Shortest Geometric Paths Analysis in Structural Biology

The surface of a macromolecule, such as a protein, represents the contact point of any interaction that molecule has with solvent, ions, small molecules or other macromolecules. Analyzing the surface of macromolecules has a rich history but analyzing the distances from this surface to other surfaces or volumes has not been extensively explored. Many important questions can be answered quantitatively through these analyses. These include: what is the depth of a pocket or groove on the surface? what is the overall depth of the protein? how deeply are atoms buried from the surface? where are the tunnels in a protein? where are the pockets and what are their shapes? A single algorithm to solve one graph problem, namely Dijkstra’s shortest paths algorithm, forms the basis for algorithms to answer these many questions. Many distances can be measured, for instance the distance from the convex hull to the molecular surface while avoiding the interior of the surface is defined as Travel Depth. Alternatively, the distance from the surface to every atom can be measured, giving a measure of the Burial Depth of given residues. Measuring the minimum distance to the protein surface for all points in solvent, combined with topological guidance, allows tunnels to be located. Analyzing the surface from the deepest Travel Depth upwards allows pockets to be catalogued over the entire protein surface for additional shape analysis. Ligand binding sites in proteins are significantly deep, though this does not affect the binding affinity. Hyperthermostable proteins have a less deep surface but bury atoms more deeply, forming more spherical shapes than their mesophilic counterparts. Tunnels through proteins can be identified, for the first time tunnels that are winding or bifurcated can be analyzed. Pockets can be found all over the protein surface and these pockets can be tracked through time series, mutational series, or over protein families. All of these results are new and for the first time provide quantitative and statistical verification of some previous hypotheses about protein shape

Toll-like receptor signaling and stages of addiction

Athina Markou and her colleagues discovered persistent changes in adult behavior following adolescent exposure to ethanol or nicotine consistent with increased risk for developing addiction. Building on Dr. Markou's important work and that of others in the field, researchers at the Bowles Center for Alcohol Studies have found that persistent changes in behavior following adolescent stress or alcohol exposure may be linked to induction of immune signaling in brain. This study aims to illuminate the critical interrelationship of the innate immune system (e.g., toll-like receptors [TLRs], high-mobility group box 1 [HMGB1]) in the neurobiology of addiction. This study reviews the relevant research regarding the relationship between the innate immune system and addiction. Emerging evidence indicates that TLRs in brain, particularly those on microglia, respond to endogenous innate immune agonists such as HMGB1 and microRNAs (miRNAs). Multiple TLRs, HMGB1, and miRNAs are induced in the brain by stress, alcohol, and other drugs of abuse and are increased in the postmortem human alcoholic brain. Enhanced TLR-innate immune signaling in brain leads to epigenetic modifications, alterations in synaptic plasticity, and loss of neuronal cell populations, which contribute to cognitive and emotive dysfunctions. Addiction involves progressive stages of drug binges and intoxication, withdrawal-negative affect, and ultimately compulsive drug use and abuse. Toll-like receptor signaling within cortical-limbic circuits is modified by alcohol and stress in a manner consistent with promoting progression through the stages of addiction

Pool boiling on modified surfaces using R-123

This article has been made available through the Brunel Open Access Publishing Fund.Saturated pool boiling of R-123 was investigated for five horizontal copper surfaces modified by different treatments, namely, an emery-polished surface, a fine sandblasted surface, a rough sandblasted surface, an electron beam-enhanced surface, and a sintered surface. Each 40-mm-diameter heating surface formed the upper face of an oxygen-free copper block, electrically heated by embedded cartridge heaters. The experiments were performed from the natural convection regime through nucleate boiling up to the critical heat flux, with both increasing and decreasing heat flux, at 1.01 bar, and additionally at 2 bar and 4 bar for the emery-polished surface. Significant enhancement of heat transfer with increasing surface modification was demonstrated, particularly for the electron beam-enhanced and sintered surfaces. The emery-polished and sandblasted surface results are compared with nucleate boiling correlations and other published data. © 2014 Syed W. Ahmad, John S. Lewis, Ryan J. McGlen, and Tassos G. Karayiannis Published with license by Taylor & Francis

Early stage adoption of ISO/IEC 29110 software project management practices: a case study

The ISO/IEC 29110 standard has at its core a Management and Engineering Guide [1] which are targeted at very small entities (enterprises, organizations, departments or projects) having up to 25 people [2], to assist them unlock the potential benefits of using standards which are specifically designed to address their needs. This paper discusses the role and structure of Project Management in the ISO/IEC 29110 standard and the design and development of project management support documentation. In particular this paper describes a case study of an early adopter of ISO/IEC 29110 project management practices and their experiences with implementing these in an industrial context

Epstein-Barr virus-specific methylation of human genes in gastric cancer cells

<p>Abstract</p> <p>Background</p> <p>Epstein-Barr Virus (EBV) is found in 10% of all gastric adenocarcinomas but its role in tumor development and maintenance remains unclear. The objective of this study was to examine EBV-mediated dysregulation of cellular factors implicated in gastric carcinogenesis.</p> <p>Methods</p> <p>Gene expression patterns were examined in EBV-negative and EBV-positive AGS gastric epithelial cells using a low density microarray, reverse transcription PCR, histochemical stains, and methylation-specific DNA sequencing. Expression of PTGS2 (COX2) was measured in AGS cells and in primary gastric adenocarcinoma tissues.</p> <p>Results</p> <p>In array studies, nearly half of the 96 human genes tested, representing 15 different cancer-related signal transduction pathways, were dysregulated after EBV infection. Reverse transcription PCR confirmed significant impact on factors having diverse functions such as cell cycle regulation (<it>IGFBP3</it>, <it>CDKN2A, CCND1, HSP70, ID2, ID4)</it>, DNA repair <it>(BRCA1, TFF1</it>), cell adhesion (<it>ICAM1</it>), inflammation (<it>COX2</it>), and angiogenesis (<it>HIF1A</it>). Demethylation using 5-aza-2'-deoxycytidine reversed the EBV-mediated dysregulation for all 11 genes listed here. For some promoter sequences, CpG island methylation and demethylation occurred in an EBV-specific pattern as shown by bisulfite DNA sequencing. Immunohistochemistry was less sensitive than was western blot for detecting downregulation of COX2 upon EBV infection. Virus-related dysregulation of COX2 levels <it>in vitro </it>was not recapitulated <it>in vivo </it>among naturally infected gastric cancer tissues.</p> <p>Conclusions</p> <p>EBV alters human gene expression in ways that could contribute to the unique pathobiology of virus-associated cancer. Furthermore, the frequency and reversability of methylation-related transcriptional alterations suggest that demethylating agents have therapeutic potential for managing EBV-related carcinoma.</p

Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4)

PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3′5′ adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of moexipril is functionally able to induce phosphorylation of the Hsp20 by cAMP dependent protein kinase A. Our data suggest that moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window

On rotational excitations and axial deformations of BPS monopoles and Julia-Zee dyons

It is shown that Julia-Zee dyons do not admit slowly rotating excitations. This is achieved by investigating the complete set of stationary excitations which can give rise to non-vanishing angular momentum. The relevant zero modes are parametrized in a gauge invariant way and analyzed by means of a harmonic decomposition. Since general arguments show that the solutions to the linearized Bogomol'nyi equations cannot contribute to the angular momentum, the relevant modes are governed by a set of electric and a set of non self-dual magnetic perturbation equations. The absence of axial dipole deformations is also established.Comment: 22 pages, Revtex, no figure

The effects of creatine supplementation combined with resistance training on regional measures of muscle hypertrophy: a systematic review with meta-analysis.

The purpose of this paper was to carry out a systematic review with meta-analysis of randomized controlled trials that examined the combined effects of resistance training (RT) and creatine supplementation on regional changes in muscle mass with direct imaging measures of hypertrophy. Moreover, we performed regression analyses to determine the potential influence of covariates. We included trials of at least 6 weeks in duration that examined the combined effects of creatine supplementation and RT on site-specific direct measures of hypertrophy (magnetic resonance imaging [MRI], computed tomography [CT] or ultrasound) in healthy adults. A total of 44 outcomes were analyzed across 10 studies that met inclusion criteria. Univariate analysis of all standardized outcomes showed a pooled mean estimate of 0.11 (95% Credible Interval [CrI]: -0.02 to 0.25) providing evidence of a very small effect favoring creatine supplementation when combined with RT, compared to RT and placebo. Multivariate analyses found similar small benefits for the combination of creatine supplementation and RT on changes in upper and lower body muscle thickness (0.10-0.16 cm). Analyses of moderating effects indicated a small superior benefit for creatine supplementation on younger compared to older adults (0.17 [95% CrI: -0.09 to 0.45]). In conclusion, results suggest that creatine supplementation combined with RT promotes a small increase in direct measures of skeletal muscle hypertrophy in both the upper and lower body

Erasmus Language students in a British University – a case study

Students’ assessment of their academic experience is actively sought by Higher Education institutions, as evidenced in the National Student Survey introduced in 2005. Erasmus students, despite their growing numbers, tend to be excluded from these satisfaction surveys, even though they, too, are primary customers of a University. This study aims to present results from bespoke questionnaires and semi-structured interviews with a sample of Erasmus students studying languages in a British University. These methods allow us insight into the experience of these students and their assessment as a primary customer, with a focus on language learning and teaching, university facilities and student support. It investigates to what extent these factors influence their levels of satisfaction and what costs of adaptation if any, they encounter. Although excellent levels of satisfaction were found, some costs affect their experience. They relate to difficulties in adapting to a learning methodology based on a low number of hours and independent learning and to a guidance and support system seen as too stifling. The results portray this cohort’s British University as a well-equipped and well-meaning but ultimately overbearing institution, which may indicate that minimising costs can eliminate some sources of dissatisfaction