Short-chain fatty acids suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in experimental autoimmune encephalomyelitis mice.

The function of astrocytes in response to gut microbiota-derived signals has an important role in the pathophysiological processes of central nervous system (CNS) diseases. However, the specific effects of microbiota-derived metabolites on astrocyte activation have not been elucidated yet. Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL/6 mice as a classical MS model. The alterations of gut microbiota and the levels of short-chain fatty acids (SCFAs) were assessed after EAE induction. We observed that EAE mice exhibit low levels of Allobaculum, Clostridium_IV, Clostridium_XlVb, Lactobacillus genera, and microbial-derived SCFAs metabolites. SCFAs supplementation suppressed astrocyte activation by increasing the level of tryptophan (Trp)-derived AhR ligands that activating the AhR. The beneficial effects of SCFAs supplementation on the clinical scores, histopathological alterations, and the blood brain barrier (BBB)-glymphatic function were abolished by intracisterna magna injection of AAV-GFAP-shAhR. Moreover, SCFAs supplementation suppressed the loss of AQP4 polarity within astrocytes in an AhR-dependent manner. Together, SCFAs potentially suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in EAE mice. Our study demonstrates that SCFAs supplementation may serve as a viable therapy for inflammatory disorders of the CNS.

Risk factors for converting traditional wards to temporary intensive care units during the COVID-19 pandemic: Insights from nurses' perspectives.

BACKGROUND: The surge in critically ill COVID-19 patients caused a shortage of intensive care unit (ICU) beds. Some hospitals temporarily transformed general wards into ICUs to meet this pressing health care demand. AIM: This study aims to evaluate and analyse the risk factors in temporary ICU from the perspective of nurses. By identifying these factors, the goal is to provide actionable insights and recommendations for effectively establishing and managing temporary ICUs in similar crisis scenarios in the future. STUDY DESIGN: The study was conducted in China within a public hospital. Specifically, it focused on examining 62 nurses working in a temporary ICU that was converted from an infectious disease ward. The research utilized the Hazard Vulnerability Analysis (HVA) scoring method to identify potential threats, evaluate their probability, estimate their impact on specific organizations or regions and calculate the relative risk associated with such occurrences. RESULTS: Staff demonstrated the highest risk percentage (32.74%), with Stuff (16.11%), Space (15.19%) and System (11.30%) following suit. The most critical risk factors included insufficient knowledge and decision-making competence in critical care (56.14%), lacking decision-making abilities and skills in renal replacement therapy care (55.37%), inadequate decision-making capacity and relevant skills in respiratory support care (50.64%), limited decision-making capability in circulatory support care (45.73%) and unfamiliarity with work procedures or systems (42.09%). CONCLUSIONS: Urgent implementation of tailored training and support for temporary ICU nurses is paramount. Addressing capability and skill-related issues among these nurses supersedes resource availability, infrastructure, equipment and system considerations. Essential interventions must target challenges encompassing nurses' inability to perform critical treatment techniques autonomously and ensure standardized care. These measures are designed to heighten patient safety and elevate care quality during emergencies. These findings offer a viable avenue to mitigate potential moral distress, anxiety and depression among nurses, particularly those transitioning from non-critical care backgrounds. These nurses swiftly assimilate into temporary ICUs, and the study's insights offer practical guidance to alleviate their specific challenges. RELEVANCE TO CLINICAL PRACTICE: The study on risk factors for converting traditional wards into temporary ICU during the COVID-19 pandemic, especially from the perspective of nurses, provides crucial insights into the challenges and requirements for effectively establishing and managing these emergency settings. The findings highlight several key areas of concern and opportunities for improvement directly related to clinical practice, particularly in situations where there is a rapid need to adapt to increased demands for critical care. By addressing the identified risk factors through enhanced training, support systems, resource management, process improvements and cultivating a culture of adaptability, not only can the quality of care in temporary ICUs be improved, but also can the health care system be better prepared for future emergencies. These actions will help mitigate the risks associated with such conversions, ultimately benefiting patient safety, staff well-being and the overall effectiveness of health care services in crises.

Simple and effective serum biomarkers potential for predicting status epilepticus in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis who also present with status epilepticus (SE) often have a poor prognosis. The aim of this study is to explore simple and effective predictors for anti-NMDAR encephalitis accompanied with SE. METHODS: We retrospectively analyzed 65 anti-NMDAR encephalitis patients from January 2015 to December 2018 who admitted to the Third Affiliated Hospital of Sun Yat-sen University. Patients were divided into SE group and non-SE groups. Their pre-treatment data and 3-month follow-up data were retrospectively analyzed. RESULTS: The results showed that compared with the non-SE group, the levels of serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) in anti-NMDAR encephalitis patients with SE decreased significantly before treatment. Additionally, the levels of serum UA and HDL-C increased while the level of C-reactive protein (CRP) decreased 3 months after treatment in the SE group. Compared with the non-SE group, the SE patients had higher modified Rankin scale (mRS) scores before (mRS1) and after treatment (mRS2). Serum UA concentrations before treatment showed significantly negative correlations with mRS1 (r = - 0.407, p < 0.01) and mRS2 (r = - 0.458, p < 0.001), while the level of serum CRP before treatment had strong positive correlations with mRS1 (r = 0.304, p < 0.05) and mRS2 (r = 0.301, p < 0.05) in anti-NMDAR encephalitis patients. The receiver operating characteristic curve demonstrated that the combined detection of UA, HDL-C and CRP before treatment had a significantly higher value (the area under the curve = 0.848; 95% confidence interval [CI], 0.74-0.957; p < 0.001) to predict anti-NMDAR encephalitis accompanied with SE than that of single detection. CONCLUSIONS: Hence, the combined detection of serum UA, HDL-C and CRP before treatment may be simple and effective indicators for predicting SE in anti-NMDAR encephalitis, which may be helpful in early stages to remind clinicians to be alert to the emergence of SE.

Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice.

BACKGROUND: Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood-brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-ß, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. RESULTS: Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood-brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-ß, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. CONCLUSIONS: Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

Single cell sequencing analysis identifies genetics-modulated ORMDL3+ cholangiocytes having higher metabolic effects on primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear. RESULTS: We constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations for PBC. Based on our multi-omics integrative analysis, 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P < 0.05). The risk gene of ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). The ORMDL3+ cholangiocytes have prominently higher metabolism activity score than ORMDL3- cholangiocytes (P = 1.38 × 10-15). Compared with ORMDL3- cholangiocytes, there were 77 significantly differentially expressed genes among ORMDL3+ cholangiocytes (FDR < 0.05), and these significant genes were associated with autoimmune diseases-related functional terms or pathways. The ORMDL3+ cholangiocytes exhibited relatively high communications with macrophage and monocyte. Compared with ORMDL3- cholangiocytes, the VEGF signaling pathway is specific for ORMDL3+ cholangiocytes to interact with other cell populations. CONCLUSIONS: To the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3+ cholangiocytes with higher metabolism activity play important immune-modulatory roles in the etiology of PBC.

The inverse association between parity and bone health is independent of lifestyle in postmenopausal Chinese women.

This study aimed to investigate the association between parity and bone mineral density in postmenopausal Chinese women, as well as the interference of physical activity and sedentary time on this association. A total of 1,712 participants were enrolled in this study. Participants were separated into three groups according to the number of parities: group 1, 1-2; group 2, 3-4; group 3, ≥5. Physical activity level was assessed according to the International Physical Activity Questionnaire. Calcaneus bone mineral density (BMD) and bone quality were assessed by qualitative ultrasound. As a result, logistic regression showed that compared to that in group 1, the risk of fracture in group 3 was increased significantly (p < 0.001). A greater number of parities was associated with a lower BMD, broadband ultrasonic attenuation (BUA), quantitative ultrasound index (QUI), speed of sound (SOS), and T-score among the three groups after adjustment for age (All p for trend < 0.05). The number of parities was an independent factor negatively correlated with BMD, BUA, QUI, SOS and T-score (All p < 0.05). BMD, BUA, QUI, SOS, and T-score were significantly increased in the physically a participants independent of parity (all p < 0.05), and decreased in the sedentary participants independent of parity (p < 0.05, except BUA). A great number of parities was negatively associated with bone health. Physical activity was positively correlated and sedentary time was negatively correlated with bone health independent of parity.

Acetylcholine regulates the development of experimental autoimmune encephalomyelitis via the CD4+ cells proliferation and differentiation.

Purpose of the study: Multiple sclerosis is a CD4+ T cell mediated autoimmune disease characterized by inflammatory demyelination in the central nervous system. Acetylcholine (ACh) has been reported to be released by T lymphocytes and plays as an inflammation and immune regulator through the participation of T cells. However, both attenuated and aggravated effects of ACh in inflammation were found. The aim of this study is to further investigate the role of ACh in experimental autoimmune encephalomyelitis (EAE).Materials and methods: The left cervical vagotomy was performed to inhibit ACh release with the sham-operation as control. ACh in cerebral cortex and splenocytes culture supernatants of EAE mice were determined. Interleukin-6, interferon-γ, interleukin-4 and interleukin-17A in brain and splenocytes culture supernatants were evaluated by enzyme-linked immunosorbent assay. The proportion of CD4+ T cells and subsets were assessed by flow cytometry.Results: Compared with the sham-operation group, improved clinical and pathological parameters as well as decreased interleukin-6, interferon-γ, interleukin-4 and interleukin-17A were found in EAE mice with vagotomy suppressing the ACh. Marked reductions of CD4+ and CD4+ChAT+ cells, as well as significant decrease in Th1 with a bias to Th2 in Th1/Th2 balance and increased ChAT+Th2 proportion in the spleen were also observed in vagotomized mice.Conclusions: These findings emphasize that inhibiting ACh release by vagotomy can ameliorate the exacerbation of EAE through suppressing CD4+ T cells proliferation and regulating the differentiation of Th1, Th2 and Th17.

Overexpression of a synthetic insect-plant geranyl pyrophosphate synthase gene in Camelina sativa alters plant growth and terpene biosynthesis.

MAIN CONCLUSION: A novel plastidial homodimeric insect-plant geranyl pyrophosphate synthase gene is synthesized from three different cDNA origins. Its overexpression in Camelina sativa effectively alters plant development and terpenoid metabolism. Geranyl pyrophosphate synthase (GPPS) converts one isopentenyl pyrophosphate and dimethylallyl pyrophosphate to GPP. Here, we report a synthetic insect-plant GPPS gene and effects of its overexpression on plant growth and terpenoid metabolism of Camelina sativa. We synthesized a 1353-bp cDNA, namely PTP-MpGPPS. This synthetic cDNA was composed of a 1086-bp cDNA fragment encoding a small GPPS isomer of the aphid Myzus persicae (Mp), 240-bp Arabidopsis thaliana cDNA fragment encoding a plastidial transit peptide (PTP), and a 27-bp short cDNA fragment encoding a human influenza hemagglutinin tag peptide. Structural modeling showed that the deduced protein was a homodimeric prenyltransferase. Confocal microscopy analysis demonstrated that the PTP-MpGPPS fused with green florescent protein was localized in the plastids. The synthetic PTP-MpGPPS cDNA driven by 2 × 35S promoters was introduced into Camelina (Camelina sativa) by Agrobacterium-mediated transformation and its overexpression in transgenic plants were demonstrated by western blot. T2 and T3 progeny of transgenic plants developed larger leaves, grew more and longer internodes, and flowered earlier than wild-type plants. Metabolic analysis showed that the levels of beta-amyrin and campesterol were higher in tissues of transgenic plants than in those of wild-type plants. Fast isoprene sensor analysis demonstrated that transgenic Camelina plants emitted significantly less isoprene than wild-type plants. In addition, transcriptional analyses revealed that the expression levels of gibberellic acid and brassinosteroids-responsive genes were higher in transgenic plants than in wild-type plants. Taken together, these data demonstrated that this novel synthetic insect-plant GPPS cDNA was effective to improve growth traits and alter terpenoid metabolism of Camelina.

Separation and determination of flavonoids in three traditional chinese medicines by capillary electrophoresis with amperometric detection.

Flavonoids are important active ingredients in many traditional Chinese medicines. In this paper, capillary electrophoresis with amperometric detection was employed to separate and detect eight flavonoids, rutin, quercetrin, quercetin, kaempferol, kaempferide, catechin, apigenin, and luteolin, in a home-made capillary electrophoresis device. Under the separation voltage of 2000 V, the eight flavonoids could be completely separated within 33 min in 18 mM borax running buffer at pH 10.2. Good linear relationships were obtained for all analytes and the detection limits for flavonoids ranged from 0.46 to 0.85 µM. Then, the method was applied to separate and determine the flavonoids in three traditional Chinese medicines, hippophae rhamnoides, hypericum perforatum, and cacumen platycladi. Finally, rutin, kaempferol, quercetin, and quercetrin were discovered in these medicines and the concentrations ranged from 0.28 to 9.94 mg/g. The recoveries of flavonoids ranged from 84.7 to 113%, which showed the high reliability of this method.

High-speed separation and detection of amino acids in laver using a short capillary electrophoresis system.

A high-speed separation method of capillary MEKC with LIF detection had been developed for separation and determination of amino acids in laver. The CE system comprised a manual slotted-vial array (SVA) for sample introduction that could improve the separation efficiency by reducing injection volume. Using a capillary with 80 mm effective separation length, the separation conditions for amino acids were optimized. Applied with the separation electric field strength of 300 V/cm, the ten amino acids could be completely separated within 2.5 min with 10 mol/L Na2HPO4-NaOH buffer (pH = 11.5) including 30 mmol/L SDS. Theoretical plates for amino acids ranged from 72,000 to 40,000 (corresponding to 1.1-2.0 µm plate heights) and the detection limits were between 25 and 80 nmol/L. Finally, this method was applied to analyze the composition of amino acids in laver and eight known amino acids could be found in the sample. The contents of five amino acids, tyrosine, glutamic acid, glycine, lysine, and aspartic acid that could be completely separated in real sample were determined. The recoveries ranged from 82.3% to 123% that indicated the good reliability for this method in laver sample analysis.

Randomized trial of autologous bone marrow mesenchymal stem cells transplantation for hepatitis B virus cirrhosis: regulation of Treg/Th17 cells.

BACKGROUND AND AIM: Liver cirrhosis is one of the major consequences of hepatitis B virus (HBV) infection, and transplantation of autologous bone marrow mesenchymal stem cells (ABMSCs) is one of promising therapies for patients with HBV-related liver cirrhosis (HBV-LC). However, the mechanism is unclear. The aim of the current study was to explore the role of Treg/Th17 cells in ABMSCs transplantation in patients with HBV-LC. METHODS: In this prospective study, 56 patients were enrolled and randomly assigned to transplantation group and control group. After 24-week follow-up, 39 patients completed the study (20 cases in transplantation group and 19 cases in control group). The Model for End-Stage Liver Disease scores, liver function, changes of Treg/Th17 cells, as well as related transcription factors and serum cytokines, were determined. RESULTS: Although patients in both groups showed significant improvement after Entecavir treatment, ABMSC transplantation further improved patients' liver function. Moreover, there was a significant increase in Treg cells and a marked decrease in Th17 cells in the transplantation group compared with control, leading to an increased Treg/Th17 ratio. Furthermore, mRNA levels of Treg-related transcription factor (Foxp3) and Th17-related transcription factor (RORγt) were increased and decreased, respectively. In addition, serum transforming growth factor-ß levels were significantly higher at early weeks of transplantation, while serum levels of interleukin-17, tumor necrosis factor-α, and interleukin-6 were significantly lower in patients in the transplantation group compared with control. CONCLUSION: ABMSCs transplantation was effective in improving liver function in patients with HBV-LC, which was mediated, at least in part, through the regulation of Treg/Th17 cell balance.

Self-management in patients with metabolic dysfunction-associated steatotic liver disease: influencing factors and impact on readmission.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disease. OBJECTIVE: This study aimed to investigate the self-management ability of patients with MASLD, analyse related factors that may affect self-management ability and evaluate the impact of this ability on readmission. METHODS: The study recruited patients with MASLD admitted to the Department of Infectious Diseases, First Affiliated Hospital of Wenzhou Medical University, between February and October 2021 using the random sampling method. The MASLD diagnosis was based on the guidelines for the prevention and treatment of MASLD. An analysis of patients' self-management ability was conducted using the self-management ability scale for patients with MASLD. Multiple linear regression analysis was used to analyse the factors influencing this self-management ability, and the readmission rate within 1 year was tracked. The patients were rediagnosed as having MASLD upon readmission to the hospital. RESULTS: A total of 241 baseline data items and self-management scale scores for patients with MASLD were collected and investigated. In our study, the normal score range for the self-management scale was 31-155 points, and the self-management scale scores for patients with MASLD was 91.24 ± 16.98, with a low level of self-management accounting for 52.7% and a medium level accounting for 44.8%. The results of the multiple linear regression analysis revealed that marital status, smoking history, fatty liver severity and education were the main factors affecting self-management ability (P < 0.05). The readmission rates were 18.25%, 7.48% and 0%, respectively, after 1 year of follow-up; the difference in survival distribution was statistically significant (P < 0.05). CONCLUSION: The self-management ability of patients with MASLD is relatively low and is primarily influenced by factors such as marital status, smoking history, the severity of fatty liver disease and level of education, which also affect the readmission rate of patients within 1 year.

An analysis of the relationship of triglyceride glucose index with gastric cancer prognosis: A retrospective study.

AIMS/INTRODUCTION: Gastric cancer, one of the most common malignant tumors worldwide, is affected by insulin resistance. The triglyceride glucose (TYG) index is considered a surrogate indicator of insulin resistance; however, its prognostic value in patients with gastric cancer remains obscure. This study aimed to determine whether the TYG index could predict the long-term prognosis of patients with gastric cancer after radical resection gastrectomy. MATERIALS AND METHODS: We retrospectively analyzed patients with gastric cancer who underwent radical resection gastrectomy. The preoperative TYG index was calculated using the patients' laboratory data. Patients were divided into two groups based on a high or low TYG index. We observed overall survival and evaluated the clinical application value of the index using Cox proportional hazards regression to calculate independent parameters. A prediction model was also established. RESULTS: In total, 822 patients with gastric cancer were included. The high and low TYG index groups comprised 353 and 469 patients, respectively. The overall survival time was significantly longer in the high-index group than in the low-index group. In the multivariate analysis, TYG index, preoperative age, surgical procedure, tumor node metastasis (TNM) stage, N stage, and postoperative complications (all p < 0.01) were considered independent prognostic predictors. Based on the multivariate analysis, the riglyceride glucose (TYG) index hazard ratio was 0.70 (95% confidence interval, 0.54-0.89, p = 0.004). CONCLUSIONS: We established a model with a high clinical application value and clinical practice relevance to predict the prognosis of gastric cancer. In this model, TYG was an independent protective factor for gastric cancer prognosis.

High normal alanine aminotransferase is an indicator for better response to antiviral therapy in chronic hepatitis B.

Background: Evidence shows people living with CHB even with a normal ALT (40U/L as threshold) suffer histological disease and there is still little research to evaluate the potential benefit of antiviral benefits in them. Methods: We retrospectively examined 1352 patients who underwent liver biopsy from 2017 to 2021 and then obtained their 1-year follow-up data to analyze. Results: ALT levels were categorized into high and low, with thresholds set at >29 for males and >15 for females through Youden's Index. The high normal ALT group showed significant histological disease at baseline (56.43% vs 43.82%, p< 0.001), and better HBV DNA clearance from treatment using PSM (p=0.005). Similar results were obtained using 2016 AASLD high normals (male >30, female >19). Further multivariate logistic analysis showed that high normal ALT (both criterias) was an independent predictor of treatment (OR 1.993, 95% CI 1.115-3.560, p=0.020; OR 2.000, 95% CI 1.055-3.793, p=0.034) Both of the models had higher AUC compared with current scoring system, and there was no obvious difference between the two models (AUC:0.8840 vs 0.8835). Conclusion: Male >30 or female >19 and Male >29 or female>15 are suggested to be better thresholds for normal ALT. Having a high normal ALT in CHB provides a potential benefit in antiviral therapy.

Ultrasensitive detection of aggregated α-synuclein using quiescent seed amplification assay for the diagnosis of Parkinson's disease.

BACKGROUND: Seed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson's disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation. METHODS: We introduced a modified form of SAA, known as Quiescent SAA (QSAA), and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies (control group). Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies. Additionally, skin samples were collected from 214 PD patients and 208 control subjects. Data were analyzed from April 2019 to May 2023. RESULTS: QSAA successfully amplified αSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils. In the skin samples from 214 PD cases and 208 non-PD cases, QSAA demonstrated high sensitivity (90.2%) and specificity (91.4%) in differentiating between PD and non-PD cases. Notably, more αSyn aggregates were detected by QSAA compared to immunofluorescence with the pS129-αSyn antibody in consecutive slices of both brain and skin samples. CONCLUSION: We introduced the new QSAA method tailored for in situ amplification of αSyn aggregates in brain and skin samples while maintaining tissue integrity, providing a streamlined approach to diagnosing PD with individual variability. The integration of seeding activities with the location of deposition of αSyn seeds advances our understanding of the mechanism underlying αSyn misfolding in PD.

Association between follicle-stimulating hormone and nonalcoholic fatty liver disease in postmenopausal women with type 2 diabetes mellitus.

BACKGROUND AND AIM: Follicle-stimulating hormone (FSH) was negatively associated with nonalcoholic fatty liver disease (NAFLD) in women older than 55 years old. People with obesity and diabetes had higher prevalence of NAFLD. Thus, we aimed to explore the association between FSH and NAFLD in postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A total of 583 postmenopausal women with T2DM with an average age of 60.22 ± 6.49 were recruited in this cross-sectional study through January 2017 to May 2021. Anthropological data, biochemical indexes, and abdominal ultrasound results were retrospectively collected. Abdominal ultrasound was used to diagnose NAFLD. FSH was measured by enzymatic immunochemiluminescence and divided into tertiles for further analysis. The logistic regression was used to assess the association of FSH with prevalent NAFLD. Likelihood ratio tests were used to assess the interactions between groups. RESULTS: A total of 332 (56.94%) postmenopausal women had NAFLD. Compared with postmenopausal women in the lowest tertile of FSH, postmenopausal women in the highest tertile of FSH had lower prevalence of NAFLD (p < .01). After adjusting for age, diabetes duration, metabolism-related indicators, and other sex-related hormones, FSH was inversely associated with NAFLD (odds ratio: 0.411, 95% confidence intervals: 0.260-0.651, p < .001). In subgroup analysis, there were no significant interactions of FSH with strata of metabolic factors on the association of NAFLD. CONCLUSION: FSH was negatively and independently associated with NAFLD in postmenopausal women with type 2 diabetes mellitus. It might be a potential index for screening and identifying individuals with high risk of NAFLD in postmenopausal women.

Plk1 promotes renal tubulointerstitial fibrosis by targeting autophagy/lysosome axis.

The prevalence of chronic kidney disease (CKD) has been increasing over the past decades. However, no effective therapies are available for delaying or curing CKD. Progressive fibrosis is the major pathological feature of CKD, which leads to end-stage renal disease (ESRD). The present study showed that Polo-like kinase 1 (Plk1) was upregulated in the kidneys of CKD patients and mice subjected to unilateral ureteral obstruction (UUO) with location in proximal tubules and tubulointerstitial fibroblasts. Pharmacological inhibition, genetic silencing or knockout of Plk1 attenuated obstructive nephropathy due to suppressed fibroblast activation mediated by reduced autophagic flux. We found Plk1 plays a critical role in maintaining intralysosomal pH by regulating ATP6V1A phosphorylation, and inhibition of Plk1 impaired lysosomal function leading to blockade of autophagic flux. In addition, Plk1 also prevented partial epithelial-mesenchymal transition (pEMT) of tubular epithelial cells via autophagy pathway. In conclusion, this study demonstrated that Plk1 plays a pathogenic role in renal tubulointerstitial fibrosis by regulating autophagy/lysosome axis. Thus, targeting Plk1 could be a promising strategy for CKD treatment.

Serum ammonia variation predicts mortality in patients with hepatitis B virus-related acute-on-chronic liver failure.

Background: Hyperammonemia is critical to the development of hepatic encephalopathy (HE) and is associated with mortality in end-stage liver disease. This study investigated the clinical value of ammonia variation in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients. Methods: A total of 276 patients with HBV-ACLF were retrospectively recruited. Patients' ammonia levels were serially documented. Baseline ammonia, Peak ammonia (highest level), and Trough ammonia (lowest level) were particularly corrected to the upper limit of normal (AMM-ULN). The primary endpoint was 28-day mortality. Results: The 28-day, 3-month, and 12-month mortality rates were 19.2, 25.7, and 28.2%, respectively. A total of 51 (18.4%) patients had overt HE (grade 2/3/4). Peak AMM-ULN was significantly higher in patients with overt HE and non-survivors compared with their counterparts (P < 0.001). Following adjustment for significant confounders, high Peak AMM-ULN was an independent predictor of overt HE (hazard ratio, 1.031, P < 0.001) and 28-day mortality (hazard ratio, 1.026, P < 0.001). The cut-off of Peak AMM-ULN was 1.8, determined by using the X-tile. Patients with Peak AMM-ULN appearing on days 1-3 after admission had a higher proportion of overt HE and mortality compared to other groups. Patients with decreased ammonia levels within 7 days had better clinical outcomes than those with increased ammonia. Conclusion: Serum Peak ammonia was independently associated with overt HE and mortality in HBV-ACLF patients. Serial serum ammonia may have prognostic value.

CE-ESI-MS separation of divalent organic and inorganic anions using a tricationic complexing reagent.

A tricationic ion-pairing reagent, 1,3,5-1-butyl-3-methyl-1H-imidazol-3-ium-2,4,6-trimethylbenzene, was used to form complexes with doubly charged anions for their subsequent analysis by capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS) in the positive-ion mode. This methodology offers the advantages of greater versatility and sensitivity relative to direct detection of the anions in negative-ion mode, and it can be realized by a number of possible complexation strategies, including pre-column, on-column, and post-column modes. Three model anions, sulfate [SO4²â»], thiosulfate [TSFA, S2O3²â»], and benzenedisulfonate [BZDS, C6H4(SO3)2²â»], were amenable to complexation with the tricationic reagent, yielding singly charged cations with greater mass-to-charge (m/z) ratios than the native analytes. By utilizing optimized parameters obtained through previous work with dicationic reagents and singly charged anions, including the CE separation buffer composition and pH, the concentration of the dicationic reagent, the mode of complexation, the nebulizing gas pressure, and the sheath liquid composition, it was possible to develop a robust CE-ESI-MS method appropriate for the analysis of divalent anions in a mixture.

Evaluation of the association of mercury(II) with some dicysteinyl tripeptides.

The present study was undertaken to gain insight into the associations of mercury(II) with dicysteinyl tripeptides in buffered media at pH 7.4. We investigated the effects of increasing the distance between cysteinyl residues on mercury(II) associations and complex formations. The peptide-mercury(II) formation constants and their associated thermodynamic parameters in 3-(N-morpholino)propanesulfonic acid (MOPS) buffered solutions were evaluated by isothermal titration calorimetry. Complexes formed in different relative ratios of mercury(II) to cysteinyl peptides in ammonium formate buffered solutions were characterized by LTQ Orbitrap mass spectrometry. The results from these studies show that n-alkyl dicysteinyl peptides (CP 1-4), and an aryl dicysteinyl peptide (CP 5) can serve as effective "double anchors" to accommodate the coordination sites of mercury(II) to form predominantly one-to-one Hg(peptide) complexes. The aryl dicysteinyl peptide (CP 5) also forms the two-to-two Hg(2)(peptide)(2) complex. In the presence of excess peptide, Hg(peptide)(2) complexes are also detected. Notably, increasing the distance between the ligating groups or "anchor points" in CP 1-5 does not significantly affect their affinity for mercury(II). However, the enthalpy change (ΔH) values (ΔH(1) ~ -91 kJ mol(-1) and ΔH(2) ~ -66 kJ mol(-1)) for complex formation between CP 4 and 5 with mercury(II) are about one and a half times larger than the related values for CP 1, 2 and 3 (ΔH(1) ~ -66 kJ mol(-1) and ΔH(2) ~ 46 kJ mol(-1)). The corresponding entropy change (ΔS) values (ΔS(1) ~ -129 J K(-1) mol(-1) and ΔS(2) ~ -116 J K(-1) mol(-1)) of the structurally larger dicysteinyl peptides CP 4 and 5 are less entropically favorable than for CP 1, 2 and 3 (ΔS(1) ~ -48 J K(-1) mol(-1) and ΔS(2) ~ -44 J K(-1) mol(-1)). Generally, these associations result in a decrease in entropy, indicating that these peptide-mercury complexes potentially form highly ordered structures. The results from this study show that dicysteinyl tripeptides are effective in binding mercury(II) and they are promising motifs for the design of multi-cysteinyl peptides for binding more than one mercury(II) ion per peptide.