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Blood–brain barrier (BBB) disruption contributes to neurodegenerative diseases. Loss of tight junction (TJ) proteins in cerebral endothelial cells (ECs) is a leading cause of BBB breakdown. We recently reported that miR‐195 provides vasoprotection, which urges us to explore the role of miR‐195 in BBB integrity. Here, we found cerebral miR‐195 levels decreased with age, and BBB leakage was significantly increased in miR‐195 knockout mice. Furthermore, exosomes from miR‐195‐enriched astrocytes increased endothelial TJ proteins and improved BBB integrity. To decipher how miR‐195 promoted BBB integrity, we first demonstrated that TJ proteins were metabolized via autophagic–lysosomal pathway and the autophagic adaptor p62 was necessary to promote TJ protein degradation in cerebral ECs. Next, proteomic analysis of exosomes revealed miR‐195‐suppressed thrombospondin‐1 (TSP1) as a major contributor to BBB disruption. Moreover, TSP1 was demonstrated to activate selective autophagy of TJ proteins by increasing the formation of claudin‐5‐p62 and ZO1‐p62 complexes in cerebral ECs while TSP1 impaired general autophagy. Delivering TSP1 antibody into the circulation showed dose‐dependent reduction of BBB leakage by 20%–40% in 25‐month‐old mice. Intravenous or intracerebroventricular injection of miR‐195 rescued TSP1‐induced BBB leakage. Dementia patients with BBB damage had higher levels of serum TSP1 compared to those without BBB damage (p = 0.0015), while the normal subjects had the lowest TSP1 (p < 0.0001). Taken together, the study implies that TSP1‐regulated selective autophagy facilitates the degradation of TJ proteins and weakens BBB integrity. An adequate level of miR‐195 can suppress the autophagy–lysosome pathway via a reduction of TSP1, which may be important for maintaining BBB function. [ABSTRACT FROM AUTHOR]

Immune‐mediated necrotizing myopathy (IMNM) has emerged as a new subgroup of idiopathic inflammatory myopathy in the past decade, associated with the presence of two autoantibodies against signal recognition particle and 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR). We aim to analyze the clinical, pathological, and imaging phenotypes of the patients with anti‐HMGCR myopathy in our cohort. Five patients with anti‐HMGCR myopathy have been enrolled who were all female; three were pediatric and two were adult patients. The muscle pathology of patients met the diagnostic criteria of IMNM. On muscle magnetic resonance imaging, adductors were earliest affected while lower legs were relatively preserved with highest degree of involvement in medial head of gastrocnemius. In upper extremities, biceps brachii was the most severely involved, followed by triceps. All patients were refractory to steroid mono‐therapy. For pediatric patients, all three patients eventually became responsive to steroid with either intravenous immunoglobulin or rituximab despite variable motor function recovered at present due to different intervention timing. For adult patients, one with statin exposure responded well to steroid and azathioprine use and the motor function returned to the baseline. The other adult patient finally got stabilized and slowly improved with steroid and methotrexate 13 years after the start of therapy. The creatine kinase (CK) levels of all patients were decreased along with clinical severity. In conclusion, muscle imaging might be of help for the diagnosis. Treatment with immuno‐suppressants could be considered together with steroid from the beginning. [ABSTRACT FROM AUTHOR]

Background: Patients with kidney disease, especially those receiving hemodialysis, presented a higher risk of cognitive impairment and brain white matter damage than those without kidney disease. Previous research suggests an association between lower bone marrow densities and cognitive impairments. However, the study investigating the relationship between bone turnover biomarkers and brain white matter damage in hemodialysis patients is sparse. Methods: The enrolled hemodialysis participants were examed on the Fazekas scale of brain magnetic resonance imaging (MRI) white matter lesions and measured 8 bone turnover proteins using the Luminex bead‐based multiplex assay. The Fazekas scale of periventricular lesions was from grade 0 to grade 3. Multivariable ordinal regression and logistic regression models were examined to determine the independent relationship between bone turnover proteins and the Fazekas scale of periventricular lesions. Results: In 59 hemodialysis patients, older patients had more periventricular lesions on the Fazekas scale, which was connected with a worse Mini‐Mental State Examination score (MMSE). The serum level of sclerostin, one of eight bone turnover proteins, displayed a dose‐response relationship (P value for trend = 0.004), meaning that a greater sclerostin level was connected with a lower grade on the Fazekas scale. Both the ordinal regression model (odds ratio [OR] 0.886; 95% confidence interval [CI] 0.828‐0.947, P value 0.001) and the logistic regression model (odds ratio [OR] 0.828; 95% 0.712‐0.963, P value = 0.014) determined a negative association between sclerostin and the Fazekas scale of periventricular lesions after complete adjustment for potential confounders. Conclusions: The brain white matter damage was inversely correlated with the level of circulating sclerostin. Our finding suggested a possible connection between bone turnover proteins and brain damage. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor ( PDGF) can promote vascular smooth muscle cells ( VSMCs) to switch from the quiescent contractile phenotype to synthetic phenotype, which contributes to atherosclerosis. We aimed to investigate the role of micro RNA let-7g in phenotypic switching. Bioinformatics prediction was used to find let-7g target genes in the PDGF/mitogen-activated protein kinase kinase kinase 1 ( MEKK1)/extracellular signal-regulated kinase ( ERK)/Krüppel-like factor-4 ( KLF4) signalling pathway that affects VSMC phenotypic switching. The luciferase reporter assay and let-7g transfection were used to confirm let-7g target genes. Two contractile proteins alpha-smooth muscle actin (α- SMA) and calponin were VSMC-specific genes and were measured as the indicators for VSMC phenotype. Lentivirus carrying the let-7g gene was injected to apolipoprotein E knockout (apoE−/−) mice to confirm let-7g's effect on preventing atherosclerosis. Through the PDGF/ MEKK1/ ERK/ KLF4 signalling pathway, PDGF- BB can inhibit α- SMA and calponin. The PDGFB and MEKK1 genes were predicted to harbour let-7g binding sites, which were confirmed by our reporter assays. Transfection of let-7g to VSMC also reduced PDGFB and MEKK1 levels. Moreover, we showed that let-7g decreased phosphorylated- ERK1/2 while had no effect on total ERK1/2. KLF4 can reduce VSMC-specific gene expression by preventing myocardin-serum response factor ( SRF) complex from associating with these gene promoters. The immunoprecipitation assay showed that let-7g decreased the interaction between KLF4 and SRF. Further experiments demonstrated that let-7g can increase α- SMA and calponin levels to maintain VSMC in the contractile status. Injection of lentivirus carrying let-7g gene increased let-7g's levels in aorta and significantly decreased atherosclerotic plaques in the apoE−/− mice. We demonstrated that let-7g reduces the PDGF/ MEKK1/ ERK/ KLF4 signalling to maintain VSMC in the contractile status, which further reduce VSMC atherosclerotic change. [ABSTRACT FROM AUTHOR]

Although use of the Internet for job searching is rapidly increasing, the motivations for using electronic recruitment (e-recruitment) services by job seekers have seldom been addressed. Derived from the extended theory of planned behavior, this study develops a research model for the empirical examination of factors affecting job seeker intentions to use job-search websites. Utilizing data collected from 174 participants in Taiwan, various relationships in the research model are tested using structural equation modeling approach. The results showed that job seeker attitude, subjective norm, and perceived behavioral control significantly affected their intentions to use job-search websites. Also, perceived usefulness and perceived ease of use showed a significant effect on attitude, interpersonal influence on subjective norm, and perceived ease of use and self-efficacy on perceived behavioral control. However, external influence was found to be an insignificant predictor of subjective norm. In addition to providing further insight into the factors that influence job seeker intentions to use job-search websites, this study offers valuable suggestions for subsequent research and practitioners investigating the use of e-recruitment services. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor (PDGF) can promote vascular smooth muscle cells (VSMCs) to switch from the quiescent contractile phenotype to synthetic phenotype, which contributes to atherosclerosis. We aimed to investigate the role of microRNA let-7g in phenotypic switching. Bioinformatics prediction was used to find let-7g target genes in the PDGF/mitogen-activated protein kinase kinase kinase 1 (MEKK1)/extracellular signal-regulated kinase (ERK)/Krüppel-like factor-4 (KLF4) signalling pathway that affects VSMC phenotypic switching. The luciferase reporter assay and let-7g transfection were used to confirm let-7g target genes. Two contractile proteins alpha-smooth muscle actin (α-SMA) and calponin were VSMC-specific genes and were measured as the indicators for VSMC phenotype. Lentivirus carrying the let-7g gene was injected to apolipoprotein E knockout (apoE -/- ) mice to confirm let-7g's effect on preventing atherosclerosis. Through the PDGF/MEKK1/ERK/KLF4 signalling pathway, PDGF-BB can inhibit α-SMA and calponin. The PDGFB and MEKK1 genes were predicted to harbour let-7g binding sites, which were confirmed by our reporter assays. Transfection of let-7g to VSMC also reduced PDGFB and MEKK1 levels. Moreover, we showed that let-7g decreased phosphorylated-ERK1/2 while had no effect on total ERK1/2. KLF4 can reduce VSMC-specific gene expression by preventing myocardin-serum response factor (SRF) complex from associating with these gene promoters. The immunoprecipitation assay showed that let-7g decreased the interaction between KLF4 and SRF. Further experiments demonstrated that let-7g can increase α-SMA and calponin levels to maintain VSMC in the contractile status. Injection of lentivirus carrying let-7g gene increased let-7g's levels in aorta and significantly decreased atherosclerotic plaques in the apoE -/- mice. We demonstrated that let-7g reduces the PDGF/MEKK1/ERK/KLF4 signalling to maintain VSMC in the contractile status, which further reduce VSMC atherosclerotic change., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)