Prediction of electrostatic effects of engineering of protein charges

Accurate prediction of electrostatic effects on catalytic activity is an essential component of protein design. Site-directed mutagenesis of charged groups in subtilisin of Bacillus amyloliquefaciens has provided experimental measurements of electrostatic interactions which may be used to test such theoretical methods. The pKa of the histidine of the active site has been perturbed by +0.08 to -1.0 units by modifying one or two residues. Electrostatic effects in proteins can be modelled by the algorithm of Warwicker and Watson, which uses classical electrostatics and considers both the charge position and the shape of the molecule. Here we report that the algorithm can model several pKa shifts in subtilisin to fair accuracy.     

化学和湿度传感器用聚合物膜的制备方法

使用紫外辐射溶液聚合方法研究了化学／湿度传感器用聚合物膜的制备方法．本方法制备的膜厚度在5～100μm区间可控,信号响应好,可重复．     

Mitochondrial genetic variation within and between Holbrookia lacerata lacerata and Holbrookia lacerata subcaudalis,the spot-tailed earless lizards of Texas

ABSTRACT

We examined genetic relationships among individuals and populations of the species Holbrookia lacerata, the spot-tailed earless lizard, using whole mitochondrial genomes. Lizards were collected from south, central and west Texas. We found significant amounts of genetic structure among populations and evidence of two major reciprocally monophyletic groups of spot-tailed earless lizards in Texas. Holbrookia lacerata lacerata occurs on the Edwards Plateau and adjacent regions of West Texas north of the Balcones Escarpment, while Holbrookia lacerata subcaudalis occurs in South Texas and adjacent Mexico south of the Balcones Escarpment. These two recognised subspecies correspond to the two clades we discovered. Holbrookia l. lacerata occupies much of its historical range at sometimes high population densities, while populations of H. l. subcaudalis appear to be highly fragmented based on recent observations compared to their historical range.     

The functional role of sodium taurocholate cotransporting polypeptide NTCP in the life cycle of hepatitis B,C and D viruses

Chronic hepatitis B, C and D virus (HBV, HCV and HDV) infections are a major cause of liver disease and cancer worldwide. Despite employing distinct replication strategies, the three viruses are exclusively hepatotropic, and therefore depend on hepatocyte-specific host factors. The sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes that mediates the transport of bile acids, plays a key role in HBV and HDV entry into hepatocytes. Recently, NTCP has been shown to modulate HCV infection of hepatocytes by regulating innate antiviral immune responses in the liver. Here, we review the current knowledge of the functional role and the molecular and cellular biology of NTCP in the life cycle of the three major hepatotropic viruses, highlight the impact of NTCP as an antiviral target and discuss future avenues of research.     

What’s right about Carnap, Neurath and the Left Vienna Circle thesis: a refutation

This paper rejects as unfounded a recent criticism of research on the so-called left wing of the Vienna Circle and the claim that it sported a political philosophy of science. The demand for ‘specific, local periodized claims’ is turned against the critic. It is shown (i) that certain criticisms of Red Vienna’s leading party cannot be transferred to the members of the Circle involved in popular education, nor can criticism of Carnap’s Aufbau be transferred to Neurath’s unified science project; (ii) that neither with regard to Carnap nor to Neurath does the criticism raise points that either engage with the thesis proposed or stand up to closer scrutiny; (iii) that the main thesis attacked is just what I had warned the claim that the Vienna Circle had a political philosophy of science should not be understood as. The question whether theirs is ‘political enough’ today can and should be discussed without distortion of the historical record.     

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ～ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.     

Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy

Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.