Conformations of immunoglobulin hypervariable regions

On the basis of comparative studies of known antibody structures and sequences it has been argued that there is a small repertoire of main-chain conformations for at least five of the six hypervariable regions of antibodies, and that the particular conformation adopted is determined by a few key conserved residues. These hypotheses are now supported by reasonably successful predictions of the structures of most hypervariable regions of various antibodies, as revealed by comparison with their subsequently determined structures.     

Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491

Neisseria meningitidis causes bacterial meningitis and is therefore responsible for considerable morbidity and mortality in both the developed and the developing world. Meningococci are opportunistic pathogens that colonize the nasopharynges and oropharynges of asymptomatic carriers. For reasons that are still mostly unknown, they occasionally gain access to the blood, and subsequently to the cerebrospinal fluid, to cause septicaemia and meningitis. N. meningitidis strains are divided into a number of serogroups on the basis of the immunochemistry of their capsular polysaccharides; serogroup A strains are responsible for major epidemics and pandemics of meningococcal disease, and therefore most of the morbidity and mortality associated with this disease. Here we have determined the complete genome sequence of a serogroup A strain of Neisseria meningitidis, Z2491. The sequence is 2,184,406 base pairs in length, with an overall G+C content of 51.8%, and contains 2,121 predicted coding sequences. The most notable feature of the genome is the presence of many hundreds of repetitive elements, ranging from short repeats, positioned either singly or in large multiple arrays, to insertion sequences and gene duplications of one kilobase or more. Many of these repeats appear to be involved in genome fluidity and antigenic variation in this important human pathogen.     

The genome sequence of the food-borne pathogen Campylobacter jejuni reveals hypervariable sequences

Campylobacter jejuni, from the delta-epsilon group of proteobacteria, is a microaerophilic, Gram-negative, flagellate, spiral bacterium-properties it shares with the related gastric pathogen Helicobacter pylori. It is the leading cause of bacterial food-borne diarrhoeal disease throughout the world. In addition, infection with C. jejuni is the most frequent antecedent to a form of neuromuscular paralysis known as Guillain-Barré syndrome. Here we report the genome sequence of C. jejuni NCTC11168. C. jejuni has a circular chromosome of 1,641,481 base pairs (30.6% G+C) which is predicted to encode 1,654 proteins and 54 stable RNA species. The genome is unusual in that there are virtually no insertion sequences or phage-associated sequences and very few repeat sequences. One of the most striking findings in the genome was the presence of hypervariable sequences. These short homopolymeric runs of nucleotides were commonly found in genes encoding the biosynthesis or modification of surface structures, or in closely linked genes of unknown function. The apparently high rate of variation of these homopolymeric tracts may be important in the survival strategy of C. jejuni.     

Beta-helix structure and ice-binding properties of a hyperactive antifreeze protein from an insect

Insect antifreeze proteins (AFP) are considerably more active at inhibiting ice crystal growth than AFP from fish or plants. Several insect AFPs, also known as thermal hysteresis proteins, have been cloned and expressed. Their maximum activity is 3-4 times that of fish AFPs and they are 10-100 times more effective at micromolar concentrations. Here we report the solution structure of spruce budworm (Choristoneura fumiferana) AFP and characterize its ice-binding properties. The 9-kDa AFP is a beta-helix with a triangular cross-section and rectangular sides that form stacked parallel beta-sheets; a fold which is distinct from the three known fish AFP structures. The ice-binding side contains 9 of the 14 surface-accessible threonines organized in a regular array of TXT motifs that match the ice lattice on both prism and basal planes. In support of this model, ice crystal morphology and ice-etching experiments are consistent with AFP binding to both of these planes and thus may explain the greater activity of the spruce budworm antifreeze.     

Preferential deletion of exons in Duchenne and Becker muscular dystrophies

Duchenne and Becker muscular dystrophy (DMD and BMD) genes are located in Xp21 on the short arm of the X chromosome. DMD patients display a much more severe clinical course than BMD patients, and yet about 10% of cases of each have been reported to have deletions for parts of the gene. Using a complementary DNA subclone of the DMD gene we have screened 66 DMD and BMD patients who had not previously shown deletions with the probes then available. Fifteen patients have a deletion of this part of the gene, indicating a higher deletion frequency in this region (22%). Exons were deleted in five severely affected DMD patients and in ten BMD patients. Significantly, most of these deletions begin in the same region of the cDNA, which implies that there is a common mechanism for the generation of many of these mutations. An apparently identical deletion in one family gave classical BMD in two brothers (presenting in their teens) and only very mild muscle weakness in their 86-year-old great-great-uncle. Taking these data together with data using the probes previously published, we are able to detect deletions directly in 40% of our families requiring antenatal diagnosis or carrier detection.     

Association of phosphorylation of the T3 antigen with immune activation of T lymphocytes

In human T lymphocytes the antigen receptor (Ti) is associated non-covalently on the cell surface with the invariant T3 antigen which comprises 3 chains: two glycosylated polypeptides of relative molecular mass 26,000 (Mr 26K) and 21K (gamma and delta) and one non-N-glycosylated polypeptide of Mr 19K (epsilon). The proposed function of T3 is to transduce the activation signals delivered via the antigen receptor. Recently we have shown that phorbol esters, which stimulate protein kinase C, can induce phosphorylation of the gamma subunit of the T3 antigen. But the critical question is whether T3 phosphorylation occurs as a normal consequence of immune activation of T lymphocytes. In this respect, it has been shown that immune stimulation of murine T cells results in phosphorylation of Ti-associated polypeptides that may be the functional analogues of the human T3 antigen. We have therefore monitored T3 phosphorylation after exposure of human T cells to antigen or phytohaemagglutinin (PHA). The data show that both stimuli initiate phosphorylation of the gamma subunit of the T3 antigen which indicates that T3 phosphorylation is a physiological response to immune activation.     

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.     

地幔柱存在的依据

从一些成熟的观察我们可推测地幔中至少有几个地幔柱, 这并不需要什么假设. 的确, 如果我们对地球早期热状态的假设合理的话, 那么用成熟的定量流体动力学模型不难预测地幔柱的存在. 一些其他重要的观察, 特别是溢流玄武岩和裂谷有关的岩浆活动, 也被证实与物理推论基本一致. 最近有人宣称用地震层析成像方法探测到地幔柱, 这应该说是地幔柱存在的最直接证据, 但地幔柱尾部很难被检测到, 因此该探测结果尚须进一步检验. 尽管地幔柱假说的可行性仍存在重要问题, 但地幔柱假说似乎很值得继续研究. 尽管如此, 许多与板块无关的岩浆活动与地幔柱的关系并不清楚或可能无关. 最近的研究表明化学组成造成的浮力变化会使得地幔柱动力学变得更复杂. 这可用以解释比纯热地幔柱更宽泛的现象, 包括“无柱头”的热点轨迹.     

Locating the ‘culture wars’ in laboratory animal research: national constitutions and global competition

The increasingly global scope of biomedical research and testing using animals is generating disagreement over the best way to regulate laboratory animal science and care. Despite many common aims, the practices through which political and epistemic authority are allocated in the regulations around animal research varies internationally, coming together in what can be identified as different national constitutions. Tensions between these periodically erupt within the laboratory animal research community as a ‘cultural war’ between those favouring centralised control and those advocating local flexibility. Drawing on long-term engagement with key events and actors in these policy debates, I propose these national differences in the constitution of animal research can be understood through the intersection of two key variables: i) the location of institutional responsibility to permit research projects and ii) the distribution of epistemic authority to shape research practices. These variables are used to explain the development of different policy frameworks in the UK, Europe, and the USA, and identify where there is convergence and divergence in practice. Concluding, I suggest the way these approaches are combined and enacted in different countries reflects different national civic epistemologies, which are coming into conflict in the increasingly global networks of laboratory animal science.     

高成形性镁合金板材的成分优化

镁是最轻的金属结构材料。然而，镁合金板材具有织构强，室温成形性差的瓶颈难题，限制其广泛应用。虽然研究发现在Mg–Zn–Zr合金体系同添加钙或钆能弱化织构，提高成形性，但这两种元素添加后对的效果尚未有过系统比较和研究。本文旨在展现微合金添加钆和钙对于显微结构和力学性能的影响规律。本文发现，Mg–Zn–Gd–Zr 与 Mg–Zn–Ca–Zr轧板有类似的弱织构，但是Mg–Zn–Gd–Zr轧板的延伸率和成形性高于Mg–Zn–Ca–Zr。当在Mg–1Zn–0.5Zr合金中添加0.4wt%钆、0.2wt%钙时能获得最高的室温延伸率，其深冲成形性可以和铝合金板材6016相媲美。当钙的含量从0.2wt%提升至0.5wt%后，合金板材的延伸率与成形性下降，其主要原因是钙的过量添加导致了晶界脆化，降低了晶界韧性从而裂纹容易从晶界处萌生并扩展。