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In this study, research on a pile group system was conducted using shaking table tests under four working conditions: a natural foundation and pile-spacing conditions of 3D, 3.5D, and 4D (D is the diameter of the pile). The time histories of the excess pore pressure ratio and settlement were analyzed. It was determined that pile foundations improved the anti-liquefaction performance of the soil, and the effect was much greater when the pile spacing was 3D. In addition, the settlement dynamic amplification factor (SDAF) was proposed and calculated at different vibration times. The result was fitted with a linear relationship, and the correlation coefficient was relatively high. During the aseismic design of the pile foundation bearing capacity, the SDAF was multiplied by the static load, and the results showed that in the dynamic design of the pile foundation, the dynamic problem can be transformed into a static analysis, which can provide a reference for the design of the vertical bearing capacity of pile foundations under seismic force.

The Ti/TiN multi-layer film was prepared on the depleted uranium (DU) substrate by cathodic arc ion plating equipment. The character of multi-layer film was studied by SEM, XRD and AES, revealed that the surface was composed of small compact particle and the cross-section had a multi-layer structure. The fretting wear performance under different frequencies was performed by a MFT-6000 machine with a ball-on-plate configuration. The wear morphology was analyzed by white light interferometer, OM and SEM with an EDX. The result shows the Ti/TiN multi-layer film could greatly improve the fretting wear performance compared to the DU substrate. The fretting wear running and damaged behavior are strongly dependent on the film and test frequency. The fretting region of DU substrate and Ti/TiN multi-layer under low test frequency is gross slip. With the increase of test frequency, the fretting region of Ti/TiN multi-layer change from gross slip to mixed fretting, then to partial slip.

Purpose To compare the outcomes of patients with ascending type (T4&N0-1) and descending type (T1-2&N3) of nasopharyngeal carcinoma (NPC) treated with concurrent chemoradiotherapy (CCRT), neoadjuvant chemotherapy (NACT) + intensity-modulated radiotherapy (RT) or NACT + CCRT. Methods Retrospective analysis of 839 patients with ascending or descending types of NPC treated at a single institution between October 2009 to February 2012. CCRT was delivered to 236 patients, NACT + RT to 302 patients, and NACT + CCRT to 301 patients. Results The 4-year overall survival rate, distant metastasis-free survival rate, local relapse-free survival rate, nodal relapse-free survival rate, loco-regional relapse-free survival rate, and progression free survival rate were 75.2% and 73.4% (P = 0.114), 85.7% and 74.1% (P = 0.008), 88.8% and 97.1% (P = 0.013), 96.9% and 94.1% (P = 0.122), 86.9% and 91.2% (P = 0.384), 73.7% and 66.2% (P = 0.063) in ascending type and descending type. Subgroup analyses indicated that NACT + RT significantly improved distant metastasis-free survival rate and progression-free survival rate when compared with CCRT in the ascending type, and there were no significant differences between the survival curves of NACT +RT and NACT + CCRT. For descending type, there were no significant differences among the survival curves of NACT +RT, CCRT, and NACT + CCRT groups, and the survival benefit mainly came from CCRT. Conclusions Compared with NACT + CCRT or CCRT, NACT + RT may be a reasonable approach for ascending type. Although concurrent chemotherapy was effective in descending type, NACT + CCRT may be a more appropriate strategy for descending type.

A sequencing batch reactor fed mainly by acetate was operated to perform enhanced biological phosphorus removal (EBPR). A short-term pH shock from 7.0 to 6.0 led to a complete loss of phosphate-removing capability and a drastic change of microbial communities. 16S rRNA gene pyrosequencing showed that large proportions of glycogen accumulating organisms (GAOs) (accounted for 16% of bacteria) bloomed, including Candidatus Competibacter phosphatis and Defluviicoccus-related tetrad-forming organism, causing deteriorated EBPR performance. The EBPR performance recovered with time and the dominant Candidatus Accumulibacter (Accumulibacter) clades shifted from Clade IIC to IIA while GAOs populations shrank significantly. The Accumulibacter population variation provided a good opportunity for genome binning using a bi-dimensional coverage method, and a genome of Accumulibacter Clade IIC was well retrieved with over 90% completeness. Comparative genomic analysis demonstrated that Accumulibacter clades had different abilities in nitrogen metabolism and carbon fixation, which shed light on enriching different Accumulibacter populations selectively.

BACKGROUND:To investigate the clinical efficacy and treatment toxicity of volume-modulated arc therapy (VMAT) for nasopharyngeal carcinoma (NPC). MATERIAL AND METHODS:205 VMAT-treated NPC patients from our cancer center were prospectively entrolled. All patients received 68-70 Gy irradiation based on the planning target volume of the primary gross tumor volume. Acute and late toxicities were graded according to the Common Terminology Criteria for Adverse Events v3.0 and Radiation Therapy Oncology Group Late Radiation Morbidity Scoring Criteria. RESULTS:The median follow-up period was 37.3 months (range, 6.3-45.1 months). The 3-year estimated local failure-free survival, regional failure-free survival, locoregional failure-free survival, distant metastasis-free survival, disease-free survival and overall survival were 95.5%, 97.0%, 94.0%, 92.1%, 86.8% and 97.0%, respectively. Cox regression analysis showed primary gross tumor volume, N stage and EBV-DNA to be independent predictors of VMAT outcomes (P < 0.05). The most common acute and late side effects were grade 2-3 mucositis (78%) and xerostomia (83%, 61%, 34%, and 9% at 3, 6, 12 and 24 months after VMAT), respectively. CONCLUSIONS:VMAT for the primary treatment of NPC achieved very high locoregional control with a favorable toxicity profile. The time-saving benefit of VMAT will enable more patients to receive precision radiotherapy.

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington's disease, Alzheimer's, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase-8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors. We show Car8 null mutant mice (MT) exhibit mechanical allodynia and thermal hyperalgesia. Dorsal root ganglia (DRG) from MT also demonstrate increased steady-state ITPR1 phosphorylation (pITPR1) and cytoplasmic free calcium release. Overexpression of Car8 wildtype protein in MT nociceptors complements Car8 deficiency, down regulates pITPR1 and abolishes thermal and mechanical hypersensitivity. We also show that Car8 nociceptor overexpression alleviates chronic inflammatory pain. Finally, inflammation results in downregulation of DRG Car8 that is associated with increased pITPR1 expression relative to ITPR1, suggesting a possible mechanism of acute hypersensitivity. Our findings indicate Car8 regulates the ITPR1-cytosolic free calcium pathway that is critical to nociception, inflammatory pain and possibly other neuropathological states. Car8 and ITPR1 represent new therapeutic targets for chronic pain.

To evaluate risk via inhalation exposure of polybrominated diphenyl ethers (PBDEs) in office environment, thirty-six pairs air samples including PM2.5 (particles with aerodynamic diameter less than 2.5 μm), PM10 (particles with aerodynamic diameter less than 10 μm), total suspended particles (TSP) with matching gas phase were collected in office environment in Shanghai, China. The average concentrations of PM2.5, PM10 and TSP were 20.4, 27.2 and 50.3 μg/m3, respectively. Σ15PBDEs mean concentrations in PM2.5, PM10, TSP and gas phase were 51.8, 110.7, 148 and 59.6 pg/m3, respectively. Much more PBDEs distributed in fine fractions than coarse ones. PBDEs congener profiles found in PM2.5, PM10 and TSP (dominated by BDE-209) were different from that in gas phase (dominated by the tri- to penta-BDEs). Approximately 3.20 pg/kg/d PM2.5 bound PBDEs can be inhaled into the lung; 3.62 pg/kg/d PM10-PM2.5(particles with aerodynamic diameter of 2.5-10 μm) bound PBDEs tended to be deposited in the upper part of respiratory system, and the intake of PBDEs via gas-phase was 2.74 pg/kg/d. The exposure of PBDEs was far below the minimal risk levels (MRLs), indicating lower risk from PBDEs via inhalation in the studied office in Shanghai.

Purpose To report the incidence of and risk factors for mastoiditis after intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC). Patients and Methods Retrospective analysis of pretreatment and follow-up magnetic resonance imaging (MRI) data for 451 patients with NPC treated with IMRT at a single institution. The diagnosis of mastoiditis was based on MRI; otomastoid opacification was rated as Grade 0 (none), 1 (mild), 2 (moderate) or 3 (severe) by radiologists blinded to clinical outcome. This study mainly focused on severe mastoiditis; patients were divided into three groups: the G0M (Grade 0 mastoiditis before treatment) group, G1-2M (Grade 1 to 2 mastoiditis before treatment) group and G3M (Grade 3 mastoiditis before treatment) group. The software SAS9.3 program was used to analyze the data. Results For the entire cohort, the incidence of Grade 3 mastoiditis was 20% before treatment and 31%, 19% and 17% at 3, 12 and 24 months after radiotherapy, respectively. In the G0M group, the incidence of severe mastoiditis was 0% before treatment and 23%, 15% and 13% at 3, 12 and 24 months after radiotherapy, respectively. Multivariate analysis revealed T category (OR=0.68, 95% CI = 0.469 to 0.984), time (OR=0.668, 95% CI = 0.59 to 0.757) and chemotherapy (OR=0.598, 95% CI = 0.343 to 0.934) were independent factors associated with severe mastoiditis in the G0M group after treatment. Conclusions Mastoiditis, as diagnosed by MRI, occurs as a progressive process that regresses and resolves over time in patients with NPC treated using IMRT.

Background This study aimed to evaluate initial hyperleukocytosis and neutrophilia as prognostic indicators in patients with nasopharyngeal carcinoma. Methods A retrospective analysis of 5,854 patients identified from a cohort of 6,035 patients diagnosed with nasopharyngeal carcinoma was performed with initial hyperleukocytosis and neutrophilia analyzed as prognostic factors. Multivariate Cox proportional hazards analyses were applied. Results Hyperleukocytosis was observed in 508 patients (8.7%). Multivariate analysis showed that initial hyperleukocytosis was an independent predictor of death (HR 1.40, 95%CI 1.15–1.70, p = 0.001), progression (HR 1.25, 95%CI 1.06–1.47, p = 0.007) and, marginally, distant metastasis (HR 1.21, 95%CI 0.97–1.52, p = 0.088). Neutrophilia was also an independent predictor of death (HR 1.46, 95%CI 1.18–1.81, p = 0.001), progression (HR 1.31, 95%CI 1.10–1.56, p = 0.003), and distant metastasis (HR 1.29, 95%CI 1.02–1.65, p = 0.036), after adjusting for prognostic factors and excluding hyperleukocytosis. Conclusion Initial hyperleukocytosis and neutrophilia were independent, poor prognostic factors and may be convenient and useful biological markers for survival of patients with nasopharyngeal carcinoma.

Human APOBEC3G (hA3G) is a cytidine deaminase that restricts replication of certain viruses. We have previously reported that hA3G was a host restriction factor against hepatitis C virus (HCV) replication, and hA3G stabilizers showed a significant inhibitory activity against HCV. However, the molecular mechanism of hA3G against HCV remains unknown. We show in this study that hA3G’s C-terminal directly binds HCV non-structural protein NS3 at its C-terminus, which is responsible for NS3’s helicase and NTPase activity. Binding of hA3G to the C-terminus of NS3 reduced helicase activity, and therefore inhibited HCV replication. The anti-HCV mechanism of hA3G appeared to be independent of its deamination activity. Although early stage HCV infection resulted in an increase in host hA3G as an intracellular response against HCV replication, hA3G was gradually diminished after a long-term incubation, suggesting an unknown mechanism(s) that protects HCV NS3 from inactivation by hA3G. The process represents, at least partially, a cellular defensive mechanism against HCV and the action is mediated through a direct interaction between host hA3G and HCV NS3. We believe that understanding of the antiviral mechanism of hA3G against HCV might open an interesting avenue to explore hA3G stabilizers as a new class of anti-HCV agents.

BackgroundPotato virus Y (PVY, genus Potyvirus) causes substantial economic losses in solanaceous plants. Routine screening for PVY is an essential part of seed potato certification, and serological assays are often used. The commercial, commonly used monoclonal antibodies, MAb1128, MAb1129, and MAb1130, recognize the viral coat protein (CP) of PVY and distinguish PVYN strains from PVYO and PVYC strains, or detect all PVY strains, respectively. However, the minimal epitopes recognized by these antibodies have not been identified.Methodology/principal findingsSPOT peptide array was used to map the epitopes in CP recognized by MAb1128, MAb1129, and MAb1130. Then alanine replacement as well as N- and C-terminal deletion analysis of the identified peptide epitopes was done to determine critical amino acids for antibody recognition and the respective minimal epitopes. The epitopes of all antibodies were located within the 30 N-terminal-most residues. The minimal epitope of MAb1128 was 25NLNKEK30. Replacement of 25N or 27N with alanine weakened the recognition by MAb1128, and replacement of 26L, 29E, or 30K nearly precluded recognition. The minimal epitope for MAb1129 was 16RPEQGSIQSNP26 and the most critical residues for recognition were 22I and 23Q. The epitope of MAb1130 was defined by residues 5IDAGGS10. Mutation of residue 6D abrogated and mutation of 9G strongly reduced recognition of the peptide by MAb1130. Amino acid sequence alignment demonstrated that these epitopes are relatively conserved among PVY strains. Finally, recombinant CPs were produced to demonstrate that mutations in the variable positions of the epitope regions can affect detection with the MAbs.Conclusions/significanceThe epitope data acquired can be compared with data on PVY CP-encoding sequences produced by laboratories worldwide and utilized to monitor how widely the new variants of PVY can be detected with current seed potato certification schemes or during the inspection of imported seed potatoes as conducted with these MAbs.

Objective To evaluate the efficacy of continuous positive airway pressure (CPAP) on serum testosterone in men with obstructive sleep apnea (OSA). Methods Two reviewers independently searched PubMed, Cochrane library, Embase and Web of Science before June 2014. Information on characteristics of subjects, study design, pre- and post-CPAP treatment of serum total testosterone, free testosterone and sexual hormone blinding protein (SHBG) was extracted for analysis. Results A total of 7 studies with 9 cohorts that included 232 men were pooled into meta-analysis. There was no change of total testosterone levels before and after CPAP treatment in OSA men (standardized mean difference (SMD) = -0.14, 95%CI: -0.63 to 0.34, z = 0.59, p = 0.558), even subdivided by CPAP therapeutic duration (>3 months). Meanwhile, no significant differences in free testosterone and SHBG were detected after CPAP treatment (SMD = 0.16, 95%CI: -0.09 to 0.40, z = 1.25, p = 0.211 and SMD = -0.58, 95%CI: -1.30 to 0.14, z = 1.59, p = 0.112, respectively). Conclusion CPAP has no influence on testosterone levels in men with OSA, further large-scale, well-design interventional investigation is needed.

Objectives To assess erectile function in middle-aged and older men with asexuality status and further analyze their specific reasons for this condition. Subjects and Methods Men who had regular sexual intercourse attempts (sex frequency≥1 time per month) were classified into mild erectile dysfunction (ED), moderate to severe ED and non-ED according to International Index of Erectile Function-5, and men having no sexual intercourse attempts for at least 6 months were defined as having an asexuality status. The risk factors associated with ED were collected in a sample of 1,531 Chinese men aged 40 to 80 years, and the self-report reasons for asexuality were recorded in asexual cohort individually. Comparative analyses and multivariate regression models were conducted among these groups. Results The prevalence rates of ED and asexuality status were 49.9% and 37.2%. The asexuality status group had higher risk factors than the moderate to severe ED group in terms of old age (age≥65, adjusted odds ratio (OR) 17.69 versus (Vs.) 7.19), diabetes (crude OR: 2.40 Vs. 2.36) and hypertension (crude OR: 1.78 Vs. 1.72). The specific reasons for the asexuality status were “erectile difficulty” (52.9%), “do not care about sexuality” (53.5%)”, “no longer necessary to have sexuality at this age” (47.7%), “severe stress” (44.4%), “severe fatigue” (26.3%) and “masturbation” (26.9%). Conclusions Men with an asexual status suffer from higher risk factors for ED than men with moderate to severe ED. The majority of this asexual status could be attributed to a full ED, although the reasons for this transient asexuality also involved sexual attitudes and interests, sexual partners and masturbation.

Background Low serum albumin is predictive of poor survival in nasopharyngeal carcinoma (NPC). We evaluated the ability of the pretreatment albumin/globulin ratio (AGR) to predict long-term mortality in patients with NPC. Methods This retrospective study examined an unselected cohort of 694 patients with NPC who had documented pretreatment total serum protein and serum albumin levels (ALB). AGR was calculated as [AGR = ALB/(total serum protein - ALB)]. Survival analysis was used to evaluate the predictive value of AGR. Results Multivariate analysis demonstrated that a low pretreatment serum AGR (

Background The incidence of diabetes is increasing. But the impact of diabetes and prediabetes on survival of patients with nasopharyngeal carcinoma (NPC) has received little evaluation. Methods In a cohort of 5,860 patients, we compared the disease specific survival (DSS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) of patients with diabetes, prediabetes and normoglycemia defined by pretreatment fasting plasma glucose (FPG) using Kaplan–Meier method, log-rank test and Cox proportional hazards model. Results Comparing to normoglycemic patients, the diabetic and the prediabetic were generally older, fatter, had hypertension, heart diseases and hyperlipaemia and usually received radiotherapy alone. But both the diabetic and the prediabetic had similar DSS, LRFS and DMFS to normoglycemic patients, even adjusting for such important factors as age, gender, smoking, drinking, hypertension, heart diseases, body mass index, hyperlipaemia, titer of VCA-IgA and EA-IgA, pathology, T-stage, N-stage, chemotherapy and radiotherapy (P>0.05 for all). Additionally, the findings remained unchanged in sensitivity analysis by excluding patients with known diabetes history and in subgroups of the various factors. Conclusions The diabetic and prediabetic NPC patients had similar survival to normoglycemic NPC patients. These data, in the largest reported cohort, are the first to evaluate the association between diabetes, prediabetes and the survival in NPC. The findings are relevant to patient management and provided evidence of the effect on this disease exerted by comorbidities.

Overproduction of N-terminal pyroglutamate (pGlu)-modified proteins utilizing Escherichia coli or eukaryotic cells is a challenging work owing to the fact that the recombinant proteins need to be recovered by proteolytic removal of fusion tags to expose the N-terminal glutaminyl or glutamyl residue, which is then converted into pGlu catalyzed by the enzyme glutaminyl cyclase. Herein we describe a new method for production of N-terminal pGlu-containing proteins in vivo via intracellular self-cleavage of fusion tags by tobacco etch virus (TEV) protease and then immediate N-terminal cyclization of passenger target proteins by a bacterial glutaminyl cyclase. To combine with the sticky-end PCR cloning strategy, this design allows the gene of target proteins to be efficiently inserted into the expression vector using two unique cloning sites (i.e., SnaB I and Xho I), and the soluble and N-terminal pGlu-containing proteins are then produced in vivo. Our method has been successfully applied to the production of pGlu-modified enhanced green fluorescence protein and monocyte chemoattractant proteins. This design will facilitate the production of protein drugs and drug target proteins that possess an N-terminal pGlu residue required for their physiological activities.

BackgroundIndoxyl sulfate and p-cresyl sulfate are unique microbial co-metabolites. Both co-metabolites have been involved in the pathogenesis of accelerated cardiovascular disease and renal disease progression. Available evidence suggests that indoxyl sulfate and p-cresyl sulfate may be considered candidate biomarkers of the human enterotype and may help to explain the link between diet and cardiovascular disease burden.Objective and designInformation on clinical determinants and heritability of indoxyl sulfate and p-cresyl sulfate serum is non-existing. To clarify this issue, the authors determined serum levels of indoxyl sulfate and p-cresyl sulfate in 773 individuals, recruited in the frame of the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO study).ResultsSerum levels of indoxyl sulfate and p-cresyl sulfate amounted to 3.1 (2.4-4.3) and 13.0 (7.4-21.5) μM, respectively. Regression analysis identified renal function, age and sex as independent determinants of both co-metabolites. Both serum indoxyl sulfate (h2 = 0.17) and p-cresyl sulfate (h2 = 0.18) concentrations showed moderate but significant heritability after adjustment for covariables, with significant genetic and environmental correlations for both co-metabolites.LimitationsFamily studies cannot provide conclusive evidence for a genetic contribution, as confounding by shared environmental effects can never be excluded.ConclusionsThe heritability of indoxyl sulfate and p-cresyl sulfate is moderate. Besides genetic host factors and environmental factors, also renal function, sex and age influence the serum levels of these co-metabolites.

Background Remifentanil, an ultra-short-acting opioid, is widely used for pain control during surgery. However, regular dose (RD) remifentanil exacerbates postoperative pain in a dose-dependent manner. Recent studies suggest that high-dose (HD) remifentanil offers sustained analgesia in experimental studies. We thus hypothesized that intraoperative administration of high-dose remifentanil may attenuate postoperative pain. Methods In this prospective, randomized, double blind, controlled clinical study, sixty patients undergoing thyroidectomy (18–60 years-of-age) received an intraoperative infusion of 0.2 (RD group) or 1.2 μg kg−1min−1 (HD group) remifentanil during thyroidectomy. A visual analogue scale (VAS) was used to measure pain intensity. Mechanical pain threshold on the forearm was assessed using von Frey filaments before surgery (baseline), 2 h postoperatively and 18–24 h postoperatively. The primary outcome was to compare the difference of VAS score at different time points after operation and morphine consumption 24 h postoperatively between RD and HD groups. The second outcome was to compare the difference of mechanical pain thresholds in the forearm postoperatively between RD and the HD groups. Results VAS scores were lower 30 min postoperatively in the HD group (1.29±1.67, 95% CI 0.64–1.94) compared with the RD group (2.21±1.67, 95% CI 1.57–2.84) (t = 3.427, p = 0.0043, RD group vs. HD group). Postoperative morphine consumption was much lower in the HD group compared with the RD group (1.27±1.88 mg vs. 0.35±1.25 mg, p = 0.033). In both groups, mechanical pain threshold was decreased 18–24 h postoperatively (2.93±0.209 Ln(g) vs. 3.454±2.072 Ln(g), p = 0.032 in RD group; 2.910±0.196 Ln(g) vs. 3.621±0.198 Ln(g), p = 0.006 in HD group, 18–24 h postoperatively vs baseline). Conclusions Intraoperative administration of high-dose remifentanil decreased VAS scores and morphine consumption postoperatively. Thus, modulation of intraoperative opiates may be a simple and effective method of postoperative pain management. Trial Registration This trial is registered in ClinicalTrials.gov, with the Name: Effect of Higher Doses of Remifentanil on Postoperative Pain in Patients Undergoing Thyroidectomy, and ID number: NCT01761149.

Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutation is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition. The NBS1 gene codes for a protein, Nbs1(p95/Nibrin), involved in the processing/repair of DNA double-strand breaks. Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. Recent studies have shown that heterozygous NBS1 mice exhibited a higher incidence of HCC than did wild-type mice. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of human primary liver cancer, including HBV-associated HCC and intrahepatic cholangiocarcinoma (ICC). Eight missense NBS1 mutations were identified in six of 64 (9.4%) HCCs and two of 18 (11.1%) ICCs, whereas only one synonymous mutation was found in 89 control cases of cirrhosis and chronic hepatitis B. Analysis of the functional consequences of the identified NBS1 mutations in Mre11-binding domain showed loss of nuclear localization of Nbs1 partner Mre11, one of the hallmarks for Nbs1 deficiency, in one HCC and two ICCs with NBS1 mutations. Moreover, seven of the eight tumors with NBS1 mutations had at least one genetic alteration in the TP53 pathway, including TP53 mutation, MDM2 amplification, p14ARF homozygous deletion and promoter methylation, implying a synergistic effect of Nbs1 disruption and p53 inactivation. Our findings provide novel insight on the molecular pathogenesis of primary liver cancer characterized by mutation inactivation of NBS1, a DNA repair associated gene.

6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one (DB-02) is a member of the newly reported synthetic anti-HIV-1 compounds dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines, S-DACOs. In vitro anti-HIV-1 activity and resistance profile studies have suggested that DB-02 has very low cytotoxicity (CC50>1mM) to cell lines and peripheral blood mononuclear cells (PBMCs). It displays potent anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 2.40 to 41.8 nM). Studies on site-directed mutagenesis, genotypic resistance profiles revealed that V106A was the major resistance contributor for the compound. Molecular docking analysis showed that DB-02 located in the hydrophobic pocket with interactions of Lys101, Val106, Leu234, His235. DB-02 also showed non-antagonistic effects to four approved antiretroviral drugs. All studies indicated that DB-02 would be a potential NNRTI with low cytotoxicity and improved activity.

Tibetia and Gueldenstaedtia are two morphologically similar and small genera in Fabaceae, with distributions largely corresponding to the Sino-Himalayan and Sino-Japanese subkingdoms in eastern Asia, respectively. These two genera have confusing relationships based on morphology; therefore, we aimed to provide a clear understanding of their phylogenetic and biogeographic evolution within eastern Asia. In our investigations we included 88 samples representing five Gueldenstaedtia species, five Tibetia species, and outgroup species were sequenced using five markers (nuclear: ITS; chloroplast: matK, trnL-F, psbA-trnH and rbcL). Our phylogenetic results support (1) the monophyly of Tibetia and of Gueldenstaedtia, respectively; and (2) that Tibetia and Gueldenstaedtia are sister genera. Additionally, our data identified that Tibetia species had much higher sequence variation than Gueldenstaedtia species. Our results suggest that the two genera were separated from each other about 17.23 million years ago, which is congruent with the Himalayan orogeny and the uplift of the Tibetan Plateau in the mid Miocene. The divergence of Tibetia and Gueldenstaedtia is strongly supported by the separation of the Sino-Himalayan and Sino-Japanese region within eastern Asia. In addition, the habitat heterogeneity may accelerate the molecular divergence of Tibetia in the Sino-Himalayan region.

Myocardial depression is an important contributor to mortality in sepsis. We have recently demonstrated that α2-adrenoceptor (AR) antagonist, yohimbine (YHB), attenuates lipopolysaccharide (LPS)-induced myocardial depression. However, the mechanisms for this action of YHB are unclear. Here, we demonstrated that YHB decreased nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) levels in the myocardium and plasma, attenuated cardiac and hepatic dysfunction, but not kidney and lung injuries in endotoxemic mice. Immunohistochemical analysis revealed that cardiac α2A-AR was mostly located in sympathetic nerve presynaptic membrane; YHB decreased cardiac α2A-AR level and promoted cardiac norepinephrine (NE) release in endotoxemic mice. Reserpine that exhausted cardiac NE without markedly decreasing plasma NE level abrogated the inhibitory effects of YHB on cardiac TNF-α and iNOS expression as well as cardiac dysfunction, but not the suppressive effects of YHB on plasma TNF-α and NO elevation in LPS-challenged mice. Furthermore, both reserpine and YHB significantly inhibited LPS-induced myocardial apoptosis. α1-AR, β2-AR, but not β1-AR antagonists reversed the inhibitory effect of YHB on LPS-stimulated myocardial apoptosis. However, β1-AR antagonist attenuated LPS-caused cardiomyocyte apoptosis, partly abolished the protective effect of YHB on the left ventricular ejection fraction in endotoxemic mice. Altogether, these findings indicate that YHB attenuates LPS-induced cardiac dysfunction, at least in part, through blocking presynaptic α2A-AR and thus increasing cardiac NE release. YHB-elevated cardiac NE improves cardiac function via suppressing cardiac iNOS and TNF-α expression, activating β1-AR and inhibiting cardiomyocyte apoptosis through α1- and β2-AR in endotoxemic mice. However, cardiac β1-AR activation promotes LPS-induced cardiomyocyte apoptosis.

Heat-stress cognate 70 (Hsc70) is a host factor that helps hepatitis C virus (HCV) to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC) of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD50>1000 mg/kg). As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations.

Cardiomyocyte apoptosis is an important event in doxorubicin (DOX)-induced cardiac injury. The aim of the present study was to investigate the protection of berberine (Ber) against DOX- triggered cardiomyocyte apoptosis in neonatal rat cardiomyocytes and rats. In neonatal rat cardiomyocytes, Ber attenuated DOX-induced cellular injury and apoptosis in a dose-dependent manner. However, Ber has no significant effect on viability of MCF-7 breast cancer cells treated with DOX. Ber reduced caspase-3 and caspase-9, but not caspase-8 activity in DOX-treated cardiomyocytes. Furthermore, Ber decreased adenosine monophosphate-activated protein kinase α (AMPKα) and p53 phosphorylation at 2 h, cytosolic cytochrome c and mitochondrial Bax levels and increased Bcl-2 level at 6 h in DOX-stimulated cardiomyocytes. Pretreatment with compound C, an AMPK inhibitor, also suppressed p53 phosphorylation and apoptosis in DOX-treated cardiomyocytes. DOX stimulation for 30 min led to a loss of mitochondrial membrane potential and a rise in the AMP/ATP ratio. Ber markedly reduced DOX-induced mitochondrial membrane potential loss and an increase in the AMP/ATP ratio at 1 h and 2 h post DOX exposure. In in vivo experiments, Ber significantly improved survival, increased stroke volume and attenuated myocardial injury in DOX-challenged rats. TUNEL and Western blot assays showed that Ber not only decreased myocardial apoptosis, caspase-3 activation, AMPKα and p53 phosphorylation, but also increased Bcl-2 expression in myocardium of rats exposed to DOX for 84 h. These findings indicate that Ber attenuates DOX-induced cardiomyocyte apoptosis via protecting mitochondria, inhibiting an increase in the AMP/ATP ratio and AMPKα phosphorylation as well as elevating Bcl-2 expression, which offer a novel mechanism responsible for protection of Ber against DOX-induced cardiomyopathy.

Chrysanthemum L. (Asteraceae-Anthemideae) is a genus with rapid speciation. It comprises about 40 species, most of which are distributed in East Asia. Many of these are narrowly distributed and habitat-specific. Considerable variations in morphology and ploidy are found in this genus. Some species have been the subjects of many studies, but the relationships between Chrysanthemum and its allies and the phylogeny of this genus remain poorly understood. In the present study, 32 species/varieties from Chrysanthemum and 11 from the allied genera were analyzed using DNA sequences of the single-copy nuclear CDS gene and seven cpDNA loci (psbA-trnH, trnC-ycf6, ycf6-psbM, trnY-rpoB, rpS4-trnT, trnL-F, and rpL16). The cpDNA and nuclear CDS gene trees both suggest that 1) Chrysanthemum is not a monophyletic taxon, and the affinity between Chrysanthemum and Ajania is so close that these two genera should be incorporated taxonomically; 2) Phaeostigma is more closely related to the Chrysanthemum+Ajania than other generic allies. According to pollen morphology and to the present cpDNA and CDS data, Ajania purpurea is a member of Phaeostigma. Species differentiation in Chrysanthemum appears to be correlated with geographic and environmental conditions. The Chinese Chrysanthemum species can be divided into two groups, the C. zawadskii group and the C. indicum group. The former is distributed in northern China and the latter in southern China. Many polyploid species, such as C. argyrophyllum, may have originated from allopolyploidization involving divergent progenitors. Considering all the evidence from present and previous studies, we conclude that geographic and ecological factors as well as hybridization and polyploidy play important roles in the divergence and speciation of the genus Chrysanthemum.