A Holistic Evolutionary and 3D Pharmacophore Modelling Study Provides Insights into the Metabolism,Function, and Substrate Selectivity of the Human Monocarboxylate Transporter 4 (hMCT4)

Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy.     

The mechanical property and phase structures of wheat proteins/polyvinyl alcohol blends studied by high-resolution solid-state NMR

The phase structures of thermally processed wheat proteins (WP) and polyvinyl alcohol (PVOH) blends were studied by solid-state high-resolution NMR spectroscopy. The intermolecular interactions among the multi-component systems and the behavior of each component in the blends on scales of nanometers were examined. The mechanical properties of the blends were also measured and related to the phase structure studies. The results indicated that the polymer chains of WP could be homogeneously mobilized when thermally processed with glycerol and water as plasticisers, but the glycerol predominately associated with WP rather than PVOH in the blends. The intermolecular hydrogen bonding interactions between WP and PVOH caused some extent of miscibility in the system on scales of nanometers especially when the PVOH content was low. The tensile strength and modulus of the blends were improved as compared to WP. However, the intermolecular interactions were relatively weak and could not be further enhanced by increasing PVOH component in the blends. The particle miscible WP/PVOH blends contained plasticised WP and PVOH phases in conjunction with the miscible WP/PVOH phase. Increasing the PVOH content in the blends did not result in an increase of the percentage of the miscible phase and the blends tented to be immiscible while the elongation of the blends was reduced when increasing the PVOH content in the blends.     

Rationally designed inhibitors as tools for comparing the mechanism of squalene-hopene cyclase with oxidosqualene cyclase

The inhibition of squalene-hopene cyclase (SHC) (E.C. 5.4.99.-), an enzyme of bacterial membranes catalyzing the formation of pentacyclic sterol-like triterpenes, was studied by using different classes of compounds originally developed as inhibitors of oxidosqualene cyclase (OCS) (E.C. 5.4.99.7), the enzyme of eukaryotes responsible for the formation of tetracyclic precursors of sterols. The mechanism of cyclization of squalene by SHC, beginning with a protonation of the 2,3 double bond by an acidic residue of the enzyme, followed by a series of electrophilic additions of the carbocationic intermediates to the double bonds, is similar to the mechanism of cyclization of 2,3-oxidosqualene by OSC. The inhibitors studied included: (i) analogs of the carbocationic intermediates formed during cyclization, such as aza-analogs of squalene and 2,3-oxidosqualene; (ii) affinity-labeling inhibitors bearing a methylidene reactive group; and (iii) vinyldioxidosqualenes and vinylsulfide derivatives of the substrates. Comparison of the results obtained with the two enzymes, SHC and OSC, showed that many of the most effective inhibitors of OSC were also able to inhibit SHC, while some derivatives acted as specific inhibitors. Differences could be easily explained on the basis of the different substrate specificity of the two enzymes.     

Synthesis and catalytic activity of optically active polymers containing oxime groups

Optically active polymers containing oxime groups have been prepared: (i) by partial quaternization of poly(4-vinyl pyridine) (P4VP) with phenacyloxime bromide and with (+)-(S)-1-bromo-2-methylbutane; and (ii) by reaction of the copolymer from 4VP and (+)-(S)-5-methyl-1-hepten-3-one with hydroxylamine. These polymers have been used as catalysts for the esterolysis of esters of p-nitrophenol with non-chiral and with chiral acids. The kinetic parameters of the catalytic process are markedly dependent on the structure of polymer and substrate. A moderate chiral discrimination of the antipodes of p-nitrophenyl 2-methylbutanoate is observed with the catalyst obtained from the copolymer of 4VP with (+)-(S)-5-methyl-1-hepten-3-one.     

How the risk of failure in lifetime of tempered glass depends on the size of NiS inclusions and heat soak test duration

The probability of breakage in service lifetime of heat-tempered glass panes contaminated by nickel sulfide inclusions is estimated with a multiscale micromechanically motivated statistical theory, which considers the effects of the heat soak test (HST). Short and long HSTs differently affect the phase transformation of NiS of diverse chemical composition, whose increase in volume can break the glass. The main hypothesis, corroborated by experiments, is that there is a lower limit for the size of NiS stones below which no crack can be initiated from the volumetric expansion. The catastrophic propagation of nucleated fractures in the long term is modeled through a rescaled critical stress intensity factor, which accounts for the subcritical crack propagation and the slow phase transformation of NiS. A parametric analysis evidences how the failure probability is strongly affected by these parameters, depending on the holding time in the HST. Tailored experimental activity is suggested for the proper calibration of the model.     

Aberrant protein expression in plasma and kidney tissue during experimental obstructive nephropathy

Kidney failure is a major health problem worldwide. Patients with end-stage renal disease require intensive medical support by dialysis or kidney transplantation. Current methods for diagnosis of kidney disease are either invasive or insensitive, and renal function may decline by as much as 50% before it can be detected using current techniques. The goal of this study was, therefore, to identify biomarkers of kidney disease (associated with renal fibrosis) that can be used for the development of a non-invasive clinical test for early disease detection. We utilized two protein-profiling technologies (SELDI-TOF MS and 2-D) to screen the plasma and kidney proteome for aberrantly expressed proteins in an experimental mouse model of unilateral uretric obstruction, which mimics the pathology of human renal disease. Several differentially regulated proteins were detected at the plasma level of day-3-obstructed animals, which included serum amyloid A1, fibrinogen α, haptoglobin precursor protein, haptoglobin and major urinary proteins 11 and 8. Differentially expressed proteins detected at the tissue level included ras-like activator protein 2, haptoglobin precursor protein, malate dehydrogenase, α enolase and murine urinary protein (all p<0.05 versus controls). Immunohistochemistry was used to confirm the up-regulation of fibrinogen. Interestingly, these proteins are largely separated into four major classes: (i) acute-phase reactants (ii) cell-signaling molecules (iii) molecules involved in cell growth and metabolism and (iv) urinary proteins. These results provide new insights into the pathology of obstructive nephropathy and may facilitate the development of specific assay(s) to detect and monitor renal fibrosis.     

A well‐conditioned and optimally convergent XFEM for 3D linear elastic fracture

A variation of the extended finite element method for three‐dimensional fracture mechanics is proposed. It utilizes a novel form of enrichment and point‐wise and integral matching of displacements of the standard and enriched elements in order to achieve higher accuracy, optimal convergence rates, and improved conditioning for two‐dimensional and three‐dimensional crack problems. A bespoke benchmark problem is introduced to determine the method's accuracy in the general three‐dimensional case where it is demonstrated that the proposed approach improves the accuracy and reduces the number of iterations required for the iterative solution of the resulting system of equations by 40% for moderately refined meshes and topological enrichment. Moreover, when a fixed enrichment volume is used, the number of iterations required grows at a rate which is reduced by a factor of 2 compared with standard extended finite element method, diminishing the number of iterations by almost one order of magnitude. Copyright © 2015 John Wiley & Sons, Ltd.     

Dipyridamole technetium-99m Sestamibi imaging in the diagnosis of syndrome X

In a middle-aged woman with anginal chest pain and a normal-appearing angiogram, dypiridamole technetium-99m Sestamibi scintigraphy, a noninvasive method, provided the diagnosis of syndrome X and was used in follow-up to monitor the course of disease.     

Sensitivity analysis of the rice model WARM in Europe: Exploring the effects of different locations,climates and methods of analysis on model sensitivity to crop parameters

Sensitivity analysis studies how the variation in model outputs can be due to different sources of variation. This issue is addressed, in this study, as an application of sensitivity analysis techniques to a crop model in the Mediterranean region. In particular, an application of Morris and Sobol' sensitivity analysis methods to the rice model WARM is presented. The output considered is aboveground biomass at maturity, simulated at five rice districts of different countries (France, Greece, Italy, Portugal, and Spain) for years characterized by low, intermediate, and high continentality. The total effect index of Sobol' (that accounts for the total contribution to the output variation due a given parameter) and two Morris indices (mean μ and standard deviation σ of the ratios output changes/parameter variations) were used as sensitivity metrics. Radiation use efficiency (RUE), optimum temperature (T_opt), and leaf area index at emergence (LAI_ini) ranked in most of the combinations site × year as first, second and third most relevant parameters. Exceptions were observed, depending on the sensitivity method (e.g. LAI_ini resulted not relevant by the Morris method), or site-continentality pattern (e.g. with intermediate continentality in Spain, LAI_ini and T_opt were second and third ranked; with low continentality in Portugal, RUE was outranked by T_opt). Low σ values associated with the most relevant parameters indicated limited parameter interactions. The importance of sensitivity analyses by exploring site × climate combinations is discussed as pre-requisite to evaluate either novel crop-modelling approaches or the application of known modelling solutions to conditions not explored previously. The need of developing tools for sensitivity analysis within the modelling environment is also emphasized.     

Biomechanical behavior and histological organization of the three-layered passive esophagus as a function of topography

The zero-stress state of the mucosa-submucosa and two muscle esophageal layers has been delineated, but their multi-axial response has not, because muscle dissection may not leave tubular specimens intact for inflation/extension testing. The histomechanical behavior of the three-layered porcine esophagus was investigated in this study, through light microscopic examination and uniaxial tension, with two-dimensional strain measurement in pairs of orthogonally oriented specimens. The two-dimensional Fung-type strain-energy function described suitably the pseudo-elastic tissue response, affording faithful simulations to our data. Differences in the scleroprotein content and configuration were identified as a function of layer, topography, and orientation, substantiating the macromechanical differences found. In view of the failure and optimized material parameters, the mucosa-submucosa was stronger and stiffer than muscle, associating it with a higher collagen content. A notable topographical distribution was apparent, with data for the abdominal region differentiated from that for the cervical region, owing to the existence of inner muscle with a circumferential arrangement and of outer muscle with a longitudinal arrangement in the former region, and of both muscle layers with oblique arrangement in the latter region, with thoracic esophagus being a transition zone. Tissue from the mucosa-submucosa was stronger and stiffer longitudinally, relating with a preferential collagen reinforcement along that axis, but more extensible in the orthogonal axis.