Structural Mechanism of CCM3 Heterodimerization with GCKIII Kinases

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Highlights? Crystal structure of CCM3-MST4 heterodimeric complex ? Structural mechanism driving CCM3-GCKIII heterodimerization ? Conformational changes required for CCM3-GCKIII heterodimerization ? Synergistic effects of CCM3-MST4 complex on cell proliferation and migration     

中药金樱子的研究应用概况

本文就国内外对中药金樱子的化学成分及其提取分离方法、药理学研究和临麻应用作了综述,为金樱子的综合开发提供依据。     

Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment

This study, using mouse embryonic fibroblast (MEF) cells derived from ROCK1^−/− and ROCK2^−/− mice, is designed to dissect roles for ROCK1 and ROCK2 in regulating actin cytoskeleton reorganization induced by doxorubicin, a chemotherapeutic drug. ROCK1^−/− MEFs exhibited improved actin cytoskeleton stability characterized by attenuated periphery actomyosin ring formation and preserved central stress fibers, associated with decreased myosin light chain 2 (MLC2) phosphorylation but preserved cofilin phosphorylation. These effects resulted in a significant reduction in cell shrinkage, detachment, and predetachment apoptosis. In contrast, ROCK2^−/− MEFs showed increased periphery membrane folding and impaired cell adhesion, associated with reduced phosphorylation of both MLC2 and cofilin. Treatment with inhibitor of myosin (blebbistatin), inhibitor of actin polymerization (cytochalasin D), and ROCK pan-inhibitor (Y27632) confirmed the contributions of actomyosin contraction and stress fiber instability to stress-induced actin cytoskeleton reorganization. These results support a novel concept that ROCK1 is involved in destabilizing actin cytoskeleton through regulating MLC2 phosphorylation and peripheral actomyosin contraction, whereas ROCK2 is required for stabilizing actin cytoskeleton through regulating cofilin phosphorylation. Consequently, ROCK1 and ROCK2 can be functional different in regulating stress-induced stress fiber disassembly and cell detachment.     

Temporal Discounting Is Associated with an Increased Risk of Mortality among Community-Based Older Persons without Dementia

Background

Temporal discounting is an important determinant of many health and financial outcomes, but we are not aware of studies that have examined the association of temporal discounting with mortality.

Methods

Participants were 406 older persons without dementia from the Rush Memory and Aging Project, a longitudinal cohort study of aging. Temporal discounting was measured using standard preference elicitation questions. Individual discount rates were estimated using a well-established hyperbolic function and used to predict the risk of mortality during up to 5 years of follow-up.

Results

The mean estimate of discounting was 0.45 (SD = 0.33, range: 0.08–0.90), with higher scores indicating a greater propensity to prefer smaller immediate rewards over larger but delayed ones. During up to 5 years of follow-up (mean = 3.6 years), 62 (15% of 406) persons died. In a proportional hazards model adjusted for age, sex, and education, temporal discounting was associated with an increased risk of mortality (HR = 1.103, 95% CI 1.024, 1.190, p = 0.010). Thus, a person with the highest discount rate (score = 0.90) was about twice more likely to die over the study period compared to a person with the lowest discount rate (score = 0.08). Further, the association of discounting with mortality persisted after adjustment for the level of global cognitive function, the burden of vascular risk factors and diseases, and an indicator of psychological well being (i.e., purpose in life).

Conclusion

Temporal discounting is associated with an increased risk of mortality in old age after accounting for global cognitive function and indicators of physical and mental health.     

巨噬细胞吞噬过程中膜磷脂流动性和受体流动性的关系

本文用ＦＲＡＰ（ｆｌｕｏｒｅｓｃｅｎｃｅｒｅｃｏｖｅｒｙａｆｔｅｒｐｈｏｔｏｂｌｅａｃｈｉｎｇ）技术,测量了静息状态和刀豆素Ａ刺激不同时间后巨噬细胞膜磷脂、ＣｏｎＡ受体扩散系数和荧光恢复率的变化。结果显示ＣｏｎＡ刺激后膜磷脂和ＣｏｎＡ受体的扩散系数和荧光恢复率均较静息状态的巨噬细胞明显降低,磷脂流动性的变化与ＣｏｎＡ受体流动性的变化呈正相关。提示受体介导内吞导致的膜磷脂流动性的降低,可能是由于配体与细胞膜上受体结合形成配体－受体复合体,增加了受体的负荷,使受体的流动性降低,进而使膜磷脂的流动性降低。巨噬细胞内吞过程中膜磷脂和ＣｏｎＡ受体流动性的降低,可能还与ＣｏｎＡ刺激后巨噬细胞胞浆ｐＨ值有关。     

热激处理对冷藏蚕豆种子褐变和有关酶活性的影响

研究了45℃30、60和120s短期热激处理对蚕豆种子在1℃贮藏期间褐变和有关酶活性的影响。结果表明,采用45℃ 60s热激处理可显著降低蚕豆在冷藏期间的呼吸强度、PPO和PAL活性,抑制MDA和总酚含量及褐变度的上升,延缓叶绿素和Vc含量的下降。从而起到延缓衰老和保持品质的作用。45℃热处理120s使2周后MDA含量和褐变度上升及Vc含量下降较快,这可能是由于组织受到了热伤害造成的。     

Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5-/-mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway.     

Cloning,expression, and characterization of a human 4'-phosphopantetheinyl transferase with broad substrate specificity

A single candidate 4'-phosphopantetheine transferase, identified by BLAST searches of the human genome sequence data base, has been cloned, expressed, and characterized. The human enzyme, which is expressed mainly in the cytosolic compartment in a wide range of tissues, is a 329-residue, monomeric protein. The enzyme is capable of transferring the 4'-phosphopantetheine moiety of coenzyme A to a conserved serine residue in both the acyl carrier protein domain of the human cytosolic multifunctional fatty acid synthase and the acyl carrier protein associated independently with human mitochondria. The human 4'-phosphopantetheine transferase is also capable of phosphopantetheinylation of peptidyl carrier and acyl carrier proteins from prokaryotes. The same human protein also has recently been implicated in phosphopantetheinylation of the alpha-aminoadipate semialdehyde dehydrogenase involved in lysine catabolism (Praphanphoj, V., Sacksteder, K. A., Gould, S. J., Thomas, G. H., and Geraghty, M. T. (2001) Mol. Genet. Metab. 72, 336-342). Thus, in contrast to yeast, which utilizes separate 4'-phosphopantetheine transferases to service each of three different carrier protein substrates, humans appear to utilize a single, broad specificity enzyme for all posttranslational 4'-phosphopantetheinylation reactions.     

广州市风水林群落空间异质性及其对区域物种多样性的贡献

以广州地区村边风水林为研究对象,选取了67个风水林斑块,并在每个斑块内建立了一个20m×20m的样方,调查了其胸径大于1cm的植物组成。首先以种面积关系外推法和非参数法估计了风水林群落对区域生物多样性的贡献;然后以加法准则拆分了gamma多样性,以分析风水林群落物种组成的异质性;最后根据每个风水林群落的物种丰富度、稀有种(在所有群落中只出现一次的物种)数目和谱系多样性分析了在保护中需要优先考虑的区域。结果发现：（1）广州地区风水林群落至少保存了32.74%的区域物种多样性;（2）gamma多样性(184)中绝大部分由beta多样性(163.43)构建,只有很小部分来自于alpha多样性(20.57)。这表明风水林群落在物种组成上具有较高的空间异质性,要想尽可能多地保护风水林内物种多样性,就需要尽可能多地保护风水林群落斑块;（3）相对于平原地区,位于山区的风水林群落具有更高的物种丰富度和谱系多样性以及更多的稀有种数目。在保护资金和土地资源有限的情况下,位于山区的风水林群落应该给予优先考虑。