Computational Analysis of the Regulation of EGFR by Protein Tyrosine Phosphatases

AbstractThe tyrosine phosphorylated epidermal growth factor receptor (EGFR) initiates numerous cell signaling pathways. Although EGFR phosphorylation levels are ultimately determined by the balance of receptor kinase and protein tyrosine phosphatase (PTP) activities, the kinetics of EGFR dephosphorylation are not well understood. Previous models of EGFR signaling have generally neglected PTP activity or computed PTP activity by considering data that do not fully reveal the kinetics and compartmentalization of EGFR dephosphorylation. We developed a compartmentalized, mechanistic model to elucidate the kinetics of EGFR dephosphorylation and the coupling of this process to phosphorylation-dependent EGFR endocytosis. Model regression against data from HeLa cells for EGFR phosphorylation response to EGFR activation, PTP inhibition, and EGFR kinase inhibition led to the conclusion that EGFR dephosphorylation occurs at the plasma membrane and in the cell interior with a timescale that is smaller than that for ligand-mediated EGFR endocytosis. The model further predicted that sufficiently rapid dephosphorylation of EGFR at the plasma membrane could potentially impede EGFR endocytosis, consistent with recent experimental findings. Overall, our results suggest that PTPs regulate multiple receptor-level phenomena via their action at the plasma membrane and cell interior and point to new possibilities for targeting PTPs for modulation of EGFR dynamics

A LASSO-based approach to analyzing rare variants in genetic association studies

Genetic markers with rare variants are spread out in the genome, making it necessary and difficult to consider them in genetic association studies. Consequently, wisely combining rare variants into “composite” markers may facilitate meaningful analyses. In this paper, we propose a novel approach of analyzing rare variant data by incorporating the least absolute shrinkage and selection operator technique. We applied this method to the Genetic Analysis Workshop 17 data, and our results suggest that this new approach is promising. In addition, we took advantage of having 200 phenotype replications and assessed the performance of our approach by means of repeated classification tree analyses. Our method and analyses were performed without knowledge of the underlying simulating model. Our method identified 38 markers (in 65 genes) that are significantly associated with the phenotype Affected and correctly identified two causal genes, SIRT1 and PDGFD

Laxative activities of Mareya micrantha (Benth.) Müll. Arg. (Euphorbiaceae) leaf aqueous extract in rats

<p>Abstract</p> <p>Background</p> <p><it>Mareya micrantha </it>(Benth.) Müll. Arg. (Euphorbiaceae) is a shrub that is commonly used in Côte d'Ivoire (West Africa) for the treatment of constipation and as an ocytocic drug. The present study was carried out to investigate the laxative activity of <it>Mareya micrantha </it>in albino's Wistar rats.</p> <p>Methods</p> <p>Rats were divided in 5 groups of 5 animals each, first group as control, second group served as standard (sodium picosulfate) while group 3, 4 and 5 were treated with leaf aqueous extract of <it>Mareya micrantha </it>at doses of 100, 200 and 400 mg/kg body weight (b.w.), <it>per os </it>respectively. The laxative activity was determined based on the weight of the faeces matter. The effects of the leaves aqueous extract of <it>Mareya micrantha </it>and castor oil were also evaluated on intestinal transit, intestinal fluid accumulation and ions secretion.</p> <p>Results</p> <p>Phytochemicals screening of the extract revealed the presence of flavonoids, alkaloids, tannins, polyphenols, sterols and polyterpenes. The aqueous extract of <it>Mareya micrantha </it>applied orally (100, 200 and 400 mg/kg; <it>p.o</it>.), produced significant laxative activity and reduced loperamide induced constipation in dose dependant manner. The effect of the extract at 200 and 400 mg/kg (<it>p.o</it>.) was similar to that of reference drug sodium picosulfate (5 mg/kg, <it>p.o</it>). The same doses of the extract (200 and 400 mg/kg, <it>p.o</it>.) produced a significant increase (p < 0.01) of intestinal transit in comparison with castor oil (2 mL) (p < 0.01). Moreover, the extract induced a significant enteropooling and excretion of Cl^-, Na⁺, K⁺and Ca²⁺in the intestinal fluid (p < 0.01).</p> <p>Conclusions</p> <p>The results showed that the aqueous extract of <it>Mareya micrantha </it>has a significant laxative activity and supports its traditional use in herbal medicine.</p

Fifth European Dirofilaria and Angiostrongylus Days (FiEDAD) 2016

Peer reviewe

Predictors of poor retention on antiretroviral therapy as a major HIV drug resistance early warning indicator in Cameroon: results from a nationwide systematic random sampling

Retention on lifelong antiretroviral therapy (ART) is essential in sustaining treatment success while preventing HIV drug resistance (HIVDR), especially in resource-limited settings (RLS). In an era of rising numbers of patients on ART, mastering patients in care is becoming more strategic for programmatic interventions. Due to lapses and uncertainty with the current WHO sampling approach in Cameroon, we thus aimed to ascertain the national performance of, and determinants in, retention on ART at 12 months

Supercritical storage of hydrogen and oxygen for mobile fuel cell space applications

This report discusses the modeling and preliminary design of a system for the supercritical storage of hydrogen and oxygen for mobile fuel cell space applications, including rovers, spacesuits, and construction equipment. This system must operate on both low and zero gravity space missions requiring all reactant storage to be as a single phase to avoid sloshing while maintaining high storage efficiency. The purpose of this study is to develop a tank design for both fuel cell reactants, quantify heat duties throughout preparation and operation, and determine the optimal storage conditions. In addition, a preliminary schematic and control system for the system is developed based on the theoretical model. This study confirms that such a system is indeed plausible and could conceivably power the next generation of Lunar and Martian exploration. It was determined that the heat duties required to maintain the supercritical system are manageable, meaning the system is entirely feasible. Additionally, the system can be designed safely and efficiently within the stringent mass and volume constraints

Establishing the Learning Curve of Robotic Sacral Colpopexy in a Start-up Robotics Program

STUDY OBJECTIVE: To determine the learning curve of the following segments of a robotic sacral colpopexy: preoperative setup, operative time, postoperative transition, and room turnover. DESIGN: A retrospective cohort study to determine the number of cases needed to reach points of efficiency in the various segments of a robotic sacral colpopexy (Canadian Task Force II-2). SETTING: A university-affiliated community hospital. PATIENTS: Women who underwent robotic sacral colpopexy at our institution from 2009 to 2013 comprise the study population. INTERVENTIONS: Patient characteristics and operative reports were extracted from a patient database that has been maintained since the inception of the robotics program at Winthrop University Hospital and electronic medical records. Based on additional procedures performed, 4 groups of patients were created (A-D). MEASUREMENTS AND MAIN RESULTS: Learning curves for each of the segment times of interest were created using penalized basis spline (B-spline) regression. Operative time was further analyzed using an inverse curve and sequential grouping. A total of 176 patients were eligible. Nonparametric tests detected no difference in procedure times between the 4 groups (A-D) of patients. The preoperative and postoperative points of efficiency were 108 and 118 cases, respectively. The operative points of proficiency and efficiency were 25 and 36 cases, respectively. Operative time was further analyzed using an inverse curve that revealed that after 11 cases the surgeon had reached 90% of the learning plateau. Sequential grouping revealed no significant improvement in operative time after 60 cases. Turnover time could not be assessed because of incomplete data. CONCLUSIONS: There is a difference in the operative time learning curve for robotic sacral colpopexy depending on the statistical analysis used. The learning curve of the operative segment showed an improvement in operative time between 25 and 36 cases when using B-spline regression. When the data for operative time was fit to an inverse curve, a learning rate of 11 cases was appreciated. Using sequential grouping to describe the data, no improvement in operative time was seen after 60 cases. Ultimately, we believe that efficiency in operative time is attained after 30 to 60 cases when performing robotic sacral colpopexy. The learning curve for preoperative setup and postoperative transition, which is reflective of anesthesia and nursing staff, was approximately 110 cases

Wind Power Suitability in Worcester, Massachusetts

The goal of this project was to identify criteria needed to determine the suitability of potential wind turbine sites in Worcester, Massachusetts. The report first discusses physical, environmental, economic, and social factors that affect the suitability of potential wind power sites. We then completed a case study for a site in downtown Worcester, directly applying the criteria. Our hope is the project will raise local awareness of renewable energy and illustrate the practicality of a clean energy project