NADPH oxidase-dependent H2O2 production mediates salicylic acid-induced salt tolerance in mangrove plant Kandelia obovata by regulating Na+/K+ and redox homeostasis.

Salicylic acid (SA) is known to enhance salt tolerance in plants. However, the mechanism of SA-mediated response to high salinity in halophyte remains unclear. Using electrophysiological and molecular biological methods, we investigated the role of SA in response to high salinity in mangrove species, Kandelia obovata, a typical halophyte. Exposure of K. obovata roots to high salinity resulted in a rapid increase in endogenous SA produced by phenylalanine ammonia lyase pathway. The application of exogenous SA improved the salt tolerance of K. obovata, which depended on the NADPH oxidase-mediated H2O2. Exogenous SA and H2O2 increased Na+ efflux and reduced K+ loss by regulating the transcription levels of Na+ and K+ transport-related genes, thus reducing the Na+/K+ ratio in the salt-treated K. obovata roots. In addition, exogenous SA-enhanced antioxidant enzyme activity and its transcripts, and the expressions of four genes related to AsA-GSH cycle as well, then alleviated oxidative damages in the salt-treated K. obovata roots. However, the above effects of SA could be reversed by diphenyleneiodonium chloride (the NADPH oxidase inhibitor) and paclobutrazol (a SA biosynthesis inhibitor). Collectively, our results demonstrated that SA-induced salt tolerance of K. obovata depends on NADPH oxidase-generated H2O2 that affects Na+/K+ and redox homeostasis in response to high salinity.

m6 A deposition is regulated by PRMT1-mediated arginine methylation of METTL14 in its disordered C-terminal region.

The N6-methyladenosine (m6 A) RNA modification serves crucial functions in RNA metabolism; however, the molecular mechanisms underlying the regulation of m6 A are not well understood. Here, we establish arginine methylation of METTL14, a component of the m6 A methyltransferase complex, as a novel pathway that controls m6 A deposition in mammalian cells. Specifically, protein arginine methyltransferase 1 (PRMT1) interacts with, and methylates the intrinsically disordered C terminus of METTL14, which promotes its interaction with RNA substrates, enhances its RNA methylation activity, and is crucial for its interaction with RNA polymerase II (RNAPII). Mouse embryonic stem cells (mESCs) expressing arginine methylation-deficient METTL14 exhibit significantly reduced global m6 A levels. Transcriptome-wide m6 A analysis identified 1,701 METTL14 arginine methylation-dependent m6 A sites located in 1,290 genes involved in various cellular processes, including stem cell maintenance and DNA repair. These arginine methylation-dependent m6 A sites are associated with enhanced translation of genes essential for the repair of DNA interstrand crosslinks; thus, METTL14 arginine methylation-deficient mESCs are hypersensitive to DNA crosslinking agents. Collectively, these findings reveal important aspects of m6 A regulation and new functions of arginine methylation in RNA metabolism.

Splicing defects in rare diseases: transcriptomics and machine learning strategies towards genetic diagnosis.

Genomic variants affecting pre-messenger RNA splicing and its regulation are known to underlie many rare genetic diseases. However, common workflows for genetic diagnosis and clinical variant interpretation frequently overlook splice-altering variants. To better serve patient populations and advance biomedical knowledge, it has become increasingly important to develop and refine approaches for detecting and interpreting pathogenic splicing variants. In this review, we will summarize a few recent developments and challenges in using RNA sequencing technologies for rare disease investigation. Moreover, we will discuss how recent computational splicing prediction tools have emerged as complementary approaches for revealing disease-causing variants underlying splicing defects. We speculate that continuous improvements to sequencing technologies and predictive modeling will not only expand our understanding of splicing regulation but also bring us closer to filling the diagnostic gap for rare disease patients.

Bortezomib restrains M2 polarization and reduces CXCL16-associated CXCR6+CD4 T cell chemotaxis in bleomycin-induced pulmonary fibrosis.

BACKGROUND: The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been shown to have dual effects on fibrosis, with bleomycin exacerbating pulmonary fibrosis and bortezomib alleviating tissue fibrotic processes. Understanding the intricate interplay between chemotherapeutic drugs, immune responses, and pulmonary fibrosis is likely to serve as the foundation for crafting tailored therapeutic strategies. METHODS: A model of bleomycin-induced pulmonary fibrosis was established, followed by treatment with bortezomib. Tissue samples were collected for analysis of immune cell subsets and functional assessment by flow cytometry and in vitro cell experiments. Additionally, multi-omics analysis was conducted to further elucidate the expression of chemokines and chemokine receptors, as well as the characteristics of cell populations. RESULTS: Here, we observed that the expression of CXCL16 and CXCR6 was elevated in the lung tissue of a pulmonary fibrosis model. In the context of pulmonary fibrosis or TGF-ß1 stimulation in vitro, macrophages exhibited an M2-polarized phenotype and secreted more CXCL16 than those of the control group. Moreover, flow cytometry revealed increased expression levels of CD69 and CXCR6 in pulmonary CD4 T cells during fibrosis progression. The administration of bortezomib alleviated bleomycin-induced pulmonary fibrosis, accompanied by reduced ratio of M2-polarized macrophages and decreased accumulation of CD4 T cells expressing CXCR6. CONCLUSIONS: Our findings provide insights into the key immune players involved in bleomycin-induced pulmonary fibrosis and offer preclinical evidence supporting the repurposing strategy and combination approaches to reduce lung fibrosis.

Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection.

BACKGROUND: A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. METHODS: In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months. RESULTS: A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups. CONCLUSIONS: In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).

Dynamic and Asymmetrical Ion Concentration Polarization in Dual Nanopipettes.

Dual nanopipettes with two channels have been receiving great attention due to the convenient experimental setup and multiple measuring channels in sensing applications at nanoscale, while the involved dynamic and asymmetrical ion transport processes have not been fully elucidated. In this paper, both experimental and simulation methods are used to investigate the dynamic mass transport processes inside dual nanopipettes with two well-separated channels. The results present that the ion transport resistance through the two channels (R12) is always the add-up of the individual ones (R13 + R23) with respect to the bulk solutions, at various ionic strengths and scan rates. A constant zero-current potential is obtained when loading an asymmetrical electrolyte concentration in the two channels, and the zero-potential current displays a good linear relationship with the bulk concentration outside the pipet. Besides revealing the dynamic and asymmetrical concentration polarization in the dual nanopipettes, these results would also further promote the better usage of dual nanopipettes in electrochemical sensing and imaging applications.

Brassinosteroid enhances salt tolerance via S-nitrosoglutathione reductase and nitric oxide signaling pathway in mangrove Kandelia obovata.

Brassinosteroid (BR) has been shown to modulate plant tolerance to various stresses. S-nitrosoglutathione reductase (GSNOR) is involved in the plant response to environment stress by fine-turning the level of nitric oxide (NO). However, whether GSNOR is involved in BR-regulated Na+ /K+ homeostasis to improve the salt tolerance in halophyte is unknown. Here, we firstly reported that high salinity increases the expression of BR-biosynthesis genes and the endogenous levels of BR in mangrove Kandelia obovata. Then, salt-induced BR triggers the activities and gene expressions of GSNOR and antioxidant enzymes, thereafter decrease the levels of malondialdehyde, hydrogen peroxide. Subsequently, BR-mediated GSNOR negatively regulates NO contributions to the reduction of reactive oxygen species generation and induction of the gene expression related to Na+ and K+ transport, leading to the decrease of Na+ /K+ ratio in the roots of K. obovata. Finally, the applications of exogenous BR, NO scavenger, BR biosynthetic inhibitor and GSNOR inhibitor further confirm the function of BR. Taken together, our result provides insight into the mechanism of BR in the response of mangrove K. obovata to high salinity via GSNOR and NO signaling pathway by reducing oxidative damage and modulating Na+ /K+ homeostasis.

Multitask deep learning for prediction of microvascular invasion and recurrence-free survival in hepatocellular carcinoma based on MRI images.

BACKGROUND AND AIMS: Accurate preoperative prediction of microvascular invasion (MVI) and recurrence-free survival (RFS) is vital for personalised hepatocellular carcinoma (HCC) management. We developed a multitask deep learning model to predict MVI and RFS using preoperative MRI scans. METHODS: Utilising a retrospective dataset of 725 HCC patients from seven institutions, we developed and validated a multitask deep learning model focused on predicting MVI and RFS. The model employs a transformer architecture to extract critical features from preoperative MRI scans. It was trained on a set of 234 patients and internally validated on a set of 58 patients. External validation was performed using three independent sets (n = 212, 111, 110). RESULTS: The multitask deep learning model yielded high MVI prediction accuracy, with AUC values of 0.918 for the training set and 0.800 for the internal test set. In external test sets, AUC values were 0.837, 0.815 and 0.800. Radiologists' sensitivity and inter-rater agreement for MVI prediction improved significantly when integrated with the model. For RFS, the model achieved C-index values of 0.763 in the training set and ranged between 0.628 and 0.728 in external test sets. Notably, PA-TACE improved RFS only in patients predicted to have high MVI risk and low survival scores (p < .001). CONCLUSIONS: Our deep learning model allows accurate MVI and survival prediction in HCC patients. Prospective studies are warranted to assess the clinical utility of this model in guiding personalised treatment in conjunction with clinical criteria.

Relationship between exposure to metalworking fluids and nonalcoholic fatty liver disease.

OBJECTIVE: The relationship between metalworking fluids (MWFs) and nonalcoholic fatty liver disease (NAFLD) has not been previously explored. We aim to investigate the relationship between occupational exposure to MWFs and the prevalence of NAFLD and to determine the cumulative exposure threshold per day. METHODS: In 2020, 2079 employees were selected randomly from one computer numerical control machining factory in Wuxi for a questionnaire survey, and occupational health examinations were conducted at the affiliated branch of Wuxi Eighth People's Hospital. MWF samples were collected within the factory using the National Institute for Occupational Safety and Health (NIOSH) 5524 method. NAFLD was defined as having a hepatic steatosis index (HSI) ≥ 36 without significant alcohol consumption. The relationship between NAFLD and MWFs was analyzed using logistic regression, and the daily exposure threshold was calculated using R software. RESULTS: MWF exposure was found to be a risk factor for NAFLD in exposed workers compared to the non-exposed group. The OR for NAFLD in workers exposed to MWFs compared to controls was 1.42 (95% CI: 1.04-1.95). An increased risk of NAFLD was shown to be associated with an increasing dose. The daily exposure dose threshold to MWFs was found to be 6.54 mg/m3 (OR = 2.09, 95% CI: 1.24-3.52). CONCLUSION: An association between occupational exposure to MWFs and NAFLD was found. As the concentration of exposure rose, the prevalence of NAFLD was also escalated.

Association between occupational noise and obesity: a retrospective cohort study in China.

OBJECTIVES: To determine the relationship between occupational noise, and obesity and body mass index (BMI) changes. METHODS: Baseline data were collected from participants (n = 1264) who were followed for 6 years in a retrospective study. The noise exposure level (LAeq,8h) was determined by equivalent continuous weighted sound pressure levels using the fixed-point surveillance method for noise monitoring. The cumulative noise exposure (CNE) level was determined using the equal energy formula, which is based on exposure history and level. RESULTS: The incidence of obesity at low (RR = 2.364, 95% CI 1.123-4.739]), medium (RR = 3.921, 95% CI 1.946-7.347]), high (RR = 5.242, 95% CI 2.642-9.208]), and severe noise levels (RR = 9.322, 95% CI 5.341-14.428]) was higher risk than the LAeq,8h control level. The risk of obesity among participants exposed to low (RR = 2.957, 95% CI 1.441-6.068]) and high cumulative noise levels (RR = 7.226, 95% CI 3.623-14.415]) was greater than the CNE control level. For every 1 dB(A) increase in LAeq,8h, the BMI increased by 0.063 kg/m2 (95% CI 0.055-0.071], SE = 0.004). For every 1 dB(A) increase in the CNE, the BMI increased by 0.102 kg/m2 (95% CI 0.090-0.113], SE = 0.006). CONCLUSIONS: Occupational noise is related to the incidence of obesity. The occupational noise level and occupational noise cumulative level were shown to be positively correlated with an increase in BMI.

Association between exposure to metalworking fluid aerosols, occupational noise and chronic kidney disease: a cross-sectional study in China.

BACKGROUND: Chronic kidney disease (CKD) carries a high public health burden yet little is known about the relationship between metalworking fluid (MWF) aerosols, occupational noise and CKD. We aimed to explore the relationship between occupational MWF aerosols, occupational noise and CKD. METHODS: A total of 2,738 machinists were sampled from three machining companies in Wuxi, China, in 2022. We used the National Institute for Occupational Safety and Health (NIOSH) method 5524 to collect individual samples for MWF aerosols exposure, and the Chinese national standard (GBZ/T 189.8-2007) method to test individual occupational noise exposure. The diagnostic criteria for CKD were urinary albumin/creatinine ratio (UACR) of ≥ 30 mg/g and reduced renal function (eGFR < 60 mL.min- 1. 1.73 m- 2) lasting longer than 3 months. Smooth curve fitting was conducted to analyze the associations of MWF aerosols and occupational noise with CKD. A segmented regression model was used to analyze the threshold effects. RESULTS: Workers exposed to MWF aerosols (odds ratio [OR] = 2.03, 95% confidence interval [CI]: 1.21-3.41) and occupational noise (OR = 1.77, 95%CI: 1.06-2.96) had higher prevalence of CKD than nonexposed workers. A nonlinear and positive association was found between increasing MWF aerosols and occupational noise dose and the risk of CKD. When daily cumulative exposure dose of MWF aerosols exceeded 8.03 mg/m3, the OR was 1.24 (95%CI: 1.03-1.58), and when occupational noise exceeded 87.22 dB(A), the OR was 1.16 (95%CI: 1.04-1.20). In the interactive analysis between MWF aerosols and occupational noise, the workers exposed to both MWF aerosols (cumulative exposure ≥ 8.03 mg/m3-day) and occupational noise (LEX,8 h ≥ 87.22 dB(A)) had an increased prevalence of CKD (OR = 2.71, 95%CI: 1.48-4.96). MWF aerosols and occupational noise had a positive interaction in prevalence of CKD. CONCLUSIONS: Occupational MWF aerosols and noise were positively and nonlinearly associated with CKD, and cumulative MWF aerosols and noise exposure showed a positive interaction with CKD. These findings emphasize the importance of assessing kidney function of workers exposed to MWF aerosols and occupational noise. Prospective and longitudinal cohort studies are necessary to elucidate the causality of these associations.

Identical clinical outcomes between neutral and classic targeted alignments after high tibial osteotomy in medial meniscus posterior root tear: a prospective randomized study.

PURPOSE: This study aimed to compare the clinical and radiographic outcomes and arthroscopic findings after high tibial osteotomy (HTO) between neutral and classic targeted coronal alignments in patients with medial meniscus posterior root tears (MMPRTs). METHODS: Ninety-eight patients with MMPRT were prospectively enrolled in the final cohort and randomized into two groups. Fifty-two patients with the targeted alignment through the Fujisawa point (60-62.5% of the entire tibial plateau width measured from the medial side) during HTO were included in group A, whereas 46 patients with the targeted alignment through the point at 50-55% of the tibial plateau width were included in group B. The clinical and radiographic outcomes and second-look arthroscopic findings were statistically compared for comprehensive assessments. RESULTS: After a mean follow-up of 37.1 months, we found no significant differences between the two groups regarding the final Lysholm (p = 0.205) and Hospital for Special Surgery scores (p = 0.084). However, we only observed significant differences between the two groups in terms of the final hip-knee-ankle angle, weight-bearing line ratio, and medial proximal tibial angle (p < 0.001). Second-look arthroscopy did not reveal a significant difference in meniscal healing rate (p = 0.786). CONCLUSIONS: Performing HTO with the aim to achieve neutral alignment leads to similar clinical outcomes in patients with MMPRT compared to classic alignment. Although subsequent research is required, the current study provides clinical evidence for the safety and efficacy of the new targeted alignment during HTO, which may avoid long-term complications associated with overcorrection when using the traditional technique.

Evaluating the prognostic significance of p53 and TP53 mutations in HPV-negative hypopharyngeal carcinoma patients: a 5-year follow-up retrospective study.

PURPOSE: To evaluate prognostic significance of human papillomavirus (HPV) in hypopharyngeal squamous cell carcinoma patients, and to investigate the effect of p53 and TP53 mutations on the prognosis of patients. METHODS: A total of 111 patients were enrolled in our retrospective study. HPV infection status was detected in formalin-fixed paraffin-embedded tissue by real-time multiplex PCR test. p53 expression was evaluate by immunohistochemical staining. TP53 exon mutations were analyzed by PCR amplification and Sanger sequencing. HPV infection status, p53 expression and TP53 mutation were compared with clinical outcome including overall survival and recurrence-free survival by Kaplan-Meier method and Log-rank test. RESULTS: Of the 111 investigated patients, 18 (16.22%) were positive for HPV infection. HPV(-) patients have a worse clinical outcome than HPV(+) patients. TP53 mutations have similar mutation rates in patients with and without HPV (55.56% vs. 41.94%). p53 and TP53 mutation were not associated with prognosis of patients in HPV(-) patients. TP53 disruptive mutations were found both in patients with or without HPV infection. Furthermore, TP53 non-disruptive mutation had a significantly better clinical outcome than those with disruptive mutation in HPV(-) patients. CONCLUSION: Our results showed that HPV infection status is a strong prognostic indicator of survival. p53 and TP53 mutations do not appear to significantly impact survival in HPV(-) patients. TP53 disruptive mutation is associated with reduced survival in HPV(-)/TP53 mutation patients.

Anammox-Mediated Hydroxyapatite Granules: Physicochemical Properties, 3D Hierarchy, and Biofilm Thickness.

Biomineralization inspired the development of simultaneous biological transformations and chemical precipitation for simultaneous nitrogen removal and phosphorus recovery from wastewater, which could compensate for the incapacity of phosphorus management in the new biological route of anaerobic ammonium oxidation (anammox). In this study, we strengthened anammox-mediated biomineralization by long-term feeding of concentrated N, P, and Ca substrates, and a self-assembled matrix of anammox bacteria and hydroxyapatite (HAP) was fabricated in a granular shape, defined as HAP-anammox granules. HAP was identified as the dominant mineral using elemental analysis, X-ray diffraction, and Raman spectroscopy. The intensive precipitation of HAP resulted in a higher inorganic fraction and substantially improved settleability of anammox biomass, which facilitated HAP precipitation by acting as nucleation and metabolically elevated pH. By using X-ray microcomputed tomography, we visually represented the hybrid texture of interwoven HAP pellets and biomass, the core-shell layered architecture of different-sized HAP-anammox granules, and their homogeneously regulated thickness of the outer biofilm (from 118 to 635 µm). This unique architecture endows HAP-anammox granules with outstanding settleability, active biofilm, and tightly bonded biofilm with the carrier, which may explain the excellent performance of these HAP-anammox granules under various challenging operational conditions in previous studies.

Follicle-stimulating hormone is negatively associated with nonalcoholic fatty liver disease in a Chinese elderly population: a retrospective observational study.

BACKGROUND: Several studies have explored the connection between follicle-stimulating hormone (FSH) and nonalcoholic fatty liver disease (NAFLD). However, the impact of FSH elevation on NAFLD remains a topic of debate. Hence, this investigation aimed to evaluate the potential correlation between FSH levels and NAFLD in the aging population. METHODS: This was a retrospective observational cross-sectional study between July 2017 and August 2018 in our hospital. We used data obtained from 455 patients over 60 years old. Anthropometrics and laboratory tests were performed for each patient. NAFLD was diagnosed by sonographic features and the fatty liver index (LFI). RESULTS: Of the 455 patients, 200 (43.96%) had NAFLD on their ultrasound and 169 (37.14%) had NAFLD according to the LFI. An intraclass correlation coefficient of the two methods was 80.4% (P < 0.001). People with NAFLD on their ultrasound showed lower FSH levels (52.68 vs. 61.39 IU/L) and more unfavorable metabolic profiles. FSH was negatively correlated with age, alanine aminotransferase, estradiol, testosterone, systolic blood pressure, waist, body mass index, fasting blood glucose, postload plasma glucose and positive associated with total cholesterol, high-density lipoprotein-cholesterol and low-density lipoprotein-cholesterol by Spearman correlation analysis (all P < 0.05). By controlling for all confounding factors, the odds ratios (OR) of FSH for NAFLD were determined in elderly individuals, both men and women, aged 60-70 years and over 70 years. These ORs were found to be 0.937, 0.982, 0.983, and 0.973, respectively, with corresponding 95% confidence intervals (CI) of 0.892-0.984 (P = 0.009), 0.971-0.993 (P = 0.002), 0.967-0.999 (P = 0.033), and 0.958-0.989 (P = 0.001). In addition, our findings demonstrated no significant correlation between FSH and advanced fibrosis when adjusting for potential covariates. The OR for advanced fibrosis was 0.979 (95% CI, 0.938-1.022, P = 0.339). Additionally, ROC curve analysis showed an optimal cut-off value of 66.91 for women and 15.25 for men for NAFLD diagnosis. CONCLUSIONS: There was an inverse relationship observed between levels of FSH in the blood serum and NAFLD in the elderly population. These findings suggest that reduced FSH levels might serve as a potential risk factor or biomarker for NAFLD in the elderly.

Dual-edged effects and mechanisms of hydroxylamine in partial denitrification-anaerobic ammonium oxidation system.

The combination of partial denitrification (PD) and anaerobic ammonium oxidation (anammox) is a novel and promising nitrogen removal process. Regulating the synergistic reaction between denitrifiers and anammox bacteria (AnAOB) is the key to achieving stable and efficient PD-anammox performance. In this study, 10 mg/L of hydroxylamine (NH2OH) was considered to efficiently promote the bacterial activity, microbial energy flow, and the synergy of functional microflora. As a result, the nitrogen removal rate (NRR) significantly increased from 0.05 to 0.30 g N/L/d in parallel with an increase in the nitrogen loading rate (NLR) from 0.10 to 0.40 g N/L/d. However, the dual-edged effect of NH2OH was also confirmed. The long-term presence of NH2OH caused overgrowth of complete-denitrifying bacteria and decreased the NRR to 0.11 g N/L/d. Additionally, NH2OH enhanced nitrous oxide (N2O) emissions via chemical pathways as well as enhanced denitrification Fortunately, the inhibition caused by NH2OH was reversible by stopping the dosing, the reactor restored to stable operation with an NRR of 0.27 g N/L/d. Analysis of metabolic intensity and pathways revealed the effecting process and mechanism of NH2OH on the PD-anammox system. This study verified the dual-edged effects and mechanisms of NH2OH, therefore proving a theoretical basis and technical reference for the application of PD-anammox.

Mucin1 induced trophoblast dysfunction in gestational diabetes mellitus via Wnt/ß-catenin pathway.

BACKGROUND: To elucidate the role of Mucin1 (MUC1) in the trophoblast function (glucose uptake and apoptosis) of gestational diabetes mellitus (GDM) women through the Wnt/ß-catenin pathway. METHODS: Glucose uptake was analyzed by plasma GLUT1 and GLUT4 levels with ELISA and measured by the expression of GLUT4 and INSR with immunofluorescence and Western blotting. Apoptosis was measured by the expression of Bcl-2 and Caspase3 by Western blotting and flow cytometry. Wnt/ß-catenin signaling measured by Western blotting. In vitro studies were performed using HTR-8/SVneo cells that were cultured and treated with high glucose (HG), sh-MUC1 and FH535 (inhibitor of Wnt/ß-catenin signaling). RESULTS: MUC1 was highly expressed in the placental trophoblasts of GDM, and the Wnt/ß-catenin pathway was activated, along with dysfunction of glucose uptake and apoptosis. MUC1 knockdown resulted in increased invasiveness and decreased apoptosis in trophoblast cells. The initial linkage between MUC1, the Wnt/ß-catenin pathway, and glucose uptake was confirmed by using an HG-exposed HTR-8/SVneo cell model with MUC1 knockdown. MUC1 knockdown inhibited the Wnt/ß-catenin signaling pathway and reversed glucose uptake dysfunction and apoptosis in HG-induced HTR-8/SVneo cells. Meanwhile, inhibition of Wnt/ß-catenin signaling could also reverse the dysfunction of glucose uptake and apoptosis. CONCLUSIONS: In summary, the increased level of MUC1 in GDM could abnormally activate the Wnt/ß-catenin signaling pathway, leading to trophoblast dysfunction, which may impair glucose uptake and induce apoptosis in placental tissues of GDM women.

Disparities in the level of COVID-19 health literacy and the associated factors among employees in long-term care facilities in Taiwan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) poses a significant threat to the safety of residents in long-term care facilities, and the staff of long-term care facilities are essential in the care and prevention of major infectious diseases and therefore require good health literacy to ensure the health of residents. The main objective of this study was to examine the health literacy of staff in long-term care facilities and analyze the factors associated with their COVID-19 health literacy in Taiwan to provide a basis for the response mechanism to emerging infectious diseases. METHODS: A cross-sectional survey with a structured questionnaire by a convenience sample method and to assess the COVID-19 health literacy of caregivers working in long-term care facilities in this study. The COVID-19 health literacy scale was a self-administered scale designed to combine the concept of "health literacy" with the 3 levels and 5 stages of preventive medicine. A total of 385 workers from 10 long-term care facilities were surveyed as the study sample, and the validated questionnaires were statistically analyzed using SPSS version 22.0 statistical software. A multivariate logistic regression model was used to establish the associated factors of the COVID-19 health literacy level. RESULTS: Overall, the mean COVID-19 health literacy score was 88.7 ± 10.4 (range: 58-105). Using a quartile scale, 92 (23.9%) of the study participants had low health literacy (health literacy score < 82), 190 (49.3%) had average health literacy (health literacy score 82-98), and the remaining 103 (26.8%) had good health literacy (health literacy score 99-105). Statistical analysis revealed significant differences (p < 0.05) in the COVID-19 health literacy score by demographic variables (education, job category, number of daily service users, and training related to infectious disease prevention and control) of the study population. The logistic regression analysis of the COVID-19 health literacy level (> 82 vs. ≤82) showed a significant difference in the study sample by gender (male vs. female, OR = 2.46, 95% CI = 1.15-5.26), job category (nurse practitioner vs. caregiver, OR = 7.25, 95% CI = 2.46-21.44), monthly service hours (> 160 h vs. 40-79 h, OR = 0.044, 95% CI = 0.07-0.97), experience caring for confirmed COVID-19 patients (yes vs. no, OR = 0.13, 95% CI = 0.02-0.98), and training related to infectious disease prevention and control (yes vs. no, OR = 2.8, 95% CI = 1.52-5.15). CONCLUSIONS: This study recommends that facilities provide immediate updated COVID-19 information to staff, especially frontline caregivers, and specifically enhance COVID-19 infection control education training for all facility staff to eliminate health literacy disparities.

Berberine plays a cardioprotective role by inhibiting macrophage Wnt5a/ß-catenin pathway in the myocardium of mice after myocardial infarction.

Myocardial infarction (MI) is one of the diseases with high fatality rate. Berberine (BBR) is a monomer compound with various biological functions. And some studies have confirmed that BBR plays an important role in alleviating cardiomyocyte injury after MI. However, the specific mechanism is unclear. In this study, we induced a model of MI by ligation of the left anterior descending coronary artery and we surprisingly found that BBR significantly improved ventricular remodeling, with a minor inflammatory and oxidative stress injury, and stronger angiogenesis. Moreover, BBR inhibited the secretion of Wnt5a/ß-catenin pathway in macrophages after MI, thus promoting the differentiation of macrophages into M2 type. In summary, BBR effectively improved cardiac function of mice after MI, and the potential protective mechanism was associated with the regulation of inflammatory responses and the inhibition of macrophage Wnt5a/ß-catenin pathway in the infarcted heart tissues. Importantly, these findings supported BBR as an effective cardioprotective drug after MI.

A Convolutional Neural Network and Graph Convolutional Network Based Framework for AD Classification.

The neuroscience community has developed many convolutional neural networks (CNNs) for the early detection of Alzheimer's disease (AD). Population graphs are thought of as non-linear structures that capture the relationships between individual subjects represented as nodes, which allows for the simultaneous integration of imaging and non-imaging information as well as individual subjects' features. Graph convolutional networks (GCNs) generalize convolution operations to accommodate non-Euclidean data and aid in the mining of topological information from the population graph for a disease classification task. However, few studies have examined how GCNs' input properties affect AD-staging performance. Therefore, we conducted three experiments in this work. Experiment 1 examined how the inclusion of demographic information in the edge-assigning function affects the classification of AD versus cognitive normal (CN). Experiment 2 was designed to examine the effects of adding various neuropsychological tests to the edge-assigning function on the mild cognitive impairment (MCI) classification. Experiment 3 studied the impact of the edge assignment function. The best result was obtained in Experiment 2 on multi-class classification (AD, MCI, and CN). We applied a novel framework for the diagnosis of AD that integrated CNNs and GCNs into a unified network, taking advantage of the excellent feature extraction capabilities of CNNs and population-graph processing capabilities of GCNs. To learn high-level anatomical features, DenseNet was used; a set of population graphs was represented with nodes defined by imaging features and edge weights determined by different combinations of imaging or/and non-imaging information, and the generated graphs were then fed to the GCNs for classification. Both binary classification and multi-class classification showed improved performance, with an accuracy of 91.6% for AD versus CN, 91.2% for AD versus MCI, 96.8% for MCI versus CN, and 89.4% for multi-class classification. The population graph's imaging features and edge-assigning functions can both significantly affect classification accuracy.