专业教育模式的转变

当不同的人聚集在一起组成一个合作团体时,相互之间很快就会产生矛盾冲突.不同职业的人有其特有的语言和活动范围.这给他们与其他人交流造成了麻烦(Hooper-Briar andLawson,1994).在互助、配合和合作间存在着很大的不同.合作是三者中最高等级的活动.个体间互助和配合时并不需要改动他们原先从事的活动.但在合作中,人们期望新的合作实体能创造出一些个人或组织无法单独创造出的成果(Corrigan,2000).大学可以设计出一种跨学科的模式.在这种模式中,一些合作的专业团体能致力于支持与帮助社区中的家庭和孩子们.对于将来的教育工作者来说,跨学科合作将成为他们与家庭和孩子沟通时极为重要的一项技能.未成年人怀孕、辍学、青少年犯罪、虐待儿童以及对儿童的健康护理问题正引起国内人士及国外诸多社会团体的普遍关注.这些复杂的情况,要求我们在对教育工作范围的评价上要有一套完全不同的方法,在对待教育工作范围的态度上要有所改变.这一套方法就包括健康护理各项服务的合作和联结、学校机构和周围其他多部门环境的调节和预防.前面提到的跨学科合作模式主要强调对未来的领导者、教育者和人类服务的提供者的专业培养.设计这种模式旨在让参与者获得一种知识,掌握一种技能,培养一种性情.这种所谓的知识、技能和性情是想像的,它包含了来自各学科的多种观点,如:看护养育、社会工作、教育工作、咨询服务、法律执行、物理治疗和心理学.     

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades.     

Two types of muscarinic acetylcholine receptors in Drosophila and other arthropods

Muscarinic acetylcholine receptors (mAChRs) play a central role in the mammalian nervous system. These receptors are G protein-coupled receptors (GPCRs), which are activated by the agonists acetylcholine and muscarine, and blocked by a variety of antagonists. Mammals have five mAChRs (m1–m5). In this study, we cloned two structurally related GPCRs from the fruit fly Drosophila melanogaster, which, after expression in Chinese hamster ovary cells, proved to be muscarinic acetylcholine receptors. One mAChR (the A-type; encoded by gene CG4356) is activated by acetylcholine (EC₅₀, 5 × 10^?8 M) and muscarine (EC₅₀, 6 × 10^?8 M) and blocked by the classical mAChR antagonists atropine, scopolamine, and 3-quinuclidinyl-benzilate (QNB), while the other (the B-type; encoded by gene CG7918) is also activated by acetylcholine, but has a 1,000-fold lower sensitivity to muscarine, and is not blocked by the antagonists. A- and B-type mAChRs were also cloned and functionally characterized from the red flour beetle Tribolium castaneum. Recently, Haga et al. (Nature 2012, 482: 547–551) published the crystal structure of the human m2 mAChR, revealing 14 amino acid residues forming the binding pocket for QNB. These residues are identical between the human m2 and the D. melanogaster and T. castaneum A-type mAChRs, while many of them are different between the human m2 and the B-type receptors. Using bioinformatics, one orthologue of the A-type and one of the B-type mAChRs could also be found in all other arthropods with a sequenced genome. Protostomes, such as arthropods, and deuterostomes, such as mammals and other vertebrates, belong to two evolutionarily distinct lineages of animal evolution that split about 700 million years ago. We found that animals that originated before this split, such as cnidarians (Hydra), had two A-type mAChRs. From these data we propose a model for the evolution of mAChRs.     

Folding and assembly defects of pyruvate dehydrogenase deficiency-related variants in the E1α subunit of the pyruvate dehydrogenase complex

The pyruvate dehydrogenase complex (PDC) bridges glycolysis and the citric acid cycle. In human, PDC deficiency leads to severe neurodevelopmental delay and progressive neurodegeneration. The majority of cases are caused by variants in the gene encoding the PDC subunit E1α. The molecular effects of the variants, however, remain poorly understood. Using yeast as a eukaryotic model system, we have studied the substitutions A189V, M230V, and R322C in yeast E1α (corresponding to the pathogenic variants A169V, M210V, and R302C in human E1α) and evaluated how substitutions of single amino acid residues within different functional E1α regions affect PDC structure and activity. The E1α A189V substitution located in the heterodimer interface showed a more compact conformation with significant underrepresentation of E1 in PDC and impaired overall PDC activity. The E1α M230V substitution located in the tetramer and heterodimer interface showed a relatively more open conformation and was particularly affected by low thiamin pyrophosphate concentrations. The E1α R322C substitution located in the phosphorylation loop of E1α resulted in PDC lacking E3 subunits and abolished overall functional activity. Furthermore, we show for the E1α variant A189V that variant E1α accumulates in the Hsp60 chaperonin, but can be released upon ATP supplementation. Our studies suggest that pathogenic E1α variants may be associated with structural changes of PDC and impaired folding of E1α.