Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes

Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy.     

Different roles of the human Orc6 protein in the replication initiation process

In eukaryotes, binding of the six-subunit origin recognition complex (ORC) to DNA provides an interactive platform for the sequential assembly of pre-replicative complexes. This process licenses replication origins competent for the subsequent initiation step. Here, we analyze the contribution of human Orc6, the smallest subunit of ORC, to DNA binding and pre-replicative complex formation. We show that Orc6 not only interacts with Orc1–Orc5 but also with the initiation factor Cdc6. Biochemical and imaging experiments reveal that this interaction is required for licensing DNA replication competent. Furthermore, we demonstrate that Orc6 contributes to the interaction of ORC with the chaperone protein HMGA1a (high mobility group protein A1a). Binding of human ORC to replication origins is not specified at the level of DNA sequence and the functional organization of origins is poorly understood. We have identified HMGA1a as one factor that might direct ORC to AT-rich heterochromatic regions. The systematic analysis of the interaction between ORC and HMGA1a revealed that Orc6 interacts with the acidic C-terminus of HMGA1a and also with its AT-hooks. Both domains support autonomous replication if targeted to DNA templates. As such, Orc6 functions at different stages of the replication initiation process. Orc6 can interact with ORC chaperone proteins such as HMGA1a to facilitate chromatin binding of ORC and is also an essential factor for pre-RC formation.     

Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75)

The non-receptor tyrosine kinase Src is a critical regulator of cytoskeletal contraction, cell adhesion, and migration. In normal cells, Src activity is stringently controlled by Csk-dependent phosphorylation of Src(Y530), and by Cullin-5-dependent ubiquitinylation, which affects active Src(pY419) exclusively, leading to its degradation by the proteosome. Previous work has shown that Src activity is also limited by Cdk5, a proline-directed kinase, which has been shown to phosphorylate Src(S75). Here we show that this phosphorylation promotes the ubiquitin-dependent degradation of Src, thus restricting the availability of active Src. We demonstrate that Src(S75) phosphorylation occurs in vivo in epithelial cells, and like ubiquitinylation, is associated only with active Src. Preventing Cdk5-dependent phosphorylation of Src(S75), by site-specific mutation of S75 or by Cdk5 inhibition or suppression, increases Src(Y419) phosphorylation and kinase activity, resulting in Src-dependent cytoskeletal changes. In transfected cells, ubiquitinylation of Src(S75A) is about 35% that of wild-type Src-V5, and its half-life is approximately 2.5-fold greater. Cdk5 suppression leads to a comparable decrease in the ubiquitinylation of endogenous Src and a similar increase in Src stability. Together, these findings demonstrate that Cdk5-dependent phosphorylation of Src(S75) is a physiologically significant mechanism of regulating intracellular Src activity.     

Beta-carotene affects gene expression in lungs of male and female <Emphasis Type="Italic">Bcmo1</Emphasis><Superscript>−/−</Superscript> mice in opposite directions

Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1 ^−/−) mice, which are—like humans—able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1 ^−/− mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1 ^−/− mice. Testosterone levels were higher after BC supplementation only in Bcmo1 ^−/− mice, which had, unlike wild-type (Bcmo1 ^+/+) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice.     

Immune biology of Ag-specific γδ T cells in infections

Accumulating evidence suggests that human γδ T cells act as non-classical T cells and contribute to both innate and adaptive immune responses in infections. Vγ2 Vδ2 T (also termed Vγ9 Vδ2 T) cells exist only in primates, and in humans represent a dominant circulating γδ T-cell subset. Primate Vγ2 Vδ2 T cells are the only γδ T cell subset capable of recognizing microbial phosphoantigen. Since nonhuman primate Vγ2 Vδ2 T cells resemble their human counterparts, in-depth studies have been undertaken in macaques to understand the biology and function of human Vγ2 Vδ2 T cells. This article reviews the recent progress for immune biology of Vγ2 Vδ2 T cells in infections.     

试论图书馆联盟在信息网格应用中的作用

介绍了信息网格和图书馆联盟的涵义,阐述了网格技术应用过程中的问题,探讨了图书馆联盟在信息网格应用中的作用,指出图书馆联盟作为图书馆际合作组织,在信息网格时代应利用信息网格技术推动图书馆际间资源共享,提高图书馆信息服务质量和能力,促进信息网格的信息连通,使其逐渐成熟。     

Approximate Controllability for Degenerate Heat Equation with Bilinear Control

This paper investigates the nonnegative approximate controllability for the one-dimensional degenerate heat equation governed by bilinear control. Both non-controllability and approximate controllability are studied for the system. If the control is restricted to act on a fixed domain, it is not controllable. If the control is allowed to mobile, it is approximately controllable.     

水栖性的棘胸蛙身体大小不随环境水热梯度及净初级生产力梯度而分化

之前的研究发现不同地理种群棘胸蛙(Quasipaa spinosa)的身体大小随着环境生产力以及年最低温的降低而增大,因为更大的身体利于在生产力水平较低的环境中耐受饥饿并利于在寒冷的环境条件下保存热量.然而在种间水平上进行的相关研究发现:由于大部分时间生活在水体这种相对稳定的环境中,水栖性无尾类的身体大小并不受宏观水热波动的影响.为了更好地探究这个问题,我们以棘胸蛙为研究对象,在之前的基础上选择更多的研究地点及更多的环境因子,研究其身体大小的地理分化格局并探究潜在机制.与之前的发现不同,作为一种水栖性无尾类,棘胸蛙的身体大小并不受环境水热梯度以及净初级生产力梯度的影响.导致这种现象的原因可能是水栖性的生境偏好缓和了棘胸蛙受到的来自宏观环境水热波动的影响,所以它们并不通过改变身体大小来适应宏观环境梯度.此外由于棘胸蛙的肉食性,环境初级生产力并不能有效地衡量其食物供给,其身体大小是否受到食物供给量的影响仍有待深入探究.     

论桥梁抗震模型建立分析的目的

文章论述了桥梁抗震评估的建立模型和分析手段,其目的是用结构位移、构件受力及变形对桥梁地震反应进行定量化分析。     

二次母线接有谐波源时谐波电流危害预测估算的分析

具有谐波源的变电所母线,谐波电流的危害程度.可用文中(1).(8).(9)式和表2简捷地进行分析、判断谐波的谐振次数、母线电压畸变率和谐波电流允许值,借以说明谐波电流危害。并用该三式对谐波调研资料进行了分析与对比计算,结果完全符合实际情况,故三式具有普遍意义和应用价值。