913 research outputs found
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
Identification and Empiric Evaluation of New Inhibitors of the Multidrug Transporter P-Glycoprotein (ABCB1)
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
OSTĪ± 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 alphaābeta (OSTĪ±āOSTĪ²), an important contributor to intestinal bile acid (BA) reabsorption in the enterohepatic circulation.1, 2 Here, we identified the first case of OSTĪ± deficiency in a child with unexplained elevated liver transaminases, cholestasis, and congenital diarrhea
Patientsā perspectives on the implementation of intra-dialytic cyclingāa phenomenographic study
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