, and identify evidence gaps that limit clinical confidence. This scoping review was reported in accordance with PRISMA-ScR. PubMed/MEDLINE, Embase, and Scopus were systematically searched for studies published from 2000 to 2025. Additional records were identified through Google Scholar and reference list searching. Randomized controlled trials, prospective and retrospective cohorts, and cross-sectional studies were eligible. Data were charted and synthesized descriptively. Fifty-nine studies were included (8 randomized controlled trials, 11 prospective cohorts, 38 retrospective cohorts, 2 cross-sectional), most involving children aged 7 to 12 years. Achieved transverse dentoalveolar expansion with clear aligners was lower than planned, particularly posteriorly and at gingival levels. Comparative studies suggested greater posterior and palatal changes with rapid maxillary expansion. Mandibular advancement aligners were associated with Class II sagittal improvement, with responses varying by skeletal maturity and dentoskeletal pattern. Evidence for incisor correction, molar movement, vertical outcomes, airway, oral health, patient-reported outcomes, and smile esthetics remained limited. Clear aligners in mixed dentition demonstrate indication-dependent predictability influenced by movement type, anatomical region, and growth stage. Clinical confidence remains limited by retrospective evidence, heterogeneous outcome measures, and insufficient standardized reporting of post-treatment stability.
Urban transport affordability remains a major policy concern in rapidly urbanizing Sub-Saharan African cities. Despite extensive theoretical work on transport economics, empirical evidence quantifying structural determinants of perceived public transportation cost in secondary African cities remains limited. This study examined the association between economies of scale, road maintenance and upkeep, fuel and energy subsidy, and fare infrastructure integration on perceived public transportation cost in Adama City, Ethiopia. A cross-sectional study was conducted among transport associations, driver training institutions, and regulatory officials (n = 181; response rate 88%). Data were analysed using multiple linear regression. The regression model was statistically significant (F (4,176) = 63.42, p < 0.001) and explained 59% of the variance in transportation cost (R² = 0.59; adjusted R² = 0.57). Economies of scale showed the strongest inverse association (β = -0.41, p < 0.001), followed by fuel and energy subsidy (β = -0.29, p < 0.01), road maintenance (β = -0.18, p < 0.05), and fare infrastructure integration (β = -0.16, p < 0.05). Structural and policy-level interventions targeting system scale, infrastructure quality, and coordinated fare systems may substantially reduce perceived urban transport costs. The findings contribute empirical evidence from Ethiopia to the broader literature on urban transport economics.
Radiotherapy remains a cornerstone for non‑small cell lung cancer (NSCLC). However, its efficacy is frequently limited by radioresistance, a phenomenon closely associated with cancer stem-like cells (CSCs). Although our previous work demonstrated that epicatechin (EC) sensitizes NSCLC cells to ionizing radiation (IR), whether this effect involves modulation of CSCs and the underlying mechanisms remain to be elucidated. A radioresistant NSCLC cell line (A549RR) was established via fractionated irradiation and employed in both in vitro assays and murine xenograft models. To assess its radiosensitizing potential, EC was administered prior to IR exposure. Cell viability and colony formation capacity were measured to evaluate radiosensitivity. Putative targets of EC were predicted using network pharmacology and validated through molecular docking. The direct interaction between EC and CXCL8 was examined by cellular thermal shift assay (CETSA). The functional relevance of CXCL8 in EC-mediated effects was assessed through both loss-of-function (shRNA-mediated knockdown) and gain-of-function (CXCL8 overexpression) approaches. CSC properties were evaluated by tumor sphere formation assays and immunoblotting for stemness markers. EC significantly enhanced NSCLC radiosensitivity both in vitro and in vivo, concomitant with marked suppression of CSC stemness. CXCL8 was identified as a direct functional target of EC: its expression was substantially upregulated in radioresistant cells but downregulated upon EC treatment. CETSA confirmed a direct interaction between EC and CXCL8 in cells. Functionally, CXCL8 knockdown suppressed cell viability, colony formation capacity, and CSC properties in A549RR cells. Conversely, overexpression of CXCL8 abrogated EC-induced radiosensitization and restored CSC phenotypes in both cellular and xenograft models. EC overcomes NSCLC radioresistance by directly targeting CXCL8, thereby disrupting CSC-like traits.
Precise quantification of the causative agent of syphilis, Treponema pallidum (T. pallidum) is critical for advancing research in pathogenesis, treatment response, and vaccine development. However, current methods have certain limitations. Dark-field microscopy (DFM) suffers from low sensitivity, poor reproducibility, and strong operator dependence, while quantitative PCR (qPCR) offers high precision but is time-consuming, technically demanding, and reliant on high-quality, consistent commercial reagents. This methodological bottleneck highlights the urgent need for a technique that integrates the speed and simplicity of direct detection with the precision, objectivity, and throughput of an automated assay. Herein, to bridge this gap, we propose a strategy for rapid, high-throughput quantification of T. pallidum using a novel, fluorescence-based flow cytometric assay implemented on an automated urine analyzer (the Sysmex UF-5000 analyzer). The assay demonstrated a limit of detection of 7.02 × 10³T. pallidum/mL and excellent precision (all coefficients of variation < 20%). It showed strong quantitative agreement with qPCR across a wide dynamic range (4.98 × 103-2.10 × 107T. pallidum/mL), with an excellent correlation (r = 0.9967), without significant proportional or constant bias (Passing-Bablok slope = 1.003). Bland-Altman analysis confirmed a close agreement (mean difference: -1.14 × 105T.pallidum/mL). In contrast, DFM exhibited substantially higher variability (CVs 15.19-83.52%) and failed to detect low-concentration samples. Operationally, the flow cytometric assay provides results within 30 s per sample at a low consumable cost (approximately $0.35 per test), outperforming DFM in objectivity and throughput and qPCR in both speed and cost-effectiveness. In summary, this novel flow cytometric assay effectively overcomes the historical challenges associated with T.pallidum quantification. This automated, precise, and rapid assay integrates the simplicity of direct detection with the accuracy of molecular quantification, offering a standardized and practical tool to enhance research in syphilis microbiology, pharmacology, and immunology, paving the way for more reproducible and translatable scientific discoveries.
Postoperative stroke can undermine the benefits of endovascular stenting for cerebrovascular stenosis. This trial investigated whether adjunctive remote ischemic conditioning (RIC) improves cerebral blood flow (CBF) regulation and reduces the risk of postoperative stroke. A total of 104 patients with intracranial or extracranial cerebrovascular stenosis who underwent endovascular stenting were enrolled and randomized to receive either RIC or sham-RIC (1:1). The intervention was administered twice daily for 7 consecutive days postoperatively. CBF regulation was assessed bilaterally using transfer function analysis of spontaneous blood pressure and CBF oscillations at baseline and on day 7 or at discharge. The primary outcomes were phase difference (PD) and gain, whereas the secondary outcomes were 90-day stroke incidence and safety. Significantly higher PD values were observed in the RIC group than in the sham-RIC group on the affected side (40.67° [26.76°-58.28°] vs. 20.51° [10.90°-41.73°], P < 0.001) and the unaffected side (36.04° [21.66°-54.53°] vs. 26.80° [11.94°-44.83°], P = 0.022), indicating improved CBF regulation. Intragroup comparisons revealed significant PD improvement from baseline to day 7 or discharge in the RIC group (affected side: 20.57° [8.70°-34.24°] vs. 40.67° [26.76°-58.28°], P < 0.001; unaffected side: 26.06° [8.70°-44.37°] vs. 36.04° [27.66°-54.53°], P = 0.001). The 90-day stroke incidence was significantly lower in the RIC group (0.00% vs. 9.62%, P = 0.022). Adjunctive RIC safely enhanced CBF regulation and substantially reduced postoperative stroke in patients after cerebrovascular stenting, suggesting a promising non-pharmacological strategy to improve outcomes. This trial was registered at ClinicalTrials.gov (NCT05970653).
Phosphorylation is one of the most prevalent and dynamic post-translational modifications. It regulates aspects of cellular signaling, metabolism, and disease progression. Comprehensive characterization of phosphoproteins and their phosphorylation remain analytically challenging due to their low abundance, the dynamic nature of the phosphorylation, substoichiometric modification levels, and the complexity of biological matrices. However, recent advancements in enrichment strategies have substantially increased the depth and precision of phosphoproteomics analyses using mass spectrometry. Strategies such as immobilized metal ion affinity chromatography and metal oxide affinity chromatography refine the selective isolation of phosphorylated peptides from complex mixtures. Emerging materials, such as advanced metal nanoparticles, MXenes, and carbon-based nanostructures, are increasingly being used in phosphoproteomics enrichment due to their inherent features such as high surface areas, easily tunable surface chemistry, and strong structural stability, which provide enhanced enrichment efficiency and selectivity. Here, we outline strategies and innovations in phosphoprotein enrichment materials in quantitative proteomics MS platforms.
Mental health conditions such as depression, anxiety, and stress are commonly assessed using self-reported questionnaires and limited wearable physiological measures. However, reliance on subjective reporting, restricted sensor modalities such as heart rate variability and electrodermal activity, and small or homogeneous datasets may limit generalizability. We aimed to evaluate whether wearable optical sensing of microcirculation and tissue metabolism enables objective assessment of stress-related mental health states. We conducted a prospective observational study including 132 adults aged 18 to 94 years (58% female) from 19 countries. Participants underwent repeated fingertip measurements using a non-invasive wearable device combining laser Doppler flowmetry and fluorescence spectroscopy to capture microvascular perfusion and metabolic signals. Frequency-domain features were extracted using wavelet analysis. Depression, anxiety, and stress levels were assessed using a standardized 21-item questionnaire. Multiple machine learning models were evaluated under subject-wise validation, and model interpretability was assessed using Shapley-based feature attribution. Here we show that ensemble-based models distinguish individuals with stress-related symptoms from those without with a receiver operating characteristic area under the curve of 0.72 and a precision-recall area under the curve of 0.89 under subject-wise validation. Microcirculatory variability and metabolic fluorescence features contribute substantially to prediction performance. Demographic variables, including sex, age, body mass index, and heart rate, are associated with increased stress-related risk. Wearable optical sensing combined with interpretable machine learning provides physiological signatures associated with stress-related mental health conditions. This framework supports development of scalable and data-driven tools for objective mental health monitoring. Mental health problems such as stress, anxiety, and depression affect millions of people worldwide. These conditions are usually assessed using questionnaires, which rely on how people describe their own feelings. In this study, we explore whether a wearable device can help measure mental health using physical signals from the body. The device records small changes in blood flow and tissue activity from the fingertip. We collected data from 132 adults across 19 countries and compared these signals with mental health questionnaire results. We found that patterns in blood flow and tissue activity are linked to stress-related symptoms. This approach may help develop new tools for simple, non-invasive mental health monitoring in everyday life.
Plastic waste from healthcare is an increasing environmental challenge, particularly in resource-intensive clinical pathways such as dialysis. Peritoneal dialysis (PD) generates large quantities of single-use plastic materials, making its waste stream a priority for sustainable intervention. Conventional disposal through incineration contributes substantially to greenhouse gas emissions (GHG) and produces hazardous ash. Pyrolysis, a chemical recycling process that converts mixed plastic waste into usable outputs, has been proposed as a lower-carbon alternative. This study aimed to estimate the change in GHG emissions and key environmental co impacts if a hospital nephrology service were to switch its PD plastic waste treatment from incineration to pyrolysis. A comparative life cycle assessment (LCA) was conducted for the management of 1 kg of plastic waste from PD. OpenLCA modelling with established life cycle inventory datasets was used to quantify environmental impacts across multiple categories. Two scenarios were assessed: full incineration and a combined system in which pyrolysis was used with a 10% residual fraction sent to incineration. Impact categories included climate change, freshwater ecotoxicity, marine eutrophication, human toxicity, mineral resource use and water consumption. Sensitivity Analysis were also undertaken. The combined pyrolysis system with 10% residual incineration generated a net climate change impact of -0.230 CO₂e per kg of healthcare plastic waste managed, compared with +1.996 CO₂e per kg under full incineration. Across all sixteen environmental impact categories assessed, the pyrolysis pathway demonstrated lower impacts than conventional incineration. Pyrolysis generated net environmental credits in seven categories, including climate change, non-renewable energy use, freshwater eutrophication and photochemical oxidant formation. Pyrolysis shows clear potential as a lower-carbon alternative for managing plastic waste from PD and could support efforts to align clinical waste management with broader sustainability goals. Despite these environmental advantages, economic constraints and differing national regulations currently limit widespread adoption. The findings indicate that pyrolysis may play an important role in reducing the environmental burden of plastic waste in high-volume clinical services. Further work is needed to evaluate the operational feasibility of this approach and to position pyrolysis within a wider set of sustainable waste management strategies.
This chapter summarizes the current knowledge on the practical, methodological, and interpretative aspects of applying metaproteomics in water biotechnology. We outline the full metaproteomic workflow-from sampling and protein extraction to LC-MS/MS acquisition, database construction, quantitative analysis, and bioinformatic interpretation-and emphasize critical considerations specific to complex matrices such as EPS-rich biofilms, granular sludge, and low-biomass drinking water. Case studies illustrate how metaproteomics can clarify mechanisms of micropollutant degradation, nitrogen-transforming pathways, biofilm functional architecture, and microbial resilience under operational stress. Recent advances in data-independent acquisition, metagenome-informed databases, and integrative multi-omics are shown to substantially improve depth, reproducibility, and functional resolution. Finally, we discuss emerging applications in wastewater-based epidemiology, where metaproteomics complement nucleic-acid-based surveillance by enabling the detection of large biomolecule biomarkers of population health and industrial activity. Although metaproteomics is already being applied across a wide range of water cycle contexts and is producing promising, robust results, several challenges, including limitations in analytical chemistry, database completeness, and bioinformatics workflows, continue to hinder its broader implementation. Continued technical research and innovation are therefore essential to fully unlock its potential in water biotechnology.
Our understanding of the influence of ancestral background on genetically determined expression remains limited, especially when gene expression models are applied to studies from different or multiple populations. We perform transcriptome-wide association studies of 6 psychiatric conditions, leveraging gene expression models trained in cohorts with different proportions of African, European, and Indigenous American genetic ancestries. For comparison, we repeat each transcriptome-wide association study using a model trained in individuals of predominantly European ancestry. We identify 1416 statistically significant gene-level associations (false discovery rate adjusted p < 0.05) across the 6 diagnoses, of which 62% are uniquely detected by the admixed gene models. Notably, we observe high correlation (ρ>0.92) in the gene-level effects on disease risk across ancestries, a statistic that remains robust for results that only reach statistical significance in one population. The genes identified by the admixed models implicate more neurophysiological features (as measured by brain imaging) associated with diagnostic symptoms. Overall, admixed gene expression models greatly extend the yield of transcriptome-wide association studies and substantially enhance validation, enabling more precise mapping of genetic effects to underlying pathophysiological mechanisms and highlighting potential avenues for therapeutic development.
Embankment-related roadway departure crashes pose significant safety risks due to slope geometry, vehicle instability, and elevated impact forces, yet limited research addresses how injury mechanisms vary across roadway environments and over time. This study examines embankment-related crash severity using Texas Crash Records Information System (CRIS) data from 2021 to 2024, employing a hybrid framework combining Random Parameters Logit models with Heterogeneity in Means (RPLHM), partially constrained temporal stability testing, and Natural Language Processing (NLP) based narrative analysis. The framework captures persistent and time-varying effects of roadway geometry, environmental conditions, crash characteristics, and driver attributes across three severity outcomes: no injury, possible/non-incapacitating injury, and fatal/incapacitating injury. Results reveal that roadway alignment, lighting conditions, fixed-object involvement, and occupant protection consistently shape severity, while heterogeneity in geometric and environmental factors indicates strong context-dependent risk patterns. Curved alignments and certain roadway environments increase the likelihood of severe injury, whereas seatbelt use substantially increases the probability of non-injury, though its protective effect varies across contexts. Temporal analyses show that while several determinants remain stable, selected parameters exhibit year-specific variation. Narrative topic modeling highlights recurring mechanisms involving loss of control, slope interaction, and environmental influences. These findings underscore that uniform countermeasures are insufficient and emphasize, the need for context-specific roadside design, slope treatment, speed management, and occupant protection strategies.
Infants with cleft lip and/or palate (CL/P) may experience feeding difficulties that place them at increased risk of growth faltering. However, data comparing anthropometric outcomes between infants with CL/P and non-cleft infants in Indonesia remain limited. This study aimed to compare anthropometric indicators of undernutrition between infants with CL/P and infants without craniofacial anomalies evaluated at the same hospital. This cross-sectional study included 174 infants aged <1 year (87 with CL/P and 87 without craniofacial anomalies). Anthropometric data were obtained from electronic medical records at a single cleft center and the paediatric department of the same hospital. Length-for-age z-scores (LAZ) and weight-for-length z-scores (WLZ) were calculated according to World Health Organization (WHO) Child Growth Standards. Stunting was defined as LAZ <-2 standard deviations (SD), and wasting as WLZ <-2 SD. Associations between CL/P and anthropometric status were analysed using χ² tests. The mean age was 6.0 ± 3.9 months in the CL/P group and 5.6 ± 2.6 months in the comparison group. Infants with CL/P had a significantly higher prevalence of stunting than infants without craniofacial anomalies (52.9% vs. 5.7%; P < 0.001). No significant difference was observed in wasting between the groups (2.3% vs. 2.3%; P = 0.069). Anthropometric status was not associated with cleft type (P = 0.989). Infants with CL/P demonstrated a substantially higher prevalence of stunting, an indicator of chronic growth restriction, whereas wasting, an indicator of acute undernutrition, did not differ between groups. These findings suggest that growth deficits in infants with CL/P may accumulate gradually over time rather than manifest primarily as acute nutritional deterioration. Infants with CL/P may be vulnerable to chronic growth restriction during early life. Strengthening early feeding assessment, nutritional surveillance, caregiver education, breastfeeding support, and multidisciplinary cleft care may help reduce growth faltering and improve outcomes.
Pathological scars are characterized by persistent fibroblast activation and excessive extracellular matrix (ECM) deposition. Although oxidative stress and dysregulated NRF2 signaling contribute to TGF-β1-mediated fibrosis in internal organs, their roles in cutaneous pathological scarring remain unclear. Secretome-based cell-free therapies have shown regenerative and antifibrotic potential, but whether lipoaspirate-derived secretome can restore fibroblast redox homeostasis and thereby attenuate pathological scarring is unknown. Lipoaspirate fluid obtained during standard tumescent liposuction was processed by 100-kDa ultrafiltration to generate lipoaspirate-derived secretome (LA), while secretome from adipose-derived stromal cell (ADSC) culture supernatant served as a comparator (CS). LA and CS were characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting for EV markers. In vivo efficacy was evaluated in a rabbit ear scar model with weekly intradermal LA injection, followed by gross, histological, collagen, and qPCR assessments. Comparative proteomic profiling of LA and CS was performed using data-independent acquisition LC-MS/MS with enrichment analysis, and paired human scar and normal skin samples were analyzed by single-cell RNA sequencing. In vitro, TGF-β1-stimulated fibroblasts were treated with LA or CS, and NRF2 involvement was assessed using the inhibitor ML385 or Nrf2-targeting siRNA. Redox balance, NRF2 signaling, and profibrotic responses were assessed by fluorometric assays, qPCR, and immunoblotting. LA showed a substantially higher particle yield than CS and contained abundant extracellular vesicles. Weekly intradermal LA injections reduced scar formation and improved collagen organization in the rabbit ear model. Comparative proteomics of LA versus CS highlighted cytoprotective pathways, including glutathione metabolism and NRF2-associated antioxidant signaling. Analyses of human scar tissues revealed elevated NOX4 expression, increased 4-HNE, and impaired NRF2-associated antioxidant signaling in scar fibroblasts. In vitro, both LA and CS attenuated TGF-β1-driven profibrotic fibroblast activation, whereas LA showed greater antioxidant activity, including stronger suppression of oxidative stress-related responses and improved GSH/GSSG balance. Pharmacological inhibition and genetic silencing of NRF2 partially reversed the antioxidant and antifibrotic effects of LA. Lipoaspirate-derived secretome (LA) is a clinically accessible cell-free therapeutic candidate for pathological scarring. LA restores redox homeostasis, in part through NRF2-associated antioxidant signaling, attenuates TGF-β1-driven profibrotic fibroblast activation, and improves scar remodeling in vivo. These findings support LA as a promising cell-free strategy for attenuating pathological scar formation.
Species elevational shifts are well-documented responses to climate change, with many moving upslope to track suitable conditions. However, these shifts can vary considerably in both direction and rate, and the underlying causes of this variability are not well understood. This study examines how elevational shifts depend on geographical zones along with species' climatic niches, global prevalence, and evolutionary history by analyzing paired lower and upper edge shifts across 845 plant and animal species records worldwide. We find distinct effects of these drivers on upper versus lower distribution limits. Tropical species experienced more rapid upward shifts of their lower edges than did temperate species. Species with warmer and wetter optimal climatic niches displayed faster upper-edge shifts, while those only with wetter ones showed more rapid lower-edge shifts. Globally prevalent species expanded their distributions with climate change by combining faster upper-edge advances with slower lower-edge contractions, likely reflecting their drier climatic adaptation. Importantly, these ecological effects overlapped substantially with phylogenetic effects, and phylogenetic conservatism independently explained a notable portion of the variation in elevational responses. These findings highlight the complexity of evolutionary history and ecological processes in shaping species' climate responses and underscore the climate vulnerability of some species due to their evolutionary inertia.
Semilocal density functionals such as the Perdew-Burke-Ernzerhof (PBE) functional substantially underestimate experimental band gaps. Hybrid functionals address this band gap problem by admixing a fraction of Fock exchange to semilocal exchange. The optimal mixing parameter depends on the specific material and can be identified as the inverse dielectric constant (dielectric-dependent hybrid functional, DDH). Here, we show that dielectric constants obtained using the r2SCAN meta-GGA functional are significantly more accurate than dielectric constants obtained using the semilocal PBE functional. We propose the DD-r2SCANH functional, a dielectric-dependent hybrid functional based on r2SCAN. DD-r2SCANH can outperform the standard PBE-based DDH in terms of band gaps and other electronic structure properties. Particularly marked improvements are obtained for narrow-gap semiconductors such as Ge and InAs, where PBE wrongly predicts a metallic phase, but r2SCAN opens a band gap.
The roles of Contactin-2 (CNTN2) and ferroptosis in heart failure and cardiac remodeling remain incompletely understood. CNTN2 was significantly upregulated in hypertrophic cardiomyopathy patients and heart failure mice. In cardiomyocyte specific CNTN2 conditional knockout (CNTN2 cKO) mice, transverse aortic constriction (TAC) induced markedly exacerbated heart failure, cardiac remodeling and ferroptosis compared to control mice. Ferroptosis inhibition substantially attenuated heart failure in CNTN2 cKO mice subjected to TAC, indicating that enhanced ferroptosis contributes to the detrimental effects of CNTN2 deficiency. RNA sequencing identified NUPR1, a ferroptosis repressor, as a downstream molecule of CNTN2. Mechanistically, CNTN2 activated the Lyn/eIF2α/ATF4 pathway to regulate NUPR1. CNTN2 overexpression attenuated Angiotensin II-induced cardiomyocyte ferroptosis and pathological remodeling, whereas these protective effects were abolished by Lyn or NUPR1 inhibitors. We further revealed CNTN2 and Lyn interacted with each other, and that CNTN2 interacted with Lyn through its 1-328aa domain. In vivo NUPR1 overexpression via AAV9 significantly mitigated TAC-induced heart failure and cardiac remodeling in CNTN2 cKO mice. Our study demonstrates that CNTN2 protects against pressure overload induced heart failure and cardiac remodeling by regulating ferroptosis through the Lyn/eIF2α/ATF4/NUPR1 pathway, suggesting CNTN2 as a potential therapeutic target.
Compression garments are commonly designed using elongation-based pattern reduction, but the validity of this approach under controlled static wearing conditions remains insufficiently verified. This study examined whether upper-arm sleeves designed from tensile elongation properties produced consistent compression responses during wear. Three knitted PET/PU fabrics with distinct structural characteristics were tested in wale, course, and bias directions, and 27 sleeve conditions were fabricated using single-layer, identical-material double-layer, and hybrid-material double-layer configurations. Clothing pressure, tissue viscoelastic response (frequency), and perceived compression were assessed. Despite the use of the same elongation-based design logic, compression responses varied substantially with fabric directionality and layering configuration. Bias-direction and several double-layer conditions produced excessive compression or non-wearable states. Layered structures showed nonlinear pressure amplification, indicating that compression was not governed by simple additive or linear effects. Although clothing pressure, tissue response, and perceived compression were generally associated, their magnitudes and rankings were not consistently aligned across conditions. These findings indicate that elongation-based pattern reduction alone may not ensure uniform compression in knitted compression sleeves and suggest the need for an integrated design framework that considers fabric anisotropy, layering structure, tissue response, and wearer perception.
Standing sedation is frequently required in donkeys for minor surgical and diagnostic procedures, yet information on the cardiac safety of α2-adrenoceptor agonists and opioid combinations in this species is limited. This study evaluated the echocardiographic effects of intravenous medetomidine, butorphanol, and their combination in clinically healthy donkeys. Sixty donkeys were randomly assigned to four groups (n = 15/group) to receive intravenous saline (control group, CG), medetomidine group (10 µg/kg, MG), butorphanol group (50 µg/kg, BG), or medetomidine-butorphanol group (10 µg/kg + 50 µg/kg, MBG). Butorphanol was administered 5 min after medetomidine in the MBG. M-mode echocardiography was performed from a right parasternal short-axis view at baseline and at 5, 15, 30, 45, 60, 90, and 120 min after treatment. Left ventricular internal diameter (LVID), interventricular septal thickness (IVST), and left ventricular posterior wall thickness (LVPW) were measured at end-diastole (d) and end-systole (s). Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), stroke volume (SV), ejection fraction (EF%), and fractional shortening (FS%) were calculated. Data were analyzed using a repeated-measures general linear model. Medetomidine alone was associated with significant reductions in EF% and FS%, together with significant changes in LVIDs and LVIDd. SV was also significantly lower in the medetomidine group than in the control group during the main post-treatment period; however, SV and the calculated LV volumes were interpreted cautiously because they are load-dependent variables derived from linear M-mode measurements. These changes were accompanied by an increase in LVIDs and a reduction in IVSs, indicating transient depression of conventional left ventricular systolic indices and altered loading conditions. Butorphanol alone produced only minor, parameter-specific changes in LVID, IVST, and most echocardiographic indices, with no consistent clinically relevant deterioration compared with baseline or the CG. In contrast, the MBG showed marked changes in ventricular dimensions and calculated indices from 15 to 60 min; however, these findings were interpreted cautiously because the calculated systolic indices are load-dependent. Intravenous medetomidine, butorphanol, and their combination exert distinct and protocol-dependent effects on left ventricular dimensions and systolic function in donkeys. Medetomidine alone substantially and transiently depresses systolic performance, whereas butorphanol alone is comparatively cardiovascular-sparing. The medetomidine-butorphanol combination may be considered for standing sedation in clinically healthy donkeys; however, its echocardiographic effects should be interpreted cautiously as load-dependent changes, and cardiovascular monitoring remains advisable.