Cross-sectional and longitudinal associations of magnesium intake and cognition in the Healthy Aging Longitudinal Study in Taiwan.

PURPOSE: Previous cross-sectional studies have shown that higher magnesium intake is associated with better cognitive function, particularly in individuals with sufficient vitamin D status. The aim of this study was to evaluate the longitudinal associations between magnesium intake and cognitive impairment in a community-based cohort study in Taiwan. METHODS: The study population included 5663 community-dwelling adults aged ≥ 55 years old recruited from 2009 to 2013 and followed up from 2013 to 2020. Magnesium intake was evaluated from a validated food frequency questionnaire at baseline. Cognitive performance was measured at baseline and follow-up for participants' Mini-Mental Status Examination (MMSE), Digit Symbol Substitution Test (DSST), and Clock-Drawing Test (CDT), and impairment was defined as MMSE < 24, DSST < 21, and CDT < 3, respectively. Multivariate logistic regression models were used to examine the associations and were stratified by sex and plasma vitamin D levels (≥ 50 or < 50 nmol/L). RESULTS: Higher baseline magnesium intake was associated with lower odds of a poor performance on the MMSE in both men and women (4th vs. 1st. quartile: OR = 0.43, 95% CI = 0.23-0.82, ptrend < 0.01 in men and OR = 0.53, 95% CI = 0.29-0.97, ptrend = 0.12 in women) and on the DSST in men (OR = 0.23, 95% CI = 0.09-0.61, ptrend < 0.01) at follow-up. Inverse associations between baseline magnesium intake and a poor performance on the MMSE or DSST were observed in men regardless of vitamin D status. CONCLUSION: Our study suggested that higher magnesium intake was associated with the development of cognitive impairment in men in a median follow-up period of 6 years.

Dietary Inflammatory Patterns Are Associated With Serum TGs and Insulin in Adults: A Community-Based Study in Taiwan.

BACKGROUND: Dietary patterns related to inflammation have become a focus of disease prevention but the patterns may vary among populations. OBJECTIVES: The study was conducted to determine Taiwanese dietary inflammatory patterns and evaluate their associations with biomarkers of lipid and glucose. METHODS: Data were taken from 5664 community-dwelling individuals aged ≥55 y recruited in 2009-2013 in the Healthy Aging Longitudinal Study in Taiwan (HALST). Dietary data were obtained from an FFQ. An empirical dietary inflammatory pattern (EDIP) was derived from reduced rank regression models that explained the serum high-sensitivity CRP, plasma IL-6, and TNF receptor 1. Cross-sectional associations between dietary scores and biomarkers of total cholesterol (TC); HDL cholesterol; LDL cholesterol; TG; and ratios of TG/HDL cholesterol, TG/TC, fasting glucose, insulin, and HbA1c were analyzed via multiple linear regression and adjusted for major confounders. The false-discovery rate (FDR)-adjusted P < 0.05 was considered statistically significant. Abdominal obesity was defined as a waist circumference of ≥90 cm for men and ≥80 cm for women. RESULTS: Higher EDIP-HALST scores were associated with higher TG (per score increment: 1.62%, 95% CI: 0.58%, 2.76%; PFDR = 0.01), TG/HDL cholesterol (2.01%, 95% CI: 0.67%, 3.37%; PFDR = 0.01), and TG/TC (1.42%, 95% CI: 0.41%, 2.43%; PFDR = 0.01) and nonlinearly associated with insulin, with those in the middle tertile had the highest serum insulin concentrations (means: 5.12 µIU/mL, 95% CI: 4.78, 5.78; PFDR = 0.04) in men, but not in women. No heterogeneity was detected between sexes. The associations with TG (1.23%, 95% CI: 0.19, 2.23%; Ptrend = 0.02), TG/HDL cholesterol (1.62%, 95% CI: 0.30%, 2.96%; Ptrend = 0.02), and TG/TC (1.11%, 95% CI: 0.11%, 2.13%; Ptrend = 0.03) were stronger in participants with abdominal obesity, but were borderline associated in participants with normal abdominal circumferences (all Ptrend = 0.05). CONCLUSIONS: Inflammatory diets, as measured via EDIP-HALST, are associated with serum TG concentration, particularly in participants with abdominal obesity. These findings may suggest that developing disease prevention strategies using dietary inflammatory patterns may be different by populations. J Nutr 20xx;x:xx.

Ampicillin exacerbates acetaminophen-induced acute liver injury by inducing intestinal microbiota imbalance and butyrate reduction.

BACKGROUND AND AIMS: Antibiotics (ATBx) and acetaminophen (APAP) are widely used worldwide. APAP is the most common cause of acute liver injury (ALI) and might be used in combination with ATBx in clinics. However, the impact of ATBx on APAP-induced ALI has rarely been studied. METHODS: First, we compared the effects of seven ATBx on APAP-induced ALI. Then, we analysed faecal, serum and liver samples to investigate the impact of the gut microbiota on this process. Finally, we assessed the role of short-chain fatty acids in this process. RESULTS: In this work, we found that the ALI was significantly aggravated in the mice treated with ampicillin (Amp) instead of other ATBx. Amp exposure reduced the diversity and altered the composition of gut microbiota. The altered gut microbiota aggravated APAP-induced ALF, which was proven by faecal microbiota transplantation from ATBx-treated mice. Metagenomic analysis showed a significantly decreased Lactobacillus abundance in Amp-treated mice. Gavage with Lactobacillus, especially Lactobacillus rhamnosus, significantly reversed the severer ALF induced by APAP and Amp. Moreover, Lactobacillus supplementation increased butyrate-producing clostridia and lowered butyrate levels in Amp-treated mice. In accordance, butyrate supplementation could also alleviate Amp-aggravated ALI. In addition, inhibition of nuclear factor erythroid 2-related factor 2 counteracted the protective effect of butyrate on aggravated ALI induced by Amp and APAP. CONCLUSION: Together, this study revealed a potential health impact of Amp that may exacerbate liver damage when co-exposed to excess APAP.

Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis.

Nonalcoholic steatohepatitis (NASH) is the major cause of liver dysfunction. Animal and population studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) is implicated in fatty liver disease. However, the role of ALDH2 in NASH and the underlying mechanisms remains unclear. To address this issue, ALDH2 knockout (ALDH2-/-) mice and wild-type littermate mice were fed a methionine-and choline-deficient (MCD) diet to induce a NASH model. Fecal, serum, and liver samples were collected and analyzed to investigate the impact of the gut microbiota and bile acids on this process. We found that MCD-fed ALDH2-/- mice exhibited increased serum pro-inflammation cytokines, hepatic inflammation and fat accumulation than their wild-type littermates. MCD-fed ALDH2-/- mice exhibited worsened MCD-induced intestinal inflammation and barrier damage, and gut microbiota disorder. Furthermore, mice receiving microbiota from MCD-fed ALDH2-/- mice had increased severity of NASH compared to those receiving microbiota from MCD-fed wild-type mice. Notably, the intestinal Lactobacillus was significantly reduced in MCD-fed ALDH2-/- mice, and gavage with Lactobacillus cocktail significantly improved MCD-induced NASH. Finally, we found that ALDH2-/- mice had reduced levels of bile salt hydrolase and specific bile acids, especially lithocholic acid (LCA), accompanied by downregulated expression of the intestinal FXR-FGF15 pathway. Supplementation of LCA in ALDH2-/- mice upregulated intestinal FXR-FGF15 pathway and alleviated NASH. In summary, ALDH2 plays a critical role in the development of NASH through modulation of gut microbiota and bile acid. The findings suggest that supplementing with Lactobacillus or LCA could be a promising therapeutic approach for treating NASH exacerbated by ALDH2 deficiency.

Polylactic Acid-Based Biomaterials in Wound Healing: A Systematic Review.

OBJECTIVE: To examine (1) the effectiveness of polylactic acid (PLA)-based biomaterials in wound healing, (2) their effects on wound infection prevention, and (3) their safety compared with existing biomaterials. DATA SOURCES: Data sources included PubMed, MEDLINE, Cochrane Library, CINAHL (Cumulative Index to Nursing and Allied Health Literature), CNKI (China National Knowledge Infrastructure), WEIPU, and WANFANG databases. STUDY SELECTION: Investigators included 14 studies discussing the effects of PLA-based biomaterials in cutaneous wound healing published from 2000 to 2021. DATA EXTRACTION: Authors extracted the following information from the selected studies: general information, study type, type of wound, PLA-based biomaterials and techniques, study period, outcome measures, and results. DATA SYNTHESIS: Polylactic acid-based biomaterials may promote wound healing through wound area repair, collagen deposition, angiogenesis, and cell activities, which are related to the good biocompatibility, biodegradability, and moisture management properties of PLA. A proper product structure may also help. Both the native PLA materials and PLA blends seem to be antibacterial, although more evidence is needed for the native PLA products. Because there was no severe adverse event or obvious cytotoxicity observed in the included studies, PLA-based biomaterials are likely safe. CONCLUSIONS: Polylactic acid-based biomaterials may be good wound dressing materials, although more evidence is needed to support their broader application in wound care.

Association between periodontitis treatment and dementia in Taiwanese adults.

BACKGROUND: The chronic systemic inflammatory response in periodontitis may be a potential risk factor for dementia, especially in adults. This study determined the association between periodontal treatment and dementia in adults and evaluated the effect of regular scaling treatment on the risk of dementia in this population. METHODS: This case-control study identified 18,930 patients with a dementia-related diagnosis from the Taiwan National Health Insurance Research Database. Scaling and periodontal emergency treatments were evaluated after 1 year and 3 years. Using multivariable logistic regression analysis to evaluate the association between periodontal emergency treatment and dementia risk. RESULTS: The results showed that scaling treatment rates were lower in the dementia cohort than the non-dementia cohort after 1 and 3 years. Patients who received periodontal emergency treatment within 3 years had a significantly increased risk of dementia. Furthermore, patients with periodontitis who did not receive scaling treatment within 3 years had a higher risk of dementia than patients without periodontitis (OR, 1.22; 95% CI, 1.10-1.35). CONCLUSION: This study demonstrated that periodontitis and dementia are associated, and that periodontitis is a risk factor for dementia in adults. The risk of dementia was dependent on the periodontal health status of adults, and our findings suggest that regular scaling can reduce the incidence of dementia in adults. Therefore, regular and routine scaling treatment is suggested for adults.

Microplastic concentrations in river water and bed sediments in a tropical river: implications for water quality monitoring.

Recent increase in awareness of the extent of microplastic contamination in marine and freshwater systems has heightened concerns over the ecological and human health risks of this ubiquitous material. Assessing risks posed by microplastic in freshwater systems requires sampling to establish contamination levels, but standard sampling protocols have yet to be established. An important question is whether sampling and assessment should focus on microplastic concentrations in the water or the amount deposited on the bed. On three dates, five replicated water and bed sediment samples were collected from each of the eight sites along the upper reach of the Semenyih River, Malaysia. Microplastics were found in all 160 samples, with mean concentrations of 3.12 ± 2.49 particles/L in river water and 6027.39 ± 16,585.87 particles/m2 deposited on the surface of riverbed sediments. Fibres were the dominant type of microplastic in all samples, but fragments made up a greater proportion of the material on the bed than in the water. Within-site variability in microplastic abundance was high for both water and bed sediments, and very often greater than between-site variability. Patterns suggest that microplastic accumulation on the bed is spatially variable, and single samples are therefore inadequate for assessing bed contamination levels at a site. Sites with the highest mean concentrations in samples of water were not those with the highest concentrations on the bed, indicating that monitoring based only on water samples may not provide a good picture of either relative or absolute bed contamination levels, nor the risks posed to benthic organisms.

An Energy-Restricted Diet Including Yogurt, Fruit, and Vegetables Alleviates High-Fat Diet-Induced Metabolic Syndrome in Mice by Modulating the Gut Microbiota.

BACKGROUND: The importance of the composition of an energy-restricted diet in the treatment of metabolic syndrome (MetS) is unknown. OBJECTIVES: In this study we aimed to investigate the benefits of a novel dietary treatment (50% calorie restriction diet composed of yogurt, fruit, and vegetables [CR-YD]) in mice with MetS. METHODS: Forty 7-wk-old male C57BL/6 J mice were randomly assigned to 4 groups (n = 10/group) that were fed for 14 wk ad libitum with a normal diet (ND; 10%:70%:20% energy from fat: carbohydrate: protein) or for 12 wk with a high-fat diet (HFD; 60:20:20) or the HFD followed by 2 wk of feeding with a 50% calorie-restricted HFD (CR-HFD) or YD (CR-YD, 21.2%:65.4%:13.4% energy). Body weight, fat deposition, hepatic steatosis, serum concentrations of inflammatory biomarkers, and glucose homeostasis were assessed. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in MetS. RESULTS: The HFD group had 50% greater body weight and 475% greater fat deposition than the ND group (P < 0.05). Compared with the HFD group, the CR-HFD and CR-YD groups had 22% and 31% lower body weight and 49% and 75% less fat deposition, respectively (P < 0.05). Compared with the CR-HFD group, the CR-YD group had 11% lower body weight, 96% less fat deposition, 500% less hepatic steatosis, 75% lower glucose, and 450% more hepatic Akkermansia bacteria (P < 0.05). The CR-YD group also had 50% lower histopathology scores and 1.35-fold higher levels of Claudin4 than the CR-HFD group (P < 0.05). The HFD + CR-YD fecal group had 10.6% lower body weight, 119% lower steatosis, and 17.9% lower glucose (P < 0.05) than the HFD + CR-HFD fecal group. CONCLUSIONS: Compared with CR alone, the CR-YD diet has a better therapeutic effect in mice with HFD-induced MetS.

Relative contributions of different local sources to riverborne microplastic in a mixed landuse area within a tropical catchment.

Information on the relative contributions of microplastics coming from different sources is important to help prioritise measures to reduce river contamination levels and limit human and ecological health risks. This paper reports on work which aimed to quantitatively assess the relative concentrations and types of microplastic delivered from differed sources to a second order river. The study was undertaken in a mixed landuse area within a rapidly urbanising catchment in Malaysia. Over a six-week period, water samples were collected from road culverts and drains in residential and industrial areas across the area to assess microplastic concentrations, while inputs from atmospheric deposition and wastewater treatment plants (WWTPs) were also quantified. Microplastic fibres and fragments were the dominant material in all sources, with the majority consisting of styrene-butadiene rubber and nylon. Culverts draining main roads were the main contributor to riverborne microplastic, delivering 42.20 ± 35.29 particles/L directly to the river channel. Road inputs were up to seven times greater than those from residential (8.53 ± 9.91 particles/L) and industrial (5.67 ± 4.88 particles/L) areas. The five WWTPs had removal efficiencies of between 30.95 ± 5.51% and 69.94 ± 22.17%, with their outflows delivering microplastics to the river in concentrations similar to those in uncontrolled residential and industrial drains. Atmospheric deposition across the study area was estimated to be 76.07 ± 32.85 particles/m2/day (=8.35 ± 5.11 particles/L). Mitigation strategies in the study area should focus on improving management of water draining roads, and re-routing discharges from domestic and industrial areas to WWTPs rather than allowing them to flow directly to the river. The low efficiencies of some of the WWTPs are not unusual, and indicate the need for additional water treatment to deal with microplastic present in wastewater.

Association of leukocyte mitochondrial DNA copy number with longitudinal C-reactive protein levels and survival in older adults: a cohort study.

BACKGROUND: Systemic chronic inflammation occurs with age. The association of the leukocyte mitochondrial DNA copy number, a measure of mitochondrial function in aging, with the temporal profile of serum high-sensitivity C-reactive protein and mortality risk remains uncertain. The objectives of this study were to examine the association of the leukocyte mitochondrial DNA copy number with longitudinal high-sensitivity C-reactive protein levels and the association of the longitudinal high-sensitivity C-reactive protein levels with mortality risk. METHODS: This prospective cohort study included 3928 adults aged ≥ 55 years without systemic inflammation in the baseline examination of the Healthy Aging Longitudinal Study in Taiwan, which started in 2009. Each participant received leukocyte mitochondrial DNA copy number measurement using a fluorescence-based quantitative polymerase chain reaction at baseline, serum high-sensitivity C-reactive protein measurements at baseline and the follow-up examination five years later, and the ascertainment of all-cause death (until November 30, 2021). The relationships among the leukocyte mitochondrial DNA copy number, longitudinal serum high-sensitivity C-reactive protein levels, and time to all-cause mortality were examined using the joint longitudinal and survival modeling analysis. RESULTS: Of the 3928 participants (mean age: 69 years; 2060 [52%] were women), 837 (21%) died during follow-up. In the adjusted analysis, one standard deviation lower natural log-transformed baseline leukocyte mitochondrial DNA copy number was associated with an increase of 0.05 (95% confidence interval [CI], 0.02 to 0.08) standard deviation in serum high-sensitivity C-reactive protein in subsequent years. An increase of 1 standard deviation in instantaneous high-sensitivity C-reactive protein levels was associated with a hazard ratio (HR) for all-cause mortality of 1.22 (95% CI, 1.14 to 1.30). Similar results were obtained after further adjusting for baseline high-sensitivity C-reactive protein levels (HR [95% CI], 1.27 [1.16 to 1.38]) and after excluding those with serum high-sensitivity C-reactive protein above 10 mg/L (HR [95% CI], 1.21[1.11 to 1.31]) or 3 mg/L (HR [95% CI], 1.19 [1.06 to 1.31]) during follow-up. CONCLUSIONS: A lower leukocyte mitochondrial DNA copy number was associated with persistently higher high-sensitivity C-reactive protein levels. Moreover, these higher time-varying high-sensitivity C-reactive protein levels were instantaneously associated with a higher risk of death.

Exploring the factors affecting preschool educators' health teaching capacity of life skills using the PRECEDE model: a study of preschool educators in northern Taiwan.

BACKGROUND: The purpose of this study was to apply the Predisposing, Reinforcing, and Enabling Constructs in Educational Diagnosis and Evaluation (PRECEDE) model to analyze the factors influencing preschool educators' ability to teach health education through life skills. METHODS: This cross-sectional study utilized stratified random sampling and administered survey questionnaires to 503 preschool educators in public and private kindergartens in Taipei City and New Taipei City in 2019. Descriptive and hierarchical regression analyses were conducted. The PRECEDE model demonstrated a significant correlation between the enabling, reinforcing, and predisposing factors explored in this study and the preschool educators' ability to teach health education through life skills. RESULTS: The variables explained 25% of the total variance in the ability to teach health education through life skills. When controlled in individual layers, the background variables and the enabling, reinforcing, and predisposing factors demonstrated explanatory powers of 6, 5, 7, and 7%, respectively, with respect to the ability to teach health education by utilizing life skills. CONCLUSIONS: Enhancement of the enabling, reinforcing, and predisposing factors can improve preschool educators' ability to teach health education through life skills. The support provided by the governmental policies for related training can facilitate the effective implementation of health promotion programs in kindergartens. Preschool educators must also receive on-the-job training to facilitate the effective transaction of the health education curriculum. Health classes centered on life skills in kindergartens are vital and must be incorporated into the curricula.

Cross-Correlations between Scientific Physical Fitness, Body Mass Index Distribution, and Overweight/Obesity Risks among Adults in Taiwan.

Background and Objectives: Health-related physical fitness reduces the risk of chronic disease, promotes quality of life, and has enormous economic benefits considering the global health care costs resulting from obesity. However, relatively limited information is available regarding the dose-response relationship between scientific physical fitness and obesity risk. This study aimed to determine the associations of scientific physical fitness with body mass index (BMI) distribution and overweight/obesity risk among adults aged 23-64 years in Taiwan. Materials and Methods: We conducted a cross-sectional study and reviewed data derived from the Scientific Physical Fitness Testing Program, Sports Administration, Ministry of Education, Taiwan. Responses from 16,939 participants from the database (7761 men and 9178 women, aged 23-64 years) were collected in this study. Each participant completed a series of scientific physical fitness measurements, including cardiorespiratory fitness (3 min progressive knee-up and step [3MPKS] test), muscular fitness (hand grip strength), and flexibility (sit-and-reach test). Anthropometric measurements included body height, weight, and BMI. The quartiles of scientific physical fitness results were identified as the dependent variable in the multiple linear and multiple logistic regression analysis to determine the associations of the scientific physical fitness measurements with BMI distribution and overweight/obesity risk, as well as the dose-response relationship. Results: The 3MPKS test was significantly associated with BMI (quartile 1 (Q1): ß = 1.900; quartile 2 (Q2): ß = 1.594; quartile 3 (Q3): ß = 1.079 for men, and Q1: ß = 1.454; Q2: ß = 0.882; Q3: ß = 0.555 for women), overweight (Q1: odds ratio (OR) = 2.117; Q2: OR = 2.056; Q3: OR = 2.063 for men, and Q1: OR = 3.036; Q2: OR = 2.542; Q3: OR = 1.959 for women), and obesity (Q1: OR = 6.530; Q2: OR = 5.747; Q3: OR = 3.557 for men, and Q1: OR = 3.238; Q2: OR = 1.431 for women) risk compared with quartile 4 (Q4) as the reference group with a dose-response relationship. In addition, relative hand grip strength was significantly associated with BMI (Q2: ß = -0.922; Q3: ß = -1.865; Q4: ß = -3.108 for men, and Q2: ß = -1.309; Q3: ß = -2.161; Q4: ß = -2.759 for women), overweight (Q2: OR = 0.806; Q3: OR = 0.697; Q4: OR = 0.278 for men, and Q2: OR = 0.667; Q3: OR = 0.398; Q4: OR = 0.228 for women), and obesity (Q1: OR = 0.528; Q2: OR = 0.206; Q3: OR = 0.049 for men, and Q1: OR = 0.351; Q2: OR = 0.129; Q3: OR = 0.051 for women) risk compared with Q1 as the reference group with a dose-response relationship. Conclusions: Higher levels of performance of the 3MPKS and relative grip strength tests were associated with lower BMI and overweight/obesity risk in both sexes. However, the sit-and-reach test was only partially related to BMI and overweight/obesity risk in both sexes. Cardiorespiratory fitness and muscular fitness were effective predictors of BMI distribution and overweight/obesity risk in Taiwanese adults.

[Pregnancy Outcomes and Prognosis of Fetal Ventriculomegaly: A Retrospective Cohort Study].

Objective: To evaluate the pregnancy outcomes and neurodevelopment prognosis of subjects prenatally diagnosed with fetal ventriculomegaly (VM). Methods: All the subjects with VM diagnosed by ultrasound and were admitted and treated at West China Second Hospital, Sichuan University between March 2011 and September 2020 were retrospectively enrolled for a chohort study, while non-VM subjects of the same period were selected with a random number table to form the control group. Pregnancy outcomes of the two groups were compared, and the fetuses of both groups were followed up after birth for further assessment and comparison of their neurodevelopmental prognosis. Results: The live birth rate of the VM group was lower than that of the control group (77.63% [229/295] vs. 94.31% [265/281], P<0.001). Furthermore, the proportion of subjects that were transferred to NICU for monitoring and observation after birth was higher in the VM group than that of the control group (20.96% [48/229] vs. 4.53% [12/265], P<0.001). During the follow-up, it was found that the rate of neurodevelopmental abnormalities of the VM group was significantly higher than that of the control group (11.79% [27/229] vs. 1.90% [5/265], P<0.001). Moreover, neurodevelopmental abnormalities of VM fetuses were correlated to the following factors, the degree of VM ( P=0.010), intrauterine progression of VM ( P=0.024), and whether the postnatal cranial ultrasound result was suggestive of VM ( P=0.001). In addition, postnatal cranial ultrasound suggestive of VM was found to be an independent risk factor for neurodevelopmental abnormalities ( OR=9.434, 95% CI: 1.791-49.688, P=0.008). Conclusion: VM reduces the fetal live birth rate and may increase the risks of neurodevelopmental abnormalities after birth. All VM fetuses should be closely followed up for neurodevelopment status after birth, especially those with severe VM, intrauterine progression, and postnatal cranial ultrasound indicative of VM.

The ESCRT-III molecules regulate the apical targeting of bile salt export pump.

BACKGROUND: The bile salt export pump (BSEP) is a pivotal apical/canalicular bile salt transporter in hepatocytes that drives the bile flow. Defects in BSEP function and canalicular expression could lead to a spectrum of cholestatic liver diseases. One prominent manifestation of BSEP-associated cholestasis is the defective canalicular localization and cytoplasmic retention of BSEP. However, the etiology of impaired BSEP targeting to the canalicular membrane is not fully understood. Our goal was to discover what molecule could interact with BSEP and affect its post-Golgi sorting. METHODS: The human BSEP amino acids (a.a.) 491-630 was used as bait to screen a human fetal liver cDNA library through yeast two-hybrid system. We identified a BSEP-interacting candidate and showed the interaction and colocalization in the co-immunoprecipitation in hepatoma cell lines and histological staining in human liver samples. Temperature shift assays were used to study the post-Golgi trafficking of BSEP. We further determine the functional impacts of the BSEP-interacting candidate on BSEP in vitro. A hydrodynamically injected mouse model was established for in vivo characterizing the long-term impacts on BSEP. RESULTS: We identified that charged multivesicular body protein 5 (CHMP5), a molecule of the endosomal protein complex required for transport subcomplex-III (ESCRT-III), interacted and co-localized with BSEP in the subapical compartments (SACs) in developing human livers. Cholestatic BSEP mutations in the CHMP5-interaction region have defects in canalicular targeting and aberrant retention at the SACs. Post-Golgi delivery of BSEP and bile acid secretion were impaired in ESCRT-III perturbation or CHMP5-knockdown hepatic cellular and mouse models. This ESCRT-III-mediated BSEP sorting preceded Rab11A-regulated apical cycling of BSEP. CONCLUSIONS: Our results showed the first example that ESCRT-III is essential for canalicular trafficking of apical membrane proteins, and provide new targets for therapeutic approaches in BSEP associated cholestasis.

Calorie restriction conferred improvement effect on long-term rehabilitation of ischemic stroke via gut microbiota.

Calorie restriction can modulate the gut microbiota and protect against many diseases including ischemic stroke. However, the role of calorie-restriction-induced microbiota alteration remained unknown in ischemic stroke rehabilitation. Here we conducted 30% reduction of caloric intake on mice for four weeks, to evaluate its role on ischemic stroke rehabilitation. Significantly, this calorie restriction led to better long-term rehabilitation in comparison of normal control. Notably, the transplantation of gut microbiome from calorie-restriction-treated mice to post-stroke mice was eligible to obtain better long-term rehabilitation of stroke mice. Bifidobacterium identified by 16 S ribosomal RNA sequencing were enriched in those of calorie-restriction mice. Then we administrated Bifidobacterium to stroke mice and found Bifidobacterium treatment could successfully improve the long-term rehabilitation of cerebral ischemia mice. Furthermore, the metabolomics analysis revealed a panel of upshifting metabolites, suggesting that calorie restriction greatly altered the gut microbiota composition and its metabolism. Hence, we discovered the novel effect of CR on long-term rehabilitation of ischemic stroke and the underlying role of gut microbiota, which might provide novel thoughts for the clinical post-stroke rehabilitation.

Poor health-related physical fitness performance increases the overweight and obesity risk in older adults from Taiwan.

BACKGROUND: The purpose of the present study was to investigate the associations between health-related physical fitness performance and overweight/obesity risk among Taiwanese healthy older adults. METHODS: A secondary dataset from the nationwide survey was applied in this study. Data from a total of 21,630 respondents aged 65-96 years were collected in this study. Demographic characteristics, life habits, perceived health status, anthropometric assessments, and health-related physical fitness measurements from this dataset were analyzed using the chi-square test, one-way analysis of variance, and logistic regression analysis. RESULTS: The results indicated that overweight and obesity significantly associated with health-related physical fitness performance in the Taiwanese older adult population. In particular, the upper extremity muscular endurance scores of older adults with poor activity and physical fitness scores revealed obesity as a critical indicator of health-related physical fitness performance. CONCLUSIONS: Future studies can use muscle quality or body fat classification to predict obesity in older adults, which could more precisely portray the relationship between obesity and health-related physical fitness performance.

Potent Neutralizing Human Monoclonal Antibodies Preferentially Target Mature Dengue Virus Particles: Implication for Novel Strategy for Dengue Vaccine.

The four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The envelope (E) protein is the major target of neutralizing antibodies and contains 3 domains (domain I [DI], DII, and DIII). Recent studies reported that human monoclonal antibodies (MAbs) recognizing DIII, the D1/DII hinge, the E-dimer epitope, or a quaternary epitope involving DI/DII/DIII are more potently neutralizing than those recognizing the fusion loop (FL) of DII. Due to inefficient cleavage of the premembrane protein, DENV suspensions consist of a mixture of mature, immature, and partially immature particles. We investigated the neutralization and binding of 22 human MAbs to DENV serotype 1 (DENV1) virions with differential maturation status. Compared with FL MAbs, DIII, DI/DII hinge, and E-dimer epitope MAbs showed higher maximum binding and avidity to mature particles relative to immature particles; this feature may contribute to the strong neutralizing potency of such MAbs. FL-specific MAbs required 57 to 87% occupancy on mature particles to achieve half-maximal neutralization (NT50), whereas the potently neutralizing MAbs achieved NT50 states at 20 to 38% occupancy. Analysis of the MAb repertoire and polyclonal sera from patients with primary DENV1 infection supports the immunodominance of cross-reactive anti-E antibodies over type-specific antibodies. After depletion with viral particles from a heterologous DENV serotype, the type-specific neutralizing antibodies remained and showed binding features shared by potent neutralizing MAbs. Taken together, these findings suggest that the use of homogeneous mature DENV particles as an immunogen may induce more potent neutralizing antibodies against DENV than the use of immature or mixed particles.IMPORTANCE With an estimated 390 million infections per year, the four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The dengue vaccine Dengvaxia was licensed; however, its low efficacy among dengue-naive individuals and increased risk of causing severe dengue in children highlight the need for a better understanding of the role of human antibodies in immunity against DENV. DENV suspensions contain mature, immature, and partially immature particles. We investigated the binding of 22 human monoclonal antibodies (MAbs) to the DENV envelope protein on particles with different maturation states. Potently neutralizing MAbs had higher relative maximum binding and avidity to mature particles than weakly neutralizing MAbs. This was supported by analysis of MAb repertoires and polyclonal sera from patients with primary DENV infection. Together, these findings suggest that mature particles may be the optimal form of presentation of the envelope protein to induce more potent neutralizing antibodies against DENV.

Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges.

OBJECTIVE: To test the application of a target enrichment next-generation sequencing (NGS) jaundice panel in genetic diagnosis of pediatric liver diseases. STUDY DESIGN: We developed a capture-based target enrichment NGS jaundice panel containing 42 known disease-causing genes associated with jaundice or cholestasis and 10 pathway-related genes. During 2015-2017, 102 pediatric patients with various forms of cholestasis or idiopathic liver diseases were tested, including patients with initial diagnosis of cholestasis in infancy, progressive familial intrahepatic cholestasis, syndromic cholestasis, Wilson disease, and others. RESULTS: Of the 102 patients, 137 mutations/variants in 44 different genes were identified in 84 patients. The genetic disease diagnosis rate was 33 of 102 (32.4%). A total of 79 of 102 (77.5%) of patients had at least 1 heterozygous genetic variation. Those with progressive intrahepatic cholestasis or syndromic cholestasis in infancy had a diagnostic rate of 62.5%. Disease-causing mutations, including ATP8B1, ABCB11, ABCB4, ABCC2, TJP2, NR1H4 (FXR), JAG1, AKR1D1, CYP7B1, PKHD1, ATP7B, and SLC25A13, were identified. Nine patients had unpredicted genetic diagnosis with atypical phenotype or novel mutations in the investigational genes. We propose an NGS diagnosis classification categorizing patients into high (n = 24), moderate (n = 9), or weak (n = 25) levels of genotype-phenotype correlations to facilitate patient management. CONCLUSIONS: This panel enabled high-throughput detection of genetic variants and disease diagnosis in patients with a long list of candidate causative genes. A NGS report with diagnosis classification may aid clinicians in data interpretation and patient management.

Annonaceous acetogenin mimic AA005 suppresses human colon cancer cell growth in vivo through downregulation of Mcl-1.

Annonaceous acetogenins are a well-established family of natural products with significant bioactivities, especially high cytotoxic and antitumor activities. AA005 is an annonaceous acetogenin mimic that has shown significant cytotoxicity against a variety of cancer cell lines, but its in vivo antitumor effects have not been demonstrated so far, and its anticancer mechanisms remain ambiguous. In this study, we investigated the effects of AA005 on human colon cancer cell lines in vivo. Human colon carcinoma cell line SW620 xenograft nude mice were treated with AA005 (5 mg/kg/day, i.p.) for 21 days. AA005 administration markedly inhibited the tumor growth via promoting nuclear translocation of apoptosis-inducing factor (AIF) and inducing AIF-dependent cell death. Subsequent studies in human colon carcinoma cell lines SW620 and RKO in vitro revealed that after the colon cancer cells exposed to AA005, downregulation of a B-cell lymphoma 2 family protein, myeloid cell leukemia-1 (Mcl-1), was an early event due to the inhibition of Mcl-1 mRNA level and protein synthesis in a time-dependent manner. Intriguingly, knockdown of Mcl-1 using small interfering RNA markedly accelerated the nuclear translocation of AIF and upregulation of receptor interacting protein-1, and enhanced AA005-mediated lethality, whereas ectopic expression of Mcl-1 substantially attenuated AA005-mediated lethality in the colon cancer cells. Finally, silencing Mcl-1 expression markedly enhanced AA005-induced lethality in SW620 xenograft nude mice, demonstrating a pivotal role of Mcl-1 downregulation in mediating the in vivo antitumor effects of AA005. Taken together, this study demonstrates for the first time the anticancer effects of AA005 against human colon cancer cell lines in vivo, which is mediated through the downregulation of Mcl-1.

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases.

BACKGROUND: Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis. MAIN BODY: The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway. SHORT CONCLUSION: Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.