Mechanism of regulating the expression of λN gene by ribosomal protein at translational level

In ribosomal protein S12 mutant or L24 mutant the expression of λN gene was depressed at translational level. To study its mechanism the λN gene region of λN -lacZ gene fusion was trimmed from its 5′ end to 3′ end with DNA exonuclease III (DNA cxoIII) in order to alter the TIR (translational initiation region) and the ding region of λN gene. After DNA sequencing 23 species of different λN-lacZ fused genes were obtained. The β-galactosidase activities of these deletants in ribosomal protein mutant were compared with that in wild type strain. The result indicated that (i) S12 mutant could affect 305 subunit’s binding to the TIR of λN gene messenger and cause the difficulty in forming 30s initiation complex and then decrease the efficiency of translational initiation; (ii) in S12 mutant the coding region of λN gene alw affected the expression λN gene; (iii) in L24 mutant the inhibition of λN gene expression was not related to translational initiation and the 5′ end of the coding region of λN gene, but related to the 3′ end of λN gene. Project supported by the National Natural Science Foundation of China (Grant Nos. 39480014, 39570162) and Chinese Academy of Sciences.     

Ethical issues associated with HIV phylogenetics in HIV transmission dynamics research: A review of the literature using the Emanuel Framework

The reduced costs of DNA sequencing and the use of such data for HIV‐1 clinical management and phylogenetic analysis have led to a massive increase of HIV‐1 sequences in the last few years. Phylogenetic analysis has shed light on the origin, spread and characteristics of HIV‐1 epidemics and outbreaks. Phylogenetic analysis is now also being used to advance our knowledge of the drivers of HIV‐1 transmission in order to design effective interventions. However, HIV phylogenetic analysis presents unique ethical challenges, which have not been fully explored. This review presents an analysis of what appear to be key ethical issues in HIV phylogenetics in the hope of stimulating further conceptual and empirical work in this rapidly emerging area. We structure the review using the Emanuel Framework, a systematic, holistic framework, which has been adapted for use in developing countries, which bear the brunt of the HIV‐1 pandemic.     

环状RNA的生物特征及其在植物中的研究进展

环状RNA(circular RNA,circRNA)是真核细胞中广泛存在的一类由3′末端和5′末端共价结合形成的环状非编码RNA(non-coding RNA,ncRNA)。越来越多的研究表明,circRNA具有种类丰富、结构稳定、序列保守以及细胞或组织特异性表达等特点。circRNA具有很多潜在的功能,例如作为天然小RNA(microRNA,miRNA)海绵体吸附并调控miRNA的活性,与转录调控元件结合或与蛋白互作调控基因的转录等。目前关于circRNA的研究多集中在动物和人体中,在植物中的研究还较少,仅在水稻(Oryza sativa)、拟南芥(Arabidopsis thaliana)、小麦(Triticum aestivum)、猕猴桃(Actinidia chinensis)、番茄(Solanum lycopersicum)和大豆(Glycine max)等中鉴定到了circRNA的存在,并且其作用机理尚不清楚。该文主要针对circRNA的分类、形成机制、分子特征、相关研究方法以及在植物中的主要研究进展进行综述,并对目前植物circRNA研究中存在的问题进行了分析总结。     

品管圈在提升研究型医院品质中的运用与实践探索

为探索医院转型发展的策略和路径,第三军医大学新桥医院积极开展医院品质建设,通过“建组织、树理念、引方法、培团队、推活动、管过程、享成果”七步流程,建立了研究型医院品质管理新模式。并以“品管圈”为牵引,使员工不仅要增强发现问题的意识,学会运用科学的管理工具解决问题,更要具备研究型的理念思路去创新管理的方法和手段,以实现“以患者为中心,以员工为导向,持续质量改进”的全面质量管理目标。     

2015年中国微生物遗传学研究领域若干重要进展

中国微生物遗传学研究在2015年取得了重要进展。本文回顾了2015年度中国本土科研团队在微生物遗传学领域取得的若干重要科研进展,扼要介绍了若干重点论文,展示了中国科学家在本领域的学术贡献。在基础微生物遗传学领域,明确了调控基因表达的一系列重要生物大分子的组成、结构和功能,解析了微生物免疫系统识别外源核酸片段的分子基础,阐明了多个微生物来源重要活性物质的生物合成途径及新颖的酶学反应过程,发现了微生物基因表达调控的新机理,在微生物发育、进化与群体行为生物学方面也取得一定进展。在工业微生物遗传学方面,阐明了微生物制造及其分子基础。在病原微生物遗传学方面,研究了多个致病菌的遗传调控,明晰了致病菌-宿主相互作用的遗传机制,在基因组水平解析了微生物耐药、新发病原和环境微生物的遗传机理,为致病菌防控新措施的研发提供了基础。在微生物多样性与环境微生物遗传学方面,展示了利用微生物遗传多样性的特点通过催化获得特定手性的化合物具有较好应用前景,肠道微生物组学研究方兴未艾。     

Posttranslational Modifications in Type I Collagen from Different Tissues Extracted from Wild Type and Prolyl 3-Hydroxylase 1 Null Mice

Type I collagen extracted from tendon, skin, and bone of wild type and prolyl 3-hydroxylase 1 (P3H1) null mice shows distinct patterns of 3-hydroxylation and glycosylation of hydroxylysine residues. The A1 site (Pro-986) in the α1-chain of type I collagen is almost completely 3-hydroxylated in every tissue of the wild type mice. In contrast, no 3-hydroxylation of this proline residue was found in P3H1 null mice. Partial 3-hydroxylation of the A3 site (Pro-707) was present in tendon and bone, but absent in skin in both α-chains of the wild type animals. Type I collagen extracted from bone of P3H1 null mice shows a large reduction in 3-hydroxylation of the A3 site in both α-chains, whereas type I collagen extracted from tendon of P3H1 null mice shows little difference as compared with wild type. These results demonstrate that the A1 site in type I collagen is exclusively 3-hydroxylated by P3H1, and presumably, this enzyme is required for the 3-hydroxylation of the A3 site of both α-chains in bone but not in tendon. The increase in glycosylation of hydroxylysine in P3H1 null mice in bone was found to be due to an increased occupancy of normally glycosylated sites. Despite the severe disorganization of collagen fibrils in adult tissues, the D-period of the fibrils is unchanged. Tendon fibrils of newborn P3H1 null mice are well organized with only a slight increase in diameter. The absence of 3-hydroxyproline and/or the increased glycosylation of hydroxylysine in type I collagen disturbs the lateral growth of the fibrils.     

The benefit sharing vision of H3Africa

One of the central ethical tenets of research in developing countries is the sponsor's obligation to benefit host participants and communities. Two known models of benefits provision dominate the ethical discourse of research in developing countries. The first model, known as the “reasonable availability,” endorses the obligation to provide interventions proven to be effective at the end of a study. This contrasts with the second model, known as “fair benefits,” which endorses other forms of benefits that host communities may deem as fair beyond those derived directly from the study's findings. This paper explores a third benefit model consistent with the writings of the Human Hereditary and Health in Africa (H3Africa) research initiative. The H3Africa—a North‐South collaborative initiative predicated by U.S. National Institutes of Health, the Wellcome Trust and the African Society of Human Genetics upholds a benefit model that endorses capacity building as the primary obligation of its research agenda. This is evident by the endorsement of mechanisms to strengthen capacity building in its research projects. While capacity building remains a plausible means of improving the expertise, quality and independence of research in Africa, sustainable measures are needed to realizing the full potential for African‐led research on the continent.     

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.