Modeling ATP-Binding Cassette G2 (ABCG2) Substrate Specificity

How well can we predict efflux by ATP-binding cassette G2? It is estimated that there will be about 1.6 million new cases of cancer and half a million cancer deaths in the US during 2015.ATP-binding cassette (ABC) efflux transporters such as ABCG2 are overexpressed in chemotherapy-resistant cancer cells. Anticancer drugs are prone to efflux by these transporters. Being able to identify drugs that are effluxed is of great interest in drug discovery.The current arsenal of methods used to detect efflux are not easily adaptable to high throughput formats and are limited in scope, making experimental analysis an expensive prospect. Hence, computational analysis of efflux is of interest. We accumulated a dataset of ABCG2 substrates and non-substrates which contains 179 substrates and 110 non-substrates. This dataset forms the basis for all studies reported herein. We attempted to identify descriptors capable of segregating substrates and non-substrates, ending up with Log P, Polar Volume, Atom Count, Radius of Gyration, Binding Energy, Length, and Width. They had significant differential distribution that could be used to build mathematical models to fulfil our goals. A statistical learning method that creates non-linear models called Support Vector Machine generated the best predictive models. This model demonstrated between 75-80% accuracy in identifying substrates and non-substrates. Importantly our model suggests mechanistic details of the efflux process; previous reports have suggested that Arg482 in ABCG2 is critical for transport of substrates. In conclusion, we were able to address efflux of chemotherapeutic agents by the ABCG2 efflux pump using a mathematical modeling approach.https://scholarscompass.vcu.edu/uresposters/1130/thumbnail.jp

Private Transactions in Public Places: An Exploration of the Impact of the Computer Environment on Public Transactional Web Site Use

Organizations and governments continue to advance toward using electronic means to interact with their customers. However, the use of this medium presents an access-to-service issue for people across the digital divide who do not have private Internet access from their homes. Publicly-available computers connected to the Internet are an important and expanding source of Internet access for consumers. Still, we do not know if people are willing to engage in e-commerce transactions in such environments. We expand the Facilitating Conditions construct of Triandis\u27 (1980) modified theory of reasoned action to develop a model of transactional Web site use in public environments that incorporates the physical and virtual computer environments associated with publicly accessible computers, moderated by the individual\u27s need for privacy. The model was tested in public libraries, and the results indicate that the virtual and physical facilitating conditions of a public computer are determinants of e-commerce use in a public environment, and the user\u27s need for privacy moderates these relationships

Timelines of Transportation Infrastructure Delivery 2000 to 2018 in Toronto, Canada and London, UK

This paper explores the timelines of large transportation infrastructure delivery, from first proposal to construction and opening in London, UK and Toronto, Canada. The goal of the paper is to identify both how long it takes projects to go from idea to delivery, the relative time of different stages in the delivery process, and if projects with long timelines see physical or technological changes in their design. This work contributes to two ongoing discussions around the speed of infrastructure delivery, one that argues infrastructure moves too slowly and major efforts are needed to speed delivery and another that argues that good infrastructure thinking requires time to breathe and care should be taken in rushing through the delivery process. Detailed delivery timelines from initial proposal to construction or operation are developed for 26 transportation projects (16 in Toronto and 10 in London) between the years 2000 and 2018. For each project the timelines of inception, approval, planning, procurement, environmental assessment, construction and operational phases are identified and compared. Long informal gestation periods are identified for many projects, particularly for linear projects. In many instances the informal gestation period dwarfs the time projects spent in formal planning. This research highlights the need to expand the conception of timeliness of infrastructure delivery to include the lengthy periods of informal debate and planning that can span years and build up community expectations about the imminence of a project, even before it has received formal assessment or approval

An econometric analysis of the desktop computer hardware market

The purpose of this study was to compare six competing econometric models which depict the relationship between hardware characteristics and machine cost for the desktop computer market. The Box-Cox methodology and multiyear data were used to facilitate this comparison. The analysis validated that the Box-Cox methodology is a viable means for evaluating competing model formulations within the field of information systems research. The results were consistent with past research that suggested a double natural log model formulation for representing the functional relationships among variables when modeling machine cost as a function of hardware attributes. Further, the more complex power transformation model formulations suggested by the Box-Cox methodology did not significantly outperform the more traditional and simpler double natural log model. More specifically, the results indicated that variables related to primary memory and microchip tedinology have the largest impact on machine cost. Additionally, variables related to madiine connectivity, machine expandability, and year of observation were also found to be significant explanatory variables for machine cost

Distinguishing different stages of Parkinson's disease using composite index of speed and pen-pressure of sketching a spiral

The speed and pen-pressure while sketching a spiral are lower among Parkinson's disease (PD) patients with higher severity of the disease. However, the correlation between these features and the severity level (SL) of PD has been reported to be 0.4. There is a need for identifying parameters with a stronger correlation for considering this for accurate diagnosis of the disease. This study has proposed the use of the Composite Index of Speed and Pen-pressure (CISP) of sketching as a feature for analyzing the severity of PD. A total of 28 control group (CG) and 27 PD patients (total 55 participants) were recruited and assessed for Unified Parkinson's Disease Rating Scale (UPDRS). They drew guided Archimedean spiral on an A3 sheet. Speed, pen-pressure, and CISP were computed and analyzed to obtain their correlation with severity of the disease. The correlation of speed, pen-pressure, and CISP with the severity of PD was -0.415, -0.584, and -0.641, respectively. Mann-Whitney U test confirmed that CISP was suitable to distinguish between PD and CG, while non-parametric k-sample Kruskal-Wallis test confirmed that it was significantly different for PD SL-1 and PD SL-3. This shows that CISP during spiral sketching may be used to differentiate between CG and PD and between PD SL-1 and PD SL-3 but not SL-2

A practical comparison of methods for detecting transcription factor binding sites in ChIP-seq experiments

<p>Abstract</p> <p>Background</p> <p>Chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) is increasingly being applied to study transcriptional regulation on a genome-wide scale. While numerous algorithms have recently been proposed for analysing the large ChIP-seq datasets, their relative merits and potential limitations remain unclear in practical applications.</p> <p>Results</p> <p>The present study compares the state-of-the-art algorithms for detecting transcription factor binding sites in four diverse ChIP-seq datasets under a variety of practical research settings. First, we demonstrate how the biological conclusions may change dramatically when the different algorithms are applied. The reproducibility across biological replicates is then investigated as an internal validation of the detections. Finally, the predicted binding sites with each method are compared to high-scoring binding motifs as well as binding regions confirmed in independent qPCR experiments.</p> <p>Conclusions</p> <p>In general, our results indicate that the optimal choice of the computational approach depends heavily on the dataset under analysis. In addition to revealing valuable information to the users of this technology about the characteristics of the binding site detection approaches, the systematic evaluation framework provides also a useful reference to the developers of improved algorithms for ChIP-seq data.</p

Effect of Nano-TiO₂ Particles on Wear and Corrosion Behaviour of AA6063 Surface Composite Fabricated by Friction Stir Processing

In this investigation, the effect of nano-TiO₂ particles on wear and corrosion behaviour of AA6063 surface nanocomposites produced viavia friction stir processing (FSP) was studied. Microstructure analysis of fabricated surface nanocomposites was done with scanning electron microscope and found that TiO₂ nanoparticles are uniformly dispersed in the stir zone. The surface nanocomposites were characterized by hardness, wear and corrosion tests. The results revealed that the microhardness increases due to the presence of hard TiO₂ nanoparticles than as AA6063 alloy. The FSPed surface nanocomposites exhibited low frictional coefficient, excellent wear resistance and adequate corrosion resistance at 40 mm/min and as compared to that of the as cast alloy.Исследовано влияние наночастиц TiO₂ на характер износа и коррозии поверхностных нанокомпозитов сплава AA6063, полученных с помощью обработки трением с перемешиванием. Проведён анализ поверхностных нанокомпозитов методом сканирующей электронной микроскопии и показано, что наночастицы TiO₂ равномерно распределены в зоне перемешивания. Для характеризации поверхностных нанокомпозитов были использованы испытания на твёрдость, износостойкость и коррозионную стойкость. Показано, что микротвёрдость повышается по сравнению со сплавом AA6063 благодаря наличию наночастиц TiO₂. Обработанные методом трения с перемешиванием поверхностные нанокомпозиты обладают низким коэффициентом трения, отменной износостойкостью и адекватной коррозионной стойкостью при 40 мм/мин по сравнению со сплавом в литом состоянии.Досліджено вплив наночастинок TiO₂ на характер зношування та корозії поверхневих нанокомпозитів стопу AA6063, одержаних за допомогою оброблення тертям з перемішуванням. Проведено аналізу одержаних поверхневих нанокомпозитів методою сканувальної електронної мікроскопії та встановлено, що наночастинки TiO₂ рівномірно розподілені в зоні перемішування. Для характеризації поверхневих нанокомпозитів було використано випробування на твердість, зносостійкість і корозійну стійкість. Показано, що мікротвердість підвищується у порівнянні зі стопом AA6063 завдяки наявності наночастинок TiO₂. Оброблені методою тертя з перемішуванням поверхневі нанокомпозити мають низький коефіцієнт тертя, відмінну зносостійкість й адекватну корозійну стійкість при 40 мм/хв. у порівнянні зі стопом у литому стані

Chronic Cough, Reflux, Postnasal Drip Syndrome, and the Otolaryngologist

Objectives. Chronic cough is a multifactorial symptom that requires multidisciplinary approach. Over the last years, general practitioners refer increasingly more chronic cough patients directly to the otolaryngologist. The aim of this paper is to highlight the issues in diagnosis and management of chronic cough patients from the otolaryngologist perspective. Design. Literature review. Results. Gastroesophageal reflux and postnasal drip syndrome remain one of the most common causes of chronic cough. Better diagnostic modalities, noninvasive tests, and high technology radiological and endoscopic innovations have made diagnosis of these difficult-to-treat patients relatively easier. Multidisciplinary assessment has also meant that at least some of these cases can be dealt with confidently in one stop clinics. Conclusions. As the number of referrals of chronic cough patients to an Ear Nose Throat Clinic increases, the otolaryngologist plays a pivotal role in managing these difficult cases