FUDNC1-dependent mitophagy ameliorate motor neuron death in an amyotrophic lateral sclerosis mouse model.

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1G93A or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1G93A mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1G93A mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1G93A mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.

Disease and Economic Burden of Kashin-Beck Disease - China, 2021 .

What is already known about this topic?: Kashin-Beck disease (KBD) is a chronic and degenerative osteoarthropathy characterized by cartilage degeneration. It is an endemic disease that is highly prevalent among the Chinese population and poses a significant health risk. What is added by this report?: This is the first national report on the economic burden of KBD in China. According to the data from 2021, KBD has caused significant disease and economic burdens. The most substantial reduction in healthy life expectancy was observed among patients with degree II severity and those aged 60 years and older, resulting in a total indirect economic burden of 112.74 million Chinese Yuan (CNY). What are the implications for public health practice?: The results of this study will contribute to informing the development of tailored prevention and control strategies by the government. These strategies will include targeted policies and recommendations for appropriate healthcare and financial subsidies, which will be based on the demographic characteristics of the endemic areas.

Safety and neutralization antibody levels of inactivated SARS-CoV-2 vaccine in adult patients with Myasthenia Gravis: a prospective observational cohort study.

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction. No cohort study has investigated the efficacy of inactivated vaccines in patients with MG. MATERIALS AND METHODS: This prospective observational cohort study included healthy controls (HCs) and patients with MG with or without immunosuppressive treatment. Vaccination occurred between May and December 2021. Patients with MG were subjected to a clinical scale assessment for disease severity. The neutralization antibodies (Nabs) levels were measured in all participants using the pseudovirus neutralization assay. RESULTS: Twenty-one patients (Female/Male:10/11); age median [interquartile range (IQR)]: 43 [30, 56]) were included in this study. Two patients (2/21) were lost during follow-up after enrollment. No sustained vaccine-related adverse effects occurred in any visit of patients with MG. No exacerbation of MG was observed. Acetylcholine receptor antibody (AChR-Ab) levels showed no statistically significant changes between the first and second visit (median [IQR]: 2.22 [0.99, 2.63] nmol/L vs. 1.54 [1.07, 2.40] nmol/L, p = 0.424). However, levels of AChR-Ab decreased at the third visit (median [IQR]: 2.22 [0.96, 2.70] nmol/L vs. 1.69 [0.70, 1.85] nmol/L, p = 0.011). No statistically significant difference in Nabs levels was found between HCs and patients with MG (median [IQR]: 102.89 [33.13, 293.86] vs. 79.29 [37.50, 141.93], p = 0.147). DISCUSSION: The safety of the SARS-CoV-2 inactivated vaccine was reconfirmed in this study. No significant difference in Nabs level was found between patients with MG and HCs. Nabs levels correlated with AChR-Ab levels before vaccination and ΔAChR-Ab levels.

The Dose-Response Effect of Fluoride Exposure on the Gut Microbiome and Its Functional Pathways in Rats.

Metabolic activities within the gut microbiome are intimately linked to human health and disease, especially within the context of environmental exposure and its potential ramifications. Perturbations within this microbiome, termed "gut microbiome perturbations", have emerged as plausible intermediaries in the onset or exacerbation of diseases following environmental chemical exposures, with fluoride being a compound of particular concern. Despite the well-documented adverse impacts of excessive fluoride on various human physiological systems-ranging from skeletal to neurological-the nuanced dynamics between fluoride exposure, the gut microbiome, and the resulting dose-response relationship remains a scientific enigma. Leveraging the precision of 16S rRNA high-throughput sequencing, this study meticulously examines the ramifications of diverse fluoride concentrations on the gut microbiome's composition and functional capabilities within Wistar rats. Our findings indicate a profound shift in the intestinal microbial composition following fluoride exposure, marked by a dose-dependent modulation in the abundance of key genera, including Pelagibacterium, Bilophila, Turicibacter, and Roseburia. Moreover, discernible alterations were observed in critical functional and metabolic pathways of the microbiome, such as D-lyxose ketol-isomerase and DNA polymerase III subunit gamma/tau, underscoring the broad-reaching implications of fluoride exposure. Intriguingly, correlation analyses elucidated strong associations between specific bacterial co-abundance groups (CAGs) and these shifted metabolic pathways. In essence, fluoride exposure not only perturbs the compositional equilibrium of the gut microbiota but also instigates profound shifts in its metabolic landscape. These intricate alterations may provide a mechanistic foundation for understanding fluoride's potential toxicological effects mediated via gut microbiome modulation.

Clinical application of a modified predeposit autologous red blood cell apheresis in multistage spinal fusion: a single-center retrospective study.

Purpose: This study aimed to evaluate the efficacy and safety of predeposit autologous RBC apheresis (PARA) in patients undergoing multilevel spinal fusion surgery. Methods: A total of 112 patients from January 2020 to June 2022 were divided into two groups according to PARA: the PARA group (n = 51) and the control group (n = 61). The baseline characteristics of the patients, outcomes, transfusion cost, hospitalization cost, length of stay, complications, and changes in hemoglobin and hematocrit levels between the two groups were compared. Results: The baseline characteristics were similar in both groups. No significant differences were found in functional outcomes, including VAS score (p = 0.159), ODI score (p = 0.214), JOA score (p = 0.752), and SF-36 score (p = 0.188) between the PARA and control groups. The amount and rate of intraoperative and perioperative allogeneic RBC transfusion were significantly higher in the control group than in the PARA group (p < 0.001). The postoperative (9.04 ± 3.21 vs. 11.05 ± 3.84, p = 0.004) and total length of stay (15.78 ± 3.79 vs. 17.36 ± 4.08, p = 0.038) in the PARA group were significantly lower than those in the control group, respectively. Despite no difference in hospitalization cost (p = 0.737), the total blood transfusion cost in the PARA group was significantly lower, compared with the control group (p < 0.001). For safety evaluation, there were no significant differences in Hb and Hct levels between the two groups at admission, on postoperative day 1, and postoperative day 3, respectively (p > 0.05). Moreover, the number of postoperative infections in the PARA group was significantly lower than that in the control group (p = 0.038). Conclusion: PARA was a novel, safe, and highly efficient technique for mass autologous blood preparation in a quite short preparation time. This method could significantly reduce the amount of allogeneic blood transfusion and length of stay, which could provide a theoretical basis for following clinical practice about the technique.

Intrauterine Infusion of Leukocyte-Poor Platelet-Rich Plasma Is an Effective Therapeutic Protocol for Patients with Recurrent Implantation Failure: A Retrospective Cohort Study.

BACKGROUND: The clinical application of autologous leukocyte-poor platelet-rich plasma (LP-PRP) in patients with recurrent implantation failure (RIF) is rare. This retrospective observational cohort study aimed to evaluate the efficacy of LP-PRP intrauterine infusion in patients with RIF. METHODS: Patients with RIF undergoing frozen embryo transfer (FET) from January 2019 to December 2021 (n = 118) were enrolled, with those undergoing LP-PRP intrauterine infusion as the PRP group (n = 64), and those receiving no LP-PRP treatment as the control group (n = 54). The beta-human chorionic gonadotropin (ß-hCG)-positive rate, clinical pregnancy rate (CPR), live birth rate (LBR), and miscarriage rate (MR) per ET cycle were compared. RESULTS: The ß-hCG-positive rate (57.8% vs. 38.9%, p = 0.041), CPR (45.3% vs. 24.5%, p = 0.022), and LBR per ET cycle (42.2% vs. 18.5%, p = 0.009) were higher in the PRP group than in the control group, and the three variables (62.5% vs. 41.2%, p = 0.040, 47.5% vs. 23.5%, p = 0.033, and 47.5% vs. 20.6%, p = 0.027) in the PRP group transferred with the blastocyst-stage embryos were also higher than those in the control group. The MR was similar in all groups. CONCLUSIONS: The LP-PRP treatment could improve the ß-hCG-positive rate, CPR, and LBR in RIF patients undergoing FET cycles.

Single-cell mapping reveals dysregulation of immune cell populations and VISTA+ monocytes in myasthenia gravis.

The pathogenesis and progression of myasthenia gravis (MG), an autoimmune disease, involve abnormal function and composition of several immune cell populations. However, details of this dysregulation remain unclear. We performed a cross-section analysis using cytometry time-of-flight on blood samples from 12 generalized MG without glucocorticoid or other immunosuppressant treatment, and 10 sex- and age-matched healthy controls. Combining data from an external validation cohort (MG n = 38, control n = 21), bulk-RNA sequencing and single-cell RNA sequencing, alterations in immune cell populations and differential expression of immune check point were revealed. Several switched memory B cell subsets (CD3- CD19+ CD27+ IgD- CD38+/-) were increased in MG patients. The number of HLA- DQ- CD38+ naïve B cells was higher in MG patients and correlated with the quantitative MG score (QMG). Among NK cells, the number of CD56+ CD16+ NK cells and CD56+ CD16+ CD8+ NK cells were decreased in MG patients and positively correlated with QMG. VISTA+ monocytes were increased in MG patients. Classical T cell subsets showed no significant change; however, the expression of VISTA, LAG3, CTLA4, and CXCR5 was higher in T cells from MG patients. The expression of CD38 was higher in neutrophils from MG patients. The external validation cohort validated the dysregulation of NK cell subtypes, and differences were also observed in subgroups of patients. Bulk-RNA sequencing also revealed increased mRNA expression of VSIR in monocytes of MG patients compared to those from healthy controls, and the antigen presentation and processing pathway was identified as enriched in the functional characterization of VISTA+ monocytes via single-cell RNA sequencing. Our study revealed alterations in several immune cell subsets and identified potential cellular biomarkers for MG diagnosis and disease severity assessment. In addition, the abnormal expression of multiple immune checkpoints in MG provides further rationale for the investigation of immune-checkpoint-related therapy.

A novel RHD allele, with c.491A > T (p.Asp164Val) mutation, identified via family pedigree analysis.

A Chinese Han man was confirmed to carry an RHD variation by serological tests, and exons 1 through 10 of the RHD gene were analyzed by sequence-specific primer-polymerase chain reaction. To clarify the nature of this mutation, Sanger sequencing was used and a c.491A > T mutation was identified in exon 4. The proband inherited this mutation from his father, as determined from a family pedigree.

Associations of SAA1 gene polymorphism with lipid lelvels and osteoporosis in Chinese women.

BACKGROUND: The development of osteoporosis is associated with several risk factors, such as genetic polymorphisms and enviromental factors. This study assessed the correlation between SAA1 gene rs12218 polymorphism and HDL-C lelvels and osteoporosis in a population of Chinese women. METHODS: A total of 387 postmenopausal female patients who were diagnosed with osteoporosis (case group) based on bone mineral density measurements via dual-energy x-ray absorptiometry and 307 females with no osteoporosis (control group) were included in this study. Correlations between SAA1 gene rs12218 polymorphism and osteoporosis and HDL-C level were investigated through the identification of SAA1 gene rs12218 polymorphism genotypes using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The TT genotype of rs12218 was more frequently in osteoporosis patients than in control subjects (P <0.001). And the rs12218 was found to be associated with plasma TG, HDL-C, LDL-C, and BMD levels in osteoporosis patients (P<0.05). CONCLUSIONS: The present results indicate that both osteoporosis and lipids levels are associated with the TT genotype of rs12218 in the human SAA1 gene.