A comparative analysis of the substrate permissiveness of HCV and GBV-B NS3/4A proteases reveals genetic evidence for an interaction with NS4B protein during genome replication

The hepatitis C virus (HCV) serine protease (NS3/4A) processes the NS3-NS5B segment of the viral polyprotein and also cleaves host proteins involved in interferon signaling, making it an important target for antiviral drug discovery and suggesting a wide breadth of substrate specificity. We compared substrate specificities of the HCV protease with that of the GB virus B (GBV-B), a distantly related nonhuman primate hepacivirus, by exchanging amino acid sequences at the NS4B/5A and/or NS5A/5B cleavage junctions between these viruses within the backbone of subgenomic replicons. This mutagenesis study demonstrated that the GBV-B protease had a broader substrate tolerance, a feature corroborated by structural homology modeling. However, despite efficient polyprotein processing, GBV-B RNAs containing HCV sequences at the C-terminus of NS4B had a pseudo-lethal replication phenotype. Replication-competent revertants contained second-site substitutions within the NS3 protease or NS4B N-terminus, providing genetic evidence for an essential interaction between NS3 and NS4B during genome replication.     

Increased bile acids in enterohepatic circulation by short-term calorie restriction in male mice

Previous studies showed glucose and insulin signaling can regulate bile acid (BA) metabolism during fasting or feeding. However, limited knowledge is available on the effect of calorie restriction (CR), a well-known anti-aging intervention, on BA homeostasis. To address this, the present study utilized a “dose–response” model of CR, where male C57BL/6 mice were fed 0, 15, 30, or 40% CR diets for one month, followed by BA profiling in various compartments of the enterohepatic circulation by UPLC-MS/MS technique. This study showed that 40% CR increased the BA pool size (162%) as well as total BAs in serum, gallbladder, and small intestinal contents. In addition, CR “dose-dependently” increased the concentrations of tauro-cholic acid (TCA) and many secondary BAs (produced by intestinal bacteria) in serum, such as tauro-deoxycholic acid (TDCA), DCA, lithocholic acid, ω-muricholic acid (ωMCA), and hyodeoxycholic acid. Notably, 40% CR increased TDCA by over 1000% (serum, liver, and gallbladder). Interestingly, 40% CR increased the proportion of 12α-hydroxylated BAs (CA and DCA), which correlated with improved glucose tolerance and lipid parameters. The CR-induced increase in BAs correlated with increased expression of BA-synthetic (Cyp7a1) and conjugating enzymes (BAL), and the ileal BA-binding protein (Ibabp). These results suggest that CR increases BAs in male mice possibly through orchestrated increases in BA synthesis and conjugation in liver as well as intracellular transport in ileum.     

Prostitution and Drugs

Abstract

There are several reports that the bark of the rainforest tree Galbulimima belgraveana (F. Muell.) Sprague has been chewed for its psychoactive properties in Papua New Guinea. Twenty-eight alkaloids have been isolated from Galbulimima bark. There is no direct pharmacological evidence that any of these alkaloids are psychoactive. Two different pharmacological explanations for the reported psychoactive properties of Galbulimima bark are offered.     

内关穴治疗心脏过早搏动的特异性临床研究

目的通过针刺单穴内关与悬钟穴治疗早搏的疗效比较,观察内关穴治疗早搏的相对特异性,证明内关穴治疗早搏的临床疗效。方法根据纳入标准共入组60例,其中脱落10例,实际完成50例,内关组30例,悬钟组20例。采用随机对照试验,单盲法。并分别进行动态心电图检测,进行统计学处理,比较内关与悬钟治疗早搏的疗效。结果针刺内关穴治疗早搏疗效优于针刺悬钟穴治疗。结论内关穴相对于悬钟穴在早搏的治疗中具有特异性。这一研究结果可为规范腧穴的主治作用及临床选穴提供科学的试验依据。     

Association between the arrested decline in cardiovascular disease and health and social-care costs: a modelling study

BackgroundDementia and cardiovascular disease generate enormous health and social-care costs and have shared risk factors. Following decades of cardiovascular disease mortality declines in England, improvements slowed after 2011. We investigated the potential economic implications of this slowdown.MethodsWe used the IMPACT better aging model—an open-cohort, stochastic Markov model. We synthesised trends in cardiovascular disease incidence and mortality, dementia, and disability (defined as reported diagnosis, functional impairment, or measured cognitive impairment) from the English Longitudinal Study of Ageing (ELSA) and Office for National Statistics data. We projected trends for adults aged 35–100 years in England and Wales from 2019–29. We modelled undiscounted health and social-care costs (primary outcome), and quality-adjusted life-years (QALYs) under the following two scenarios: age-specific cardiovascular disease incidence continues to decline, recommencing previous downward trends (scenario one); or age-specific cardiovascular disease incidence plateaus after 2006, continuing recent trends, assuming changes in mortality reflect incidence 5 years before (scenario two). We linked 85% of ELSA participants to their Hospital Episode Statistics (HES) data, which were costed and calibrated to national estimates. Age-related social-care costs were estimated by use of reported contact hours from ELSA combined with standard reference costs. Standard catalogues were used for QALY weights.FindingsIn scenario one, changes in population size and health were projected to increase health-care costs by around 12% between 2019 and 2029, from £93·0 billion to £104·6 billion per year (in 2019 prices). Social-care costs were projected to increase by around 27%, from £8·0 billion to £10·2 billion per year. In scenario two, health-care costs were projected to increase by around 15%, from £95·3 billion to £109·6 billion, and social-care costs by around 30%, from £8·2 billion to £10·7 billion, between 2019 and 2029. The overall net monetary cost of this slowdown in cardiovascular disease decline was £17·5 billion per year (made up of 200 000 QALYs and £5·5 billion in health and social-care costs).InterpretationWe predict social-care costs will grow twice as fast as health-care costs over the next decade, even if cardiovascular disease occurrence continues to decline. Understanding the scale of the future health and social-care funding challenge might support proactive policy making. This study represents the first time ELSA data have been linked with HES data. However, we did not assess changes in health and social-care efficiency over time or the effect of spending on improving health.FundingBritish Heart Foundation     

防爆新标准及各种新标志方法

从2011年8月1日起,我国颁布引入设备保护级别EPL的新的防爆标注方法。根据国家级仪器仪表防爆安全监督检验站（NEPSI）发表的文章,结合工程应用的体会予以分析,并对新表示方法予以各种举例。     

针刺率谷穴配合穴位注射治疗神经性耳鸣疗效观察

目的观察针刺率谷穴配合穴位注射治疗神经性耳鸣的临床疗效。方法将220例神经性耳鸣患者随机分为对照组和观察组,每组110例。对照组给予常规西药治疗,观察组在对照组治疗基础上给予针刺率谷穴配合穴位注射治疗。观察两组治疗前后的耳鸣主要症状体征评分、耳鸣响度评分和耳鸣残疾量表(THI)评分变化,并比较两组临床疗效。结果治疗后,两组患者的耳鸣发生环境、对睡眠影响、持续时间、对生活工作影响、对情绪影响和主观感受6个维度评分显著降低(P<0.05),观察组低于对照组(P<0.05)。治疗后,两组耳鸣响度评分和THI评分降低(P<0.05),不同时间组内和组间比较,差异有统计学意义(P<0.05)。观察组的总有效率为95.5%,显著高于对照组的80.0%(P<0.05)。结论针刺率谷穴配合穴位注射治疗神经性耳鸣疗效显著,可有效减轻患者的耳鸣主要症状体征,降低耳鸣响度,改善耳鸣残疾程度。     

GB/T 9999—2018标准的解读及其执行中存在的问题

【目的】分析我国期刊执行GB/T 9999.1—2018《中国标准连续出版物号 第1部分:CN》和GB/T 9999.2—2018《中国标准连续出版物号 第2部分:ISSN》(以下合称GB/T 9999—2018)中存在的问题,并对GB/T 9999—2018有关期刊的部分内容进行解读,为期刊更好地执行国家标准提供参考。【方法】2019年12月,采用抽样统计方法,随机选取某图书馆订阅的2019年10—12月出版的900余种期刊中的110种,对封一、题名页、版权页(块)、目次页、封四等执行GB/T 9999—2018的情况进行查看与统计分析。【结果】随机选取的110种期刊大部分存在执行GB/T 9999—2018标准不规范问题。【结论】期刊出版单位对GB/T 9999—2018学习贯彻不够,期刊出版管理部门在期刊审读与评比中注意检查GB/T 9999—2018标准的执行情况,督促期刊出版单位严格执行国家标准。