National Health Research Institutes

We present apoCHARMM, a high-performance molecular dynamics (MD) engine optimized for graphics processing unit (GPU) architectures, designed to accelerate the simulation of complex molecular systems. The distinctive features of apoCHARMM include single-GPU support for multiple Hamiltonians, computation of a full virial tensor for each Hamiltonian, and full support for orthorhombic periodic systems in both P1 and P21 space groups. Multiple Hamiltonians on a single GPU permit rapid single-GPU multi-dimensional replica exchange methods, multi-state enveloping distribution sampling methods, and several efficient free energy methods where efficiency is gained by eliminating post-processing requirements. The combination of these capabilities enables constant-pH molecular dynamics in explicit solvent with enveloping distribution sampling, where Hamiltonian replica exchange can be performed on a single GPU with minimal host-GPU memory transfers. A full atomic virial tensor allows support for many different pressure, surface tension, and temperature ensembles. Support for orthorhombic P21 systems allows for the simulation of lipid bilayers, where the two leaflets have equalized chemical potentials. apoCHARMM uses CUDA and modern C++ to enable efficient computation of energy, force, restraint, constraint, and integration calculations directly on the GPU. This GPU-exclusive design focus minimizes host-GPU memory transfers, ensuring optimal performance during simulations, with such transfers occurring only during logging or trajectory saving. Benchmark tests demonstrate that apoCHARMM achieves competitive or superior performance when compared to other GPU-based MD engines, positioning it as a versatile and useful tool for the molecular dynamics community.

Electron signaling and oxygen level are vital for regulating neural‐cell fate and brain recovery. However, clinical challenges arise from the short half‐life and the difficulty of spatiotemporally controlled oxygen release and electric signals. In this study, a wireless‐charging sustained oxygen release from conductive microgels (SOCO) served as an antenna and an on‐demand O2 release for nerve regeneration is developed. Introducing “electromagnetic messenger”, using external alternating magnetic field (AMF) to enhance catalytic oxygen release and electrical stimulation to promote the reconstruction of blood vessels and neurons in vivo. SOCO also reduces TBI glial scarring by reducing activated microglia and stellate cells, promoting infiltration of new neurons. In whole‐brain analyses, effective somatostatin (Sst) production inhibits gamma‐aminobutyric acid (GABA) synthesis in injured areas, thereby improving brain function and behavioral recovery. Furthermore, spatial multiomics combined with single‐cell deconvolution analysis reveals the treatment reprogramming in vivo brain transcriptome of angiogenic markers (Il1a, Lgals3) and GABAergic pathway via modulation of GAD65/67 activity, guiding angiogenesis and neuronal regeneration. This in situ catalytic SOCO with noncontact AMF presents an “electromagnetic messenger”‐based therapeutics for reprogramming the neuro‐regeneration and brain function recovery in TBI.

Background We assessed the associations of visceral adiposity indexes such as Chinese Visceral Adiposity Index (CVAI), Visceral Adiposity Index (VAI), Lipid Accumulation Product (LAP), waist circumference (WC), and waist-hip ratio (WHR) with overall and specific cancer incidence in a Chinese population. Methods 332,297 individuals from the Taiwan MJ cohort (1996–2007) were included. We utilized multivariable Cox proportional hazards models to examine associations of baseline visceral adiposity indexes and cancer incidences. Sex-specific CVAI, VAI, and LAP were calculated, incorporating WC and triglycerides levels. CVAI and VAI also included body mass index and high-density lipoprotein, with CVAI further incorporating age. Results Higher CVAI was consistently associated with higher overall cancer incidence, with HRs of 1.45 (95% CI: 1.2–1.76) and 2.03 (95% CI: 1.52–2.72) for males and females, respectively, comparing the fifth quintile to the first. The HRs for WC were 1.27 (95% CI: 1.08–1.49) and 1.19 (95% CI: 1.01–1.40) for males and females, WHR was significantly associated with cancer risk in males (HR:1.28; 95% CI: 1.13–1.45), and LAP was significantly associated with cancer risk in females (HR: 1.25; 95% CI: 1.04–1.5). VAI was not associated with overall cancer incidence. Discussion CVAI is a superior clinical biomarker for predicting cancer incidence in the Chinese population compared to traditional visceral obesity indices.

Although the harmful health effects of childhood adversity have been a public health focus, the sensitive periods for its impact on different aspects of health outcomes in adolescence are unknown. We aimed to examine the effects of the timing of experiencing childhood household dysfunction on general health and depression in adolescence. Data were obtained from the Taiwan Birth Cohort Pilot Study (TBCS-P), and respondents with surveys completed from birth to 15 years were included as study participants. The primary independent variable was the timing of exposure to childhood household dysfunction with four categories– early (age 3–5), late (age 8–12), chronic, and never. The dependent variables were general health and depression at age 15. Approximately 40% of children experienced household dysfunction before age 12. Individuals exposed to childhood household dysfunction were more likely to have poor health and higher levels of depressive symptoms than those who had never experienced it. Across the timing of exposure to household dysfunction, children in the early (OR = 1.64, 95% CI = 1.09–2.49) group had the worst general health at age 15. Moreover, experiencing household dysfunction in late childhood was associated with the greatest depression scores (β = 0.62, p = 0.063), despite not reaching significance. Household dysfunction in childhood has long-term adverse effects on health in adolescence, emphasizing with early and late childhood as particularly sensitive periods for the impacts of household dysfunction on health and depression, respectively. Preventing household dysfunction in childhood and mitigating its impact are needed to ensure healthy development throughout life.

Air pollution is a risk factor for many cancers. However, the effect of air pollution on the risk of pancreatic cancer (PCA) and cholangiocarcinoma (CCA) in Taiwanese patients with remains unclear. This cross‐sectional study recruited 370 patients who were tested for serum hepatitis B surface antigen (HBsAg) and hepatitis C virus (anti‐HCV) in 2020. The diagnosis of PCA and CCA diagnosis was based on pathology. Daily estimates of air pollutants were aggregated into mean estimates for the previous year based on the date of recruitment or PCA and CCA diagnosis. Out of 370 patients, 16 patients had PCA (4.3%) and 18 patients had CCA (4.9%). The patients with PCA and CCA were older (73.4 years vs. 50.9 years; p < .001) and lived in areas with higher levels of PM 2.5 (19.3 μg/m ³ vs. 18.2 μg/m ³ ; p = .03). Logistic regression analysis revealed that the factors associated with PCA and CCA were age (Odd ration [OR]: 1.09; confidence interval (CI): 1.06–1.13; p < .001) and PM 2.5 (OR: 1.33; CI: 1.00–1.76; p = .05). The best cut‐off value for PM 2.5 level associated with PCA and CCA was 18.7 μg/m ³ (AUROC, 0.63; p = .01). We defined high level of PM 2.5 as 20 μg/m ³ . We put PM 2.5 >20 μg/m ³ and age >50 years as a covariant and logistic regression analysis revealed that the factors associated with PCA and CCA were age >50 years (OR: 24.77; CI: 3.29–86.10; p = .002) and PM 2.5 >20 μg/m ³ (OR: 2.98; CI: 1.30–6.83; p = .01). In this study, we demonstrated that PM 2.5 were associated with PCA and CCA occurrence.

Objective To investigate the levels of anxiety and depression (A&D) and the association with knowledge, attitudes, and practices among healthcare professionals (HCPs) in Taiwan, Indonesia, and Vietnam. Methods A multinational cross-sectional survey was performed to collect data from 3,556 HCPs through online platforms. The Likert scale questionnaire covered sociodemographic factors, work-related information, and COVID-19-related domains, including knowledge, attitudes, practices, working conditions and availability of personal protective equipment, changes in work and life routines due to the COVID-19 pandemic, and experiences of A&D. Multiple logistic regression models were used to evaluate the potential impact of the aforementioned domains on the levels of A&D across and between countries. Results Distinct A&D profiles emerged among the three countries. Taiwan exhibited higher A&D scores (average 2.31) than Vietnam (1.61) and Indonesia (1.93) (p < 0.001). Taiwan also showed elevated knowledge and attitudes scores. Consistent patterns were observed in responses on practices, working conditions, and pandemic impact on daily routines. Multivariate analysis showed that higher knowledge and attitudes scores were significantly associated with reduced A&D risk in Taiwan. Experiencing the greatest changes in work and daily routines was strongly linked to higher A&D risk, with adjusted odds ratios of 3.64 (95% CI: 1.41–9.45) in Indonesia, 4.13 (95% CI: 2.96–5.75) in Taiwan, and 5.14 (95% CI: 3.18–8.31) in Vietnam. Further analysis revealed that factors such as transportation, work dynamics, family time, dietary habits, and income level, but not leisure time, had varying impacts on A&D across the three countries. Conclusion A&D and COVID-19-related knowledge, attitudes, and practices vary across countries. Thus, personalized support mechanisms and interventions are needed to address the diverse needs of HCPs within specific policy and country contexts.

This study integrates an analysis of Google Trends data on divorce search volumes, Google Location History to assess stay-at-home behavior, and COVID-19 death rates from March 2020 to October 2022 across 45 countries. Using causal mediation analysis, we examined the mediating role of stay-at-home behavior on the impact of pandemic severity on divorce-related searches. Findings indicate a significant relationship between COVID-19 death rates and reduced divorce searches during the first two years, with no mediation by stay-at-home behavior. In the third year, stay-at-home behavior began significantly mediating an increase in divorce searches, especially pronounced in high-income countries. These results highlight the evolving societal responses to the pandemic and underscore the importance of adaptable support strategies in the face of changing marital dynamics during public health crises.

Excessive caloric intake and reduced energy expenditure contribute to obesity and localized fat accumulation, adversely affecting overall health. Despite advancements in obesity treatments, noninvasive approaches for targeted fat reduction remain limited. This study introduces a novel sonosensitizer microparticle, cerium-doped calcium carbonate (CaCO3:Ce), and evaluates its potential application in combination with low-intensity ultrasound (LIUS) for noninvasive body sculpting. CaCO3:Ce was synthesized via an environmentally friendly method, producing uniform 1.77 μm particles optimized for endocytosis. Energy-dispersive X-ray and X-ray photoelectron spectroscopy confirmed successful cerium doping. The particles demonstrated excellent biocompatibility and generated reactive oxygen species under LIUS exposure. Safety was validated through biochemical, hematological, and histological analyses in Sprague–Dawley rats. Animal experiments further revealed that CaCO3:Ce combined with ultrasound significantly reduced body weight growth rates, waistline measurements, and subcutaneous fat accumulation. These findings suggest that CaCO3:Ce, coupled with LIUS, offers a promising, noninvasive, and low-risk strategy for body sculpting, addressing limitations of current methodologies. Graphical abstract

Sarcoidosis is a multisystem inflammatory disease of unknown etiology. Growing evidence indicates that occupational exposure to respirable crystalline silica (RCS) is associated with an increased incidence of sarcoidosis. Yet a diagnosis of sarcoidosis rarely prompts investigation to identify preventable exposures. We sought to elucidate features that identify this important clinical syndrome of silicosarcoidosis. We assembled a multinational case series of workers with sarcoidosis who also reported occupational RCS exposure. We characterized clinical and histopathologic findings using a standardized instrument. We also assessed lung specimens using a novel quantitative microscopy technique to measure birefringent dust density in silicosarcoidosis cases and compared them to control groups. We identified 35 silicosarcoidosis cases (97% male, mean age 48 years) from the United States, Israel, and Taiwan who reported 21 ± 9 years of RCS exposure. On histology scoring, 25/29 (86%) had granulomas and 17/18 (94%) with evaluable lung tissue had lymphocytic inflammation and/or lymphoid aggregates. Common lung interstitial findings included silicotic nodules (39%), mixed‐dust macules/nodules (44%), and birefringent dust (50%). Quantitative birefringent dust density was significantly greater ( p < 0.001) in silicosarcoidosis cases compared with healthy controls (147 ± 179 vs. 12 ± 9 particles/mm ² ) but lower than in coal miners with silica‐related progressive massive fibrosis (623 ± 777). We found significant differences in the frequency of histologic abnormalities in large versus small biopsy specimens, with fewer findings of RCS exposure in smaller tissue samples. The use of the term silicosarcoidosis should enhance recognition of this significant exposure‐related granulomatous lung disease and will help guide clinical management that addresses exposure prevention in combination with appropriate pharmacologic treatment.

Objectives The benefit of high-dose trimethoprim/sulfamethoxazole (trimethoprim component ≥ 8 mg/kg/day) treatment for Stenotrophomonas maltophilia infections remains unclear. We aimed to evaluate the effect of high-dose trimethoprim/sulfamethoxazole treatment on outcomes in patients with S. maltophilia bacteraemia. Patients and methods We conducted a single-centre retrospective cohort study (2004–23) that included patients treated with trimethoprim/sulfamethoxazole for monomicrobial S. maltophilia bacteraemia. The patients were categorized into two groups based on the trimethoprim/sulfamethoxazole dose: high-dose (trimethoprim component ≥ 8 mg/kg/day) and low-dose (trimethoprim component < 8 mg/kg/day) groups for comparison. The primary endpoint was 30-day mortality. Adverse drug events between groups were also compared. Multivariable logistic regression and inverse probability of treatment weighting (IPTW) analysis were performed. Results A total of 143 patients treated with trimethoprim/sulfamethoxazole for S. maltophilia bacteraemia were included: 41 (28.7%) received the high-dose regimen, and 102 (71.3%) received the low-dose regimen. There was no significant difference in 30-day mortality between the high- and low-dose group (39.0% versus 26.5%; P = 0.139). Multivariable regression revealed that high-dose trimethoprim/sulfamethoxazole therapy was not associated with mortality (adjusted OR 1.96, 95% CI 0.75–5.10; P = 0.167) after adjustment. The IPTW-adjusted regression yielded consistent results. More adverse drug events were reported in the high-dose group (31.7% versus 12.7%, P = 0.008). Conclusions High-dose trimethoprim/sulfamethoxazole for S. maltophilia bacteraemia was not associated with improved outcomes while more frequent adverse drug events were observed. The sample size and retrospective design limit the study’s conclusions. Future studies that address these limitations are needed to confirm the results.

N- and C-terminal α-synuclein (α-syn) truncations are prevalent in Parkinson’s disease. Effects of the N- and C-terminal residues on α-syn aggregation and fibril propagation are distinct, where the N-terminus dictates fibril structure. Here, the majority of α-syn truncations are assigned by intact mass spectrometry to lysosomal activity. To delineate essential charged residues in fibril formation, we selected an N-terminal truncation (66–140) that is generated solely from soluble α-syn by asparagine endopeptidase. Ala-substitutions at K80 and E83 impact aggregation kinetics, revealing their vital roles in defining fibril polymorphism. K80, E83, and K97 are identified to be critical for fibril elongation. Based on solid-state NMR, mutational and Raman studies, and molecular dynamics simulations, a E83–K97 salt bridge is proposed. Finally, participation of C-terminal Lys residues in the full-length α-syn fibril assembly process is also shown, highlighting that individual residues can be targeted for therapeutic intervention.

Polygenic scores (PGS) are promising in stratifying individuals based on the genetic susceptibility to complex diseases or traits. However, the accuracy of PGS models, typically trained in European- or East Asian-ancestry populations, tend to perform poorly in other ethnic minority populations and their accuracies have not been evaluated for Native Hawaiians. In particular, for body mass index (BMI) and type-2 diabetes (T2D), Polynesian-ancestry individuals such as Native Hawaiians or Samoans exhibit varied distribution from other continental populations, but are understudied, particularly in the context of PGS. Using BMI and T2D as examples of metabolic traits of importance to Polynesian populations (along with height as a comparison of a similarly highly polygenic trait), here we examine the prediction accuracies of PGS models in a large Native Hawaiian sample from the Multiethnic Cohort with up to 5300 individuals. We find evidence of lowered prediction accuracies for the PGS models in some cases, particularly for height. We also find that using the Native Hawaiian samples as an optimization cohort during training does not consistently improve PGS performance. Moreover, even the best-performing PGS models among Native Hawaiians have lowered prediction accuracy among the subset of individuals most enriched with Polynesian ancestry. Our findings indicate that factors such as admixture histories, sample size, and diversity in GWAS can influence PGS performance for complex traits among Native Hawaiian samples. This study provides an initial survey of PGS performance among Native Hawaiians and exposes the current gaps and challenges associated with improving polygenic prediction models for underrepresented minority populations.

Rap1 is a DNA-binding protein conserved from yeast to mammals for its role in telomeric maintenance. Here, to explore additional functions of Candida albicans Rap1, we performed RNA sequencing analysis. Experimental validations further showed that Rap1 plays a role in iron regulation, especially under low-iron conditions. Moreover, Rap1 was involved in iron acquisition and modulation of iron-related genes. Rap1 was found to be associated with fluconazole resistance in a low-iron condition. Finally, we demonstrated that the deletion of RAP1 leads to reduced C. albicans virulence in a mouse model of infection. Together, this study reveals new functions of C. albicans Rap1, particularly in iron homeostasis, azole resistance, and virulence. IMPORTANCE Candida albicans is an important pathogenic fungus that can cause superficial to life-threatening infections. Iron is essential for almost all organisms, yet it is highly restricted within the human host to defend against pathogens. To grow and survive in the iron-limited host environment, C. albicans has evolved multiple iron acquisition mechanisms. Understanding the regulation of iron homeostasis is, therefore, critical for elucidating C. albicans pathogenesis and virulence. This study explores the novel functions of C. albicans Rap1, with a focus on its contribution to iron acquisition and utilization. Our findings further highlight how iron availability impacts antifungal resistance and virulence through Rap1, providing insight into the complex iron regulatory machinery of C. albicans .