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Background The Brief COPE instrument has been utilized to conduct research on various populations, including people living with HIV (PLWH). However, the questionnaire constructs when applied to PLWH have not been subjected to thorough factor validation. Methods A total of 258 PLWH were recruited from two provinces of China. They answered questions involving the scales of three instruments: the Brief COPE, the Perceived Social Support Scale, and the Perceived Discrimination Scale for PLWH. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were conducted. Results The CFA found a poor goodness of fit to the data. The subsequent EFA identified six preliminary factors, forming subscales with Cronbach’s alphas, which ranged from 0.61 to 0.80. Significant correlation coefficients between the subscales and measures of perceived social support and perceived discrimination were reported, giving preliminary support to the validity of the new empirical factor structure. Conclusion This study showed that the original factor structure of the Brief COPE instrument, when applied to PLWH in China, did not fit the data. Thus, the Brief COPE should be applied to various populations and cultures with caution. The new factor structure established by the EFA is only preliminary and requires further validation.

Aim： To investigate the effects of microinjection of the GABAA receptor agonist muscimol into cerebellar fastigial nucleus （FN） on stress- induced gastric mucosal damage and the underlying mechanism in rats. Methods： Stress-induced gastric mucosal damage was induced in adult male SD rats by restraining and immersing them in cold water for 3 h. GABAA receptor agonist or antagonist was microinjected into the lateral FN. The decussation of superior cerebellar peduncle （DSCP） was electrically destroyed and the lateral hypo~halamic area （LHA） was chemically ablated by microinjection of kainic acid. The pathological changes in the gastric mucosa were evaluated using TUNEL staining, immunohistochemistry staining and Western blotting. Results： Microinjection of muscimot （1.25, 2.5, and 5.0 pg） into FN significantly exacerbated the stress-induced gastric mucosal damage in a dose-dependent manner, whereas microinjection of GABAA receptor antagonist bicuculline attenuated the damage. The intensifying effect of muscimol on gastric mucosal damage was abolished by electrical lesion of DSCP or chemical ablation of LHA performed 3 d before microinjection of muscimol. Microinjection of muscimol markedly increased the discharge frequency of the greater splanchnic nerve, significantly increased the gastric acid volume and acidity, and further reduced the gastric mucosal blood flow. In the gastric mucosa, further reduced proliferation cells, enhanced apoptosis, and decreased anti-oxidant levels were observed following microinjection of muscimol. Conclusion： Cerebellar FN participates in the regulation of stress-induced gastric mucosal damage, and cerebello-hypothalamic circuits contribute to the process.

The gene AtCSR encodes peptidyl-prolyl cis/trans isomerases （PPIases） that accelerate energetically unfavorable cis/trans isomerization of the peptide bond preceding proline production.In our studies,we found that AtCSR was associated with cadmium （Cd）-sensitive response in Arabidopsis.Our results show that AtCSR expression was triggered by Cd-stress in wild type Arabidopsis.The expression of some genes responsible for Cd2＋ transportation into vacuoles was induced,and the expression of the iron-regulated transporter 1 （IRT1） related to Cd2＋ absorption from the environment was not induced in wild type with Cd2＋ treatment.The expression of Cd-transportation related genes was not in response to Cd-stress,whereas IRT expression increased dramatically in atcsr-2 with Cd2＋ treatment.The expression of glutathione 1 （GSH1） was consistent with GSH being much lower in atcsr-2 in comparison with the wild type with Cd2＋ treatment.Additionally,malondialdehyde （MDA）,hydrogen peroxide,and Cd2＋ contents,and activities of some antioxidative enzymes,differed between the wild type and atcsr-2.Hydrogen sulfide （H2S） has been confirmed as the third gas-transmitter over recent years.The findings revealed that the expression pattern of H2 S-releasing related genes and that of Cd-induced chelation and transportation genes matched well in the wild type and atcsr-2,and H2S could regulate the expression of the Cd-induced genes and alleviate Cd-triggered toxicity.Finally,one possible suggestion was given：down-regulation of atcsr-2,depending on H2S gas-transmitter not only weakened Cd2＋ chelation,but also reduced Cd2＋ transportation into vacuoles,as well as enhancing the Cd2＋ assimilation,thus rendering atcsr-2 mutant sensitive to Cd-stress.

Background： The influence of blood pressure （BP） lowering on intracerebral hemorrhage （ICH） patients is unclear. To assess the safety and efficacy of aggressive antihypertensive therapies in acute ICH patients, we carried out a systematic review and meta-analysis. Methods： PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and VIP database up to July 2014 were searched. H igh-quality randomized controlled trials were included. Low-quality trials were excluded. Serious adverse events were defined as the primary outcome. The secondary outcomes were hematoma enlargement （HE） at 24 h after onset, mortality, and favorable clinical outcome at 90 days. Results： Four high-quality trials involving a total of 1427 patients met the inclusion criteria and were analyzed. Odds ratios （ORs） of primary outcome was 0.96 （95% confidence interval [CI]： 0.82-1.13, P = 0.61）. ORs of HE at 24 h after onset, mortality and favorable clinical outcome at 90 days were 0.91 （95% CI： 0.72-1.17, P = 0.47）, 0.97 （95% CI： 0.79-1.20, P = 0.81）, 1.13 （95% CI： 0.98-1.30. P = 0.09） respectively. Conclusions： Aggressive BP management policies are safe and might have a potency of reducing HE and improving clinical outcome.

Familial hypercholesterolemia (FH) is a common monogenic autosomal dominant disorder, primarily mainly caused by pathogenic mutations in the low-density lipoprotein receptor (LDLR) gene. Through phenotypic-genetic linkage analysis, two LDLR pathogenic mutations were identified in FH families: c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr). Whole exome sequencing was conducted on the proband with familial hypercholesterolemia to identify the target gene and screen for potential pathogenic mutations. The suspicious responsible mutation sites in 14 family members were analyzed using Sanger sequencing to assess genotype-phenotype correlations. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to evaluate LDLR mRNA and protein expression. In parallel, bioinformatics tools were employed to predict structural and functional changes in the mutant LDLR. Immunofluorescence analysis revealed no significant difference in the intracellular localization of the p.Gly343Ser mutation, whereas protein expression of the p.Ala627Thr mutation was decreased and predominantly localized in the cytoplasm. Western blotting has showed that protein expression levels of the mutant variants were markedly declined in both cell lysates and supernatants. Enzyme linked immunosorbent assay has demonstrated that LDLR protein levels in the supernatant of cell culture medium was not significant different from those of the wild-type group. However, LDLR protein levels in the cell lysate of both the Gly343Ser and Ala627Thr variants groups were significantly lower than those in the wild-type group. Bioinformatic predictions further suggested that these mutations may affect post-translational modifications of the protein, providing additional insight into the mechanisms underlying the observed reduction in protein expression. In this study, we identified two heterozygous pathogenic variants in the LDLR gene, c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr), in a family with familial hypercholesterolemia. We also conducted preliminary investigations into the mechanisms by which these mutations contribute to disease pathology.

Pluripotent stem cells （PSCs） harbor constitutive DNA rePlication stress during their rapid proliferation and the consequent genome instability hampers their applications in regenerative medicine. It is therefore important to un- derstand the regulatory mechanisms of replication stress response in PSCs. Here, we report that mouse embryonic stem cells （ESCs） are superior to differentiated cells in resolving replication stress. Specifically, ESCs utilize a unique Filia-Floped protein complex-dependent mechanism to efficiently promote the restart of stalled replication forks, therefore maintaining genomic stability. The ESC-specific Filia-Floped complex resides on replication forks under normal conditions. Replication stress stimulates their recruitment to stalling forks and the serine 151 residue of Filia is phosphorylated in an ATR-dependent manner. This modification enables the Filia-Floped complex to act as a func- tional scaffold, which then promotes the stalling fork restart through a dual mechanism： both enhancing recruitment of the replication fork restart protein, Blm, and stimulating ATR kinase activation. In the Blm pathway, the scaffolds recruit the E3 ubiquitin ligase, Trim25, to the stalled replication forks, and in turn Trim25 tethers and concentrates Blm at stalled replication forks through ubiquitination. In differentiated cells, the recruitment of the Trim25-Blm complex to replication forks and the activation of ATR signaling are much less robust due to lack of the ESC-specific Filia-Floped scaffold. Thus, our study reveals that ESCs utilize an additional and unique regulatory layer to efficient- ly promote the stalled fork restart and maintain genomic stability.

Chaetomium globosum is one of the most common fungi in nature. It is best known for producing chaetoglobosins; however, the molecular basis of chaetoglobosin biosynthesis is poorly understood in this fungus. In this study, we utilized RNA inter- ference （RNAi） to characterize a polyketide synthase gene, pks-1, in C. globosum that is involved in the production of chaeto- globosin A. When pks-1 was knocked down by RNAi, the production of chaetoglobosin A dramatically decreased. Knock-down mutants also displayed a pigment-deficient phenotype. These results suggest that the two polyketides, melanin and chaetoglobosin, are likely to share common biosynthetic steps. Most importantly, we found that pks-I also plays a critical role in sporulation. The silenced mutants ofpks-1 lost the ability to produce spores. We propose that polyketides may modulate cellular development via an unidentified action. We also suggest that C. globosum pks-1 is unique because of its triple role in melanin formation, chaetoglobosin biosynthesis and sporulation. This work may shed light on chaetoglobosin biosynthesis and indicates a relationship between secondary metabolism and fungal morphogenesis.

Few effective therapeutic options are currently available for the treatment of non-small cell lung cancer （NSCLC） with brain metastases （BM）. Recent evidence shows that NSCLC patients with BMs respond well to afatinib, but little is known about the underlying mechanisms. In this study, we evaluated the efficacy of afatinib in treatment of BMs in mice and investigated whether afatinib could actively penetrate the brain-blood barrier and bind to its target. NSCLC BM model was established in nude mice by intracerebral injection of PC-9.luc cells. The tumors were measured weekly using in vivo quantitative biotuminescence. The mice are administrated afatinib （15, 30 mg.kg-1.d-1, ig） for 14 d. The antitumor efficacy of afatinib was determined by tumor growth inhibition （TGI）, which was calculated as [1-（change of tumor volume in treatment group/control group）×100]. Pharmacokinetic characteristics were measure in mice receiving a single dose of afatinib （30 mg/kg, ig）. Pharmacodynamics of afatinib was also assessed by detecting the expression of pEGFR （Tyr1068） in brain tumor loci using immunohistochemistry. Administration of afatinib （15, 30 mg.kg-1.d-1） dose-dependently inhibited PC-9 tumor growth in the brain with a TGI of 90.2% and 105%, respectively, on d 14. After administration of afatinib （30 mg/kg）, the plasma concentration of afatinib was 91.4±31.2 nmol/L at 0.5 h, reached a peak （417.1±119.9 nmol/L） at 1 h, and was still detected after 24 h. The cerebrospinal fluid （CSF） concentrations followed a similar pattern. The T1/2 values of afatinib in plasma and CSF were 5.0 and 3.7 h, respectively. The AUC（0-24h） values for plasma and CSF were 2375.5 and 29.1 nmol/h, respectively. The plasma and CSF concentrations were correlated （r=0.844, P〈0.01）. Pharmacodynamics study showed that the expression levels of pEGFR were reduced by 90% 1 h after afatinib administration. The Emax was 86.5%, and the EC50 was 0.26 nmol/L. A positive correlation between CSF concentrations and pEGFR modulation was revealed. Afatinib penetrates the BBB in NSCLC BM mice and contributes to the brain tumor response. The CSF exposure level is correlated with the plasma level, which in turn is correlated with the modulation of pEGFR in the tumor tissues. The results support for the potential application of afatinib in NSCLC patients with BMs.