Stochastic Robustness: Towards a Comprehensive Robustness Tool

Stochastic robustness is a simple technique to determine the robustness of linear, time-invariant systems by Monte Carlo methods. Stochastic stability robustness has been described previously. Those results are extended here to provide insight into control system design for performance. Together, stochastic stability and performance robustness concepts constitute a comprehensive tool that can be used to analyze control system robustness properties. As well, they offer control system design insight that can set the stage for stochastic robustness synthesis. The concept of stochastic stability robustness is reviewed, stochastic performance robustness is introduced, and stochastic robustness synthesis is described qualitatively. Confidence intervals necessary for comparing control laws statistically are presented

Stochastic Satbility and Performance Robustness of Linear Multivariable Systems

Stochastic robustness, a simple technique used to estimate the robustness of linear, time invariant systems, is applied to a single-link robot arm control system. Concepts behind stochastic stability robustness are extended to systems with estimators and to stochastic performance robustness. Stochastic performance robustness measures based on classical design specifications are introduced, and the relationship between stochastic robustness measures and control system design parameters are discussed. The application of stochastic performance robustness, and the relationship between performance objectives and design parameters are demonstrated by means of example. The results prove stochastic robustness to be a good overall robustness analysis method that can relate robustness characteristics to control system design parameters

Intravital Multiphoton Microscopy with Fluorescent Bile Salts in Rats as an In Vivo Biomarker for Hepatobiliary Transport Inhibition

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury that often goes undetected during nonclinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models. Here, we describe studies in which methods of quantitative intravital microscopy were used to identify dose-dependent effects of two known BSEP/Bsep inhibitors, 2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid (AMG-009) and bosentan, on hepatocellular transport of the fluorescent bile salts cholylglycyl amidofluorescein and cholyl-lysyl-fluorescein in rats. Results of these studies demonstrate that the intravital microscopy approach is capable of detecting Bsep inhibition at drug doses well below those found to increase serum bile acid levels, and also indicate that basolateral efflux transporters play a significant role in preventing cytosolic accumulation of bile acids under conditions of Bsep inhibition in rats. Studies of this kind can both improve our understanding of exposures needed to inhibit Bsep in vivo and provide unique insights into drug effects in ways that can improve our ability interpret animal studies for the prediction of human drug hepatotoxicity

Special Case of Partial Fraction Expansion with Laplace Transform Application

Partial fraction expansion is often used with the Laplace Transforms to formulate algebraic expressions for which the inverse Laplace Transform can be easily found. This paper demonstrates a special case for which a linear, constant coefficient, second order ordinary differential equation with no damping term and a harmonic function non-homogeneous term leads to a simplified partial fraction expansion due to the decoupling of the partial fraction expansion coefficients of s and the constant coefficients. Recognizing this special form can allow for quicker calculations and automation of the solution to the differential equation form which is commonly used to model physical systems

A Generalized Solution Method to Undamped Constant-Coefficient Second-Order ODEs Using Laplace Transforms and Fourier Series

A generalized method for solving an undamped second order, linear ordinary differential equation with constant coefficients is presented where the non-homogeneous term of the differential equation is represented by Fourier series and a solution is found through Laplace transforms. This method makes use of a particular partial fraction expansion form for finding the inverse Laplace transform. If a non-homogeneous function meets certain criteria for a Fourier series representation, then this technique can be used as a more automated means to solve the differential equation as transforms for specific functions need not be determined. The combined use of the Fourier series and Laplace transforms also reinforces the understanding of function representation through a Fourier series and its potential limitations, the mechanics of finding the Laplace transform of a differential equation and inverse transforms, the operation of an undamped system, and through programming insight into the practical application of both tools including information on the influence of the number of terms in the series solution

Predictors of Postconcussion Symptomatology in a Mild Head Injury College Population.

Mild head injury is the most common form of head injury and the majority of individuals who sustain such injuries are young adults. Following mild head injury, individuals often complain of a number of physical, cognitive, and behavioral symptoms referred to as postconcussion symptoms (PCS). The most commonly reported postconcussion symptoms are headache, dizziness, decreased concentration, memory problems, irritability, fatigue, visual disturbances, sensitivity to noise, judgement problems, and anxiety. These symptoms can persist from months to years following injury and may even be permanent and cause disability (Brown, Fann, & Grant, 1994; Gouvier, Cubic, Jones, Brantley, and Cutlip, 1992). Both organic and psychological etiologies have been suggested for persistent PCS and most investigators now believe that a combination of multiple organic and psychological factors contribute to the development and continuation of these symptoms (Bohnen & Jolles, 1992). A number of neurocognitive, psychosocial, premorbid, and injury-related variables have been implicated in the development of persistent PCS including reduced information processing, increased psychological distress, external locus of control, female gender, positive premorbid history of psychological disturbance, and previous history of head injury. However, the findings among the various research studies have been conflicting. Determining the variables that influence the development of persisting PCS is important for identifying those at risk for chronic PCS following mild head injury and subsequently for tailoring preventative and palliative intervention strategies to manage PCS. Given this information, the present study attempted to identify premorbid/injury-related, neurocognitive, and psychosocial factors associated with persistent postconcussion symptomatology among mildly head-injured college students. The findings demonstrated that current psychological distress and female gender were the best predictors of PCS; high rates of PCS were associated with the presence of either of these factors. Decreased information processing and external locus of control were also related to PCS, but the relationships were weak. Prior head injury and premorbid history of psychological problems were not related to PCS. The results suggest that emotional status and gender are more important in predicting persistent PCS than neurocognitive status, psychological history, or history of previous mild head injury

Polyadenylation regulates the stability of Trypanosoma brucei mitochondrial RNAs

Polyadenylation of RNAs plays a critical role in modulating rates of RNA turnover and ultimately in controlling gene expression in all systems examined to date. In mitochondria, the precise mechanisms by which RNAs are degraded, including the role of polyadenylation, are not well understood. Our previous in organello pulse-chase experiments suggest that poly(A) tails stimulate degradation of mRNAs in the mitochondria of the protozoan parasite Trypanosoma brucei (Militello, K. T., and Read, L. K. (2000) Mol. Cell. Biol. 21, 731-742). In this report, we developed an in vitro assay to directly examine the effects of specific 3′-sequences on RNA degradation. We found that a salt-extracted mitochondrial membrane fraction preferentially degraded polyadenylated mitochondrially and non-mitochondrially encoded RNAs over their non-adenylated counterparts. A poly(A) tail as short as 5 nucleotides was sufficient to stimulate rapid degradation, although an in vivo tail length of 20 adenosines supported the most rapid decay. A poly(U) extension did not promote rapid RNA degradation, and RNA turnover was slowed by the addition of uridine residues to the poly(A) tail. To stimulate degradation, the poly(A) element must be located at the 3′ terminus of the RNA. Finally, we demonstrate that degradation of polyadenylated RNAs occurs in the 3′ to 5′ direction through the action of a hydrolytic exonuclease. These experiments demonstrate that the poly(A) tail can act as a cis-acting element to facilitate degradation of T. brucei mitochondrial mRNAs