In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells

SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, making it a promising target for small molecule inhibition. In this study, we sought to establish a proof of concept for our in silico/in vitro hit-to-lead enzyme inhibitor development platform and to identify a lead small molecule candidate for SMYD3 inhibition. We used Schrodinger^® software to screen libraries of small molecules in silico and the five compounds with the greatest predicted binding affinity within the SMYD3 binding pocket were purchased and assessed in vitro in direct binding assays and in breast cancer cell lines. We have confirmed the ability of one of these inhibitors, Inhibitor-4, to restore normal rates of cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting wildtype cell behavior. Our results provide a proof of concept for this fast and affordable small molecule hit-to-lead methodology as well as a promising candidate small molecule SMYD3 inhibitor for the treatment of human cancer.     

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Similar to environmental factors, EDCs (endocrine-disrupting chemicals) can influence gene expression without modifying the DNA sequence. It is commonly accepted that the transgenerational inheritance of parentally acquired traits is conveyed by epigenetic alterations also known as “epimutations”. DNA methylation, acetylation, histone modification, RNA-mediated effects and extracellular vesicle effects are the mechanisms that have been described so far to be responsible for these epimutations. They may lead to the transgenerational inheritance of diverse phenotypes in the progeny when they occur in the germ cells of an affected individual. While EDC-induced health effects have dramatically increased over the past decade, limited effects on sperm epigenetics have been described. However, there has been a gain of interest in this issue in recent years. The gametes (sperm and oocyte) represent targets for EDCs and thus a route for environmentally induced changes over several generations. This review aims at providing an overview of the epigenetic mechanisms that might be implicated in this transgenerational inheritance.     

Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies

Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A–class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg^2.39, His^2.43 and Glu^3.46, which makes a polar lock with T^6.37. These alignments and models provide useful tools for understanding class B GPCR function.     

Complementarity of hydro and wind power: Improving the risk profile of energy inflows

The complementarity of two renewable energy sources, namely hydro and wind, is investigated. We consider the diversification effect of wind power to reduce the risk of water inflow shortages, an important energy security concern for hydropower-based economic zones (e.g. Québec and Norway). Our risk measure is based on the probability of a production deficit, in a manner akin to the value-at-risk, simulation analysis of financial portfolios. We examine whether the risk level of a mixed hydro-and-wind portfolio of generating assets improves on the risk of an all-hydro portfolio, by relaxing the dependence on water inflows and attenuating the impact of droughts. Copulas are used to model the dependence between the two sources of energy. The data considered, over the period 1958–2003, are for the province of Québec, which possesses large hydro and wind resources.     

Perception and expectation gaps of information systems provider skills: the impact on user satisfaction

Abstract.  Past research indicates that expectations play a crucial role in the final satisfaction of users of information systems (IS). This includes expectations regarding the skill levels exhibited by the providers of the IS services and products. Typically, the expectations are examined as gaps from perceived performance or as gaps from realistic expectations. The interaction of these gaps has not been thoroughly explored in past research, although recent theories anticipate both gaps are crucial in meeting the desires of the users. A matched pair sample of IS users and IS providers is used to collect data on expected skill levels and perceived delivery of the skills demanded. Gaps, both between these two stakeholder groups regarding expectations and within the user group regarding perceived delivery, are found to impact user satisfaction in a two-way analysis. The results indicate that expectations should be managed to higher levels and commonly understood across the user and provider groups.     

Ethical review of multi-centre research: a survey of local research ethics committees in the south Thames region

We reported a 63-year-old woman with myotonic dystrophy (MD), who had frequent swallowing disturbances and died from suffocation asphyxia. Her esophagus on CT image 30 minutes after taking semi-solid meal showed dietary remnants in the middle portion of esophagus with entire esophageal dilatation. At autopsy, there was marked atrophy in the striated muscles in the upper part and smooth muscles in the lower part of the esophagus. The site of dietary stagnation on CT image was identical to the atrophic smooth muscle layer seen at autopsy. We speculate that one of the causes of esophageal motor dysfunctions is smooth muscle atrophy. The dietary stagnation in the esophagus may increase a risk of the asphyxia. Therefore we need to keep patients at the straight position during and after dietary ingestion to prevent respiratory problems.     

Control of concentration during academic tasks.

Evaluated 3 strategies for controlling concentration during academic tasks. 82 undergraduates served as Ss. One strategy, self-initiated relaxation (SIR), required Ss to employ a combination of relaxation techniques to set and maintain constructive study and test-taking states. The 2nd strategy, self-coaching (SC), was an extension of the positive self-talk techniques developed by D. Meichenbaum (1972). Ss were taught to coach (talk) themselves into constructive states and to maintain these states during studying and test taking. Finally, a 3rd strategy that combined SIR and SC was created. Results indicate that the 3rd strategy, SIR plus SC, significantly facilitated some aspects of academic performance in comparison to a no-treatment control group. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Editorial

Editorial Introduction

Editorial     

Stability and variability of affective experience and interpersonal behavior in borderline personality disorder.

This study examined both mean levels and intraindividual variability in the mood and interpersonal behavior of individuals with borderline personality disorder (BPD) and nonclinical control participants over a 20-day event-contingent recording period. Individuals in the BPD group experienced more unpleasantly valenced affect and were less dominant, more submissive, more quarrelsome, and more extreme in overall levels of behavior than control participants. In addition to these mean-level differences, individuals with BPD also reported more intraindividual variability in overall affect valence and in pleasantly valenced affect; displayed greater variability in dominant, quarrelsome, and agreeable behaviors; and exhibited an increased tendency to "spin" among interpersonal behaviors relative to nonclinical control participants. The findings document behavioral and affective manifestations of BPD in the context of naturally occurring interpersonal situations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inhibition of Listeria monocytogenes on bologna sausages by an antimicrobial film containing mustard extract or sinigrin

The ability of Listeria (L.) monocytogenes to convert glucosinolates into antimicrobial isothiocyanates was investigated. Mustard glucosinolates in pure (sinigrin) or extract forms (sinigrin, oriental; sinalbin, yellow mustard) were used in broth media and in a polyvinyl polyethylene glycol graft copolymer (PPG) packaging film with bologna to examine their value as antimicrobial precursors for the control of L. monocytogenes viability and extension of bologna shelf-life at 4 °C. During broth tests with deodorized (myrosinase-inactivated) mustard extracts (10 d at 20 °C) or with purified sinigrin (21 d at 20 °C) L. monocytogenes was only inhibited when exogenous myrosinase was added. None the less, the organism was able to hydrolyze almost half the pure sinigrin by 21 d in tests without added enzyme. Reductions in sinigrin levels were measured by reversed-phase liquid chromatography, and in the absence of L. monocytogenes or added myrosinase the glucosinolate was stable. When pure sinigrin, oriental or yellow mustard extracts were incorporated in PPG films containing 3, 5 and 6% (w/w) of the corresponding glucosinolate and used to package bologna inoculated with 4 log CFU/g L. monocytogenes, the pathogen became undetectable in bologna packed with the oriental mustard extract at 52 d storage and remained undetectable at 70 d. The yellow mustard extract was less inhibitory and the pure sinigrin was not antimicrobial. L. monocytogenes numbers reached >7 log CFU/g in the film and untreated controls at 17 d storage. At 35 d storage, samples packed with control film contained sufficient numbers of lactic acid bacteria (LAB) (>7 log CFU/g) to be considered spoiled, whereas treatments containing mustard or sinigrin remained <7 log CFU/g LAB for ≤ 70 d. L. monocytogenes played a key role in exerting control over its own viability in bologna by hydrolysis of the glucosinolate in the oriental mustard film, but other antimicrobials in treatments may have contributed.