On the module identification for product family development

Modularity is the key to improve the cost-variety trade-off in product family development. This paper presents a methodology for identifying the constituent modules of product family. The methodology includes the following principles: (1) identify and isolate the individualized components into one module so that the product’s differentiation point is postponed; (2) identify and isolate the components with high possibility of being changed in the future into one module in order to improve the stability and commonality in the product family; (3) improve the functional independency of the modules so as to support the module configuration process and the functional extension of the product family; and (4) improve the structural independency of the modules so as to achieve higher efficiency in the module manufacturing process. These four principles are incorporated into a mathematical model and therefore the module identification problem is translated into a multi-objective combinatorial optimization problem. The problem is solved using genetic algorithm (GA). A case study is carried out on a gear reducer. Sensitivity analyses show that relative weights of each principle and different initial numbers of modules result in different module schemes.     

新疆伊犁盆地地层划分与对比

通过野外实际观察和实测剖面，结合实钻资料化验分析结果，并依据前人工作的基础。对新疆伊犁盆地的实际地层情况进行系统对比和分析，统一了多年来比较混乱的地层单位和各称，建立了伊犁地区标准地层剖面，特别是对下三叠统的巴斯干尔组和上白垩统的东沟组提出了新的更为确切的划分依据。为今后新疆伊犁地区开展其它各项工作提供了基础资料。     

Comparison on treatment of falciparum malaria with different courses of artesunate tablet

OBJECTIVE: To assess the efficacy of Artesunate on falciparum malaria. METHODS: A randomized controlled study on the treatment of 90 uncomplicated falciparum malaria patients was carried out with 400 mg of artesunate tablet as a total dose over 3 days, 600 mg over 5 days and 800 mg over 7 days. RESULTS: All patients were cured. Fever clearance time (FCT) and parasite clearance time(PCT) among the three groups were similar. Parasite recrudescence rate within 28 days was 39.3% (11/ 28) in 3 day group, 6.9% (2/29) in 5 day group and 3.4% (1/29) in 7 day group (comparing 5 day group with 3 day group, P < 0.005, comparing 7 day group with 3 day group, P < 0.005). CONCLUSION: It indicated that parasite recrudescence rate may be effectively decreased by prolonging treatment courses.     

Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type

In cultures of dissociated rat hippocampal neurons, persistent potentiation and depression of glutamatergic synapses were induced by correlated spiking of presynaptic and postsynaptic neurons. The relative timing between the presynaptic and postsynaptic spiking determined the direction and the extent of synaptic changes. Repetitive postsynaptic spiking within a time window of 20 msec after presynaptic activation resulted in long-term potentiation (LTP), whereas postsynaptic spiking within a window of 20 msec before the repetitive presynaptic activation led to long-term depression (LTD). Significant LTP occurred only at synapses with relatively low initial strength, whereas the extent of LTD did not show obvious dependence on the initial synaptic strength. Both LTP and LTD depended on the activation of NMDA receptors and were absent in cases in which the postsynaptic neurons were GABAergic in nature. Blockade of L-type calcium channels with nimodipine abolished the induction of LTD and reduced the extent of LTP. These results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the activity-induced modification of central synapses and suggest that Hebb's rule may need to incorporate a quantitative consideration of spike timing that reflects the narrow and asymmetric window for the induction of synaptic modification.     

Probing the ligand binding domain of the GluR2 receptor by proteolysis and deletion mutagenesis defines domain boundaries and yields a crystallizable construct

Ionotropic glutamate receptors constitute an important family of ligand-gated ion channels for which there is little biochemical or structural data. Here we probe the domain structure and boundaries of the ligand binding domain of the AMPA-sensitive GluR2 receptor by limited proteolysis and deletion mutagenesis. To identify the proteolytic fragments, Maldi mass spectrometry and N-terminal amino acid sequencing were employed. Trypsin digestion of HS1S2 (Chen GQ, Gouaux E. 1997. Proc Natl Acad Sci USA 94:13431-13436) in the presence and absence of glutamate showed that the ligand stabilized the S1 and S2 fragments against complete digestion. Using limited proteolysis and multiple sequence alignments of glutamate receptors as guides, nine constructs were made, folded, and screened for ligand binding activity. From this screen, the S1S21 construct proved to be trypsin- and chymotrypsin-resistant, stable to storage at 4 degrees C, and amenable to three-dimensional crystal formation. The HS1S21 variant was readily prepared on a large scale, the His tag was easily removed by trypsin, and crystals were produced that diffracted to beyond 1.5 A resolution. These experiments, for the first time, pave the way to economical overproduction of the ligand binding domains of glutamate receptors and more accurately map the boundaries of the ligand binding domain.     

Identification of common ligand binding determinants of the insulin and insulin-like growth factor 1 receptors. Insights into mechanisms of ligand binding

Insulin and insulin-like growth factor 1 (IGF-1) are peptides that share nearly 50% sequence homology. However, although their cognate receptors also exhibit significant overall sequence homology, the affinity of each peptide for the non-cognate receptor is 2-3 orders of magnitude lower than for the cognate receptor. The molecular basis for this discrimination is unclear, as are the molecular mechanisms underlying ligand binding. We have recently identified a major ligand binding site of the insulin receptor by alanine scannning mutagenesis. These studies revealed that a number of amino acids critical for insulin binding are conserved in the IGF-1 receptor, suggesting that they may play a role in ligand binding. We therefore performed alanine mutagenesis of these amino acids to determine whether this is the case. cDNAs encoding alanine-substituted secreted recombinant IGF-1 receptors were expressed in 293 EBNA cells, and the ligand binding properties of the expressed proteins were evaluated. Mutation of Phe701 resulted in a receptor with undetectable IGF-1 binding; alanine substitution of the corresponding amino acid of the insulin receptor, Phe714, produces a 140-fold reduction in affinity for insulin. Mutation of Asp8, Asn11, Phe58, Phe692, Glu693, His697, and Asn698 produces a 3.5-6-fold reduction in affinity for IGF-1. In contrast, alanine mutation of the corresponding amino acids of the insulin receptor with the exception of Asp12 produces reductions in affinity that are 50-fold or greater. The affinity of insulin for these mutants relative to wild type receptor was similar to that of their relative affinity for IGF-1 with two exceptions; the IC50 values for insulin binding to the mutants of Arg10, which has normal affinity for IGF-1, and His697, which has a 6-fold reduction in affinity for IGF-1, were both at least 2 orders of magnitude greater than for wild type receptor. The Kd values for insulin of the corresponding alanine mutants of the insulin receptor, Arg14 and His710, are 2-3 orders of magnitude greater than for wild type receptor. However, in contrast, the relative affinity of des(25-30)[PheB25 alpha-carboxamide]insulin for these IGF-1 receptor mutants is reduced only 4- and 50-fold, respectively.