Prolyl endopeptidases

This review describes the structure and function of prolyl endopeptidase (PEP) enzymes and how they are being evaluated as drug targets and therapeutic agents. The most well studied PEP family has a two-domain structure whose unique seven-blade β-propeller domain works with the catalytic domain to hydrolyze the peptide bond on the carboxyl side of internal proline residues of an oligopeptide substrate. Structural and functional studies on this protease family have elucidated the mechanism for peptide entry between the two domains. Other structurally unrelated PEPs have been identified, but have not been studied in detail. Human PEP has been evaluated as a pharmacological target for neurological diseases due to its high brain concentration and ability to cleave neuropeptides in vitro. Recently, microbial PEPs have been studied as potential therapeutics for celiac sprue, an inflammatory disease of the small intestine triggered by proline-rich gluten. Received 6 July 2006; received after revision 17 August 2006; accepted 1 November 2006     

Mantle plumes： Why the current skepticism？

The present reappraisal of the mantle plume hypothesis is perhaps the most exciting current debate in Earth science. Nevertheless, the fundamental reasons for why it has arisen are often not well understood. They are that 1） many observations do not agree with the predictions of the original model, 2） it is possible that convection of the sort required to generate thermal plumes in the Earth＇s mantle does not occur, 3） so many variants of the original model have been invoked to accommodate conflicting data that the plume hypthesis is in practice no longer testable, and 4） alternative models are viable, though these have been largely neglected by researchers. Regardless of the final outcome, the present vigorous debate is to be welcomed since it is likely to stimulate new discoveries in a way that unquestioning acceptance of the conventional plume model will not.     

Forecasting and the database: An analysis of databases for international business

A major consideration in the selection of a forecasting method for a specific situation is the type of pattern in the data. Before the data pattern is identified, the forecaster must recognize the dependence of any forecasting method upon the accompanying reliable database. This issue is discussed in the paper with reference to databases for international business.     

地幔柱: 为什么现在怀疑?

对地幔柱假说的重新评价也许是当今地球科学争论最激烈的问题. 尽管如此, 需要对地幔柱假说进行重新评价的根本原因对大部分学者而言并非十分清楚. 主要原因可归结为: (1) 许多观察与地幔柱最初模型的预测结果不符, (2) 地幔中产生热地幔柱所需要的那种对流可能并不存在, (3) 很多最初模型的衍生体被用来容纳相互矛盾的资料, 以致于地幔柱假说实际上根本无法检验, 以及 (4) 其他行之有效的模型均被长期忽视. 不管最终结果如何, 现在的激烈争论都应受欢迎, 因为争论有助于新的发现, 而不质疑地接受传统地幔柱模型则有碍于新发现.     

Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature

We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sj?gren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log(10) odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.     

A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia

We report the first identified mutation in the gene encoding human cytochrome c (CYCS). Glycine 41, invariant throughout eukaryotes, is substituted by serine in a family with autosomal dominant thrombocytopenia caused by dysregulated platelet formation. The mutation yields a cytochrome c variant with enhanced apoptotic activity in vitro. Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome c activity is not a critical regulator of most physiological apoptosis.