Islet-1 (ISL1) belongs to the LIM homeodomain transcription factor family, which is specifically expressed in certain tissue types only. Previously, we reported that ISL1 is aberrantly overexpressed in gastric cancer (GC). However, its role in GC is not clear. Here, we report that ISL1 is aberrantly upregulated not only in human gastric carcinoma tissues but also in some GC cell lines. Upregulated ISL1 expression enhanced xenografted gastric carcinoma development, while ISL1 knockdown inhibited GC growth in nude mice. ISL1 overexpression promoted GC cell proliferation, colony formation, and cell growth in soft agar, and facilitated cell cycle transition in GC cells, demonstrated an increase in the proportion of cells in the G2/M and S phases and a decrease in the proportion of cells in the G1 phase. Furthermore, we provide evidence that ISL1 is a novel regulator of the cyclin B1 (CCNB1), cyclin B2 (CCNB2) and c-myc (c-MYC) genes. ISL1 activated the expression of these genes in GC cells by binding to the conserved binding sites on their promoters or enhancers. The expression levels of the genes were decreased in response to ISL1 knockdown. Therefore, ISL1 may serve as a potential therapeutic target in GC.

The mechanism of insulin gene transcription control in response to glucose concentration is poorly defined. The islet-restricted transcription factors PDX1 and ISL1 interact with BETA2, activating insulin gene expression. However, their contribution and hierarchical organization in insulin expression control based on glucose concentration remain unknown. We investigated PDX1 and ISL1 regulation of insulin gene expression in pancreatic β cells cultured in normal (5 mM/L) and high (25 mM/L) glucose conditions. ISL1 interacted with BETA2 to maintain basic insulin gene transcriptional activity under normal glucose. The ISL1-recruited cofactors SET9 and JMJD3 facilitated insulin gene histone modifications under normal glucose. In high-glucose concentrations, PDX1 formed a complex with BETA2 to enhance insulin gene expression. PDX1 also recruited SET9 and JMJD3 to promote the activation of histone modulation on the insulin promoter. This is the first evidence transcription factors orchestrate epigenetic modifications to control insulin gene expression based on glucose concentration.

Signaling pathways play an important role in cardiogenesis. Secreted frizzled-related protein 4 (SFRP4), a member of the Wnt family, contributes to adipogenesis and tumorigenesis. However, how SFRP4 participates in cardiogenesis and the detailed molecular mechanisms involved have not been elucidated. The aim of this work was to determine cross-talk between SFRP4, integrin α1β1, and Notch1 during cardiac differentiation of P19CL6 cells. Using a well-established in vitro P19CL6 cell cardiomyocyte differentiation system, we found that SFRP4 inhibited P19CL6 cell cardiac differentiation via SFRP4 overexpression or knockdown. In addition, the SFRP4 overexpression augmented Notch1 and HES1 production. Further investigation demonstrated that SFRP4 bound to integrin α1β1 to activate the focal adhesion kinase (FAK) pathway and that phosphorylated FAK Y397 (p-FAK Y397) aided Notch intracellular domain 1 (NICD1) nuclear translocation to form a p-FAK Y397-NICD1 complex that activated the Hes1 promoter. Taken together, the cross-talk between SFRP4, integrin α1β1, and Notch1 suppresses the cardiac differentiation of P19CL6 cells.

Sepsis-induced cardiac apoptosis is one of the major pathogenic factors in myocardial dysfunction. As it enhances numerous proinflammatory factors, lipopolysaccharide (LPS) is considered the principal mediator in this pathological process. However, the detailed mechanisms involved are unclear. In this study, we attempted to explore the mechanisms involved in LPS-induced cardiomyocyte apoptosis. We found that LPS stimulation inhibited microRNA (miR)-499 expression and thereby upregulated the expression of SOX6 and PDCD4 in neonatal rat cardiomyocytes. We demonstrate that SOX6 and PDCD4 are target genes of miR-499, and they enhance LPS-induced cardiomyocyte apoptosis by activating the BCL-2 family pathway. The apoptosis process enhanced by overexpression of SOX6 or PDCD4, was rescued by the cardiac-abundant miR-499. Overexpression of miR-499 protected the cardiomyocytes against LPS-induced apoptosis. In brief, our results demonstrate the existence of a miR-499-SOX6/PDCD4-BCL-2 family pathway in cardiomyocytes in response to LPS stimulation.

Islet-1 (ISL-1), a LIM-homeodomain transcription factor, has been recently found to be essential for promoting postnatal pancreatic islet proliferation. However, the detailed mechanism has not yet been elucidated. In the present study, we investigated the mechanism by which ISL-1 promotes β-cell proliferation through regulation of CyclinD1 in HIT-T15 and NIT-1 cells, as well in rat islet mass. Our results provide the evidence that ISL-1 promotes adult pancreatic islet β-cell proliferation by activating CyclinD1 transcription through cooperation with Set7/9 and PDX-1 to form an ISL-1/Set7/9/PDX-1 complex. This complex functions in an ISL-1-dependent manner, with Set7/9 functioning not only as a histone methyltransferase, which increases the histone H3K4 tri-methylation of the CyclinD1 promoter region, but also an adaptor to bridge ISL-1 and PDX-1, while PDX-1 functions as a RNA pol II binding modulator. Furthermore, the formation of the ISL-1/Set7/9/PDX-1 complex is positively associated with insulin-like growth factor-1 treatment in NIT and HIT-T15 cells in vitro, while may be negatively correlated with age in vivo.

Autophagy plays important roles in adipogenesis and neuron development. However, how autophagy contributes to cardiac development is not well understood. The main aim of our study was to determine the association between autophagy and myocardial differentiation and its roles in this process. Using a well-established in vitro cardiomyocyte differentiation system, P19CL6 cells, we found that autophagy occurred from the early stage of cardiac differentiation. Blocking autophagy by knocking-down of autophagy-related gene Atg7 or Atg5 inhibited the cardiac differentiation of P19CL6 cells. Further investigation demonstrated that LC3 and P62 could form a complex with β-catenin and NICD, respectively, and promoted the degradation of β-catenin and NICD. Enhancing autophagy promoted the formation of complex, whereas blocking autophagy attenuated the degradation of β-catenin and NICD. Taken together, autophagy could facilitate P19CL6 cells to complete the cardiac differentiation process through blocking Wnt and Notch signaling pathways.

To address the problem of enforcing access control for library digital resources,federated authentication technologies were analyze which are widely used in the world,and CALIS unified authentication technologies that are widely deployed in China’s libraries were also analyzed.A solution integrating federated authentication and CALIS unified authentication technologies was proposed,which was developed,deployed and tested on the test-bed of CARSI federation.Test results show the proposed solution enforces effective and flexible access control for library resources.

Because of the inherent node (link) failures in wireless networks, virtual backbones should be fault-tolerant. Fault-tolerant virtual backbones were modeled as 2-connected k-dominating sets. An approximation algorithm was designed to find a 2-connected k-dominating virtual backbone in wireless ad-hoc networks by analyzing the properties of maximal independent sets in unit disk graphs and the block-cutvertex tree structure of connected graphs. The time complexity and the performance ratio of the algorithm were analyzed and proved to be a constant, respectively.

We used human angiopoietin-1 (hAng1)-modified mesenchymal stem cells (MSCs) to treat acute myocardial infarction (AMI) in rats. The hAng1 gene was transfected into cultured rat MSCs using an adenoviral vector. Five million hAng-transfected MSCS (MSCAng1) or green fluorescent protein transfected MSCs (MSCGFP) or PBS only (PBS group) were injected intramyocardially into the inbred Lewis rat hearts immediately after myocardial infarction. MSCAng1 survived in the infarcted myocardium, and expressed hAng1 at both mRNA and protein levels. The vascular density was higher in the MSCAng1 and MSCGFP groups than in the PBS group. The measurements of infarcted ventricular wall thickness, infarction area, and left ventricular diameter indicated that heart remodeling was inhibited and heart function was improved in both the MSCAng1 and MSCGFP groups. However, in contrast to the MSCGFP group, the MSCAng1 group showed enhanced angiogenesis and arteriogenesis (by 11-35%), infarction area was reduced by 30% and the left ventricular wall was 46% thicker (P < 0.05).The results indicated that hAngl-modified MSCs improved heart function, followed by angiogenic effects in salvaging ischernic myocardium and reduced cardiac remodeling. (c) 2007 Elsevier Inc. All rights reserved.

AIM:The role of Pancreatic and Duodenal Homeobox-1 (PDX-1) as a major regulator of pancreatic development determines the function and phenotype of beta cell. In this study, potential plasticity of liver cells into pancreatic endocrine cells induced by PDX-1 was evaluated.METHODS:Human hepatoma cell line HepG2 was stably transfected with mammalian expression plasmid pcDNA3-PDX encoding human PDX-1 gene. Ectopic expression of PDX-1 and insulin were detected by RT-PCR, Western blot and/or immunostaining. PDX-1(+) HepG2 cells were transplanted under renal capsule of STZ-induced diabetic nude mice (n = 16) to examine the inducing effect in vivo.RESULTS:Exogenous PDX-1 transgene was proved to express effectively in HepG2 cell at both mRNA and protein levels. The expression of endogenous insulin and some beta cell-specific differentiation markers and transcription factors were not induced in PDX-1(+) HepG2 cells. When transplanted under renal capsule of STZ-induced diabetic nude mice, PDX-1(+) HepG2 cells did not generate insulin-producing cells. These data indicated that stable transfected PDX-1 could not convert hepatoma cell line HepG2 to pancreatic cells in vitro or in vivo. Mature hepatocytes might need much more complicated or rigorous conditions to be shifted to insulin-producing cells.CONCLUSION:The expression of exogenous PDX-1 is not sufficient to induce relatively mature hepatocytes differentiating into insulin-producing cells.

Complex computational tasks are combinations of multiple independent computational subtasks related by data dependency. Grid environments bring out new challenges to their running, one of which is the normality and performance. To guarantee the running quality and survive failures, availability management and multiple quality promotion ways are adopted in the process of complex task running. It requires no or little change to legacy computational programs. Quantified user's requirements are the goal to performance measuring and availability management. In the process of a task running, the availability management framework monitors, analyzes performance measurements, controls performance degradations, and tolerates failures. Besides this, multiple auxiliary methods help improve the effectiveness of quality control, which includes: to construct computation-matched virtual environments, to raise the correctness of program running, and to decrease management costs. The grid computation running support system implemented under this design is extensible, adaptable, universal, stable and highly available.