Analysis of conformational motions and related key residue interactions responsible for a specific function of proteins with elastic network model

Protein collective motions play a critical role in many biochemical processes. How to predict the functional motions and the related key residue interactions in proteins is important for our understanding in the mechanism of the biochemical processes. Normal mode analysis (NMA) of the elastic network model (ENM) is one of the effective approaches to investigate the structure-encoded motions in proteins. However, the motion modes revealed by the conventional NMA approach do not necessarily correspond to a specific function of protein. In the present work, a new analysis method was proposed to identify the motion modes responsible for a specific function of proteins and then predict the key residue interactions involved in the functional motions by using a perturbation approach. In our method, an internal coordinate that accounts for the specific function was introduced, and the Cartesian coordinate space was transformed into the internal/Cartesian space by using linear approximation, where the introduced internal coordinate serves as one of the axes of the coordinate space. NMA of ENM in this internal/Cartesian space was performed and the function-relevant motion modes were identified according to their contributions to the specific function of proteins. Then the key residue interactions important for the functional motions of the protein were predicted as the interactions whose perturbation largely influences the fluctuation along the internal coordinate. Using our proposed methods, the maltose transporter (MalFGK₂) from E. Coli was studied. The functional motions and the key residue interactions that are related to the channel-gating function of this protein were successfully identified.     

A study of the genetic polymorphism of human inter-alpha-trypsin-inhibitor (ITI) in the Han population,Chengdu, China

Phenotypes of inter-alpha-trypsin-inhibitor (ITI) have been determined by isoelectric focusing on polyacrylamide gels followed by immunofixation. The phenotype frequencies of ITI in the Han population in Chengdu, P. R. China have been investigated using this method. In addition, family studies have been conducted in 21 families. The results show that ITI is polymorphic in the Han population in Chengdu, China. The allele frequencies are as follows: ITI*1 = 0.5763. ITI*2 = 0.4107, ITI*3 = 0.0130. ITI is thus a new and promising genetic marker that can be used in the field of forensic haematogenetics.     

Snap-25 is polarized to axons and abundant along the axolemma: an immunogold study of intact neurons

SNAP-25, synaptosomal associated protein of 25 kDa, is reported to be a t-SNARE (target receptor associated with the presynaptic plasma membrane) involved in the docking and fusion of synaptic vesicles. We present here the first ultrastructural localization of SNAP-25 in intact neurons by pre-embedding EM immunocytochemistry in rat brains, hippocampal slice cultures, and PC12 cells. In differentiated neurons, SNAP-25 labeling was clearly membrane-associated. The labeling was most prominent in the plasma membrane of axons and excluded from the plasma membranes of soma and dendrites. Furthermore, SNAP-25 did not appear to be restricted to the synaptic junctions. SNAP-25 labeling was seen in the cytoplasm of the soma and large dendrites, mostly associated with the Golgi complexes. There were also some SNAP-25 labeled tubulo-vesicular structures in the cytoplasm of the soma and the axons, but rarely in the smaller dendrites. In PC12 cells, after 5–10 minutes of high potassium (75 mM) stimulation in the presence of HRP, SNAP-25 labeling appeared, additionally, on HRP-filled early endosomes. After a longer (20–30 minutes) HRP incubation, most of the later stage endosomes and lysosomes were loaded with HRP but they were negative for SNAP-25. These results suggest that SNAP-25 is sorted out of these late endosomal compartments, and that the bulk of the SNAP-25 protein is probably recycled back to the axolemma from the early endosomes. In contrast, in those samples which were incubated with HRP for longer periods, there were still some SNAP-25–positive vesicular structures which were HRP-negative. These structures most likely represent anterograde vesicles that carry newly synthesized SNAP-25 from the soma to the axolemma by axonal transport. SNAP-25 appears to be sorted at the Golgi complex to reach the axolemma specifically. Its widespread distribution all along the axolemma does not support the view of SNAP-25 as a t-SNARE limited for synaptic exocytosis.     

The protective effect of cycloastragenol on aging mouse circadian rhythmic disorder induced by d-galactose

Aging process in mammals is associated with a decline in amplitude and a long period of circadian behaviors which are regulated by a central circadian regulator in the suprachiasmatic nucleus (SCN) and local oscillators in peripheral tissues. It is unclear whether enhancing clock function can retard aging. Using fibroblasts expressing per2::lucSV and senescent cells, we revealed cycloastragenol (CAG), a natural aglycone derivative from astragaloside IV, as a clock amplitude enhancing small molecule. CAG could activate telomerase to antiaging, but no reports focused on its effects on circadian rhythm disorders in aging mice. Here we analyze the potential effects of CAG on d -galactose-induced aging mice on the circadian behavior and expression of clock genes. For this purpose, CAG (20 mg/kg orally), was administered daily to d -galactose (150 mg/kg, subcutaneous) mice model of aging for 6 weeks. An actogram analysis of free-running activity of these mice showed that CAG significantly enhances the locomotor activity. We further found that CAG increase expressions of per2 and bmal1 genes in liver and kidney of aging mouse. Furthermore, CAG enhanced clock protein BMAL1 and PER2 levels in aging mouse liver and SCN. Our results indicated that the CAG could restore the behavior of circadian rhythm in aging mice induced by d -galactose. These data of present study suggested that CAG could be used as a novel therapeutic strategy for the treatment of age-related circadian rhythm disruption.     

Cross-Sectional Associations between Body Size,Circulating Sex-Steroid Hormones and IGF Components among Healthy Chinese Women

The incidence of breast cancer has increased in Asian countries and rates of hormone receptor (HR) negative breast cancer exceed those of Western countries. Epidemiologic data suggest that the association between body size and BC risk may vary by HR status, and could differ geographically. While body size may influence BC risk by moderating the synthesis and metabolism of circulating sex-steroid hormones, insulin-like growth factor (IGF)-1 and related binding proteins, there is a dearth of literature among Asian women. We aimed to examine these specific associations in a sample of Chinese women. In Sichuan Province 143 women aged ≥40 years were recruited through outpatient services (2011–2012). Questionnaires, anthropometric measurements, and blood samples were utilized for data collection and linear regression was applied in data analyses. Among women <50 years we observed a non-monotonic positive association between body mass index (BMI) and 17β-estradiol, and a reversed J-shaped association between BMI and IGF-1 (p ≤0.05). We observed similar associations between waist-to-hip ratio and these markers. Our finding of augmented IGF-1 among women with low body mass may have implications for understanding breast tumor heterogeneity in diverse populations and should be evaluated in larger prospective studies with cancer outcomes.     

具有阶段结构和免疫反应的病毒动力学模型的全局稳定性

研究了一类被感染细胞具有潜伏和活性两阶段以及免疫反应的病毒动力学模型.通过建立适当的Lyapunov泛函和使用LaSalle不变集原理,获得当σ≤1,ω≤1σ和σω1时,对应的未感染平衡点P,体液免疫未激活的无免疫感染平衡点M,体液免疫已激活的感染平衡点N是全局渐近稳定的充分条件.所获得结果推广了Nowak(1996)和Bangham(1997)的工作,得到了一些新结果.     

Genetic Variants Associated with Lipid Profiles in Chinese Patients with Type 2 Diabetes

Dyslipidemia is a strong risk factor for cardiovascular disease among patients with type 2 diabetes (T2D). The aim of this study was to identify lipid-related genetic variants in T2D patients of Han Chinese ancestry. Among 4,908 Chinese T2D patients who were not taking lipid-lowering medications, single nucleotide polymorphisms (SNPs) in seven genes previously found to be associated with lipid traits in genome-wide association studies conducted in populations of European ancestry (ABCA1, GCKR, BAZ1B, TOMM40, DOCK7, HNF1A, and HNF4A) were genotyped. After adjusting for multiple covariates, SNPs in ABCA1, GCKR, BAZ1B, TOMM40, and HNF1A were identified as significantly associated with triglyceride levels in T2D patients (P < 0.05). The associations between the SNPs in ABCA1 (rs3890182), GCKR (rs780094), and BAZ1B (rs2240466) remained significant even after correction for multiple testing (P = 8.85×10⁻³, 7.88×10⁻⁷, and 2.03×10⁻⁶, respectively). BAZ1B (rs2240466) also was associated with the total cholesterol level (P = 4.75×10⁻²). In addition, SNP rs157580 in TOMM40 was associated with the low-density lipoprotein cholesterol level (P = 6.94×10⁻³). Our findings confirm that lipid-related genetic loci are associated with lipid profiles in Chinese patients with type 2 diabetes.