KATP Channel Action in Vascular Tone Regulation During Septic Shock: Beyond Physiology

Septic shock is a major cause of deaths resulting from uncontrolled inflammation and circulatory failure. Recent studies suggest that the vascular isoform of ATP-sensitive K+ (KATP) channels is an important contributor to septic susceptibility. To understand the molecular mechanisms for channel regulation during sepsis, we performed studies in isolated endothelium-denuded mesenteric rings. Lipopolysaccharides (LPS) induced vascular relaxation and hyporeactivity to phenylephrine. The LPS-treated aortic smooth muscle cells displayed hyperpolarization and augmentation of KATP channel activity. Both were due to an up-regulation of Kir6.1 and SUR2B surface expression. The up-regulation relied on transcriptional and translational mechanisms, in which nuclear factor-¦ÊB (NF-¦ÊB) and Protein kinase A (PKA) played a critical role. Oxidative stress occurs during sepsis and may act as another regulatory mechanism affecting KATP channel activity and vascular contractility. We found that micromolar concentrations of H2O2 impaired the pinacidil-induced vasodilation. The effect attributed to the suppression of KATP channel activity, which can be fully produced by reactivity oxidants. Unlike the Kir6.1/SUR2B channel, the Kir6.2/SUR2B channel was insensitive to 1mM H2O2, indicating that the modulation sites are located in Kir6.1. Site-directed mutational analysis showed that three cysteine residues located in N-terminus and the core region of Kir6.1 were likely to mediate the redox-dependent channel modulation. Arginine vasopressin (AVP) is a vasoconstrictor that is successfully applied to manage sepsis. However, the downstream target of AVP is uncertain. Our studies show that AVP-induced vasoconstriction depended on V1a receptor, Protein kinase C (PKC) and KATP channel. Additionally, AVP decreased Kir6.1/SUR2B channel activity through V1a receptor. The inhibitory effect was caused by a suppression of the channel open state probability. The channel inhibition was mediated by phosphorylation of the channel protein by PKC. The widespread involvement of the vascular KATP channel in vascular responses to endotoxemia strongly suggests that the temporospatial control of channel activity may constitute an important intervention to vascular tone, blood pressure and organ-tissue perfusion in septic shock. Such a control appears feasible by targeting several modulatory mechanisms of intracellular signaling, Kir6.1/SUR2B expression, redox state and channel protein phosphorylation as demonstrated in this dissertation

Advantages of a miniature pig model in research on human hereditary hearing loss

AbstractIn medical laboratory animals, the pig is the closest species to human in evolution, except for primates. As an animal model, the pig is highly concerned by many scientists, including comparative biology, developmental biology, medical genetics. Rodents as animal model for human hearing defects has are poor producibility and reliability, due to differences in anatomical structure, evolutionary rate and metabolic rate, but these happens to be the advantages of the pig model. In this paper, we will summarize the application of miniature pig in the study of human hereditary deafness

OpenStack Swift: An Ideal Bit-Level Object Storage System for Digital Preservation

A bit-level object storage system is a foundational building block of long-term digital preservation (LTDP). To achieve the purposes of LTDP, the system must be able to: preserve the authenticity and integrity of the original digital objects; scale up with dramatically increasing demands for preservation storage; mitigate the impact of hardware obsolescence and software ephemerality; replicate digital objects among distributed data centers at different geographical locations; and to constantly audit and automatically recover from compromised states. A realistic and daunting challenge to satisfy these requirements is not only to overcome technological difficulties but also to maintain economic sustainability by implementing and continuously operating such systems in a cost-effective way. In this paper, we present OpenStack Swift, an open-source, mature and widely accepted cloud platform, as a practical and proven solution with a case study at the University of Alberta Library. We emphasize the implementation, application, cost analysis and maintenance of the system, with the purpose of contributing to the community with an exceedingly robust, highly scalable, self-healing and comparatively cost-effective bit-level object storage system for long-term digital preservation.&nbsp

Numerical Study on RC Multilayer Perforation with Application to GA-BP Neural Network Investigation

The finite element model of projectile penetrating multi-layered reinforced concrete target was established via LS-DYNA solver. The penetration model was validated with the test data in terms of residual velocity and deflection angle.  Parametric analyses were carried out through the verified penetration model. Seven influential factors for penetration conditions, including the initial velocity of projectile, initial angle of attack of projectile, initial dip angle of projectile, the first layer thickness of concrete target, the residual layer thickness of concrete target, target distance and the layer number of concrete target, were put emphasis on further analysis. Furthermore, the influence of foregoing factors on residual velocity and deflection angle of projectile were numerically obtained and discussed. Based on genetic algorithm, the BP neural network model was trained by 263 sets of data obtained from the parametric analyses, whereby the prediction models of residual velocity and attitude angle of projectile under different penetration conditions were achieved. The error between the prediction data obtained by this model and the reserved 13 sets of test data is found to be negligible