Activation of miR-9 by human papillomavirus in cervical cancer

Cervical cancer is the third most common cancer in women worldwide, leading to about 300,000 deaths each year. Most cervical cancers are caused by human papillomavirus (HPV) infection. However, persistent transcriptional activity of HPV oncogenes, which indicates active roles of HPV in cervical cancer maintenance and progression, has not been well characterized. Using our recently developed assays for comprehensive profiling of HPV E6/E7 transcripts, we have detected transcriptional activities of 10 high-risk HPV strains from 87 of the 101 cervical tumors included in the analysis. These HPV-positive patients had significantly better survival outcome compared with HPV-negative patients, indicating HPV transcriptional activity as a favorable prognostic marker for cervical cancer. Furthermore, we have determined microRNA (miRNA) expression changes that were correlated with tumor HPV status. Our profiling and functional analyses identified miR-9 as the most activated miRNA by HPV E6 in a p53-independent manner. Further target validation and functional studies showed that HPV-induced miR-9 activation led to significantly increased cell motility by downregulating multiple gene targets involved in cell migration. Thus, our work helps to understand the molecular mechanisms as well as identify potential therapeutic targets for cervical cancer and other HPV-induced cancers

Towards Structural Systems Pharmacology to Study Complex Diseases and Personalized Medicine

Genome-Wide Association Studies (GWAS), whole genome sequencing, and high-throughput omics techniques have generated vast amounts of genotypic and molecular phenotypic data. However, these data have not yet been fully explored to improve the effectiveness and efficiency of drug discovery, which continues along a one-drug-one-target-one-disease paradigm. As a partial consequence, both the cost to launch a new drug and the attrition rate are increasing. Systems pharmacology and pharmacogenomics are emerging to exploit the available data and potentially reverse this trend, but, as we argue here, more is needed. To understand the impact of genetic, epigenetic, and environmental factors on drug action, we must study the structural energetics and dynamics of molecular interactions in the context of the whole human genome and interactome. Such an approach requires an integrative modeling framework for drug action that leverages advances in data-driven statistical modeling and mechanism-based multiscale modeling and transforms heterogeneous data from GWAS, high-throughput sequencing, structural genomics, functional genomics, and chemical genomics into unified knowledge. This is not a small task, but, as reviewed here, progress is being made towards the final goal of personalized medicines for the treatment of complex diseases

In Vivo Analysis of MEF2 Transcription Factors in Synapse Regulation and Neuronal Survival

MEF2 (A–D) transcription factors govern development, differentiation and maintenance of various cell types including neurons. The role of MEF2 isoforms in the brain has been studied using in vitro manipulations with only MEF2C examined in vivo. In order to understand specific as well as redundant roles of the MEF2 isoforms, we generated brain-specific deletion of MEF2A and found that Mef2aKO mice show normal behavior in a range of paradigms including learning and memory. We next generated Mef2a and Mef2d brain-specific double KO (Mef2a/dDKO) mice and observed deficits in motor coordination and enhanced hippocampal short-term synaptic plasticity, however there were no alterations in learning and memory, Schaffer collateral pathway long-term potentiation, or the number of dendritic spines. Since previous work has established a critical role for MEF2C in hippocampal plasticity, we generated a Mef2a, Mef2c and Mef2d brain-specific triple KO (Mef2a/c/dTKO). Mef2a/c/d TKO mice have early postnatal lethality with increased neuronal apoptosis, indicative of a redundant role for the MEF2 factors in neuronal survival. We examined synaptic plasticity in the intact neurons in the Mef2a/c/d TKO mice and found significant impairments in short-term synaptic plasticity suggesting that MEF2C is the major isoform involved in hippocampal synaptic function. Collectively, these data highlight the key in vivo role of MEF2C isoform in the brain and suggest that MEF2A and MEF2D have only subtle roles in regulating hippocampal synaptic function

Integrin β3 Crosstalk with VEGFR Accommodating Tyrosine Phosphorylation as a Regulatory Switch

Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between β3 integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of β3 and VEGFR2. Specifically, the membrane-proximal motif around 801YLSI in VEGFR2 mediates its binding to non-phosphorylated β3CT, accommodating an α-helical turn in integrin bound conformation. We also show that Y747 phosphorylation of β3 enhances the above interaction. To demonstrate the importance of β3 phosphorylation in endothelial cell functions, we synthesized β3CT-mimicking Y747 phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y747 but not F747 significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y747 peptide exhibits inhibitory effect only in WT but not in β3 integrin knock-out or β3 integrin knock-in cells expressing β3 with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2

Research on Anomie Behavior of Drivers on Non-physical Isolated Urban Road Based on Game Theory

In order to overtake motor vehicles ahead, some motor vehicles tend to enter non-motorized lane illegally on non-physical isolated urban road, which cause a negative influence on non-motor vehicles. In this paper, this anomie behavior is studied by headway distribution function, fluid dynamics model and game theory. Utilize headway distribution function to calculate the probability of critical gap required for motor vehicles entering non- motorized lanes, and fluid mechanics model to analysis delay. After that, considering critical gap, delay, management expense and fine for anomie behavior, the time value functions of drivers and cyclists are established and regarded as the payment functions in mixed strategy Nash equilibrium. Finally, according to the result of Nash equilibrium, two optimal probability models are put forward. Under different circumstances of non-motor vehicle flow, motor vehicle speed, management expense and fine for anomie behavior, the first model quantified the optimal probability that drivers commit anomie behavior and the second model quantified the optimal probability that traffic department implements management. Furthermore, models can provide references for the management of anomie behavior on non-physical isolated urban road

Research on Anomie Behavior of Drivers on Non-physical Isolated Urban Road Based on Game Theory

In order to overtake motor vehicles ahead, some motor vehicles tend to enter non-motorized lane illegally on non-physical isolated urban road, which cause a negative influence on non-motor vehicles. In this paper, this anomie behavior is studied by headway distribution function, fluid dynamics model and game theory. Utilize headway distribution function to calculate the probability of critical gap required for motor vehicles entering non- motorized lanes, and fluid mechanics model to analysis delay. After that, considering critical gap, delay, management expense and fine for anomie behavior, the time value functions of drivers and cyclists are established and regarded as the payment functions in mixed strategy Nash equilibrium. Finally, according to the result of Nash equilibrium, two optimal probability models are put forward. Under different circumstances of non-motor vehicle flow, motor vehicle speed, management expense and fine for anomie behavior, the first model quantified the optimal probability that drivers commit anomie behavior and the second model quantified the optimal probability that traffic department implements management. Furthermore, models can provide references for the management of anomie behavior on non-physical isolated urban road

Dynamic Intermediate Profiles of Zeolite Catalyzed Methanol to Olefins Revealed by Reactive Molecular Dynamics

Taking the unique advantage of large-scale ReaxFF MD simulation in unravelling varied reaction pathways within one simulation, the process of methanol-to-olefin (MTO) was investigated by the combination of high-performance computing and cheminformatics-based reaction analysis. The initial stage model and the indirect pathway model for MTO were constructed to get a more complete scenario of the whole catalyzed process. The obtained dynamic profiles of dominant products, intermediates, and detailed reactions indicate that the MTO processes catalyzed over ZSM-5 with different acidic properties exhibit similar proceeding stages but with significant different pathways. The MTO process catalyzed by hydrated ZSM-5 with Al enhances the methane-formaldehyde route, H and CH3 transfer reactions, and oxidation reactions of surface methoxy species during the direct pathway, leading to CO2 production and CH2O consumption, which is barely taking place at the model catalyzed by zeolite without Al. Semiquantitative reaction networks with conversion ratios for C2H4 and C3H6 generation revealed that the MTO process is a product of multiple pathways with dozens of intermediates. The rich information, especially the comprehensive reaction network obtained from ReaxFF MD simulations would complement the experimental results and those of other theoretical research and be helpful for further development of highly efficient MTO processes