Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions

Nanoscale electrostatic actuators in liquid electrolytes: analysis and experiment

The objective of this dissertation is to analytically model a parallel plate electrostatic actuator operating in a liquid electrolyte and experimentally verify the analysis. The model assumes the system remains in thermodynamic equilibrium during actuation, which enables the ion mass balance equations and Guass Law to be combined into the Poisson-Boltzmann equation. The governing equations also include the linear momentum equation including the following forces: the electric force, the osmotic force, the spring force, the viscous damping force, and the van der Waals force. Equations are also derived for the energy stored in the actuator. The analytical results emphasize the stored energy at mechanical equilibrium and the voltage versus electrode separation behavior including the instability. The analytical results predict that the system may not be a good actuator because the displacement has a very limited stable range, although the actuator would be suitable for bistable applications. The experiment consisted of a fixed flat gold electrode and a movable gold electrode consisting of a gold sphere several micrometers in diameter mounted on the end of an Atomic Force Microscope (AFM) cantilever, which serves as the spring. The electrodes were separated by approximately 100nm of 1mM NaCl aqueous solution. The analytical results were not verified by the experiment. Relative to the analysis, the experiments did not show distinct critical points, and the experiments showed less electrode separation for a given applied electric potential. The experiments did show points at which the electrode separation versus electric potential rapidly changed slope, which may be instability points. It is suggested that this phenomenon may be due to coalesced gas bubbles on hydrophobic regions of the electrode surfaces, which are not included in the model. Although clean gold surfaces are hydrophilic, gold surfaces may become hydrophobic due to impurities

DOSAGE MATTERS: WHAT IS DOSAGE

To reduce recidivism, many correctional programs and interventions have been introduced to offenders. Though, the rate of recidivism remains exceedingly high. To improve program outcomes, it is important to match the dosage of a program to risk levels. However, there is not a standardized definition and measurement of program dosage. This thesis extends the study on identifying the definition and measurement of dosage and the effectiveness of the programs by conducting a systematic review of prior research. The results indicate that as a treatment dosage, treatment duration was more frequently used compared to treatment intensity to reduce recidivism rate of the incarcerated participants