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IntroductionThe aim of our study is to investigate the correlation of immune-related genes with clear cell renal cell carcinoma (ccRCC) prognosis and the role of immune-related genes in tumor immune microenvironment (TIME) and to build a new prognostic model and prognostic scoring system for renal cancer.Material and methodsWe downloaded the mRNA expression data of 610 samples (538 ccRCC and 72 normal tissues) from TCGA database and constructed a immune-related prognostic model using Cox regression analysis and LASSO analysis. Then we internally verified the scientific validity and accuracy of the model using Kaplan-Meier (KM) analysis and receiver operating characteristic (ROC) curves. Subsequently, Cytoscape was used to construct a TF-miRNA-mRNA network. The "CIBERSORT" package was used to perform the immune-infiltration analysis. Finally, validation of key gene expression was performed by immunohistochemistry (IHC) and quantitative reverse transcription-PCR (qRT-PCR).ResultsThe prognostic model constructed for ccRCC includes 7 genes (KLRC2, PGLYRP2, AGER, CHGA, AVPR1B, IL20RB, LAT). And it was proven to have good prognostic performance through the KM analysis and the ROC curves. We also constructed an accurate prognostic predictive scoring system by establishing a nomogram. Furthermore, the TF-miRNA-mRNA network revealed the potential mechanism of the model and the immune infiltration analysis revealed a correlation between this model and TIME.ConclusionsThe results suggest that the newly developed 7 immune-related genes model can be a practical and reliable prognostic tool for ccRCC. It also shows T cell infiltration characteristics in TIME can therefore be used as an immune biomarker for the diagnosis and treatment of ccRCC.

SUMMARYThe analysis of microbial genomes from human archaeological samples offers a historic snapshot of ancient pathogens and provides insights into the origins of modern infectious diseases. Here, through a large-scale metagenomic analysis of archeological samples, we discovered bacterial species related to modern-dayClostridium tetani, which produces the tetanus neurotoxin (TeNT) and causes the disease tetanus. We assembled draft genomes from 38 distinct human archeological samples spanning five continents and dating to as early as ~4000 BCE. These genomes had varying levels of completeness and a subset of them displayed hallmarks of ancient DNA damage. While 24 fall into knownC. tetaniclades, phylogenetic analysis revealed novelC. tetanilineages, as well as two novelClostridiumspecies (“Clostridiumsp. X and Y”) closely related toC. tetani. Within these genomes, we found 13 TeNT variants with unique substitution profiles, including a subgroup of TeNT variants found exclusively in ancient samples from South America. We experimentally tested a TeNT variant selected from a ~6000-year-old Chilean mummy sample and found that it induced tetanus muscle paralysis in mice with potency comparable to modern TeNT. Our work identifies neurotoxigenicC. tetaniin ancient DNA, newClostridiumspecies unique to ancient human samples, and a novel variant of TeNT that can cause disease in mammals.

Objective: This paper examines the benefits of the optional Kung Fu course on students’ physical health. Methods: Specific strategies promoting elective Kung Fu courses in Chinese universities are presented after analyzing the current situation of university students’ psychophysical health. Results: According to the characteristics of martial arts students, providing effective sports intervention is an important demand for educators. Its development is also an important feature of modern sports and medicine. Conclusions: According to the analysis of the general physical status of Chinese college students at the current stage, students in ordinary colleges and universities should pay more attention to the importance of sports activities for students’ physical quality and mental health education when participating in sports activities. Level of evidence II; Therapeutic studies - investigation of treatment results. RESUMO Objetivo: Este documento analisa os benefícios do curso optativo de Kung Fu sobre a saúde física dos estudantes. Métodos: As estratégias específicas em promoção de cursos eletivos de Kung Fu nas universidades chinesas são apresentadas após análise da situação atual da saúde psicofísica dos estudantes universitários. Resultados: De acordo com as características dos estudantes de artes marciais, proporcionar uma intervenção esportiva eficaz é uma demanda importante para os educadores. Seu desenvolvimento é também uma característica importante do esporte e da medicina moderna. Conclusões: De acordo com a análise do estado físico geral dos estudantes universitários chineses no estágio atual, os estudantes das faculdades e universidades comuns deveriam prestar mais atenção à importância das atividades esportivas para a qualidade física e a educação da saúde mental dos estudantes quando participam de atividades esportivas. Nível de evidência II; Estudos terapêuticos – investigação de resultados de tratamento. RESUMEN Objetivo: Este trabajo analiza los beneficios del curso optativo de kung-fu en la salud física de los estudiantes universitarios. Métodos: Se presentan las estrategias específicas para promover los cursos electivos de Kung Fu en las universidades chinas tras analizar la situación actual de la salud psicofísica de los estudiantes universitarios. Resultados: De acuerdo con las características de los alumnos de artes marciales, proporcionar una intervención deportiva eficaz es una demanda importante para los educadores. Su desarrollo es también una característica importante del deporte y de la medicina moderna. Conclusiones: Según el análisis del estado físico general de los estudiantes universitarios chinos en la etapa actual, los estudiantes de las universidades ordinarias deberían prestar más atención a la importancia de las actividades deportivas para la calidad física y la educación de la salud mental de los estudiantes cuando participan en actividades deportivas. Nivel de evidencia II; Estudios terapéuticos – investigación de resultados de tratamiento.

Background insulin receptor substrate-1 (IRS-1) rs956115 is associated with vascular risk in patients with coronary artery disease (CAD) and concomitant diabetes. CYP2C19 rs4244285 modulates clopidogrel responsiveness and predicts outcome of CAD. We designed this study to explore the association between IRS-1 rs956115, CYP2C19 rs4244285, and platelet reactivity as well as 1-year outcome in patients with CAD undergoing percutaneous coronary intervention (PCI).Methods IRS-1 rs956115, CYP2C19 rs4244285 genotypes and platelet reactivity were assessed in 1611 post-PCI patients. Major adverse cardiovascular events (MACE) which were defined as a composite of cardiovascular death, myocardial infarction and ischemic stroke over 1-year were evaluated. One-way ANOVA was used to compare the platelet reactivity among different genotypes of rs956115 and rs4244285. Multivariable Cox proportional hazard model analysis was used to estimate the association between genotypes of rs956115 and rs4244285 and risk of MACE.Results At 1 month, patients with rs956115 CG genotype had significantly lower level of residual ADP-induced platelet aggregation (PLADP) than those with CC genotype. PLADP significantly increased with the number of rs4244285 A alleles. Patients with rs956115 CG or GG genotype had a 2.09-fold higher risk of MACE than those with CC genotype (adjusted HR=2.09; 95%CI:1.04-4.19; P=0.0376), and those with rs4244285 GA genotype had a 2.19-fold higher risk than GG homozygotes (adjusted HR=2.19; 95%CI:1.13-4.24; P=0.0200). There was no significant difference in risk between AA and GG homozygotes. No interaction between rs956115 and rs4244285 was observed. Conclusions In post-PCI patients, rs956115 GG/CG and rs4244285 GA genotypes were associated with 2.09- and 2.19-fold cardiovascular risks respectively at 1-year follow-up. The effect of rs956115 appeared to be independent of known clinical predictors, while that of rs4244285 GA could be mediated by lower clopidogrel response. Trial registration: Pharmacogenetic and Pharmacokinetic Study of Clopidogrel (PPSC), NCT01968499. Registered October 17, 2013 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01968499?term=NCT01968499&draw=1&rank=1

Salidroside (SAL) is the major ingredient of Rhodiola rosea, and has been traditionally used in Chinese medicine for decades. Numerous studies have demonstrated the protective effects of SAL for myocardial ischemia. However, it is yet to be deciphered whether SAL has cardioprotective effects after myocardial infarction (MI) in vivo. In the present study, we established a mouse MI model via coronary artery ligation. The aim was to investigate whether SAL treatment could reduce mortality, improve cardiac function and attenuate myocardial remodeling in MI mice. Post-surgery, mice were randomly administered SAL or normal saline. After 21 days, SAL was found to significantly reduce mortality, improve cardiac function, reduce fibrosis and infarct size compared to normal saline. In addition, oral administration of SAL could attenuate myocardial inflammation and apoptosis and promote angiogenesis. SAL down-regulated the expression levels of TNF-α, TGF-β1, IL-1β, Bax and up-regulate the expression of Bcl-2, VEGF, Akt and eNOS. These results indicated that SAL could alleviate the pathological processes of myocardial remodeling in MI mice, and may be a potentially effective therapeutic approach for the management of clinical ischemic cardiovascular diseases.

BRCA1-associated protein 1 (BAP1) is a member of the ubiquitin C-terminal hydrolase family of deubiquitinating enzymes and is implicated in transcriptional regulation. The BAP1 gene is mutated in about 10% of patients with ccRCC, the most common form of renal cancer, suggesting that BAP1 is a tumor suppressor. However, whether BAP1 influences the progression of ccRCC tumors expressing wild-type (WT) BAP1 is unclear. Here, we assessed the expression and function of BAP1 using human ccRCC specimens and cell lines. Analysis of datasets in The Cancer Genome Atlas revealed that lower BAP1 expression is correlated with longer overall survival of ccRCC patients. We established human ccRCC cell lines with stable BAP1 knockout and performed multiomic analysis of BAP1-mediated cellular processes. BAP1 knockout downregulated proteins associated with protein synthesis, resulting in decreased cell growth. Importantly, loss of BAP1 decreased the formation of stress fibers and membrane protrusions and induced migration and invasion defects. BAP1 knockout in ccRCC cells also downregulated the expression of transcriptional repressor protein Snail and decreased the activity of Rho family GTPases, promoting the cells to undergo mesenchymal-epithelial transition. Unexpectedly, quantitative proteomics also showed that BAP1 knockout increased expression of several amino acid transporters and multiple tyrosine kinases, including the epidermal growth factor receptor. Overall, our results suggest that BAP1 regulates multiple cellular processes, and we also uncover a new role for BAP1 in controlling mesenchymal-epithelial transition in ccRCC cells.

Enterococci are a part of human microbiota and a leading cause of multidrug resistant infections. Here, we identify a family of Enterococcus pore-forming toxins (Epxs) in E. faecalis, E. faecium, and E. hirae strains isolated across the globe. Structural studies reveal that Epxs form a branch of β-barrel pore-forming toxins with a β-barrel protrusion (designated the top domain) sitting atop the cap domain. Through a genome-wide CRISPR-Cas9 screen, we identify human leukocyte antigen class I (HLA-I) complex as a receptor for two members (Epx2 and Epx3), which preferentially recognize human HLA-I and homologous MHC-I of equine, bovine, and porcine, but not murine, origin. Interferon exposure, which stimulates MHC-I expression, sensitizes human cells and intestinal organoids to Epx2 and Epx3 toxicity. Co-culture with Epx2-harboring E. faecium damages human peripheral blood mononuclear cells and intestinal organoids, and this toxicity is neutralized by an Epx2 antibody, demonstrating the toxin-mediated virulence of Epx-carrying Enterococcus.

By sorting out the theoretical relationship between cultural consciousness and international communication, this paper explores the national cultural strategy of international communication of Chinese Wushu from the perspective of cultural consciousness. Based on the cultural consciousness of the internationalization of Chinese culture, this paper holds that "global localization" has become an important strategic concept of Chinese Wushu’s foreign cultural exchange and cross-cultural communication. The strategic implementation plan of the internationalization of Wushu is the global integrated marketing communication of cross-culture, while the current strategic focus is the internationalization of Wushu’s international image subordinate to the national image of China. Based on this, this article uses computer big data technology to analyze the current situation of the spread and exchange of Chinese Wushu in the world.

Musk has been traditionally used in East Asia to alleviate the symptoms of angina pectoris. However, it remains unclear as to whether muscone, the main active ingredient of musk, has any beneficial effects on persistent myocardial ischemia in vivo. The aim of the present study was to investigate whether muscone can improve cardiac function and attenuate myocardial remodeling following myocardial infarction (MI) in mice. Mice were subjected to permanent ligation of the left anterior descending coronary artery to induce MI, and then randomly treated with muscone (2 mg/kg/day) or the vehicle (normal saline) for 3 weeks. Sham-operated mice were used as controls and were also administered the vehicle (normal saline). Treatment with muscone significantly improved cardiac function and exercise tolerance, as evidenced by the decrease in the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, as well as an increase in the left ventricular ejection fraction, left ventricular fractional shortening and time to exhaustion during swimming. Pathological and morphological assessments indicated that treatment with muscone alleviated myocardial fibrosis, collagen deposition and improved the heart weight/body weight ratio. Muscone inhibited the inflammatory response by reducing the expression of transforming growth factor (TGF)‑β1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and nuclear factor (NF)-κB. Treatment with muscone also reduced myocardial apoptosis by enhancing Bcl-2 and suppressing Bax expression. Muscone also induced the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS). Our results demonstrate that muscone ameliorates cardiac remodeling and dysfunction induced by MI by exerting anti-fibrotic, anti-inflammatory and anti-apoptotic effects in the ischemic myocardium.

Neovascularization and the formation of collateral vessels are often impaired in diabetes mellitus (DM) population compared with non-diabetics. Alterations in vascular endothelial growth factor (VEGF) signaling and endothelial nitric oxide synthase (eNOS) dysfunction have been confirmed to play a crucial role in impaired neovascularization in diabetic mice. Accumulating data have suggested that Rg1, a main component of Panax ginseng, has the ability to promote tubulogenesis of human umbilical vein endothelial cells (HUVECs) in vitro, and that the mechanism involves increased expression level of VEGF as well as increased eNOS activation. Thus, we speculated that Rg1 might also have therapeutic effects on the impairment of neovascularization in diabetic individuals. The aim of the present study was to investigate whether Rg1 could improve angiogenesis in ischemic hindlimb of diabetic mice in vivo. Our data demonstrated that Rg1 treatment resulted in improved angiogenesis in the diabetic ischemic hindlimb, and the potential mechanism might involve increased eNOS activation, upregulated VEGF expression, and inhibited apoptosis. Our results suggest that Rg1 may be used as a novel and useful adjunctive drug for the therapy of peripheral arterial disease in DM.

p27(kip1) (p27) is widely known as a potent cell cycle inhibitor in several organs, especially in the heart. However, its role has not been fully defined during the early phase of myocardial infarction (MI). In this study, we investigated the relationships between p27, vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) and NF-κB in post-MI cardiac function repair both in vivo and in the hypoxia/ischemia-induced rat myocardiocyte model. In vivo, haplo-insufficiency of p27 improved cardiac function, diminished the infarct zone, protected myocardiocytes and increased angiogenesis by enhancing the production of VEGF/HGF. In vitro, the presence of conditioned medium from hypoxia/ischemia-induced p27 knockdown myocardiocytes reduced the injury caused by hypoxia/ischemia in myocardiocytes, and this effect was reversed by VEGF/HGF neutralizing antibodies, consistent with the cardioprotection being due to VEGF/HGF secretion. We also observed that p27 bound to IKK and that p27 haplo-insufficiency promoted IKK/p65 activation both in vivo and in vitro, thereby inducing the NF-κB downstream regulator, VEGF/HGF. Furthermore, IKKi and IKK inhibitor negated the effect of VEGF/HGF. Therefore, we conclude that p27 haplo-insufficiency protects against heart injury by VEGF/HGF mediated cardioprotection and increased angiogenesis through promoting IKK activation.

Objective The relationship between admission serum calcium levels and in-hospital mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) has not been well definitively explored. The objective was to assess the predictive value of serum calcium levels on in-hospital mortality in STEMI patients. Methods From 2003 to 2010, 1431 consecutive STEMI patients admitted to the First Affiliated Hospital of Nanjing Medical University were enrolled in the present study. Patients were stratified according to quartiles of serum calcium from the blood samples collected in the emergency room after admission. Between the aforementioned groups,the baseline characteristics, in-hospital management, and in-hospital mortality were analyzed. The association of serum calcium level with in-hospital mortality was calculated by a multivariable Cox regression analysis. Results Among 1431 included patients, 79% were male and the median age was 65 years (range, 55–74). Patients in the lower quartiles of serum calcium, as compared to the upper quartiles of serum calcium, were older, had more cardiovascular risk factors, lower rate of emergency revascularization,and higher in-hospital mortality. According to univariate Cox proportional analysis, patients with lower serum calcium level (hazard ratio 0.267, 95% confidence interval 0.164–0.433, p

Inflammation plays an important role not only in the initiation and progression of atherosclerosis but also in plaque rupture of coronary artery disease (CAD) [1–3], which leads to acute coronary syndrome (ACS) or even acute myocardial infarction (AMI). It is well known that C-reactive protein (CRP) is one of the most important inflammation markers and has been proved to be an independent risk factor for CAD [4–7]. High level of CRP predicts poor clinical outcomes in patients with both stable CAD and ACS [6–9]. Compared with CRP, high-sensitivity CRP (hs-CRP) is more sensitive that can be examined in serum. However, the source of CRP or hs-CRP in CAD or ACS has not been definitively explored. One hypothesis suggested that elevated hs-CRP, which can be measured in systemic circulation, is released from unstable or ruptured plaque in coronary circulation, and then transported to systemic circulation [10]. Another hypothesis suggested that elevated hs-CRP is released from noncoronary circulation tissue (liver cells and fatty tissues) and then transported to coronary circulation, which transforms stable plaque into an unstable or ruptured one, and finally induces ACS or AMI [11,12]. Whether hs-CRP originates from systemic or coronary circulation is still a controversial issue [10–12]. Besides, monocyte is an important chronic inflammatory factor and secretes cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-a, which stimulates the production of CRP [1–4]. Large amount of monocytes may induce high level of hs-CRP, which predicates high risk of ACS or AMI for patients with CAD. Here, we compared the level of hs-CRP between systemic and coronary circulation in patients with AMI and stable CAD, as well as the difference of monocyte between patients with AMI and stable CAD. The study included 80 patients (60 patients with AMI and 20 patients with single-vessel stable CAD) hospitalized in the Department of Cardiology, the First Afflicted Hospital of Nanjing Medical University from July 2012 to April 2013. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 [5]. Informed consent was obtained from all the included patients. In the AMI group, coronary angiography was immediately performed after admission, and the time window from the onset of chest pain to the balloon dilatation ranged from 2 to 12 h. In the stable CAD group, patients received coronary angiography 1–2 days after admission. Blood sample was collected from both systemic and coronary circulation. Blood sample of systemic circulation was taken from peripheral arterial puncture, while intracoronary blood sample was taken by using a ‘Diver’ catheter over the wire to the distal site of plaque in the culprit vessel. Fasting blood sample from each site was collected in the coagulation-promoting tubes, and centrifuged at 2100 g for 10 min. Serum was separated and immediately analyzed. Serum level of hs-CRP (mg/l) was measured by the method of rate nephelometry, using Siemens BN-II Special Protein Analyzer (Bonn, Germany). Meanwhile, the level of monocytes (10/l) from systemic circulation was measured. To explore the source of hs-CRP, the difference of hs-CRP level between systemic and coronary circulation was evaluated in each patient. Paired Student’s t-test revealed that the level of hs-CRP was higher in blood sample from systemic circulation than that from coronary circulation in the AMI group (mean difference (MD): 0.67, n 1⁄4 60, 95% confidence interval (CI): 0.08–1.26, P 1⁄4 0.0266); there was no significant difference between systemic and coronary circulation in the stable CAD group (MD: 0.18, n 1⁄4 20, 95% CI: 20.03 to 0.39, P 1⁄4 0.09) (Fig. 1). There was a trend towards higher MD of hs-CRP between systemic and coronary circulation in the AMI group than that in the stable CAD Acta Biochim Biophys Sin 2014, 46: 161–162 |a The Author 2013. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmt129. Advance Access Publication 2 December 2013

Objective: Uncontrolled therapeutic gene expression and neovascularization in non-specific tissues has lowered the safety of gene therapy. The aim of the study was to identify a cardiac-specific promoter to control target gene expression in heart tissue in vitro and in vivo. Methods: Adenovirus vectors containing the firefly luciferase or hepatocyte growth factor (HGF) genes under control of the Troponin I (TnIc) or Cytomegalievirus (CMV) promoters were transfected into cell lines or injected into the left ventricular wall of Sprague Dawley (SD) rats via thoracotomy. Myocardial infarction (MI) was induced immediately before direct injection. In vivo luciferase expression was assessed using a bioluminescence imaging system. Heart function was monitored via echocardiograph intermittently for eight weeks after injection. Results: The constitutively active CMV promoter yielded luciferase expression throughout the body while luciferase expression driven by the TnIc promoter was largely restricted to the hypoxic heart. The CMV promoter was more efficient, yielding 100-1000 fold more light output than the TnIc promoter. Four weeks after injection, we observed a significant decline in the ejection fraction (EF) in saline and Ad-Null groups but a 17% increase in the Ad-CMV-HGF group. No change in EF was observed in the Ad-TnIc-HGF group. Conclusions: The adenovirus vector combined with the TnIc promoter largely restricts gene-targeted therapy in the hypoxic heart and prevents heart failure after myocardial infarction.

The fruit of Schisandra chinensis has been used in the traditional Chinese medicine for thousands of years. Accumulating evidence suggests that Schisandrin B (Sch B) has cardioprotection effect on myocardial ischemia in vitro. However, it is unclear whether Sch B has beneficial effects on continuous myocardial ischemia in vivo. The aim of the present study was to investigate whether Sch B could improve cardiac function and attenuate myocardial remodeling after myocardial infarction (MI) in mice. Mice model of MI was established by permanent ligation of the left anterior descending (LAD) coronary artery. Then the MI mice were randomly treated with Sch B or vehicle alone. After treatment for 3 weeks, Sch B could increase survival rate, improve heart function and decrease infarct size compared with vehicle. Moreover, Sch B could down-regulate some inflammatory cytokines, activate eNOS pathway, inhibit cell apoptosis, and enhance cell proliferation. Further in vitro study on H9c2 cells showed similar effects of Sch B on prevention of hypoxia-induced inflammation and cell apoptosis. Taken together, our results demonstrate that Sch B can reduce inflammation, inhibit apoptosis, and improve cardiac function after ischemic injury. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.