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Abstract Background Nephrotic syndrome (NPHS), characterized by proteinuria, hypoalbuminemia, and edema, can be caused by genetic variations. TBC1D8B was recently discovered as a novel disease-causing gene for X-linked NPHS. With only a few reported cases, the clinical manifestations associated with variants of this gene need to be further examined. Methods We recruited a newborn with NPHS complicated by acute kidney injury (AKI) and his parents and tested the potential genetic cause of the disease through trio-whole exome sequencing and Sanger sequencing. Western blotting (WB) was performed using a mutant plasmid to evaluate mutant protein expression levels. Since the TBC1D8B protein interacts with RAB proteins to catalyze the GTPase hydrolysis process, immunofluorescence (IF) can be used to verify the interaction between the TBC1D8B mutant protein and RAB11A/RAB11B, and thus to confirm its effect on the endocytosis and vesicle recycling functions of RAB proteins within the cell. Results The child, at 1 month, showed severe edema and proteinuria and unexplained coma with epilepsy. Ultrasound examination revealed multiple organ enlargement, and MRI showed nonspecific high diffusion-weighted imaging signal characteristics in the splenium of the corpus callosum. Hematoxylin and eosin staining showed diffuse inflammatory cell infiltration in the renal interstitium and multifocal renal tubule lumen expansion. Diffuse fusion of podocyte foot processes was observed under electron microscopy, indicating glomerular podocyte lesions. Genetic testing revealed a maternally inherited novel hemizygous variant, NM_017752: c.628 A > T, p.Lys210Ter, in TBC1D8B. In vitro functional experiments showed that this variant may lead to TBC1D8B protein degradation. IF results showed disrupted interaction with RAB11A/RAB11B, that then affects the biological function of RAB proteins in the process of cell intimal vesicle formation and intracellular transport. Conclusion This study will enrich the mutational and phenotypic spectra of TBC1D8B and demonstrate the potential of this gene variants to cause early-onset NPHS leading to severe kidney disease.

ObjectiveTo understand the prevalence and influencing factors of stroke among community-dwelling hypertensive patients in Nanshan district of Shenzhen city, Guangdong province, to provide a reference for hypertension management and stroke prevention and control in communities. MethodsWe collected data on 47 432 hypertensive patients with complete information registered in the Shenzhen Community Health Service Information System from January 2021 to May 2022. The prevalence of stroke among the patients was analyzed, and a multivariate unconditional logistic regression model was used to identify the main factors influencing the prevalence of stroke in this population. ResultsOf the 47 432 hypertensive patients, 3 630 (7.65%) had stroke, with a significantly higher prevalence of stroke in male hypertensive patients (8.34%, [2 144/25 696]) than in female patients (6.84%, [1 486/21 736]) (χ2 = 37.846, P < 0.001). Multivariate unconditional logistic regression analysis showed that age ≥ 65 years, hypertension for more than 5 years, smoking, diabetes, coronary heart disease, and higher creatinine levels were risk factors for stroke in patients; conversely, being female, having an education level of junior high school or higher, being physically active (not for female patients), taking antihypertensive medication, and having higher levels of low-density lipoprotein cholesterol (LDL-C) (for both male and female patients) and higher levels of total cholesterol (TC) and triglycerides (TG) (for male patients only) were protective factors against stroke. ConclusionThe prevalence of stroke among community-dwelling hypertensive patients in Nanshan district, Shenzhen city, is relatively low. Gender, age, educational level, duration of hypertension, smoking status, physical activity, diabetes, coronary heart disease, the use of antihypertensive medication, and levels of creatinine, TC, TG, and LDL-C are the main factors influencing the prevalence of stroke in this population.

Abstract Moderate leaf rolling helps to form the ideotype of rice. In this study, six independent OsRUS1-GFP overexpression (OsRUS1-OX) transgenic rice lines with rapid and dynamic leaf rolling phenotype in response to sunlight were constructed. However, the mechanism is unknown. Here, RNA-Seq approach was utilized to identify differentially expressed genes between flag leaves of OsRUS1-OX and wildtype under sunlight. 2920 genes were differentially expressed between OsRUS1-OX and WT, of which 1660 upregulated and 1260 downregulated. Six of the 16 genes in GO: 0009415 (response to water stimulus) were significantly upregulated in OsRUS1-OX. The differentially expressed genes between WT and OsRUS1-OX were assigned to 110 KEGG pathways. 42 of the 222 genes in KEGG pathway dosa04075 (Plant hormone signal transduction) were differentially expressed between WT and OsRUS1-OX. The identified genes in GO:0009415 and KEGG pathway dosa04075 were good candidates to explain the leaf rolling phenotype of OsRUS1-OX. The expression patterns of the 15 genes identified by RNA-Seq were verified by qRT-PCR. Based on transcriptomic and qRT-PCR analysis, a mechanism for the leaf rolling phenotype of OsRUS1-OX was proposed. The differential expression profiles between WT and OsRUS1-OX established by this study provide important insights into the molecular mechanism behind the leaf rolling phenotype of OsRUS1-OX.

Cyclophilin D (CypD) is regulated during the innate immune response of insects. However, the mechanism by which CypD is activated under innate immunosuppression is not understood. Microplitis bicoloratus bracovirus (MbBV), a symbiotic virus in the parasitoid wasp, Microplitis bicoloratus, suppresses innate immunity in parasitized Spodoptera litura. Here, we demonstrate that MbBV promotes the CypD acetylation of S. litura, resulting in an immunosuppressive phenotype characterized by increased apoptosis of hemocytes and MbBV-infected cells. Under MbBV infection, the inhibition of CypD acetylation significantly rescued the apoptotic cells induced by MbBV, and the point-mutant fusion proteins of CypDK125R-V5 were deacetylated. The CypD-V5 fusion proteins were acetylated in MbBV-infected cells. Deacetylation of CypDK125R-V5 can also suppress the MbBV-induced increase in apoptosis. These results indicate that CypD is involved in the MbBV-suppressed innate immune response via the CypD-acetylation pathway and S. litura CypD is acetylated on K125.

Chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide, is widely considered to be related to cigarette smoke (CS), and viral infections trigger acute exacerbation of COPD (AECOPD). Isoforskolin (ISOF) is a bioactive component from the plant Coleus forskohlii, native to Yunnan in China. It has been demonstrated that ISOF has anti-inflammatory effect on acute lung injury animal models. In the present study, we investigated the efficacy and mechanism of ISOF for the prevention and treatment of AECOPD. Mice were exposed to CS for 18 weeks and then infected with influenza virus A/Puerto Rico/8/34 (H1N1). ISOF (0.5, 2 mg/kg) was intragastrically administered once a day after 8 weeks of exposure to cigarette smoke when the body weight and lung function of model mice declined significantly. The viral load, pulmonary function, lung morphology, Th17 cells, and inflammatory cytokines in lung tissues were evaluated. The expression of nuclear factor κB (NF-κB) and NOD-like receptor pyrin domain–containing protein 3 (NLRP3) inflammasome pathways were detected. The results showed that ISOF treatment reduced the viral load in the lung homogenate, decreased the lung index of model mice, and lung pathological injuries were alleviated. ISOF also improved the pulmonary function with increased FEV0.1/FVC and decreased Rn and Rrs. The levels of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-17A, MCP-1, MIG, IP-10, and CRP) in the lung homogenate were reduced after ISOF treatment. ISOF decreased the proportion of Th17 cells in the lung tissues by the flow cytometry test, and the protein expression levels of RORγt and p-STAT3 were also decreased. Furthermore, ISOF significantly inhibited the activation of NF-κB signaling and NLRP3 inflammasome in the lung tissues of model mice. In conclusion, ISOF alleviates AECOPD by improving pulmonary function and attenuating inflammation via the downregulation of proinflammatory cytokines, Th17/IL-17 A, and NF-κB/NLRP3 pathways.

BackgroundSalmonella typhimurium (ST) causes several intestinal diseases. Polyphenols including chlorogenic acid (CGA) inhibit pathogenesis.ObjectiveThis study aimed to investigate the mechanisms of CGA in ST infection.MethodsThe intestinal pathological changes and survival rate of ST-infected mice were measured to verify the protection of CGA on ST infection. The antibacterial effects of CGA in vitro on the invasion to intestinal epithelial cells and autophagy was evaluated. The relationships among GAS5, miR-23a, and PTEN were verified. Expression of inflammation- and autophagy-related proteins was detected.ResultsCGA treatment alleviated pathological damage, improved the secretion disturbance of intestinal cytokines caused by ST infection, and reduced the mortality of mice. Intestinal GAS5 was upregulated after CGA treatment. LncRNA GAS5 competitively bound to miR-23a to upregulate PTEN and inhibit the p38 MAPK pathway. CGA regulated the p38 MAPK pathway through lncRNA GAS5/miR-23a/PTEN axis to promote autophagy in ST infection. The functional rescue experiments of miR-23a and PTEN further identified these effects.ConclusionCGA promotes autophagy and inhibits ST infection through the GAS5/miR-23a/PTEN axis and the p38 MAPK pathway.

Background: The advantages of dual pneumococcal and influenza vaccination in older adults have not been clarified and controversy remains regarding their optimal use. Methods: This meta-analysis was conducted on 25 January 2018 using PubMed, the Cochrane Library, and Embase databases. Seventeen studies were selected ultimately for meta-analysis using a multi-step approach by two separate authors. Primary outcomes were pneumonia, pneumococcal pneumonia, influenza, hospitalization, and all-cause mortality rates, and the secondary outcome was adverse effects (AEs). Results: The additive preventive effects of dual influenza and pneumococcal vaccination versus influenza vaccination alone for pneumonia and death were 15% (95% confidence interval [CI]: 4-24%) and 19% (95% CI: 6-30%), respectively. Compared with pneumococcal vaccination alone, dual influenza and pneumococcal vaccination resulted in a 24% (95% CI: 16-31%) reduction in pneumonia and a 28% (95% CI: 13-40%) reduction in death. Compared with placebo or no vaccination, the effectiveness of dual vaccination was 29% (95% CI: 14-42%) for pneumonia, 38% (95% CI: 25-49%) for death, 35% (95% CI: 22-46%) for influenza, and 18% (95% CI: 6-29%) for hospitalization. Both vaccines showed acceptable safety profiles and AEs were mild or moderate. Conclusion: Our findings highlight the importance of concomitant influenza and pneumococcal vaccination in older adults.

Abstract Background While vaccination remains the most effective method to control hepatitis B virus (HBV) infection, 5–10% of recipients exhibit non-responsiveness to the HB vaccine. Immunological analysis of strong, weak or absent protective antibody responses to the HB vaccine should provide insights into the mechanisms that contribute to non-responsiveness. Results We investigated the potential involvement of follicular helper T (Tfh) cells in the immune response to HB vaccine, and associations between the miR-17–92 cluster and Tfh cells. We recruited 12 adults who had completed the HB vaccination course during childhood. Following a booster dose of HB vaccine, hepatitis B surface antibody (HBsAb) titers, percentage of PD-1+ICOS+ circulating Tfh (cTfh) and plasma cells, and expression of miR-17–92 were assessed at baseline (before immunization) and after vaccination on days 7 and 14. Notably, the HBsAb level gradually increased after HB vaccination while the proportion of PD-1+ICOS+ cTfh cells was significantly increased on day 7 relative to baseline, so as plasma cells. Expression of miR-18a and miR-17 within the miR-17–92 cluster and HBsAb titers in CD4+ T cells were positively correlated with the PD-1+ICOS+ cTfh cells proportions after HB vaccination. Conclusions The increase in HBsAb titers was positively associated with expression of all the components of the miR-17–92 cluster except miR-19a. Our findings indicate that the miR-17–92 cluster contributes to antibody production, and miR-18a and miR-17 are involved in Tfh cells differentiation after HB vaccination.

Abstract Background No previous study has evaluated disability in older persons according to the International Classification of Functioning, Disability and Health Framework guidelines. We conducted a more comprehensive investigation of disability and associated factors among older adults receiving home-based care in rural Dongguan, a city in the central Guangdong Province of Southern China. Methods A total of 819 individuals aged ≥60 years were recruited from Dongguan home-based care system of via a two-stage selection process. We interviewed participants and assessed their ability level using the Ability Assessment for Older Adults, which defined by a combination of activity of daily living, sensory perception, mental status and social involvement. Conditional probability and Logistic regression approaches were used to assess the strength of association between each pair of conditions. Factors significantly associated with disability were identified via χ 2 tests and multinomial ordinal logistic regression. Results Of the 819 included participants (mean age 87 ±4.7 years), 75.5% were female, 76.7% had any disability, and 62.3% had a mild disability. The occurrence of any deficits significantly increased the likelihood of the co-occurrence of other deficits (odds ratio [OR] > 1, P

Background: Despite high 1-dose vaccination coverage, breakthrough varicella infections still occur. Therefore, 2-dose vaccination is recommended to enhance the immune response to the virus. However, the reported incremental vaccine effectiveness (VE) of 2-dose vaccination varies widely among studies. Methods: To determine the overall effectiveness, immunogenicity and safety of one vs. two-dose varicella vaccination, we searched five databases for articles published during 1995–2017. Results: The incremental VE/efficacy of 2-dose vaccination was 79% (95% confidence interval [CI]: 56%−90%) in randomized controlled trials，63% (95% CI: 36%−79%) in cohort studies and 81% (95% CI: 65%−90%) in case-control studies. Regarding immunogenicity, the pooled standardized mean differences (SMD) of geometric mean titer (GMT) and the pooled relative risk (RR) of seroconversion for 2-dose vs. 1-dose vaccine were 562.44 (95% CI: 471.78–653.10) and 1.03 (95% CI: 1.02–1.04), respectively. Children who received second dose vaccination were at increased risk of grade 3 redness (RR: 4.93, 95% CI: 1.89 − 12.87) and swelling of any intensity (RR: 1.34, 95% CI: 1.08 − 1.66). Conclusions: Two-dose varicella vaccination resulted in higher levels of immunogenicity and provided superior protection than 1-dose vaccination. Safety profiles showed 2-dose vaccination was well tolerated but the incidence of grade 3 redness and of any intensity was significantly higher.

The larvicidal activity of the crude petroleum ether, ethyl acetate, acetone, chloroform and ethanol extracts of Amorpha fruticosa seeds was individually assayed for toxicity against the early fourth-instar larva of the mosquito, Culex pipiens pallens after 24 h exposure. Of the tested extracts, the ethanol one exhibited the highest larvicidal activity (LC50 = 22.69 mg/L). Amorphigenin (8'-hydroxyrotenone), a rotenoid compound which exhibits a strong larvicidal activity with LC50 and LC90 values of 4.29 and 11.27 mg/L, respectively, was isolated from the ethanol extract by column chromatograpy. Its structure was elucidated by 1H-NMR, UV and IR spectral data. Furthermore, investigation of amorphigenin’s effects on mitochondrial complex I activity and protein synthesis in C. pipiens pallens larvae reveals that amorphigenin decreases mitochondrial complex I activities to 65.73% at 10.45 μmol/L, compared to the control, when NADH were used as the substrate. Meanwhile, amorphigenin at 10.45 μmol/L also caused a 1.98-fold decrease in protein content, compared to the control larvae treated with acetone only.

OBJECTIVE:To assess the immunogenicity and safety of influenza vaccine in patients with systemic lupus erythematosus (SLE). METHODS:Relevant articles were retrieved from electronic databases. Seroprotection rate, seroconversion rate and factors that increase antibody geometric mean titer (GMT) were used as indices to measure the immunogenicity. The safety of vaccine was assessed through monitoring adverse events, which included side effects and SLE exacerbations. We performed a meta-analysis of influenza vaccine seroprotection, seroconversion and adverse effects. SLE exacerbation after vaccination was comprehensively described. We used the Committee for Proprietary Medicinal Products (CPMP) guidelines to determine whether influenza can induce adequate immunogenicity in patients with SLE. RESULTS:Eighteen studies with 1966 subjects met the inclusion criteria. At least 565 of the subjects were patients with low-to-moderate SLE Disease Activity Index (SLEDAI) score or stable SLE disease. Compared with the general population, seroprotection rate in SLE patients was significantly decreased in patients with H1N1 [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.27-0.50] and H3N2 vaccination (OR = 0.48, 95% CI: 0.24-0.93), but not influenza B vaccination (OR = 0.55, 95% CI: 0.24-1.25). Seroconversion rate also significantly decreased in patients with H1N1 (OR = 0.39, 95% CI: 0.27-0.57) and influenza B (OR = 0.47, 95% CI: 0.29-0.76) vaccination, but not H3N2 vaccination (OR = 0.62, 95% CI: 0.21-1.79). However, the immunogenicity of influenza vaccine in SLE patients almost reached that of the CPMP guidelines. The OR for side effects (patients versus healthy controls) was 3.24 (95% CI: 0.62-16.76). Among 1966 patients with SLE, 32 experienced mild exacerbation of SLE and five had serious side effects for other reasons. CONCLUSION:Influenza vaccine has moderate effect on protecting patients with SLE. The side effects of influenza vaccine are not serious and are manageable. With consideration of a higher risk of SLE exacerbation and a more severe course of infection among SLE patients, influenza vaccination should be promoted among SLE patients with a low-to-moderate SLEDAI score or stable disease.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (CRISPR/Cas9) technology provides an efficient tool for editing the genomes of plants, animals and microorganisms. Glutamate:glyoxylate aminotransferase 1 (GGAT1) is a key enzyme in the photorespiration pathway; however, its regulation mechanism is largely unknown. Given that EMS-mutagenized ggat1 (Col-0 background) M2 pools have been generated, ggat1 (Ler background) should be very useful in the positional cloning of suppressor and/or enhancer genes of GGAT1. Unfortunately, such ggat1 (Ler) mutants are not currently available. In this study, CRISPR/Cas9 was used to generate ggat1 (Ler) mutants. Two GGAT1 target single-guide RNAs (sgRNAs) were constructed into pYLCRISPR/ Cas9P35S-N, and flowering Arabidopsis (Ler) plants were transformed using an Agrobacterium tumefaciens- mediated floral dip protocol. Eleven chimeric and two heterozygous GGAT1-edited T1 lines of target 1 were separately screened from positive transgenic lines. Two ggat1 homozygous mutants, CTC-deletion and T-deletion at target 1, were generated from T2 generations of the 13 T1 lines. The edited mutation sites were found to be stable through generations regardless of whether the T-DNA was present. In addition, the genetic segregation of the mutation sites obeyed the Mendelian single gene segregation rule, and no mutations were detected at the possible offtarget site. Also, the two independent ggat1 mutants had similar photorespiration phenotypes and downregulated GGAT enzyme activity. Together, these results indicate that genetically stable ggat1 (Ler) mutants were generated by CRISPR/Cas9 genome editing, and these mutants will be used to promote the positional cloning of suppressor and/or enhancer genes of GGAT1 in our subsequent study. [ABSTRACT FROM AUTHOR]

Previous studies in our laboratory found that the extract from seeds of Amorpha fruticosa in the Leguminosae family had lethal effects against mosquito larvae, and an insecticidal compound amorphigenin was isolated. In this study, the inhibitory effects of amorphigenin against the mitochondrial complex I of Culex pipiens pallens (Diptera: Culicidae) were investigated and compared with that of rotenone. The results showed that amorphigenin and rotenone can decrease the mitochondrial complex I activity both in vivo and in vitro as the in vivo IC50 values (the inhibitor concentrations leading to 50% of the enzyme activity lost) were determined to be 2.4329 and 2.5232 μmol/L, respectively, while the in vitro IC50 values were 2.8592 and 3.1375 μmol/L, respectively. Both amorphigenin and rotenone were shown to be reversible and mixed-I type inhibitors of the mitochondrial complex I of Cx. pipiens pallens, indicating that amorphigenin and rotenone inhibited the enzyme activity not only by binding with the free enzyme but also with the enzyme-substrate complex, and the values of KI and KIS for amorphigenin were determined to be 20.58 and 87.55 μM, respectively, while the values for rotenone were 14.04 and 69.23 μM, respectively. [ABSTRACT FROM AUTHOR]