Whole genome analysis to detect potential vaccine-induced changes on Shigella sonnei genome

Shigellosis or bacillary dysentery is endemic worldwide and is a significant cause of death in children less than five years of age in developing countries. There are no licensed Shigella vaccines and glycoconjugates are among the leading candidate vaccines against shigellosis today.We used whole genome sequence analysis (WGA) to find out whether immunization, with an investigational Shigella sonnei glycoconjugate, could induce selective pressure leading to changes in the genome of S. sonnei. An outbreak of culture-proven S. sonnei shigellosis which occurred immediately after vaccination in one of the cohorts of volunteers participating in a phase III trial of the vaccine in Israel created a unique condition in which the epidemic agent “co-existed” with the developing immune responses induced by the vaccine and natural infection among vaccinees who developed S. sonnei shigellosis. By comparing the whole genomes of S. sonnei isolated from vaccinees and from volunteers in the control group, we show at a very high sensitivity that a potent S. sonnei glycoconjugate that conferred 74% protective efficacy against the homologous disease did not induce changes in the genome of S. sonnei and in particular on the O-antigen gene cluster.     

Core@shell structured Co–CoO@NC nanoparticles supported on nitrogen doped carbon with high catalytic activity for oxygen reduction reaction

A composite with a hierarchical structure consisting of nitrogen doped carbon nanosheets with the deposition of nitrogen doped carbon coated Co–CoO nanoparticles (Co–CoO@NC/NC) has been synthesized by a simple procedure involving the drying of the reaction mixture containing Co(NO₃)₂, glucose, and urea and its subsequent calcination. The drying step is found to be necessary to obtain a sample with small and uniformly sized Co–CoO nanoparticles. The calcination temperature has a great effect on the catalytic activity of the final product. Specifically, the sample prepared at the calcination temperature of 800 °C shows better catalytic activity of the oxygen reduction reaction (ORR). Urea in the reaction mixture is crucial to obtain the sample with the uniformly sized Co–CoO nanoparticles and also plays an important role in improving the catalytic activity of the Co–CoO@NC/NC. Additionally, there exists a strong electronic interaction between the Co–CoO nanoparticles and the NC. Most interestingly, the Co–CoO@NC/NC is highly efficient for the ORR and can deliver an ORR onset potential of 0.961 V vs. RHE and a half-wave potential of 0.868 V vs. RHE. Both the onset and half-wave potentials are higher than those of most catalysts reported previously and even close to those of the commercial Pt/C (the ORR onset and half-wave potential of the Pt/C are 0.962 and 0.861 V vs. RHE, respectively). This, together with its high stability, strongly suggests that the Co–CoO@NC/NC could be used as an efficient catalyst for the ORR.

A simple method has been developed for the synthesis of Co–CoO@NC/NC, which exhibits high and stable performance for the ORR.     

Copper-catalyzed aerobic decarboxylative coupling between cyclic α-amino acids and diverse C–H nucleophiles with low catalyst loading

An aerobic decarboxylative cross-coupling of α-amino acids with diverse C–H nucleophiles has been realized using Cu₂(OH)₂CO₃ (1 mol%) as the catalyst under air. This protocol enables highly efficient formation of various C(sp³)–C(sp³), C(sp³)–C(sp²) and C(sp³)–C(sp) bonds under simple conditions without the use of any ligand or extra oxidant, providing a practical approach to numerous nitrogen-containing compounds in good to excellent yields. The efficiency and practicability were also demonstrated by the gram-scale experiment and three-step synthesis of a Rad51 inhibitor.

An aerobic decarboxylative cross-coupling of α-amino acids was realized using 1 mol% Cu₂(OH)₂CO₃ catalyst under ligand free conditions.     

An antibacterial collagen membrane crosslinked by the inclusion complex of β-cyclodextrin dialdehyde and ofloxacin for bacterial keratitis

Infectious keratitis is one of the leading causes of blindness in the world, especially in developing countries. Corneal transplant surgery is a feasible treatment for bacterial keratitis when drug therapy cannot be effective. However, the amount of corneal donors is far from requirements of clinical treatment and thus, the prognosis of bacterial keratitis is not satisfactory. In this study, we developed a novel antibacterial corneal repair material (β-CD-DA/OFLX-Col) for bacterial keratitis. The inclusion complex of β-cyclodextrin dialdehyde (β-CD-DA) with ofloxacin formed by host–guest interaction was used as both a drug vector and a crosslinker for further reaction with the amino groups on lysine of collagen chains. Physical properties, cytocompatibility, and antibacterial property of β-CD-DA/OFLX-Col film were characterized. The results indicated that the film was mainly transparent and possessed superior mechanical properties. Moreover, human corneal epithelial cells could adhere to the film and proliferate normally, indicating that the β-CD-DA/OFLX-Col film was non-cytotoxic and had good biocompatibility. Most importantly, the β-CD-DA/OFLX-Col film exhibited prominent antibacterial effects against E. coli and S. aureus in vitro, which could minimize the risks of infection. The prepared β-CD-DA/OFLX-Col film could greatly increase bioavailability of drugs and reduce toxic side effects, thus displaying great potential in bacterial keratitis treatment.

The synthesis of antibacterial collagen membrane crosslinked by the inclusion complex of β-cyclodextrin dialdehyde and ofloxacin.     

Combined systems pharmacology and fecal metabonomics to study the biomarkers and therapeutic mechanism of type 2 diabetic nephropathy treated with Astragalus and Leech

In our study, systems pharmacology was used to predict the molecular targets of Astragalus and Leech, and explore the therapeutic mechanism of type 2 diabetic nephropathy (T2DN) treated with Astragalus and Leech. Simultaneously, to reveal the systemic metabolic changes and biomarkers associated with T2DN, we performed ¹H NMR-based metabonomics and multivariate analysis to analyze fecal samples obtained from model T2DN rats. In addition, ELISA kits and histopathological studies were used to examine biochemical parameters and kidney tissue, respectively. Striking differences in the Pearson''s correlation of 22 biomarkers and 9 biochemical parameters were also observed among control, T2DN and treated rats. Results of systems pharmacology analysis revealed that 9 active compounds (3,9-di-O-methylnissolin; (6aR,11aR)-9,10-dimethoxy-6a,11a-dihydro-6H-benzofurano[3,2-c]chromen-3-ol; hirudin; l-isoleucine; phenylalanine; valine; hirudinoidine A–C) and 9 target proteins (l-serine dehydratase; 3-hydroxyacyl-CoA dehydrogenase; tyrosyl-tRNA synthetase; tryptophanyl-tRNA synthetase; branched-chain amino acid aminotransferase; acetyl-CoA C-acetyltransferase; isovaleryl-CoA dehydrogenase; pyruvate dehydrogenase E1 component alpha subunit; hydroxyacylglutathione hydrolase) of Astragalus and Leech were closely associated with the treatment of T2DN. Using fecal metabonomics analysis, 22 biomarkers were eventually found to be closely associated with the occurrence of T2DN. Combined with systems pharmacology and fecal metabonomics, these biomarkers were found to be mainly associated with 6 pathways, involving amino acid metabolism (leucine, valine, isoleucine, alanine, lysine, glutamate, taurine, phenylalanine, tryptophan); energy metabolism (lactate, succinate, creatinine, α-glucose, glycerol); ketone body and fatty acid metabolism (3-hydroxybutyrate, acetate, n-butyrate, propionate); methylamine metabolism (dimethylamine, trimethylamine); and secondary bile acid metabolism and urea cycle (deoxycholate, citrulline). The underlying mechanisms of action included protection of the liver and kidney, enhancement of insulin sensitivity and antioxidant activity, and improvement of mitochondrial function. To the best of our knowledge, this is the first time that systems pharmacology combined with fecal metabonomics has been used to study T2DN. 6 metabolites (n-butyrate, deoxycholate, propionate, tryptophan, taurine and glycerol) associated with T2DN were newly discovered in fecal samples. These 6 metabolites were mainly derived from the intestinal flora, and related to amino acid metabolism, fatty acid metabolism, and secondary bile acid metabolism. We hope the results of this study could be inspirational and helpful for further exploration of T2DN treatment. Meanwhile, our results highlighted that exploring the biomarkers of T2DN and therapeutic mechanisms of Traditional Chinese Medicine (TCM) formulas on T2DN by combining systems pharmacology and fecal metabonomics methods was a promising strategy.

In our study, systems pharmacology was used to predict the molecular targets of Astragalus and Leech, and explore the therapeutic mechanism of type 2 diabetic nephropathy (T2DN) treated with Astragalus and Leech.     

定量血流分数评价左心室舒张功能不全患者心肌缺血的价值

目的探讨定量血流分数(quantitative flow ratio,QFR)在诊断左心室舒张功能不全患者心肌缺血的价值。方法纳入2017年1月至2018年12月间广东省人民医院心脏超声诊断为左心室舒张功能不全但收缩功能正常,同时行冠状动脉造影及血流储备分数(fractional flow reserve,FFR)检查的患者110例。根据FFR测量值分为心肌缺血组(FFR≤0.80,n=52)和对照组(FFR>0.80,n=58)。比较两组患者的临床资料,并分别用QFR与定量冠状动脉造影(quantitative coronary angiography,QCA)两种工具分析造影图像,绘制受试者工作曲线(receiver operating characteristic curve,ROC)并评价QFR的诊断效能。结果两组患者的临床资料比较,差异无统计学意义(P>0.05)。以FFR作为参考标准,QFR的诊断效能均明显高于QCA,其中准确率[83.6%(95%CI:75.5~89.5)vs. 59.1%(95%CI:49.7~67.8)]、敏感度[75.0%(95%CI:61.7~84.9)vs. 46.2%(95%CI:33.3~59.5)]、特异度[91.4%(95%CI:81.0~96.7)vs. 70.7%(95%CI:57.9~80.9)]、阳性预测值[88.6%(95%CI:75.6~95.5)vs.58.5%(95%CI:43.4~72.3)]及阴性预测值[80.3%(95%CI:69.0~88.3)vs. 59.4%(95%CI:47.6~70.2)]比较,差异均有统计学意义(P<0.01)。QFR与QCA的阳性似然比分别为8.721 vs. 1.577,阴性似然比分别为0.274 vs.0.761。QFR与QCA诊断心肌缺血的ROC的曲线下面积分别为0.94(95%CI:0.88~0.98)和0.67(95%CI:0.58~0.76)(Z=5.167,P<0.0001)。结论 QFR比QCA能更灵敏、早期识别导致左心室舒张功能不全患者的心肌缺血情况,在指导治疗、改善患者预后方面具有重要临床意义。     

Hepatocellular carcinoma as predominant cancer subgroup accounting for sex differences in post-hepatectomy liver failure,morbidity and mortality

BackgroundExperimental evidence suggests sex dependent differences in liver regeneration. Limited evidence is available examining sex differences in post-hepatectomy liver failure (PHLF) and postoperative outcomes. Our aim was to assess the influence of sex on the outcomes after liver resection.MethodsThe hepatectomy targeted National Surgical Quality Improvement Program (NSQIP) database was assessed for associations between sex and outcomes.ResultsA total of 13,401 patients underwent elective hepatic resection between 2014-2017. PHLF was highest among male patients with hepatocellular carcinoma (HCC) (OR = 2.81,95%CI:1.40–5.62). Male sex was independently associated with increased PHLF (OR = 1.47,95%CI:1.15–1.88), major complications (OR = 1.25,95%CI:1.08–1.45), mortality (OR = 1.61,95%CI:1.03–2.50), and if only major resections were assessed (OR = 1.38,95%CI:1.03–1.84). Diagnosis specific subgroup analyses revealed that effects of sex were predominantly HCC associated.ConclusionsThis is the largest series investigating the effects of gender on outcomes after hepatic resection. We documented that women undergoing liver resection have significantly lower risk of PHLF. This difference seemed influenced by the striking increase of PHLF in male HCC patients. These hypothesis suggest that sex might play a role in preoperative risk stratification.