The HIV-1 Subtype C Epidemic in South America Is Linked to the United Kingdom

Background

The global spread of HIV-1 has been accompanied by the emergence of genetically distinct viral strains. Over the past two decades subtype C viruses, which predominate in Southern and Eastern Africa, have spread rapidly throughout parts of South America. Phylogenetic studies indicate that subtype C viruses were introduced to South America through a single founder event that occurred in Southern Brazil. However, the external route via which subtype C viruses spread to the South American continent has remained unclear.

Methodology/Principal Findings

We used automated genotyping to screen 8,309 HIV-1 subtype C pol gene sequences sampled within the UK for isolates genetically linked to the subtype C epidemic in South America. Maximum likelihood and Bayesian approaches were used to explore the phylogenetic relationships between 54 sequences identified in this screen, and a set of globally sampled subtype C reference sequences. Phylogenetic trees disclosed a robustly supported relationship between sequences from Brazil, the UK and East Africa. A monophyletic cluster comprised exclusively of sequences from the UK and Brazil was identified and dated to approximately the early 1980s using a Bayesian coalescent-based method. A sub-cluster of 27 sequences isolated from homosexual men of UK origin was also identified and dated to the early 1990s.

Conclusions

Phylogenetic, demographic and temporal data support the conclusion that the UK was a crucial staging post in the spread of subtype C from East Africa to South America. This unexpected finding demonstrates the role of diffuse international networks in the global spread of HIV-1 infection, and the utility of globally sampled viral sequence data in revealing these networks. Additionally, we show that subtype C viruses are spreading within the UK amongst men who have sex with men.     

The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine

Background

Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk.

Methodology/Principal Findings

MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate.

Conclusions

These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.     

鼻咽上皮细胞的调节性容积回缩能力及机制

用图像分析系统和通道阻断法研究了原代人胎儿鼻咽上皮细胞的调节性容积回缩(regulatoryvolumedecrease,RVD)能力及其机制。结果发现,低渗刺激可诱发鼻咽上皮细胞产生RVD,在160-240mOsmol/L范围内,RVD强弱与渗透压呈“S”形负相关(r=-0.99,P<0.05),与细胞肿胀程度呈“S”形正相关(=0.99,P<0.05)。Cl~-通道阻断剂tamoxifen(20μmol/L),ATP(10mmol/L)或NPPB(100μmol/L)对RVD阻抑率分别为100%(P<0.01),76.3%(P<0.01)和62.7%(P<0.01)。本研究表明,鼻咽上皮细胞受到低渗刺激时可产生RVD,Cl~-通道开放是其RVD的关键机制。     

Association analysis of canonical Wnt signalling genes in diabetic nephropathy

Aims/Hypothesis

Several studies have provided compelling evidence implicating the Wnt signalling pathway in the pathogenesis of diabetic nephropathy. Gene expression profiles associated with renal fibrosis have been attenuated through Wnt pathway modulation in model systems implicating Wnt pathway members as potential therapeutic targets for the treatment of diabetic nephropathy. We assessed tag and potentially functional single nucleotide polymorphisms (SNPs; n = 31) in four key Wnt pathway genes (CTNNB1, AXIN2, LRP5 and LRP6) for association with diabetic nephropathy using a case-control design.

Methods

SNPs were genotyped using Sequenom or Taqman technologies in 1351 individuals with type 1 diabetes (651 cases with nephropathy and 700 controls without nephropathy). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Adjustment for multiple testing was performed by permutation testing.

Results

Following logistic regression analysis adjusted by collection centre, duration of T1D, and average HbA1c as covariates, a single SNP in LRP6 (rs1337791) was significantly associated with DN (OR = 0.74; CI: 0.57–0.97; P = 0.028), although this was not maintained following correction for multiple testing. Three additional SNPs (rs2075241 in LRP6; rs3736228 and rs491347 both in LRP5) were marginally associated with diabetic nephropathy, but none of the associations were replicated in an independent dataset. Haplotype and subgroup analysis (according to duration of diabetes, and end-stage renal disease) also failed to reveal an association with diabetic nephropathy.

Conclusions/Interpretation

Our results suggest that analysed common variants in CTNNB1, AXIN2, LRP5 and LRP6 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes or other members of the Wnt pathway, from involvement in the pathogenesis of diabetic nephropathy as our study had limited power to detect variants with small effect size.     

Kinetics of Avibactam Inhibition against Class A,C, and D β-Lactamases

Avibactam is a non-β-lactam β-lactamase inhibitor with a spectrum of activity that includes β-lactamase enzymes of classes A, C, and selected D examples. In this work acylation and deacylation rates were measured against the clinically important enzymes CTX-M-15, KPC-2, Enterobacter cloacae AmpC, Pseudomonas aeruginosa AmpC, OXA-10, and OXA-48. The efficiency of acylation (k₂/K_i) varied across the enzyme spectrum, from 1.1 × 10¹ m⁻¹s⁻¹ for OXA-10 to 1.0 × 10⁵ for CTX-M-15. Inhibition of OXA-10 was shown to follow the covalent reversible mechanism, and the acylated OXA-10 displayed the longest residence time for deacylation, with a half-life of greater than 5 days. Across multiple enzymes, acyl enzyme stability was assessed by mass spectrometry. These inhibited enzyme forms were stable to rearrangement or hydrolysis, with the exception of KPC-2. KPC-2 displayed a slow hydrolytic route that involved fragmentation of the acyl-avibactam complex. The identity of released degradation products was investigated, and a possible mechanism for the slow deacylation from KPC-2 is proposed.     

Phytoextracts-Synthesized Silver Nanoparticles Inhibit Bacterial Fish Pathogen Aeromonas hydrophila

Fish disease is a major stumbling block towards sustainable growth of the fisheries sector. Aeromonas hydrophila, which is a major infectious aquatic pathogen is reportedly the causative agent of ulcers, fin-rot, tail-rot, hemorrhagic septicemia in fish, and has reportedly developed resistance against many of the available antibiotics. In this context, the inhibitory function of silver nanoparticles (AgNPs) against A. hydrophila was studied to evaluate its possible application in aquaculture as alternative to antibiotics. AgNPs were synthesized using the leaf extracts of subtropical plants Mangifera indica (Mango), Eucalyptus terticornis (Eucalyptus), Carica papaya (Papaya) and Musa paradisiaca (Banana). The absorbance maxima, size range and shape of the AgNPs as characterized by the UV–Vis spectroscopy, high resolution transmission electron microscopy (HR-TEM), and energy dispersive X-ray spectroscopy (EDX) were, Mangifera—442, 50–65 nm, ovular; Eucalyptus—465, 60–150 nm, oval; Carica—442, 25–40 nm, round, irregular; and Musa—454, 10–50 nm, round, irregular, respectively. Well-diffusion of these AgNPs for their antimicrobial characteristics exhibited that, the papaya leaf extract synthesized AgNPs had maximum antimicrobial activity at 153.6 μg/ml concentrations, and that from the eucalyptus leaves was least effective. As observed, the potency of the nanoparticles enhanced with the decrease in particle size, from 60–150 nm in eucalyptus to 25–40 nm in papaya. Due to its purely natural sourcing, phytosynthesized AgNPs can be applied as alternative to antibiotics and other biocides as a cost-effective and eco-friendly therapeutic agent against A. hydrophila stimulated diseases in aquatic animals.     

Regulation of phytochrome A mRNA abundance in parsley seedlings and cell-suspension cultures

A cDNA clone encoding the apoprotein of a parsley phytochrome was isolated and classified as parsley PHYA phytochrome, on the basis of a sequence homology comparison with all available phytochrome sequences. Red light pulses led to a phytochrome-dependent down-regulation of PHYA mRNA abundance in etiolated parsley seedlings to a level of 10–20% compared with the dark control. The PHYA mRNA abundance in a parsley cell suspension culture was also down-regulated by light pulses. Transient expression assays in parsley protoplasts showed light regulation of a chimeric pea PHYA promoter uidA-gene construct.     

景观：实现一个有弹性的世界

我们生活的世界是有限的。我很惭愧的承认,如果全世界的人都像大多数英国人这样生活,需要3个地球提供资源才能维持我们的生活。斯蒂芬·霍金（Stephen Hawking）教授曾经预言：“为了我们的后代能够生存下去,我们必须在有生之年制定长远计划—逃离地球”。我们知道世界气候正在发生变化;幸运的是,英国的人们并没有承受过多气候变化带来的后果。但是,世界上其他地方的人们并非同样幸运。我们需要科学和艺术知识背景的景观行业的从业者;广博的知识使我们可以理解自然系统的敏感性、预想我们的专业行为对自然系统的长期影响。我预测,随着人口增长、土地资源减少以及不可再生资源的使用叠加在一起带来的压力,社会对风景园林师会有更大的需求。因此,迫切需要吸引年轻人加入到风景园林行业。我们的风景园林教育系统必须传授风景园林行业的新从业者应对不断变化的行业挑战的技能。我非常赞赏中国国家领导人习近平主席的重要观点：提高中国人生活质量具有重要意义。本篇文章传递的观点是：提高每个人的生活质量是风景园林专业的责任;同时,我希望这是中国与英国景观专业长期合作的一个开始,我们将以共赢的方式进行合作、提供服务。     

Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914

We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drug-resistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467–474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of supercoiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of supercoiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases α and β.