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Chi-Ling Wu,1 Oswald Ndi Nfor,1 Disline Manli Tantoh,1,2 Wen-Yu Lu,1 Yung-Po Liaw1– 3 1Department of Public Health, Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan; 2Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, Taiwan; 3Institute of Medicine, Chung Shan Medical University, Taichung City, TaiwanCorrespondence: Yung-Po Liaw, Department of Public Health and Institute of Public Health, Chung Shan Medical University, No.110 Sec. 1 Jianguo N.Road, Taichung City, Taiwan, Tel +886436097501, Fax +886423248179, Email Liawyp@csmu.edu.twPurpose: Osteoporosis is a degenerative disease that affects women and men of all races. We studied the association between body mass index (BMI), rs2908004 polymorphism of the WNT16 gene, and osteoporosis using data from Taiwan Biobank (TWB).Patients and Methods: We analyzed data from 10,942 subjects aged 30 to 70. We defined osteoporosis based on a mean T-score of − 2.5 and below in the hip. Body mass index was classified following the guidelines of the Health Promotion Administration. Imputation was carried out using the IMPUTE2 (v2.3.1) program. Multiple logistic regression was used for analysis. The odds ratios (ORs) and 95% confidence interval (CI) for osteoporosis were determined.Results: In the multivariate regression model, variant rs2908004 had a significant association with osteoporosis. That is, the rs2908004-GA+AA genotype was associated with lower osteoporosis risk than the GG genotype (OR, 0.651; 95% CI = 0.544 to 0.780). Compared to normal-weight, underweight was significantly associated with a higher risk of osteoporosis (OR, 6.517; 95% CI = 4.624 to 9.186) while overweight and obesity were protective (OR, 0.176; 95% CI = 0.140 to 0.221 and 0.057; 95% CI = 0.039 to 0.083, respectively). There was an interaction between rs2908004 and BMI (p = 0.0148). Subgroup analyses (using rs2908004-GG/normal-weight as the reference group) indicated ORs of 7.66 (95% CI = 5.153 to 11.394) in the rs2908004-GG/underweight group and 3.002 (95% CI = 1.509 to 5.974) in the rs2908004-GA+AA/underweight group (95% CI = 1.509 to 5.974). Odds ratios were substantially lower in rs2908004-GG/obese, rs2908004-GG/overweight, GA+AA/normal-weight, rs2908004-GA+AA/overweight, and rs2908004-GA+AA/obese groups, respectively.Conclusion: According to our study, underweight was associated with an increased risk of osteoporosis irrespective of WNT16 rs2908004 genotypes, while overweight and obesity were associated with a lower risk.Keywords: bone health, SNP, osteoporosis, anthropometric measures

Pang-Li Liu,1 Ming-Yi Hsu,2,3 Chao-Chin Hu,4 Disline Manli Tantoh,5,6 Wen-Yu Lu,6 Oswald Ndi Nfor,6 Yung-Po Liaw5,6 1Department of Medical Sociology and Social Work, Chung Shan Medical University, Taichung, 40201, Taiwan; 2Department of Nursing, Chung Shan Medical University, Taichung, 40201, Taiwan; 3Department of Nursing, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan; 4Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung, 40201, Taiwan; 5Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan; 6Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, TaiwanCorrespondence: Yung-Po Liaw; Oswald Ndi Nfor Tel +886-932-532-370Fax +886-266-369-260Email Liawyp@csmu.edu.tw; nforoswald2@yahoo.comObjective: This study aimed to investigate the association of age and sex with metabolic syndrome (MS) in Taiwanese adults.Methods: We extracted information of 4307 men and 4783 women aged 30– 70 from the Taiwan Biobank.Results: The interaction between age and sex on MS was significant (p-value = 0.0001). After stratification by sex, men and women aged 50– 70 years (reference: 30≤age< 50 years) had a higher risk of MS. The odds ratio (OR), 95% confidence interval (CI) was 2.316, 1.936– 2.772 in men and 3.101, 2.561– 3.754 in women. After stratification by age, men aged 50– 70 years had a lower risk of MS compared to women (OR, 95% CI = 0.713, 0.598– 0.851).Conclusion: The interaction between age and sex on MS was significant. Sex-wise, both men and women aged 50– 70 years had a higher likelihood of MS. Age-wise, men aged 50– 70 years had a lower risk of MS compared to women.Keywords: metabolic syndrome, age, sex, Taiwan Biobank

ChunYan Li,1 ZhiGang Huang,2 ZheShuo Liu,1 LiQian Ci,3 ZhePeng Liu,3 Yu Liu,2 XueYing Yan,1 WeiYue Lu2 1School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, 2Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, 3School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China Abstract: Effective interaction between mucoadhesive drug delivery systems and mucin is the basis of effective local placement of drugs to play its therapeutic role after mucosal administration including vaginal use, which especially requires prolonged drug presence for the treatment of gynecological infectious diseases. Our previous report on phenylboronic acid-rich nanoparticles (PBNPs) demonstrated their strong interaction with mucin and mucin-sensitive release profiles of the model protein therapeutics interferon (IFN) in vitro, but their poor stability and obvious tendency to aggregate over time severely limited future application. In this study, sulfonate-modified PBNPs (PBNP-S) were designed as a stable mucoadhesive drug delivery system where the negative charges conferred by sulfonate groups prevented aggregation of nanoparticles and the phenylboronic acid groups ensured effective interaction with mucin over a wide pH range. Results suggested that PBNP-S were of spherical morphology with narrow size distribution (123.5 nm, polydispersity index 0.050), good stability over a wide pH range and 3-month storage and considerable in vitro mucoadhesion capability at vaginal pH as shown by mucin adsorption determination. IFN could be loaded to PBNP-S by physical adsorption with high encapsulation efficiency and released in a mucin-dependent manner in vitro. In vivo near-infrared fluorescent whole animal imaging and quantitative vaginal lavage followed by enzyme-linked immunosorbent assay (ELISA) assay of IFN demonstrated that PBNP-S could stay in the vagina and maintain intravaginal IFN level for much longer time than IFN solution (24 hours vs several hours) without obvious histological irritation to vaginal mucosa after vaginal administration to mice. In summary, good stability, easy loading and controllable release of protein therapeutics, in vitro and in vivo mucoadhesive properties and local safety of PBNP-S suggested it as a promising nanoscale mucoadhesive drug delivery system for vaginal administration of protein therapeutics. Keywords: mucoadhesion, phenylboronic acid, stability, controlled-release, protein therapeutics, nanoparticles

Xinzhe Yu,1,* Yang Di,2,* Chao Xie,3 Yunlong Song,4 Hang He,2 Hengchao Li,1 Xinming Pu,5 Weiyue Lu,3 Deliang Fu,2 Chen Jin1 1Pancreatic Surgery Department, Huashan Hospital, 2Pancreatic Disease Institute, Fudan University, 3School of Pharmacy & Key Laboratory of Smart Drug Delivery, Fudan University, 4School of Pharmacy, The Second Military Medical University, 5The State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background and objectives: Gemcitabine (Gem) is far from satisfactory as the first-line regimen for pancreatic cancer, and the emergence of albumin nanoparticles offers new hope for the delivery of Gem. In this study, Gem-loaded human serum albumin nanoparticles (Gem-HSA-NPs) were successfully synthesized, characterized, and tested on a BxPC-3 cell line both in vitro and in vivo.Materials and methods: 4-N-myristoyl-gemcitabine (Gem-C14) was obtained first by coupling myristoyl with the 4-amino group of Gem. The Gem-HSA-NPs were then prepared by nanoparticle albumin-bound technology and characterized for particle size, zeta potential, morphology, encapsulation efficiency, drug-loading efficiency, and release characteristics. Using both in vitro and in vivo studies, Gem-C14 and Gem-HSA-NPs were tested on the human pancreatic cancer cell line BxPC-3.Results: Gem-HSA-NPs showed an average particle size of 150±27 nm, and with an encapsulation rate of 82.99%±3.5% and a drug-loading rate of 10.42%±3.5%, they exhibited a favorable controlled- and sustained-release nature. In in vitro, Gem-C14 was equivalent in cytotoxicity to Gem. In in vivo, the Gem-HSA-NPs exhibited the strongest inhibitory effect on tumor growth but the lowest toxicity among the four groups.Conclusion: The enhanced in vivo efficacy of Gem-HSA-NPs toward the pancreatic cancer cell line suggests their potential role for use in the clinical field. Keywords: pancreatic cancer, gemcitabine, albumin nanoparticles, BxPC-3 cell line, in vitro study, in vivo study

Background: Ex vivo lung perfusion (EVLP) is a critical strategy to rehabilitate marginal donor lungs, thereby increasing lung transplantation (LTx) rates. Ischemia-reperfusion (I/R) injury inevitably occurs during LTx. Exploring the common mechanisms between EVLP and I/R may unveil new treatment targets to enhance LTx outcomes., Methods: We obtained datasets from the public Gene Expression Omnibus (GEO) for EVLP (GSE127055 and GSE127057) and I/R (GSE145989) processes. We performed analysis of differentially expressed genes (DEGs) and Gene Set Enrichment Analysis (GSEA). Mitochondrial genes were sourced from the MitoCarta 3.0 database. Hub mitochondrial-related DEGs (MitoDEGs) were identified using a combination of protein-protein interaction networks and machine learning methods, which were further validated in cell and mice models of EVLP., Results: GSEA analysis of DEGs following EVLP and I/R revealed significant inhibition of mitochondrial function pathways, encompassing mitochondrial central dogma, mtRNA metabolism, OXPHOS assembly factors, metals and cofactors, and heme synthesis and processing processes. Machine learning algorithms including Random Forest, LASSO, and XGBoost identified five downregulated genes (MTERF1, ACACA, COX15, OSGEPL1, and COQ9) as hub MitoDEGs for both EVLP and I/R processes. We confirmed the reduced expression of these hub MitoDEGs in endothelial cells during EVLP and observed mitochondrial damage in endothelial cells characterized by swollen morphology and cristae disappearance., Conclusions: Imbalance in mitochondrial homeostasis is a shared pathological process during EVLP and I/R-induced lung injury. The identified hub mitochondrial-related genes (MTERF1, ACACA, COX15, OSGEPL1, and COQ9) suggest promising therapeutic targets for lung injury during LTx. The downregulation of these genes indicates a significant disruption in mitochondrial function. This study provides potential mitochondrial-related therapeutic targets for I/R-induced lung injury and for donor lung repair during EVLP procedure in LTx., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Hepatocyte transplantation has shown promise for genetic diseases of the hepatocytes but to date has shown limited efficacy for non-genetic forms of severe liver injury. Limited cell engraftment and poor function of donor hepatocytes in recipient livers impacts the clinical utility of hepatocyte cell therapy. The mechanisms underpinning this are poorly understood. We explored this in a liver injury model, where predictable levels of injury and hepatocyte senescence was induced in AhCreMdm2 fl/fl mice through genetic excision of hepatocyte Mdm2., Methods: Freshly isolated mouse, or human cryopreserved hepatocytes were delivered via intrasplenic injection into AhCreMdm2 fl/fl (immune competent and deficient strains) mice. Engraftment kinetics, donor cell engraftment and host liver function were assessed. Paired transcriptomic and proteomic analyses were performed on healthy vs senescent mouse hepatocytes., Results: We found inhibition of host hepatocyte proliferation and liver injury is a requirement for donor hepatocyte engraftment and long-term repopulation, improving liver repair and function, but excessive senescence inhibited this process causing graft function decline due to transmission of senescence from host to donor cells. Paired proteomic and transcriptomic analysis of healthy vs senescent hepatocytes reveal a unique senescent signature associated with paracrine senescence. Modification of the host niche prior to transplantation with the senotherapeutic drug ABT737 improved donor cell proliferative capacity., Conclusions: The host niche impacts the initial engraftment and long-term function of transplanted hepatocytes. Targeting paracrine senescence may be a way to improve donor hepatocyte function, optimise therapy and guide translation into the clinics., Impact and Implications: Hepatocyte transplantation has shown promise for genetic diseases but has limited efficacy for acute and severe liver injury. Poor engraftment and functionality inhibit wide-spread clinical application. We show that host senescence provides a required non-competitive niche for donor hepatocytes to repopulate the recipient liver, but can paradoxically, negatively impact donor function. These findings demonstrate a requirement for a clear understanding of the host niche prior to cell transfusion. This has significant implications not only for hepatocellular therapies, but also when developing and optimising any pre-clinical and clinical cell therapies., Competing Interests: Declaration of Competing Interest S.J.F is a founder and scientific advisor of Resolution Therapeutics Ltd. S.F-G and S.J.F are founders and scientific advisors of SensiBile (both not related to this study)., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: This study investigates the gender-specific genetic influence of the single nucleotide polymorphism (SNP) rs1111875 on diabetes risk within the Taiwanese population using data from the Taiwan Biobank. Diabetes mellitus, particularly type 2 diabetes (T2D), is influenced by genetic factors, and the rs1111875 SNP near the hematopoietically expressed homeobox (HHEX) gene has been linked to T2D susceptibility., Methods: The study included 69,272 participants after excluding those from arsenic-polluted areas and those with incomplete data. Logistic regression models were used for analyses., Results: The analyses revealed that the CT genotype of rs1111875 was associated with an increased risk of diabetes (OR = 1.092, 95% CI = 1.030-1.157, P = 0.003), as was the TT genotype (OR = 1.280, 95% CI = 1.165-1.407, P < 0.001). The effect was more pronounced in women (CT: OR = 1.118, 95% CI = 1.036-1.207, P = 0.004; TT: OR = 1.404, 95% CI = 1.243-1.585, P < 0.001). Men exhibited a higher overall risk of diabetes (OR = 1.565, 95% CI = 1.445-1.694, P < 0.001) and had a higher prevalence (12.71% vs 7.80%, P < 0.001) compared to women., Conclusions: The findings underscore the importance of considering gender differences in genetic studies of diabetes and suggest that personalized diabetes management strategies should account for both genetic and gender-specific risk factors. This research contributes to the broader understanding of genetic determinants of diabetes and their interaction with gender, aiming to enhance personalized healthcare strategies for diabetes prevention and treatment., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Five brasilane-type sesquiterpenoids, including four previously undescribed compounds named xylaribrasilaids A-D, along with a known analogue, were isolated from the ethyl acetate extracts of solid fermentation from Xylaria nigripes. X. nigripes, a traditional Chinese medicinal fungus utilized for treating various ailments such as insomnia, trauma, and depression, has garnered attention due to its pharmacological potential. Their structures and absolute configurations were elucidated through comprehensive spectroscopic analysis, including NMR, HRESIMS, and experimental ECD data. In vitro bioassays were conducted to assess the neuroprotective activities of these compounds against glutamate-induced damage in PC12 cells. Remarkably, all isolated compounds demonstrated significant enhancements in cell viability while concurrently inhibiting apoptosis. Moreover, they effectively attenuated oxidative stress markers, as evidenced by increased activities of superoxide dismutase and glutathione. Furthermore, these compounds displayed the capacity to mitigate intracellular reactive oxygen species accumulation, highlighting their potential in combating oxidative stress-related neurodegenerative disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Four previously undescribed heterodimeric diketopiperazine alkaloids, expansines A-D, were identified from the solid rice medium fermented by Penicillium expansum MA147, along with one new resorcylic acid derivative and five known compounds. Their structures and relative/absolute configurations were elucidated by interpretation of their spectroscopic data, quantum chemical calculations, and chemical conversion. Some obtained compounds were evaluated for the cytotoxicity against a triple-negative breast cancer cell line MDA-MB-231, and expansine C showed an IC 50 value of 3.23 μM. In further mechanistic studies, we found that it might act by increasing the expression of ATP-binding cassette transporter A1 and reducing cellular cholesterol levels, suggesting its potential as a novel anti-cancer agent.

Background: Pressure support ventilation (PSV) is one of the most frequently used ventilator modes in the intensive care unit (ICU). The successful implementation of PSV depends on matching the patient's inspiratory effort with the ventilator support. In clinical practice, the pressure support level is usually set and adjusted according to tidal volume and respiratory rate. However, these parameters may not fully represent the patient's effort. Previous studies have shown that pressure muscle index (PMI), which is measured as the difference between the peak and plateau airway pressure during an end-inspiratory airway occlusion, could reliably determine the low and high inspiratory effort during PSV. Herein we present the study protocol for the Inspiratory effort-Targeted Pressure Support Ventilation (IT-PSV) trial to determine the effect of a PMI-targeted pressure support setting strategy on clinical outcomes in patients undergoing PSV., Methods and Analysis: This is a cluster randomized controlled trial. Sixteen ICUs in academic hospitals will be included, eight of which will be randomly allocated to the PMI-targeted group and eight to the tidal volume/respiratory rate-targeted group. Before the initiation of the study, a four-week comprehensive training program, which includes courses of PSV initiation, pressure support adjustment, and weaning process, will be conducted for all staff in the participating ICUs. Adult patients with acute hypoxic respiratory failure and undergoing PSV within 24 h will be included. Pressure support setting and adjustment will follow the strategy according to the grouping. The primary outcome is the ventilator-free days at 28 days after enrollment. The patients will be followed up until successful weaning or separation of mechanical ventilation, death, hospital discharge, or until 28 days after randomization, whichever comes first., Discussion: The IT-PSV trial will examine the effect of an inspiratory effort-targeted PSV setting strategy on the duration of mechanical ventilation. If positive, it will provide a new physiological-based PSV management that could potentially facilitate protective assisted ventilation., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT06526598., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lu, Miao, Gao, Yang, Zhang, Weng, Zhu, Liu and Zhou.)

Background: Varicose veins are a common issue for employees in jobs that require prolonged standing compared with all other employees. However, its relationship with presentations of traditional Chinese medicine constitution is unknown. This study aimed to investigate their association., Material and Methods: Data in the study were obtained from questionnaires of patients in Taiwan Biobank, enrolled from 2008 to 2020. The responses to the statement "I can see distorted blood vessels on my four limbs (varicose veins)." were categorized into none, mild, moderate, severe. and more severe, and the same scale was also used to classify breathing difficulties and hypotension., Results: A total of 11,293 participants were enrolled in the study. The prevalence of women was higher in the studied group compared with the control. Patients complained of breathing difficulties with moderate (30.49%) and severe discomfort (12.44%) in the diseased group. Regarding hypotension, 28.81% and 9.82% of the patients presented with moderate and severe hypotension, respectively. The cofactor odds ratio was 1.775 for severe breathing difficulty/moderate hypotension and 2.235 for severe breathing difficulty/severe hypotension, with statistical significance. The combined impact of breathing difficulties and hypotension increased with severity., Conclusions: Varicose veins had a higher association with breathing difficulties and hypotension as the severity of the condition worsened. The combined impact of breathing difficulties and hypotension increased as the disease progressed. Therefore, self-reported assessments can be a useful tool for evaluating patients with asymptomatic varicose veins before the development of "heart-failure-like symptoms" to reduce the risk of underdiagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Tsai, Nfor, Lu and Liaw.)

Responding to burst stimulation of parallel fibers (PFs), cerebellar Purkinje neurons (PNs) generate a convolved synaptic response displaying a fast excitatory postsynaptic current (EPSC Fast ) followed by a slow EPSC (EPSC Slow ). The latter is companied with a rise of intracellular Ca 2+ and critical for motor coordination. The genesis of EPSC Slow in PNs results from activation of metabotropic type 1 glutamate receptor (mGluR1), oligomerization of stromal interaction molecule 1 (STIM1) on the membrane of endoplasmic reticulum (ER) and opening of transient receptor potential canonical 3 (TRPC3) channels on the plasma membrane. Neuronal nitric oxide synthase (nNOS) is abundantly expressed in PFs and granule neurons (GNs), catalyzing the production of nitric oxide (NO) hence regulating PF-PN synaptic function. We recently found that nNOS/NO regulates the morphological development of PNs through mGluR1-regulated Ca 2+ -dependent mechanism. This study investigated the role of nNOS/NO in regulating EPSC Slow . Electrophysiological analyses showed that EPSC Slow in cerebellar slices of nNOS knockout (nNOS -/- ) mice was significantly larger than that in wildtype (WT) mice. Activation of mGluR1 in cultured PNs from nNOS -/- mice evoked larger TRPC3-channel mediated currents and intracellular Ca 2+ rise than that in PNs from WT mice. In addition, nNOS inhibitor and NO-donor increased and decreased, respectively, the TRPC3-current and Ca 2+ rise in PNs. Moreover, the NO-donor effectively decreased TRPC3 currents in HEK293 cells expressing WT STIM1, but not cells expressing a STIM1 with cysteine mutants. These novel findings indicate that nNOS/NO inhibits TRPC3-containig channel mediated cation influx during EPSC Slow , at least in part, by S-nitrosylation of STIM1., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Adipose tissue macrophages (ATMs) play important roles in maintaining adipose tissue homeostasis and orchestrating metabolic inflammation. Given the extensive functional heterogeneity and phenotypic plasticity of ATMs, identification of the authentically pathogenic ATM subpopulation under obese setting is thus necessitated. Herein, we performed single-nucleus RNA sequencing (snRNA-seq) and unraveled a unique maladaptive ATM subpopulation defined as ATF4 hi PDIA3 hi ACSL4 hi CCL2 hi inflammatory and metabolically activated macrophages (iMAMs), in which PDIA3 is required for the maintenance of their migratory and pro-inflammatory properties. Mechanistically, ATF4 serves as a metabolic stress sensor to transcribe PDIA3, which then imposes a redox control on RhoA activity and strengthens the pro-inflammatory and migratory properties of iMAMs through RhoA-YAP signaling. Administration of Pdia3 small interfering RNA (siRNA)-loaded liposomes effectively repressed adipose inflammation and high-fat diet (HFD)-induced obesity. Together, our data support that strategies aimed at targeting iMAMs by suppressing PDIA3 expression or activity could be a viable approach against obesity and metabolic disorders in clinical settings., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet patient demand. Alternative regenerative therapies, including cell transplantation, aim to modulate the injured microenvironment from inflammation and scarring towards regeneration. The complexity of the liver injury response makes it challenging to identify suitable therapeutic targets when relying on experimental approaches alone. Therefore, we adopted a combined in vivo-in silico approach and developed an ordinary differential equation model of acute liver disease able to predict the host response to injury and potential interventions. The Mdm2 fl/fl mouse model of senescence-driven liver injury was used to generate a quantitative dynamic characterisation of the key cellular players (macrophages, endothelial cells, myofibroblasts) and extra cellular matrix involved in liver injury. This was qualitatively captured by the mathematical model. The mathematical model was then used to predict injury outcomes in response to milder and more severe levels of senescence-induced liver injury and validated with experimental in vivo data. In silico experiments using the validated model were then performed to interrogate potential approaches to enhance regeneration. These predicted that increasing the rate of macrophage phenotypic switch or increasing the number of pro-regenerative macrophages in the system will accelerate the rate of senescent cell clearance and resolution. These results showcase the potential benefits of mechanistic mathematical modelling for capturing the dynamics of complex biological systems and identifying therapeutic interventions that may enhance our understanding of injury-repair mechanisms and reduce translational bottlenecks., (© 2024. The Author(s).)

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings., Competing Interests: Declaration of interests The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Osteoporosis is a prevalent condition marked by reduced bone density and an elevated risk of fractures, especially among postmenopausal women. Exercise plays a crucial role in preventing and managing osteoporosis, with weight-bearing and impact exercises being particularly effective in enhancing bone density and mitigating disease risk. This study investigated the relationship between various types of impact exercises and osteoporosis using data from the Taiwan Biobank (TWB). The study sample comprised 5,123 individuals without osteoporosis and 1,770 individuals with the condition. Student's t-test and logistic regression analyses were utilized to assess the associations between exercise types and osteoporosis risk. Results indicated that high-impact exercise significantly reduced the likelihood of developing osteoporosis compared to no exercise (odds ratio; OR = 0.573, 95% CI: 0.406-0.810, P = 0.002). Conversely, low-impact exercises did not show a significant overall association with osteoporosis (OR = 1.160, 95% CI: 0.932-1.445, P = 0.184). Stratified analysis by sex revealed that high-impact exercise was protective against osteoporosis in men (OR = 0.391, 95% CI: 0.202-0.755, P = 0.005), but not significantly so in women (OR = 0.671, 95% CI: 0.438-1.027, P = 0.066). These findings suggest that high-impact exercise is associated with a reduced risk of osteoporosis, particularly among Taiwanese men aged 30 to 70., (© 2024. The Author(s).)

Gamma-aminobutyric acid (GABA) signals in various non-neuronal cells including hepatocytes and some immune cells. Studies, including ours, show that type A GABA receptors (GABA A Rs)-mediated signaling occurs in macrophages regulating tissue-specific functions. Our recent study reveals that activation of GABA A Rs in liver macrophages promotes their M2-like polarization and increases HBV replication in mice. This short article briefly summarizes the GABA signaling system in macrophages and discusses potential mechanisms by which GABA signaling promotes HBV replication., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cell therapies are emerging as promising treatments for a range of liver diseases but translational bottlenecks still remain including: securing and assessing the safe and effective delivery of cells to the disease site; ensuring successful cell engraftment and function; and preventing immunogenic responses. Here we highlight three therapies, each utilising a different cell type, at different stages in their clinical translation journey: transplantation of multipotent mesenchymal stromal/signalling cells, hepatocytes and macrophages. To overcome bottlenecks impeding clinical progression, we advocate for wider use of mechanistic in silico modelling approaches. We discuss how in silico approaches, alongside complementary experimental approaches, can enhance our understanding of the mechanisms underlying successful cell delivery and engraftment. Furthermore, such combined theoretical-experimental approaches can be exploited to develop novel therapies, address safety and efficacy challenges, bridge the gap between in vitro and in vivo model systems, and compensate for the inherent differences between animal model systems and humans. We also highlight how in silico model development can result in fewer and more targeted in vivo experiments, thereby reducing preclinical costs and experimental animal numbers and potentially accelerating translation to the clinic. The development of biologically-accurate in silico models that capture the mechanisms underpinning the behaviour of these complex systems must be reinforced by quantitative methods to assess cell survival post-transplant, and we argue that non-invasive in vivo imaging strategies should be routinely integrated into transplant studies., (© 2024. The Author(s).)

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Immunotherapy has changed the landscape of treatment options for patients with hepatocellular cancer. Checkpoint inhibitors are now standard of care for patients with advanced tumours, yet the majority remain resistant to this therapy and urgent approaches are needed to boost the efficacy of these agents. Targeting the liver endothelial cells, as the orchestrators of immune cell recruitment, within the tumour microenvironment of this highly vascular cancer could potentially boost immune cell infiltration. We demonstrate the successful culture of primary human liver endothelial cells in organ-on-a-chip technology followed by perfusion of peripheral blood mononuclear cells. We confirm, with confocal and multiphoton imaging, the capture and adhesion of immune cells in response to pro-inflammatory cytokines in this model. This multicellular platform sets the foundation for testing the efficacy of new therapies in promoting leukocyte infiltration across liver endothelium as well as a model for testing cell therapy, such as chimeric antigen receptor (CAR)-T cell, capture and migration across human liver endothelium., Competing Interests: Author AW was employed by OMass Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kennedy, Davies, Hewett, Wilkinson, Oo, Lu, El Haj and Shetty.)

The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway., Competing Interests: Declaration of interests All authors except C.B., E.B., K.T.D., W.-Y.L., S.J.F., B.H., M.T.D., P.-A.C., and P.L. are or were employees of Novartis Pharma AG., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The kidney and eyes share common pathways and are thought to be closely connected. Chronic kidney disease and major eye diseases, such as cataract and glaucoma, are strongly associated with age. However, further investigation is needed to understand the joint impact of age and kidney diseases on eye diseases. In this study, we assessed the risk of eye diseases in relation to age and kidney failure in Taiwanese adults., Methods: Our study included 127,561 cancer-free volunteers aged 30 to 70 years who participated in the Taiwan Biobank (TWB) project from 2008 to 2020. Information on the main exposures (kidney failure and age) and the outcome (eye diseases, including glaucoma, cataract, xerophthalmia, and retinal detachment) was collected through questionnaires., Results: In general, kidney failure and older age were independently associated with a higher risk of eye, particularly cataract and retinal detachment: prevalence odds ratio (POR); 95% confidence interval (CI) = 2.480; 1.635-3.761 for cataract and 3.885; 1.968-7.666 for retinal detachment. A significant interaction between kidney failure and age on cataract was observed (p-value = 0.0002). Age-stratified analysis revealed a higher risk of cataract among patients with kidney failure aged below 50 (POR = 6.534; 95% CI = 2.493-17.124) and between 50 and 60 years (POR = 3.957; 95%CI = 1.986-7.881). Combining kidney failure and age (reference: no kidney failure and age < 50 years), kidney failure in all age groups was associated with a higher risk of cataract. The PORs; 95% CIs were 10.725; 4.227-27.211 for patients below 50 years, 28.487; 14.270-56.866 for those aged 50-60 years, and 43.183; 24.434-72.824 for those > 60 years. Combining cataract and age (reference: no cataract and age < 50 years), patients below 50 years had the highest risk of kidney failure (POR; 95% CI = 9.510; 3.722-24.297)., Conclusions: Our study suggests that age and kidney failure may jointly contribute to eye diseases, particularly cataract. The association between cataract and kidney failure could be bidirectional, especially in individuals below 50 years. This significant bidirectional relationship underscores the need for screening patients with cataract for kidney failure and vice versa, particularly in younger adults., (© 2024. The Author(s).)

Background: Cigarette smoking and particulate matter (PM) with aerodynamic diameter < 2.5 μm (PM 2.5 ) are major preventable cardiovascular mortality and morbidity promoters. Their joint role in metabolic syndrome (MS) pathogenesis is unknown. We determined the risk of MS based on PM 2.5 and cigarette smoking in Taiwanese adults., Methods: The study included 126,366 Taiwanese between 30 and 70 years old with no personal history of cancer. The Taiwan Biobank (TWB) contained information on MS, cigarette smoking, and covariates, while the Environmental Protection Administration (EPA), Taiwan, contained the PM 2.5 information. Individuals were categorized as current, former, and nonsmokers. PM 2.5 levels were categorized into quartiles: PM 2.5  ≤ Q1, Q1 < PM 2.5  ≤ Q2, Q2 < PM 2.5  ≤ Q3, and PM 2.5  > Q3, corresponding to PM 2.5 ≤ 27.137, 27.137 < PM 2.5  ≤ 32.589, 32.589 < PM 2.5 ≤ 38.205, and PM 2.5  > 38.205 μg/m 3 ., Results: The prevalence of MS was significantly different according to PM 2.5 exposure ( p -value = 0.0280) and cigarette smoking ( p -value < 0.0001). Higher PM 2.5 levels were significantly associated with a higher risk of MS: odds ratio (OR); 95% confidence interval (CI) = 1.058; 1.014-1.104, 1.185; 1.134-1.238, and 1.149; 1.101-1.200 for 27.137 < PM 2.5  ≤ 32.589, 32.589 < PM 2.5 ≤ 38.205, and PM 2.5  > 38.205 μg/m 3 , respectively. The risk of MS was significantly higher among former and current smokers with OR; 95% CI = 1.062; 1.008-1.118 and 1.531; 1.450-1.616, respectively, and a dose-dependent p -value < 0.0001. The interaction between both exposures regarding MS was significant ( p -value = 0.0157). Stratification by cigarette smoking revealed a significant risk of MS due to PM 2.5 exposure among nonsmokers: OR (95% CI) = 1.074 (1.022-1.128), 1.226 (1.166-1.290), and 1.187 (1.129-1.247) for 27.137 < PM 2.5  ≤ 32.589, 32.589 < PM 2.5 ≤ 38.205, and PM 2.5  > 38.205 μg/m 3 , respectively. According to PM 2.5 quartiles, current smokers had a higher risk of MS, regardless of PM 2.5 levels (OR); 95% CI = 1.605; 1.444-1.785, 1.561; 1.409-1.728, 1.359; 1.211-1.524, and 1.585; 1.418-1.772 for PM 2.5 ≤ 27.137, 27.137 < PM 2.5  ≤ 32.589, 32.589 < PM 2.5 ≤ 38.205, and PM 2.5  > 38.205 μg/m 3 , respectively. After combining both exposures, the group, current smokers; PM 2.5  > 38.205 μg/m 3 had the highest odds (1.801; 95% CI =1.625-1.995)., Conclusion: PM 2.5 and cigarette smoking were independently and jointly associated with a higher risk of MS. Stratified analyses revealed that cigarette smoking might have a much higher effect on MS than PM 2.5 . Nonetheless, exposure to both PM 2.5 and cigarette smoking could compound the risk of MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tsai, Tantoh, Lu, Chen and Liaw.)

Background: The evolution of critical care medicine and nursing has aided and enabled the rescue of a large number of patients from numerous life-threatening diseases. However, in many cases, patient health may not be quickly restored, and the long-term prognosis may not be optimistic., Objectives: In this study, we aimed to develop and validate a prediction model for accurate, precise, and objective identification of the severity of chronic critical illness (CCI) in patients., Methods: We used a retrospective case-control and prospective cohort study with no interventions. Patients diagnosed with CCI admitted to the ICU of a large metropolitan public hospital were selected. In the case-control study, 344 patients (case: 172; control:172) were enrolled to develop the prognosis prediction model of chronic critical illness (PPCCI Model); 88 patients (case:44; control: 44) in a prospective cohort study, served as the validation cohort. The discrimination of the model was measured using the area under the curve (AUC) of the receiver operating characteristic curve (ROC)., Results: Age, prolonged mechanical ventilation (PMV), sepsis or other severe infections, Glasgow Coma Scale (GCS), mean artery pressure (MAP), heart rate (HR), respiratory rate (RR), oxygenation index (OI), and active bleeding were the nine predictors included in the model. In both cohorts, the PPCCI model outperformed the Acute Physiology And Chronic Health Evaluation II (APACHE II), Modified Early Warning Score (MEWS), and Sequential Organ Failure Assessment (SOFA) in identifying deceased patients with CCI (development cohort: AUC, 0.934; 95%CI, 0.908-0.960; validation cohort: AUC, 0.965; 95% CI, 0.931-0.999)., Conclusion: The PPCCI model can provide ICU medical staff with a standardized measurement tool for assessing the condition of patients with CCI, enabling them to allocate ward monitoring resources rationally and communicate with family members.

Recent studies showed significant associations between socio-demographic, lifestyle factors, polymorphic variant rs6265, and smoking cessation behaviours. We examined rs6265 TT, TC and CC genotypes and their association with socio-demographic and other variables, including mental health status, drinking, exercise, and smoking behaviour among Taiwanese adults. Data on rs6265 were retrieved from the Taiwan Biobank, which contained genetic data collected between 2008 to 2019 from 20,584 participants (aged 30-70 years). Participants who smoked for more than 6 months prior to enrolment were categorized as smokers. If they had smoked and later quit for more than 6 months, they were classified as former smokers. Information regarding drinking, exercise, depression, and bipolar disorder were obtained through questionnaires and were categorized as either as affirmative (yes) or negative (no) responses. In contrast to previous studies, we found that the association between the polymorphism rs6265 and smoking behaviour was not significant (P-value = 0.8753). Males with lower education levels, young persons, and alcohol drinkers showed significant smoking behaviours (P-value < .0001). This population-based study indicates that rs6265 has no significant correlations with smoking cessation behaviour among adults in Taiwan., (© 2023. The Author(s).)

The cerebellum is a major site of endocannabinoid (eCB) production and signaling. The predominant eCB within the cerebellum, 2-arachidonoylglycerol (2-AG), is produced by a metabotropic glutamate receptor type 1 (mGluR1)-initiated signaling cascade within Purkinje neurons (PNs). 2-AG retrogradely stimulates cannabinoid 1 receptors (CB1Rs) located on presynaptic terminals. The activated CB1R decreases neurotransmitter release and leads to the production of nitric oxide (NO), a gaseous molecule. Recently, our group discovered that during development in mice lacking neuronal nitric oxide synthase (nNOS -/- ), PNs display an excitotoxic phenotype associated with overactivated mGluR1. Considering the importance of mGluR1 in 2-AG synthesis, the present study explored the role of nNOS-derived NO in regulating the eCB pathway within the cerebella of wildtype (WT) and nNOS -/- mice at postnatal day 7 (PD7), 2 weeks (2 W), and 7 weeks (7 W). Our analysis showed that diacylglycerol lipase α, the enzyme that catalyzes 2-AG production, was elevated at early postnatal ages, and followed by elevated levels of 2-AG in nNOS -/- cerebella compared to WT. CB1R expression in nNOS -/- cerebella was upregulated at PD7 but decreased at 2 W and 7 W when compared to age-matched WT mice cerebella. Importantly, treating organotypic nNOS -/- cerebellar slice cultures with an NO-donor-attenuated CB1R levels after 7 days in vitro. In addition, expression of the eCB hydrolases fatty acid amide hydrolase and monoacylglycerol lipase were significantly downregulated in nNOS -/- cerebella compared to WT cerebella at 7 W. Together, these results reveal a novel role for nNOS/NO in regulating eCB signaling in the cerebellum., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We determined the association of vegetarian type and status with bone mineral density (BMD) Z-scores at the spine, hip, and femoral neck. Compared to non-vegetarians, current vegetarians, especially vegans, lacto-vegetarians, and lacto-ovo-vegetarians had lower Z-scores at multiple sites. Sole reliance on a vegetarian diet might be detrimental to the bone., Purpose: The impact of vegetarian diets on BMD is contentious. We determined the association of vegetarian type and status with the spine, hip, and femoral neck BMD Z-scores., Methods: We analyzed data from 20,110 Taiwan Biobank volunteers. BMD was measured using dual-energy X-ray absorptiometry (DXA). The vegetarian status (non-, former, and current vegetarians) and type (non-vegetarians, ovo-vegetarians, lacto-vegetarians, lacto-ovo-vegetarians, and vegans) were determined using questionnaires., Results: The participants consisted of 12,910 women and 7200 men, with a mean age of 55.5 years. Based on vegetarian status (reference: non-vegetarians), current vegetarians had significantly lower BMD Z-scores at the spine (unstandardized regression coefficient, B =  - 0.195, p = 0.006), left hip (B =  - 0.125, p = 0.008), and right hip (B =  - 0.100, p = 0.027), respectively. Based on vegetarian status and type (reference: non-vegetarians), current vegans and non-vegans had notably lower BMD Z-scores at specific skeletal sites. For non-vegans, the BMD Z-scores were significant at the spine (B = -0.184, p = 0.010), left hip (B =  - 0.124, p = 0.010), and left femoral neck (B =  - 0.125, p = 0.012). For current vegans, however, the BMD Z-scores were significant only at the right hip (B =  - 0.232; p = 0.028). Nonetheless, after stratifying vegetarian diet into more subgroups, current vegans exhibited a significant reduction in BMD Z-scores at the spine and right hip, with B-coefficients of - 0.326 and - 0.238, respectively. Current lacto-vegetarians also had significantly lower Z-scores (p < 0.05) at the spine (B =  - 0.459), left hip (B =  - 0.313), and right hip (B =  - 0.214). Moreover, current lacto-ovo-vegetarians had significantly lower Z-scores at the spine (B =  - 0.175) and left hip (B =  - 0.115)., Conclusion: Current vegetarians, particularly vegans, lacto-vegetarians, and lacto-ovo-vegetarians, demonstrated significantly lower BMD Z-scores at various skeletal sites compared to non-vegetarians. Sole reliance on a vegetarian diet might be detrimental to the bone., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Objective To compare the functional status of diabetic patients with and without nephropathy and identify the items that diabetic patients with nephropathy are more likely to develop dysfunction than diabetic patients without nephropathy based on the international classification of functioning,disability and health rehabilitation set(ICF-RS).Methods A cross-sectional study was conducted.A total of 320 diabetic patients hospitalized in Guangdong Provincial Hospital of Chinese Medicine from August 2021 to February 2022 were selected and assigned into a group with nephropathy and a group without nephropathy.The general characteristics,clinical examination,and laboratory findings were compared by the t test,rank sum test,and Chi-squared test.The functional status of the patients was compared between the two groups by the t test based on the ICF-RS.Logistic regression was employed to control interferential factors between the two groups and identify the association between nephropathy and ICF-RS problematic items among diabetic patients.Results The diabetic patients with nephropathy had more problematic items in ICF-RS( P <0.001),the body function dimension( P =0.003),the activity dimension( P <0.001),and the participation dimension( P <0.001)than those without nephropathy.Moreover,the diabetic patients with nephropathy experienced severer problems in 5 body function items(energy and drive functions,sleep functions,sexual functions,exercise tolerance functions,and muscle power functions),10 activity items(transferring oneself,walking,moving around using equipment,moving around,washing oneself,caring for body parts,toileting,dressing,doing housework,and looking after one's health),and 4 participation items(using transportation,assisting others,basic interpersonal interactions,and recreation and leisure)(all P <0.05).The Logistic regression results showed that compared with the diabetic patients without nephropathy,the diabetic patients with nephropathy were more likely to develop problems in energy and drive functions( aOR =4.35,95% CI =1.28-14.79, P =0.019),emotional functions( aOR =1.88,95% CI =1.06-3.34, P =0.031),sexual functions( aOR =3.39,95% CI =1.82-6.34, P <0.001),moving around( aOR =3.11,95% CI =1.76-5.52, P <0.001),doing housework( aOR =17.48,95% CI =3.57-85.60, P <0.001),looking after one's health( aOR =1.97,95% CI =1.13-3.43, P =0.017),using transportation( aOR =2.59,95% CI =1.38-4.88, P =0.003),and recreation and leisure( aOR =2.52,95% CI =1.46-4.35, P <0.001).Conclusion Compared with the diabetic patients without nephropathy,the patients with nephropathy suffer more ICF-RS problematic items and are more likely to develop dysfunction in certain items in all the three dimensions.

Liver sinusoidal endothelial cells (LSEC) undergo significant phenotypic change in chronic liver disease (CLD), and yet the factors that drive this process and the impact on their function as a vascular barrier and gatekeeper for immune cell recruitment are poorly understood. Plasmalemma-vesicle-associated protein (PLVAP) has been characterized as a marker of LSEC in CLD; notably we found that PLVAP upregulation strongly correlated with markers of tissue senescence. Furthermore, exposure of human LSEC to the senescence-associated secretory phenotype (SASP) led to a significant upregulation of PLVAP. Flow-based assays demonstrated that SASP-driven leukocyte recruitment was characterized by paracellular transmigration of monocytes while the majority of lymphocytes migrated transcellularly. Knockdown studies confirmed that PLVAP selectively supported monocyte transmigration mediated through PLVAP's impact on LSEC permeability by regulating phospho-VE-cadherin expression and endothelial gap formation. PLVAP may therefore represent an endothelial target that selectively shapes the senescence-mediated immune microenvironment in liver disease., Competing Interests: S.S. is a consultant for Faron Pharmaceuticals., (© 2023 The Author(s).)

Macrophages display functional phenotypic plasticity. Hepatitis B virus (HBV) infection induces polarizations of liver macrophages either to M1-like pro-inflammatory phenotype or to M2-like anti-inflammatory phenotype. Gamma-aminobutyric acid (GABA) signaling exists in various non-neuronal cells including hepatocytes and some immune cells. Here we report that macrophages express functional GABAergic signaling components and activation of type A GABA receptors (GABA A Rs) promotes M2-polarization thus advancing HBV replication. Notably, intraperitoneal injection of GABA or the GABA A R agonist muscimol increased HBV replication in HBV-carrier mice that were generated by hydrodynamical injection of adeno-associated virus/HBV1.2 plasmids (pAAV/HBV1.2). The GABA-augmented HBV replication in HBV-carrier mice was significantly reduced by the GABA A R inhibitor picrotoxin although picrotoxin had no significant effect on serum HBsAg levels in control HBV-carrier mice. Depletion of liver macrophages by liposomal clodronate treatment also significantly reduced the GABA-augmented HBV replication. Yet adoptive transfer of liver macrophages isolated from GABA-treated donor HBV-carrier mice into the liposomal clodronate-pretreated recipient HBV-carrier mice restored HBV replication. Moreover, GABA or muscimol treatment increased the expression of "M2" cytokines in macrophages, but had no direct effect on HBV replication in the HepG2.2.15 cells, HBV1.3-transfected Huh7, HepG2, or HepaRG cells, or HBV-infected Huh7-NTCP cells. Taken together, these results suggest that increasing GABA signaling in the liver promotes HBV replication in HBV-carrier mice by suppressing the immunity of liver macrophages, but not by increasing the susceptibility of hepatocytes to HBV infection. Our study shows that a previously unknown GABAergic system in liver macrophage has an essential role in HBV replication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained β cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory β cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy., (© 2023. Society of Chinese Bioscientists in America (SCBA).)

Background: The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear., Aim: To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis., Methods: We assessed PD-L1 expression in human umbilical-cord-derived MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γ alone or in combination with TNF-α induces PD-L1 expression. Moreover, we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in both an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium-induced acute colitis., Results: Our results suggest that IFN-γ induction alone upregulates PD-L1 expression in hUC-MSCs while TNF-α alone does not, and that the co-induction of IFN-γ and TNF-α promotes higher expression of PD-L1. IFN-γ induces hUC-MSCs to express PD-L1, in which IFN-γ activates the JAK/STAT1 signaling pathway, up-regulates the expression of the interferon regulatory factor 1 (IRF1) transcription factor, promotes the binding of IRF1 and the PD-L1 gene promoter, and finally promotes PD-L1 mRNA. Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling. Finally, co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation, and significantly ameliorate weight loss, mucosal damage, inflammatory cell infiltration, and up-regulation of inflammatory factors in colitis mice., Conclusion: Overall, our results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1., Competing Interests: Conflict-of-interest statement: The authors confirm that this article has no conflict of interest to report., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Varicose veins (VVs), a common vascular disease is associated with a huge medical burden. The prevalence in women surpasses that in men. The role of vegetarian diets in the pathogenesis of the disease remains inconclusive. In this study, we examined the risk of VVs in vegetarian and non-vegetarian men and women., Methods: The study involved 9905 adults whose data were obtained from Taiwan Biobank between 2008 and 2020. Information on VVs, sex, and vegetarian diets was obtained from participants' self-responses to the Taiwan Biobank questionnaires., Results: The study subjects consisted of 4,142 men and 5,763 women. About 12% of men and 35% of women had VVs. Study participants were predominantly non-vegetarians (91.84% were men and 88.24% were women). Women had a higher risk of VVs than men. The odds ratio (OR); 95% confidence interval (CI) was 3.414; 2.995-3.891. There was a significant interaction between sex and vegetarian diets ( p  = 0.0034). Women were at higher risk of VVs than men both in the vegetarian (OR = 1.877, 95% CI = 1.270-2.774) and non-vegetarian (OR = 3.674, 95% CI = 3.197-4.223) groups. Based on vegetarian diets, only vegetarian men had a higher risk of VVs (OR = 1.453, 95% CI = 1.069 to 1.976). Based on the sex-stratified model, the risk of VVs was significantly higher in vegetarian men (OR = 1.457, 95% CI = 1.072-1.979), and in vegetarian and non-vegetarian women with corresponding ORs (95% CI) of 3.101 (2.528-3.803) and 3.599 (3.140-4.124), respectively., Conclusion: Women were more susceptible to varicose veins compared to men, regardless of diet. However, in terms of diet, only men who followed a vegetarian diet were at greater risk for developing VVs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tsai, Nfor, Tantoh, Lu and Liaw.)

Objective: To predict the protection probability of different clinical outcomes after reinfection with Omicron variant in symptomatic and unvaccinated COVID-19 patients who infected with prototype strain. Methods: The data used in this study were derived from a systematic review and meta-analysis which systematically searched PubMed, Embase, Web of Science, and Europe PMC databases, included published and uploaded studies of dynamic changes of neutralizing antibodies in symptomatic COVID-19 patients from 1 January 2020 to 2 October 2022 and extracted the literature information, study design, serological experiment information and antibody results. According to the scatter distribution characteristics of antibody titer data, a generalized additive model based on Gaussian distribution was used to fit the titer value of neutralizing antibody based on logarithmic conversion and the dynamic change pattern of neutralizing antibody in symptomatic and unvaccinated COVID-19 patients infected with prototype strain over time was obtained. In this study, the fitted antibody titers of patients on the 28th, 51st, and 261st day after symptom onset was selected to predict the protection probability. Results: Neutralizing antibodies produced in symptomatic and unvaccinated patients infected with prototype strain could provide protection against Omicron reinfection, and the probability of protection gradually decreased with time. Neutralizing antibody level on day 28 after symptom onset provided protection probability of 30.3% (95% CI : 20.0%-45.5%) against reinfection, 51.5% (95% CI : 33.4%-75.9%) against symptomatic reinfection, and 91.2% (95% CI : 77.1%-97.7%) against severe reinfection caused by Omicron BA.5. The protection probability against Omicron BA.1, BA.4 and BA.5 reinfections decreased significantly 261 days after symptom onset, showing 9.6%-12.9%, 18.4%-23.9% and 63.1%-70.3% against three clinical outcomes, respectively. At the same time point and against the same clinical outcome, the protection probability of BA.1 was the highest, followed by BA.4 and BA.5. Conclusions: Neutralizing antibodies induced in symptomatic and unvaccinated COVID-19 patients previously infected with the prototype strain have limited protection probability against Omicron BA.5 reinfections and symptomatic reinfections. The protection probability against Omicron BA.5 reinfections is 30.3% 28 days after symptom onset and decreases to about 10% after 261 days. However, the protection probability against severe reinfections is considerable, with over 90% 28 days after symptom onset and still exceeding 60% after 261 days.

This study aimed to investigate the possible association between nasopharyngeal carcinoma (NPC) and following open angle glaucoma (OAG). A retrospective research applying the National Health Insurance Research Database (NHIRD) of Taiwan was conducted with a follow up period from January 1, 2000 to December 31, 2016. There were 4184 and 16736 participants that selected and categorized into the NPC and non-NPC groups after exclusion. The major outcome of our study was the development of OAG according to diagnostic codes, exam and managements. The Cox proportional hazard regression was employed to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of OAG between the two groups. In this study, a numbers of 151 and 513 OAG episodes occurred in the NPC and non-NPC groups and the NPC population showed a significantly higher incidence of OAG compared to the non-NPC population in multivariable analysis (aHR: 1.293, 95% CI: 1.077-1.551, p = 0.0057). Besides, the cumulative probability of OAG was significantly higher in the NPC group than that in the non-NPC population (p = 0.0041). About other risk factor for OAG, age older than 40 years old, diabetes mellitus and persistent steroid usage were related to OAG occurrence (all p < 0.05). In conclusion, the NPC may be an independent risk factor of following OAG development., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The thymus medulla is a key site for immunoregulation and tolerance, and its functional specialisation is achieved through the complexity of medullary thymic epithelial cells (mTEC). While the importance of the medulla for thymus function is clear, the production and maintenance of mTEC diversity remains poorly understood. Here, using ontogenetic and inducible fate-mapping approaches, we identify mTEC-restricted progenitors as a cytokeratin19 + (K19 + ) TEC subset that emerges in the embryonic thymus. Importantly, labelling of a single cohort of K19 + TEC during embryogenesis sustains the production of multiple mTEC subsets into adulthood, including CCL21 + mTEC lo , Aire + mTEC hi and thymic tuft cells. We show K19 + progenitors arise prior to the acquisition of multiple mTEC-defining features including RANK and CCL21 and are generated independently of the key mTEC regulator, Relb. In conclusion, we identify and define a multipotent mTEC progenitor that emerges during embryogenesis to support mTEC diversity into adult life., (© 2023. The Author(s).)

Although anti-rheumatoid arthritis (RA) 33 antibodies have been reported to be present in various connective tissue diseases (CTDs), the clinical significance of anti-RA33 in CTDs is still obscure. This study was performed to explore the clinical significance of anti-RA33 in CTDs, especially systemic lupus erythematosus (SLE). A total of 565 patients with positive anti-nuclear antibodies who had been tested for anti-RA33 were included in this study and were further classified into RA33-positive and RA33-negative groups. The association between anti-RA33 and the clinical features of CTDs was examined. Receiver operating characteristic (ROC) analysis was performed to explore the diagnostic value of anti-RA33 in SLE and SLE-related organ involvement. The results showed that SLE was the most common disease in CTD patients positive for anti-RA33 (48.8%). Compared with the RA33-negative group, higher proportions of SLE-associated antibodies and SLE patients with a high disease activity as well as lower levels of serum complement components were observed in the RA33-positive group (all p < 0.05). Furthermore, CTD patients with positive anti-RA33 were more likely to suffer from mucocutaneous and hematological involvement as well as interstitial lung disease (all p < 0.05). ROC analysis revealed an area under the curve value of 0.634 (95% confidence interval: 0.587-0.681) for anti-RA33 in the diagnosis of SLE, with a specificity and sensitivity of 92.9% and 13.5%, respectively. Taken together, this study reveals a significant association between anti-RA33 and the clinical features of CTDs, especially SLE, indicating a potential clinical significance of anti-RA33 in the management of SLE.

Reported here is a highly enantioselective homoenolate Michael addition/esterification sequence of cyclohexadienone-tethered enals via N-heterocyclic carbene (NHC) catalysis, affording the enantiopure cis -hydrobenzofurans, cis -hydroindoles, and cis -hydroindenes. The NHC catalyst bearing a nitro group greatly enhances the stereocontrol, and a bulky N -aryl substituent of the triazolium salt in the catalyst is helpful for inhibiting the further aldol condensation after homoenolate Michael addition. The utility of this protocol is highlighted by a gram-scale experiment and versatile downstream transformations.

Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)-dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21 KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.

Background: Although previous studies have shown that aerobic and resistance exercise increase high-density lipoprotein cholesterol (HDL-C) levels, the optimal type of exercise has not been determined. Therefore, the purpose of this study was to investigate the association of jogging (a type of aerobic exercise) and weight training (a type of resistance exercise) with HDL-C levels in Taiwanese adults., Methods: The data used in this cross-sectional study were obtained from the Taiwan Biobank (TWB), which is a national health resource that contains the genetic information of Taiwanese volunteers aged 30-70 years. A total of 75,635 subjects (47,881 women and 27,754 men) were included in this study. The subjects were divided into four groups: jogging ( n = 2,278), weight training ( n = 522), mixed exercise ( n = 519), and no exercise ( n = 72,316). The TWB data were collected through questionnaires (e.g. basic characteristics, lifestyle factors, and disease history), biochemical tests, and anthropometric measurements., Results: Compared with no exercise, jogging, weight training, and mixed exercise were all associated with higher HDL-C levels (β = 2.5470, 2.6249, and 3.2117, respectively). As seen, the β value was highest for the mixed exercise group, followed by weight training and then jogging ( p for trend <0.0001)., Conclusions: In the current study, jogging and weight training were individually associated with higher levels of HDL-C. Engaging in both activities was associated with much higher levels of HDL-C. Our findings suggest that regular jogging and weight training might play an important role in increasing HDL-C levels., Competing Interests: No potential conflict of interest was reported by the authors., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Aloperine is an anti-inflammatory compound isolated from the Chinese herb Sophora alopecuroides L. Previously, our group has reported that the generation of induced Treg was promoted by aloperine treatment in a mouse colitis model. However, the effect of aloperine on effector T cell subsets remains unclear. We therefore carefully examined the effect of aloperine on the differentiation of major subsets of T helper cells. Based on our results, psoriasis, a Th17 dominant skin disease, is selected to explore the potential therapeutic effect of aloperine in vivo . Herein, we demonstrated that topical application of aloperine suppressed epidermal proliferation, erythema, and infiltration of inflammatory cells in skin lesions. Mechanistic studies revealed that aloperine suppressed the differentiation of Th17 cells directly through inhibiting the phosphorylation of STAT3 or indirectly through impairing the secretion of Th17-promoting cytokines by dendritic cells. Moreover, aloperine enhanced the conversion of Th17 into Treg via altering the pSTAT3/pSTAT5 ratio. Collectively, our study supported that aloperine possesses the capacity to affect Th17 differentiation and modulates Th17/Treg balance, thereby alleviating imiquimod (IMQ)-induced psoriasis in mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Wang, Sun, Liu, Rong, Luo, Yue, Xiao, Yang, Lu, Luo, Zhou, Zhu, Yang, Xiong, Yu, Zhang and Wang.)

Bergmann glia (BG) predominantly use glutamate/aspartate transporters (GLAST) for glutamate uptake in the cerebellum. Recently, nitric oxide (NO) treatment has been shown to upregulate GLAST function and increase glutamate uptake in vitro. We previously discovered that neuronal nitric oxide synthase knockout (nNOS -/- ) mice displayed structural and functional neuronal abnormalities in the cerebellum during development, in addition to previously reported motor deficits. Although these developmental deficits have been identified in the nNOS -/- cerebellum, it is unknown whether BG morphology and GLAST expression are also affected in the absence of nNOS in vivo. This study is the first to characterize BG morphology and GLAST expression during development in nNOS -/- mice using immunohistochemistry and western blotting across postnatal development. Results showed that BG in nNOS -/- mice exhibited abnormal morphology and decreased GLAST expression compared with wildtype (WT) mice across postnatal development. Treating ex vivo WT cerebellar slices with the NOS inhibitor L-NAME decreased GLAST expression while treating nNOS -/- slices with the slow-release NO-donor NOC-18 increased GLAST expression when compared with their respective controls. In addition, treating primary BG isolated from WT mice with the selective nNOS inhibitor 7N decreased the membrane expression of GLAST and influx of Ca 2+ /Na + , while treating nNOS -/- BG with SNAP increased the membrane expression of GLAST and Ca 2+ /Na + influx. Moreover, the effects of SNAP on GLAST expression and Ca 2+ /Na + influx in nNOS -/- BG were significantly reduced by a PKG inhibitor. Together, these results reveal a novel role for nNOS/NO signaling in BG development, regulated by a PKG-mediated mechanism., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have therefore purified human biliary epithelial cells (hBECs) from human livers that were not used for liver transplantation. hBECs were tested as a cell therapy in a mouse model of biliary disease in which the conditional deletion of Mdm2 in cholangiocytes causes senescence, biliary strictures, and fibrosis. hBECs are expandable and phenotypically stable and help restore biliary structure and function, highlighting their regenerative capacity and a potential alternative to liver transplantation for biliary disease., Competing Interests: Declaration of interests S.J.F. and J.D.M.C. are founders and scientific advisors of Resolution Therapeutics Ltd (not related to this study). D.C.H. is a founder, director, and shareholder at Stemnovate Limited and Stimuliver ApS (not related to this study)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The immune system is finely tuned to fight against infections, eradicate neoplasms, and prevent autoimmunity. Protein posttranslational modification (PTM) constitutes a molecular layer of regulation to guarantee the proper intensity of immune response. Herein, we report that UBC9-mediated protein SUMOylation plays an essential role in peripheral CD4 T-cell proliferation, but without a perceptible impact on T-cell polarization. Both conventional T-cell (Tcon) and regulatory T-cell (Treg) maintenance are differentially affected, which was likely caused by a shared deficit in cell glycolytic metabolism. Mechanistically, PDPK1 (3-phosphoinositide-dependent protein-kinase 1) was identified as a novel SUMOylation substrate, which occurred predominantly at lysine 299 (K299) located within the protein-kinase domain. Loss of PDPK1 SUMOylation impeded its autophosphorylation at serine 241 (S241), thereby leading to hypoactivation of downstream mTORC1 signaling coupled with incompetence of cell proliferation. Altogether, our results revealed a novel regulatory mechanism in peripheral CD4 T-cell homeostatic proliferation, which involves SUMOylation regulation of PDPK1-mTORC1 signaling-mediated glycolytic process., (© 2022. The Author(s).)

Background: XB130 (actin filament-associated protein 1-like 2, AFAP1L2) is a thyroid-abundant adaptor/scaffold protein. Xb130 -/- mice exhibit transient growth retardation postnatally due to congenital hypothyroidism with diminished thyroglobulin iodination and release at both embryonic and early postnatal stages due to disorganized thyroid apical membrane structure and function. We hypothesized that XB130 is crucial for polarity and folliculogenesis by mediating proper cytoskeletal structure and function in thyrocytes. Methods: Primary thyrocytes isolated from thyroid glands of Xb130 -/- mice and their wild-type littermates at postnatal week 2 were cultured in 10% Matrigel for different time periods. Folliculogenesis was studied with immunofluorescence staining, followed by confocal microscopy. Cells were also transfected to express human XB130 fused Green Fluorescent Protein (XB130-GFP) or Green Fluorescent Protein (GFP) only before morphological analysis. Cytoskeletal structures from embryo and postnatal thyroid glands were also studied. Results: In three-dimensional cultures of thyrocytes, XB130, aligned with actin filaments, participated in defining the site of apical membrane formation and coalescence to form a thyroid follicle lumen. Xb130 -/- thyrocytes displayed delayed folliculogenesis, reduced recruitment of a microtubule (MT)-associated proteins, and disorganized acetylated tubulin under the apical membrane, resulting in delayed folliculogenesis with reduced efficiency in formation of the thyroid follicle lumen. Conclusions: XB130 critically regulates thyrocyte polarization by functioning as a link between the actin filament cortex and MT network at the apical membrane of thyrocytes. Defects of adaptor scaffold proteins may affect cellular polarity and cytoskeletal structure and function and result in disorders of epithelial function, such as congenital hypothyroidism.