U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population: a cross-sectional study.

BACKGROUND: Phenotypic age acceleration, which reflects the difference between phenotypic age and chronological age, is an assessment to measure accelerated aging. Klotho is a protein related to slower aging, but its association with accelerated aging remains unclear. METHODS: Based on data from the 2007-2010 National Health and Nutrition Examination Survey, phenotypic age was calculated using chronological age and 9 aging-related biomarkers. A total of 4388 participants aged 40 to 79 years with measured serum Klotho and calculated phenotypic age were enrolled. The association between serum Klotho and phenotypic age acceleration was estimated using multivariable linear regression models. The possible nonlinear relationship was examined with smooth curve fitting. We also conducted a segmented regression model to examine the threshold effect. RESULTS: The association between serum Klotho and phenotypic age acceleration followed a U-shaped curve (p for nonlinearity < 0.001), with the inflection point at 870.7 pg/ml. The phenotypic age acceleration significantly decreased with the increment of serum Klotho (per SD increment: ß -1.77; 95% CI, -2.57 ~ -0.98) in participants with serum Klotho < 870.7 pg/ml, and increased with the increment of serum Klotho (per SD increment:ß, 1.03; 95% CI: 0.53 ~ 1.54) in participants with serum Klotho ≥ 870.7 pg/ml. CONCLUSION: There was a U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population.

Correction to: Exosomes derived from atorvastatin-modified bone marrow dendritic cells ameliorate experimental autoimmune myasthenia gravis by up-regulated levels of IDO/Treg and partly dependent on FasL/Fas pathway.

After the publication of the original article [1], it came to the authors' attention that there was an error in the originally published version of Fig. 5b. The image of CD4+CD25+ T cells of the statin-Dex group was unintentionally replaced with the image of CD4+CD25+ T cells from the control group. The correct version of Fig. 5b is published in this Erratum.

Therapeutic potential of artesunate in experimental autoimmune myasthenia gravis by upregulated T regulatory cells and regulation of Th1/Th2 cytokines.

Artesunate is a semi-synthetic derivative of a Chinese herb named Artemisia annua L. that is commonly used as an antimalarial agent in the history of traditional Chinese medicine. Many studies have reported artesunate possesses anti-inflammatory and immunoregulation properties. The present study was conducted to explore whether artesunate was effective in experimental autoimmune myasthenia gravis (EAMG) in Lewis rats. Our data showed that artesunate could improve the clinical symptoms and suppress the development of EAMG. Artesunate exerted its immunomodulatory effects by inhibiting lymphocyte proliferation and the expression of costimulatory molecules CD86, modulating Th1/Th2 cytokine expression levels, and enhancing the level of Treg cells. The final result of administration of artesunate was the decreased synthesis of anti-R97-116 IgG, IgG2a, and IgG2b antibodies. The treatment effect of artesunate was more obvious at dose of 10 mg/kg. These date suggest that artesunate might be a potential drug for the treatment of human myasthenia gravis (MG).

ROCK inhibitor abolishes the antibody response in experimental autoimmune myasthenia gravis.

The Rho/Rho kinase (ROCK) pathway serves as molecular switches in many biological processes including the immune response. ROCK inhibitors lead to amelioration of some autoimmune diseases. The present study was designed to define whether a selective ROCK inhibitor, fasudil, was effective in experimental autoimmune myasthenia gravis (EAMG) and investigate the underlying mechanisms. Here we found fasudil effectively attenuated the development of ongoing EAMG. Fasudil abolished the antibody production and function by decreasing follicular helper T cells and CD19(+) B cells, especially germinal center B cells. Moreover, fasudil reduced the expression of CD80 on lymph node mononuclear cells. These findings suggest the inhibition of ROCK might be a potential therapeutic strategy for antibody-mediated autoimmune diseases.

Exosomes derived from atorvastatin-modified bone marrow dendritic cells ameliorate experimental autoimmune myasthenia gravis by up-regulated levels of IDO/Treg and partly dependent on FasL/Fas pathway.

BACKGROUND: Previously, we have demonstrated that spleen-derived dendritic cells (DCs) modified with atorvastatin suppressed immune responses of experimental autoimmune myasthenia gravis (EAMG). However, the effects of exosomes derived from atorvastatin-modified bone marrow DCs (BMDCs) (statin-Dex) on EAMG are still unknown. METHODS: Immunophenotypical characterization of exosomes from atorvastatin- and dimethylsulfoxide (DMSO)-modified BMDCs was performed by electron microscopy, flow cytometry, and western blotting. In order to investigate whether statin-DCs-derived exosomes (Dex) could induce immune tolerance in EAMG, we administrated statin-Dex, control-Dex, or phosphate-buffered saline (PBS) into EAMG rats via tail vein injection. The tracking of injected Dex and the effect of statin-Dex injection on endogenous DCs were performed by immunofluorescence and flow cytometry, respectively. The number of Foxp3(+) cells in thymuses was examined using immunocytochemistry. Treg cells, cytokine secretion, lymphocyte proliferation, cell viability and apoptosis, and the levels of autoantibody were also carried out to evaluate the effect of statin-Dex on EAMG rats. To further investigate the involvement of FasL/Fas in statin-Dex-induced apoptosis, the underlying mechanisms were studied by FasL neutralization assays. RESULTS: Our data showed that the systemic injection of statin-Dex suppressed the clinical symptoms of EAMG rats. These statin-Dex had immune regulation functions in immune organs, such as the spleen, thymus, and popliteal and inguinal lymph nodes. Furthermore, statin-Dex exerted their immunomodulatory effects in vivo by decreasing the expression of CD80, CD86, and MHC class II on endogenous DCs. Importantly, the therapeutic effects of statin-Dex on EAMG rats were associated with up-regulated levels of indoleamine 2,3-dioxygenase (IDO)/Treg and partly dependent on FasL/Fas pathway, which finally resulted in decreased synthesis of anti-R97-116 IgG, IgG2a, and IgG2b antibodies. CONCLUSIONS: Our data suggest that atorvastatin-induced immature BMDCs are able to secrete tolerogenic Dex, which are involved in the suppression of immune responses in EAMG rats. Importantly, our study provides a novel cell-free approach for the treatment of autoimmune diseases.

Engineered Zymomonas mobilis for salt tolerance using EZ-Tn5-based transposon insertion mutagenesis system.

BACKGROUND: The cell growth and ethanol yield of Zymomonas mobilis may be detrimentally affected by salt stress frequently present in some biomass-based fermentation systems, leading to a decrease in the rate of sugar conversion to ethanol or other bioproducts. To address this problem, improving the salt tolerance of Z. mobilis is a desirable way. However, limited progress has been made in development of Z. mobilis with higher salt tolerance for some technical challenges in the past decades. Recently, transposon insertion mutant system has been widely used as a novel genetic tool in many organisms to develop mutant strains. In this study, Tn5-based transposon insertion mutagenesis system firstly used for construction of higher salt tolerance strain in Z. mobilis. RESULTS: Approximately 200 Z. mobilis ZM4 mutants were generated by using Tn5-based transposon mutagenesis system. The mutant strain ZMT2 with improved salt tolerance phenotype was obtained by screening on RM agar plates with additional 1 % NaCl. Strain ZMT2 was confirmed to exhibit better fermentation performance under NaCl stress than wild type of strain ZM4. The transposon insertion was located in ZMO1122 (himA) by genome walking. Discruption of himA gene showed that himA may play an important role in response to salt tolerance in Z. mobils. CONCLUSIONS: The mutant strain ZMT2 with a transposon insertion in himA gene of the genome showed obviously higher sugar conversion rate to ethonal under up to 2 % NaCl stress than did the wild ZM4 strain. Besides, ZMT2 exhibited shared fermentative capabilities with wild ZM4 strain under no or low NaCl stress. This report firstly showed that himA played a role in responding to NaCl stress. Furthermore, the result indicated that Tn5-based transposon mutagenesis system was a feasible tool not only for genetic engineering in Z. mobilis strain improvement, but also in tapping resistent genes.

Lentibacillus amyloliquefaciens sp. nov., a halophilic bacterium isolated from saline sediment sample.

A Gram-stain positive, non-motile, non-sporogenous, aerobic, rod-shaped and halophilic bacterium, designated LAM0015(T), was isolated from a saline sediment sample collected from Yantai City in China. The isolate was found to be able to grow at NaCl concentrations of 5-25 % (w/v) (optimum: 7-12 %), 15-45 °C (optimum: 35 °C) and pH 5.0-9.0 (optimum: 7.0). The major fatty acids were determined to be anteiso-C15:0 and anteiso-C17:0. The predominant respiratory quinone was identified as MK-7. The cell wall peptidoglycan was determined to contain meso-diaminopimelic acid. The polar lipids were found to be diphosphatidyglycerol, phosphatidylglycerol, five phospholipids and one glycolipid. The DNA G+C content was 43.1 mol% as determined by the T m method. Analysis of the 16S rRNA gene sequence indicated that the isolate belongs within the genus Lentibacillus and is closely related to Lentibacillus persicus DSM 22530(T), Lentibacillus salicampi JCM 11462(T) and Lentibacillus jeotgali JCM 15795(T) with 97.3, 96.7 and 96.4 % sequence similarity, respectively. The DNA-DNA hybridization value between LAM0015(T) and L. persicus DSM 22530(T) was 51.2 ± 1.4 %. Based on its phenotypic, phylogenetic and chemotaxonomic characteristics, strain LAM0015(T) is concluded to represent a novel species of the genus Lentibacillus, for which the name Lentibacillus amyloliquefaciens sp. nov. is proposed. The type strain is LAM0015(T) (=ACCC 06401(T) = JCM 19838(T)).

Statin-modified dendritic cells regulate humoral immunity in experimental autoimmune myasthenia gravis.

We previously demonstrated that atorvastatin induced immature dendritic cells (DCs) derived from spleen in vitro. Administration of these tolerogenic DCs led to amelioration of experimental autoimmune myasthenia gravis (EAMG). The protective effect was mainly mediated by inhibited cellular immune response, including up-regulated regulatory T cells and shifted Th1/Th17 to Th2 cytokines. The present study employed atorvastatin-modified bone marrow-derived DCs (AT-BMDCs) to explore the effect of tolerogenic DCs on humoral immune response of EAMG and further elucidate the underlying mechanisms. Our data showed that AT-BMDCs reduced the quantity and the relative affinity of pathogenic antibodies, suppressed germinal center response, decreased follicular helper T cells and IL-21, and increased regulatory B cells. These results suggest that AT-BMDCs ameliorate EAMG by regulating humoral immune response, thus providing new insights into therapeutic approaches of myasthenia gravis and other autoimmune diseases.

Caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate dendric cell IL-1-IL-17 pathway.

BACKGROUND: IL-1ß has been shown to play a pivotal role in autoimmunity. Cysteinyl aspartate-specific proteinase-1 (caspase-1) inhibitor may be an important drug target for autoimmune diseases. However, the effects of caspase-1 inhibitor on myasthenia gravis (MG) remain undefined. METHODS: To investigate the effects of caspase-1 inhibitor on experimental autoimmune myasthenia gravis (EAMG), an animal model of MG, caspase-1 inhibitor was administered to Lewis rats immunized with region 97-116 of the rat AChR α subunit (R97-116 peptide) in complete Freund's adjuvant. The immunophenotypical characterization by flow cytometry and the levels of autoantibody by ELISA were carried out to evaluate the neuroprotective effect of caspase-1 inhibitor. RESULTS: We found that caspase-1 inhibitor improved EAMG clinical symptom, which was associated with decreased IL-17 production by CD4+ T cells and γδ T cells, lower affinity of anti-R97-116 peptide IgG. Caspase-1 inhibitor decreased expression of CD80, CD86, and MHC class II on DCs, as well as intracellular IL-1ß production from DCs. In addition, caspase-1 inhibitor treatment inhibited R97-116 peptide-specific cell proliferation and decreased follicular helper T cells relating to EAMG development. CONCLUSIONS: Our results suggest that caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate DC IL-1-IL-17 pathway and provides new evidence that caspase-1 is an important drug target in the treatment of MG and other autoimmune diseases.

High-efficiency femtosecond Yb:Gd3Al(0.5)Ga(4.5)O12 mode-locked laser based on reduced graphene oxide.

A diode-pumped Yb-doped Gd(3)Al(0.5)Ga(4.5)O(12) mode-locked bulk laser based on chemically reduced graphene oxide (RGO) has been demonstrated for the first time to our best knowledge. Pulses with duration of 643 fs were produced at the central wavelength of 1041.1 nm. A maximum average output power of 0.8 W was obtained from the RGO mode-locked laser, corresponding to a slope efficiency of 20.1% and a peak power of 27.6 kW. The results indicate that RGO is suitable for obtaining high-power and high-efficiency ultrafast lasers.

Association and mediating mechanism between remnant cholesterol and first-ever stroke among the Chinese general population.

Background: Remnant cholesterol (RC) has been suggested to be implicated in atherosclerosis. The objective of the study was to evaluate the association between RC and first-ever stroke in the Chinese general population and to investigate whether the association is mediated via hypertension or diabetes. Methods: This study is a retrospective cohort analysis of participants from the China Health and Nutrition Survey. Participants without previous stroke and myocardial infarction in 2009 were enrolled and followed up in 2011 and 2015. Logistic regression analyses were adopted to explore the association of RC with stroke risk. Propensity score methods and doubly robust estimation method were used to ensure the robustness of our findings. Potential mediators were identified by mediation analyses. Results: A total of 7,035 participants were involved, and during 6 years of follow-up, 78 (1.1%) participants experienced a first-ever stroke. Participants with high RC had a significantly higher incidence of stroke (1.4% versus 0.8%; p = 0.007). High RC was associated with 74% higher stroke risk after adjusting for multiple relevant variables (odds ratio [OR], 1.74; 95% CI, 1.06-2.85). The association was consistent in analyses using propensity score methods and doubly robust estimation method. Hypertension showed a significant mediating effect on the association between RC and stroke, while the mediating effect of diabetes was not significant. Conclusion: High RC increased the risk of first-ever stroke in the Chinese general population without previous stroke and myocardial infarction, partially through the pathway of hypertension. RC might be a potential target for the primary prevention of stroke.

Enhancing ethylene glycol and ferric chloride pretreatment of rice straw by low-pressure carbon dioxide to improve enzymatic saccharification.

Ethylene glycol and ferric chloride pretreatment assisted by low-pressure carbon dioxide (1 MPa CO2) realized the targeted deconstruction of lignocelluloses at 170 °C for 5 min, achieving 98 % cellulose recovery with removal of 92 % lignin and 90 % hemicellulose. After the pretreatment, the formation of stable platform mono-phenol components would be with the destruction of the lignin-carbohydrate complexes structure, and the surface of rice straw became rough, with a less negative charge and higher specific surface area, while the enzyme adsorption rate increased by 8.1 times. Furthermore, the glucose yield of pretreated straw was remarkably increased by 5.6 times that of the untreated straw, reaching 91 % after hydrolyzed for 48 h. With Tween 80 added in concentrated solid (12 %) hydrolysis at low cellulase loading (3 FPU/g dry substrate), half of the hydrolysis time was shortened than that without Tween 80, with 45 % higher glucose yield.

Epstein-Barr virus: To be a trigger of autoimmune glial fibrillary acidic protein astrocytopathy?

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune disease of central nervous system (CNS). It is unclear whether Epstein-Barr virus (EBV) is related to autoimmune GFAP astrocytopathy. OBJECTIVE: To describe the clinical, laboratory, and imaging characteristics of patients with autoimmune GFAP astrocytopathy. METHODS: The clinical, laboratory, and imaging findings of patients are presented. The levels of GFAP in CSF were detected by ELISA. T and B cell subsets in CSF were detected by flow cytometry. GFAP-IgG in serum and cerebrospinal fluid (CSF) were tested by cell-based assay (CBA) and tissue-based assay (TBA). RESULTS: All three patients had fever, cognitive dysfunction, limb weakness, and positive GFAP-IgG with EBV infection in CSF. Enteric glia cells may involve in this disease. Typical imaging findings include the gadolinium enhancement of linear perivascular radial perpendicular to the ventricle, meningeal enhancement (especially in midbrain interpeduncal fossa), longitudinally extensive lesions involving spindle cords, and more T2/Flair-hyperintense lesions in the periventricular white matter at late stage. The patients had poor response to antiviral treatment and strong response to steroid pulse therapy. CONCLUSION: EBV could induce CNS autoimmune response in autoimmune GFAP astrocytopathy. The detection of GFAP-IgG and EBV may facilitate the early diagnosis in these patients.

The role of Gadd45b in neurologic and neuropsychiatric disorders: An overview.

Growth arrest and DNA damage-inducible beta (Gadd45b) is directly intertwined with stress-induced DNA repair, cell cycle arrest, survival, and apoptosis. Previous research on Gadd45b has focused chiefly on non-neuronal cells. Gadd45b is extensively expressed in the nervous system and plays a critical role in epigenetic DNA demethylation, neuroplasticity, and neuroprotection, according to accumulating evidence. This article provided an overview of the preclinical and clinical effects of Gadd45b, as well as its hypothesized mechanisms of action, focusing on major psychosis, depression, autism, stroke, seizure, dementia, Parkinson's disease, and autoimmune diseases of the nervous system.

Saikosaponin A improved depression-like behavior and inhibited hippocampal neuronal apoptosis after cerebral ischemia through p-CREB/BDNF pathway.

Post-stroke depression(PSD) is a common complication and associates with poor physical recovery, low quality of life and high mortality after cerebral infarction. However, the pathogenesis of PSD have not been elucidated thoroughly now, and there is a lack of effective therapy in clinic. It reported that Saikosaponin A, one of the main constituents from Chinese herb Bupleurum chinense, has pharmacological activity in anti-depression. Thus, this study aimed to elucidate the potential effects and mechanisms of Saikosaponin A on the depression-like behavior after cerebral ischemic injury in rats. The rat model of PSD was induced by middle cerebral artery occlusion(MCAO) combined with chronic unpredictable mild stress(CUMS) and isolation. Behavior tests including open field test, beam-walking test, sucrose preference and forced swimming tests were performed. Western blot and immunohistochemistry were adopted to evaluate expression of phosphorylated cAMP response element binding protein(p-CREB), brain derived neurotrophic factor(BDNF) and apoptosis-related molecules in the dentate gyrus region of rat hippocampus. The TUNEL assay was used to determine neuronal apoptosis. We found that the rats subjected to MCAO combined with CUMS and isolation experienced significant depressive-like behavior. Administration of Saikosaponin A significantly ameliorated depressive-like behavior, and inhibited neuronal apoptosis, enhanced the level of p-CREB, BDNF and Bcl-2, reduced the level of Bax, Caspase-3 in the hippocampus of PSD rats. These results revealed that Saikosaponin A improved depression-like behavior and inhibited hippocampal neuronal apoptosis after cerebral ischemia, presumably through increasing the expression of BDNF, p-CREB and Bcl-2, as well as decreasing the level of Bax, Caspase-3.

The complete mitochondrial genome of a microalgae Chlamydomonas moewusii strain XJCH-01 from Tarim Basin of Xinjiang, China.

Chlamydomonas moewusii is a microalga isolated from the Tarim Basin of Xinjiang, China. The complete mitochondrial genome sequence of C. moewusii strain XJCH-01 was determined in this study (Accession number MT015649). The mitogenome (22,887 bp, 34.58% G + C) consists of 7 protein-coding genes (PCG), discontinuous large and small subunit ribosomal RNA (rRNA), and 4 transfer RNA (tRNA) genes. The complete mitochondrial genome sequence of the C. moewusii strain XJCH-01 enriches data resources for further study in genetic and functional evolution.

Antidepressant-like effects of paeoniflorin on post-stroke depression in a rat model.

BACKGROUND: Post-stroke depression (PSD) is one of the most prevalent emotional disorders after stroke and often results in poor outcomes. However, the underlying physiopathologic mechanism and effective treatment of PSD remain poorly elucidated. OBJECTIVE: To investigate whether paeoniflorin has antidepressant-like activity in a rat model of PSD. METHODS: Rats were randomly divided into four groups: sham-operated control (Sham), PSD, paeoniflorin (with PSD) and fluoxetine group(with PSD). PSD was developed by the right middle cerebral artery occlusion followed 21 days chronic unpredictable mild stress combined (CUMS) with raised alone. Tests of sucrose preference and open field were used to assess the depression-like behavior. Neurological function was evaluated by neurological deficit score and beam balance test. Expression of phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF) in the CA1 region of the hippocampal complex was evaluated by western blot and immunofluorescence. RESULTS: Te depressive-like behaviors markedly improved after paeoniflorin and fluoxetine treatment. Furthermore, paeoniflorin treatment significantly increased BDNF and p-CREB expression in the CA1 region. CONCLUSIONS: Observed results suggested that paeoniflorin could ameliorate the symptoms and improve the functional capability of PSD rats, similar to the effect of fluoxetine. ABBREVIATIONS: PSD: post-stroke depression; CUMS: chronic unpredictable mild stress stimulation; MCAO: middle cerebral artery occlusion; OFT: open field test; SPT: sucrose preference test, NDS: neurological deficit score, BBT: beam balance test; BDNF: brain-derived neurotrophic factor protein; p-CREB: phosphorylated Cyclic-AMP responsive element binding protein.

Fastigial nucleus electrostimulation promotes axonal regeneration after experimental stroke via cAMP/PKA pathway.

Axon regeneration after cerebral ischemia in mammals is inadequate to restore function, illustrating the need to design better strategies for improving outcomes. Improvement of axon regeneration has been achieved through fastigial nucleus electrostimulation (FNS) in animal researches. However, the mechanisms underlying this neuroprotection remain poorly understood. Increasing the levels of the second messenger cyclic AMP (cAMP) enhances axon regeneration, making it an excellent candidate molecule that has therapeutic potential. In the present study, we examined the expression of cAMP signaling in ischemic brain tissues following focal cerebral ischemia. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion (MCAO). A dipolar electrode was placed into the cerebellum to stimulate the cerebellar fastigial nucleus for 1 h after ischemia. Neurological deficits and the expressions of cAMP, PKA (protein kinase A) and ROCK (Rho-kinase) were determined. Axonal regeneration was measured by upregulation of growth-associated protein 43 (GAP43). The data indicated that FNS significantly enhanced axonal regeneration and motor function recovery after cerebral ischemia. FNS also significantly increased cAMP and PKA levels after ischemic brain injury. All the beneficial effects of FNS were blocked by Rp-cAMP, an antagonist of PKA. Our research suggested that the axonal regeneration conferred by FNS was likely achieved via the regulation of cAMP/PKA pathway.