Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1.

The expression of drug efflux pump ABCB1/P-glycoprotein (P-gp), a transmembrane protein belonging to the ATP-binding cassette superfamily, is a leading cause of multidrug resistance (MDR). We previously curated a dataset of structurally diverse and selective inhibitors of ABCB1 to develop a pharmacophore model that was used to identify four novel compounds, which we showed to be potent and efficacious inhibitors of ABCB1. Here, we dock the inhibitors into a model structure of the human transporter and use molecular dynamics (MD) simulations to report the conformational dynamics of human ABCB1 induced by the binding of the inhibitors. The binding hypotheses are compared to the wider curated dataset and those previously reported in the literature. Protein-ligand interactions and MD simulations are in good agreement and, combined with LipE profiling, statistical and pharmacokinetic analyses, are indicative of potent and selective inhibition of ABCB1

The role of biomimetic hypoxia on cancer cell behaviour in 3d models: A systematic review

The development of biomimetic, human tissue models is recognized as being an important step for transitioning in vitro research findings to the native in vivo response. Oftentimes, 2D models lack the necessary complexity to truly recapitulate cellular responses. The introduction of physiological features into 3D models informs us of how each component feature alters specific cellular response. We conducted a systematic review of research papers where the focus was the introduction of key biomimetic features into in vitro models of cancer, including 3D culture and hypoxia. We analysed outcomes from these and compiled our findings into distinct groupings to ascertain which biomimetic parameters correlated with specific responses. We found a number of biomimetic features which primed cancer cells to respond in a manner which matched in vivo response

A multi-sector multi-region economic growth model of drought and the value of water: A case study in Pakistan

This study integrates ecohydrological vegetation and multi-sector multi-region economic growth models to evaluate the impacts of drought on markets and value the economic value of water. The values of several parameters of the agricultural production function are identified by applying leaf area indices that are simulated by the ecohydrological model, AgriCLVDAS. The three-sector three-region closed-economy model with the agricultural production functions of both irrigable and rainfed farmland as well as the stochastic process of precipitation and availability of river water are formulated to analyze the water rent as well as GDP growth in Pakistan under drought stress. According to the characteristics of the closed-economy model, the crop price is increased during drought periods because of the price hike in water (i.e., an increase in the marginal productivity of water, which is double that in high-water periods in Pakistan). The study further presents a way of investigating water resource management policies by applying comparative dynamics

Diversified spatial keyword search on road networks

With the increasing pervasiveness of the geo-positioning technologies, there is an enormous amount of spatio-textual objects available in many applications such as location based services and social networks. Consequently, various types of spatial keyword searches which explore both locations and textual descriptions of the objects have been intensively studied by the research communities and commercial organizations. In many important applications (e.g., location based services), the closeness of two spatial objects is measured by the road network distance. Moreover, the result diversification is becoming a common practice to enhance the quality of the search results. Motived by the above facts, in this paper we study the problem of diversified spatial keyword search on road networks which considers both the relevance and the spatial diversity of the results. An efficient signature-based inverted indexing technique is proposed to facilitate the spatial keyword query processing on road networks. Then we develop an efficient diversified spatial keyword search algorithm by taking advantage of spatial keyword pruning and diversity pruning techniques. Comprehensive experiments on real and synthetic data clearly demonstrate the efficiency of our methods

Vertical transport and electroluminescence in InAs/GaSb/InAs structures: GaSb thickness and hydrostatic pressure studies

We have measured the current-voltage (I-V) of type II InAs/GaSb/InAs double heterojunctions (DHETs) with 'GaAs like' interface bonding and GaSb thickness between 0-1200 \AA. A negative differential resistance (NDR) is observed for all DHETs with GaSb thickness $>$ 60 \AA below which a dramatic change in the shape of the I-V and a marked hysteresis is observed. The temperature dependence of the I-V is found to be very strong below this critical GaSb thickness. The I-V characteristics of selected DHETs are also presented under hydrostatic pressures up to 11 kbar. Finally, a mid infra-red electroluminescence is observed at 1 bar with a threshold at the NDR valley bias. The band profile calculations presented in the analysis are markedly different to those given in the literature, and arise due to the positive charge that it is argued will build up in the GaSb layer under bias. We conclude that the dominant conduction mechanism in DHETs is most likely to arise out of an inelastic electron-heavy-hole interaction similar to that observed in single heterojunctions (SHETs) with 'GaAs like' interface bonding, and not out of resonant electron-light-hole tunnelling as proposed by Yu et al. A Zener tunnelling mechanism is shown to contribute to the background current beyond NDR.Comment: 8 pages 12 fig

Metabolomic biomarkers of pancreatic cancer: a meta-analysis study

Pancreatic cancer (PC) is an aggressive disease with high mortality rates, however, there is no blood test for early detection and diagnosis of this disease. Several research groups have reported on metabolomics based clinical investigations to identify biomarkers of PC, however there is a lack of a centralized metabolite biomarker repository that can be used for meta-analysis and biomarker validation. Furthermore, since the incidence of PC is associated with metabolic syndrome and Type 2 diabetes mellitus (T2DM), there is a need to uncouple these common metabolic dysregulations that may otherwise diminish the clinical utility of metabolomic biosignatures. Here, we attempted to externally replicate proposed metabolite biomarkers of PC reported by several other groups in an independent group of PC subjects. Our study design included a T2DM cohort that was used as a non-cancer control and a separate cohort diagnosed with colorectal cancer (CRC), as a cancer disease control to eliminate possible generic biomarkers of cancer. We used targeted mass spectrometry for quantitation of literature-curated metabolite markers and identified a biomarker panel that discriminates between normal controls (NC) and PC patients with high accuracy. Further evaluation of our model with CRC, however, showed a drop in specificity for the PC biomarker panel. Taken together, our study underscores the need for a more robust study design for cancer biomarker studies so as to maximize the translational value and clinical implementation.This work was supported by ACS IRG-92-152-17 pilot award number AWD4470404 to KU and AKC. The authors would like to acknowledge the Metabolomics Shared Resource in Georgetown University (Washington DC, USA) partially supported by NIH/NCI/CCSG grant P30-CA05100

OSTα deficiency: A disorder with cholestasis, liver fibrosis and congenital diarrhea

Solute carrier family 51 alpha subunit (SLC51A ) encodes the alpha subunit of the heteromeric organic solute transporter alpha–beta (OSTα–OSTβ), an important contributor to intestinal bile acid (BA) reabsorption in the enterohepatic circulation.1, 2 Here, we identified the first case of OSTα deficiency in a child with unexplained elevated liver transaminases, cholestasis, and congenital diarrhea