Exome sequences and multi‐environment field trials elucidate the genetic basis of adaptation in barley

Broadening the genetic base of crops is crucial for developing varieties to respond to global agricultural challenges such as climate change. Here, we analysed a diverse panel of 371 domesticated lines of the model crop barley to explore the genetics of crop adaptation. We first collected exome sequence data and phenotypes of key life history traits from contrasting multi‐environment common garden trials. Then we applied refined statistical methods, including some based on exomic haplotype states, for genotype‐by‐environment (G×E) modelling. Sub‐populations defined from exomic profiles were coincident with barley's biology, geography and history, and explained a high proportion of trial phenotypic variance. Clear G×E interactions indicated adaptation profiles that varied for landraces and cultivars. Exploration of circadian clock‐related genes, associated with the environmentally adaptive days to heading trait (crucial for the crop's spread from the Fertile Crescent), illustrated complexities in G×E effect directions, and the importance of latitudinally based genic context in the expression of large‐effect alleles. Our analysis supports a gene‐level scientific understanding of crop adaption and leads to practical opportunities for crop improvement, allowing the prioritisation of genomic regions and particular sets of lines for breeding efforts seeking to cope with climate change and other stresses.     

新型疫苗佐剂的研究进展

与传统的灭活或活体疫苗相比,由基因工程重组抗原或化学合成多肽组成的现代疫苗往往存在免疫原性弱等问题,需要新型的免疫佐剂来增强其作用。尽管传统的铝盐佐剂是目前唯一全球公认的人用佐剂,但存在激发细胞免疫应答能力差等不足,因此,需要研发更为安全有效的人用新型佐剂,尤其是安全无毒、能够刺激较强细胞免疫应答的佐剂,以及适合粘膜疫苗、DNA疫苗和癌症疫苗的免疫佐剂。分析阐述了新型佐剂研究状况和佐剂发展方向,并进一步对新型佐剂的临床前和临床试验研究以及已批准上市的新型疫苗佐剂进行了综述。     

Retroviral vectors

The majority of clinical trials for gene therapy currently employ retroviral-mediated gene delivery. This is because the life cycle of the retrovirus is well understood and can be effectively manipulated to generate vectors that can be efficiently and safely packaged. Here, we review the molecular technology behind the generation of recombinant retroviral vectors. We also highlight the problems associated with the use of these viruses as gene therapy vehicles and discuss future developments that will be necessary to maintain retroviral vectors at the forefront of gene transfer technology.     

我国药物临床试验伦理审查能力建设发展趋势

我国药物临床试验的深入广泛开展,促进了药物临床试验伦理审查水平的提高,伦理审查能力建设也取得了长足进步。但我国药物临床试验伦理审查能力建设面临系统的评估标准及体系、持续性培训和信息化程度缺乏等问题。加强药物临床试验伦理审查能力建设是我国医药领域进一步推进的重要工作,也是继续探索研究的热点内容及医学伦理审查工作者的自身需求。     

A phase II trial of riluzole,an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling,in patients with advanced melanoma

Studies demonstrate that GRM, expressed by >60% of human melanomas, may be a therapeutic target. We performed a phase II trial of 100 mg PO bid of riluzole, an inhibitor of GRM1 signaling, in patients with advanced melanoma with the primary endpoint of response rate. Thirteen patients with GRM1‐positive tumors were enrolled. No objective responses were observed, and accrual was stopped. Stable disease was noted in six (46%) patients, with one patient on study for 42 weeks. Riluzole was well tolerated, with fatigue (62%) as the most common adverse event. Downregulation of MAPK and PI3K/AKT was noted in 33% of paired tumor biopsies. Hypothesis‐generating correlative studies suggested that downregulation of angiogenic markers and increased leukocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed interpatient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance the development of agents with improved bioavailability.     

The Case For Randomized Clinical Trials on the Treatment of Obesity

Some say that randomized clinical trials on weight loss are unnecessary (“the benefits are ‘obvious’”) and others say that such trials are not feasible because too few participants will succeed in maintaining weight loss. Although the intermediate term benefits of weight loss are beyond dispute (lowering of blood pressure, lipids, blood sugar, etc), there is no proof that these benefits will translate into long term benefits, i.e., lower rates of cardiovascular disease and/or lower overall mortality. While this extrapolation may seem obvious, the clinical trials' literature is full of unexpected, adverse side effects of theoretically appealing therapies (e.g., higher mortality with clofibrate and higher cardiovascular disease rates with estrogen treatment in men). Although there is clearly a voluntary component to food ingestion, there are also powerful physiological forces at work which impact on energy balance. For example, individuals of similar height and weight may nevertheless have widely different daily energy expenditures and hence energy requirements. It has been shown in Pima Indians that those with low energy expenditure (i.e., those who are “fuel efficient”) are more prone to future weight gain than those with high energy expenditure. Also, reduced obese individuals have lower 24-hour energy expenditure than individuals who are spontaneously at the same lean weight It appears that this deficit in energy expenditure may last for several years, if not longer, implying that reduced obese individuals must exercise far greater vigilance over their caloric intake than their spontaneously lean peers. If they allow themselves to ingest the same number of calories as the latter, they are likely to regain weight, thereby exposing themselves to charges of overeating, even though their caloric intake does not exceed that of the spontaneously lean!. Epidemiologic data do not support a benefit of weight loss. Populations such as Mexican Americans, among whom obesity is more common than in the general population, do not have excess mortality past age 45. Life expectancy in the U.S. has improved steadily since the early 1970s, despite a rising prevalence of obesity. Lastly, prospective studies have suggested that people who lose weight die at a higher rate than those who maintain a stable weight. This effect persists even after controlling for latent, subclinical disease and cigarette smoking. Although none of the above considerations prove that voluntary weight loss is bad, they indicate that this treatment should lose its hitherto privileged status and be subjected to the rigors of clinical trials as have been treatments for hypercholesterolemia and hypertension.     

Different applications of virus‐like particles in biology and medicine: Vaccination and delivery systems

Virus‐like particles (VLPs) mimic the whole construct of virus particles devoid of viral genome as used in subunit vaccine design. VLPs can elicit efficient protective immunity as direct immunogens compared to soluble antigens co‐administered with adjuvants in several booster injections. Up to now, several prokaryotic and eukaryotic systems such as insect, yeast, plant, and E. coli were used to express recombinant proteins, especially for VLP production. Recent studies are also generating VLPs in plants using different transient expression vectors for edible vaccines. VLPs and viral particles have been applied for different functions such as gene therapy, vaccination, nanotechnology, and diagnostics. Herein, we describe VLP production in different systems as well as its applications in biology and medicine. © 2015 Wiley Periodicals, Inc. Biopolymers 105: 113–132, 2016.     

阿必鲁肽：一种超长效Ⅱ型糖尿病治疗新药

阿必鲁肽(Albiglutide)为新型GLP-1受体激动剂,可通过与胰岛β细胞表面的GLP-1受体结合,激活由细胞膜偶联G蛋白调控的胞内信号传导系统,修复及促进胰岛β细胞功能,增加胰岛素的分泌,从而降低血糖浓度及糖化血红蛋白(Hb A1c)水平,是治疗Ⅱ型糖尿病的理想药物。目前开发的各种长效GLP-1受体激动剂成为近二十年糖尿病药物的研究热点。本文对一种极具市场潜力的新型GLP-1受体激动剂阿必鲁肽(Albiglutide)的分子结构、作用机制、剂量研究、药代动力学、药效学以及副作用等临床试验研究进展进行综述。