Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase

SMYD3 is a multifunctional epigenetic enzyme with lysine methyltransferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened in a biosensor-based competition assay. Diperodon was identified as an allosteric ligand; its R and S enantiomers were isolated, and their affinities to SMYD3 were determined (K_D=42 and 84 μM, respectively). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although SMYD3–HSP90 binding was confirmed (K_D=13 μM). Diperodon clearly represents a novel starting point for the design of tool compounds interacting with a druggable allosteric site, suitable for the exploration of noncatalytic SMYD3 functions and therapeutics with new mechanisms of action.     

New Insights into the Decisional Use of Process Capability Indices via Hypothesis Testing

Process capability indices C_p, C_pk, and C_pm are still nowadays widely used in industry—thanks to their easy formulation and implementation. This paper aims to give new mathematical insights in order to support their use in decision‐making via hypothesis testing. The minimum sample size usually needed in the applications to achieve fixed significance level and power is reported in light of the new mathematical aspects for C_pk and C_pm, which avoid misleading conclusions and the use of extensive numerical experiments. In addition, power curves for C_pk and C_pm, which have not previously appeared in the literature before, are also presented. Lastly, easy‐to‐follow diagrams for hypothesis testing with C_pk and C_pm and two critical scenarios for C_pm are included in the paper to facilitate the applicative use and the comprehension of the novel inferential aspects. Copyright © 2014 John Wiley & Sons, Ltd.     

A DNA Methyltransferase Modulator Inspired by Peyssonenyne Natural Product Structures

A novel epigenetic modulator that displays a DNMT1 inhibition and DNMT3A activation profile was characterized (compound 8 ). This compound is a derivative of palmitic acid that incorporates the putative reactive functional group (diynone) of the peyssonenyne natural products. Other analogues containing the diynone or an acetoxyenediyne did not show the same biological profile. In U937 human leukemia cells, diynone 8 induced cell differentiation and apoptosis, which correlated with the expression of Fas protein. Very surprisingly, diynone 8 was toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL); this unique effect was not observed with the classical DNMT inhibitor 5‐azacytidine. Therefore, compound 8 interferes in a very specific manner with signaling pathways, the activities of which differ between normal and immortalized cell types. This toxicity is reminiscent of the effects of Dnmt1 ablation on mouse fibroblasts. In fact, some of the genes deregulated by the loss of Dnmt1 are similarly deregulated by 8 , but not by the DNMT inhibitor SGI‐1027.     

How two becomes one: Functions of the corpus callosum: 1 + 1 = 1, ou comment le corps calleux unifie nos expériences.

Postulates that the corpus callosum, which transmits lateralized information across the hemispheres, may also be involved in midline fusion so that lateralized sensory experiences are felt as unique and continuous even when a stimulus crosses the midline of the body or of extra-personal space. Results from animal studies show that the neuronal organization that permits this function is both innately determined but also susceptible to environmental influences. Electrophysiological experiments confirm that the callosum is specifically involved in midline activation for the visual and somatosensory systems but less so for the auditory system, suggesting that the midline principle applies mainly to highly lateralized sensory systems. Behavioral studies with Ss having callosal pathology confirmed the hypotheses derived from the electrophysiological experiments. (English abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intercostal incisional hernia: case report

The authors report a case of intercostal incisional hernia following marsupialization of liver hydatid cyst stressing the considerable rarity of the pathology and describing the restorative procedure by intercostal plastic with polypropilene Mesh and rib's approach with stainless steel wires.     

Residential density and psychological health: The mediating effects of social support.

People report excessive, unwanted social interactions, insufficient privacy, and are observed to be more socially withdrawn under crowded living conditions. If people socially withdraw from one another as a way to cope with crowding, this could lead to an unintended side effect of breakdowns in socially supportive relationships. A breakdown in socially supportive relationships could, in turn, account for some of the pathological consequences of chronic, high density living conditions. An empirical study of 175 male heads of household among inner city residents in India suggests that the adverse effects of residential crowding on psychological health are mediated by a breakdown of social support systems. The study also points to the value of examining social support as an endogenous variable in the stress and health process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic residential crowding and children's well-being: an ecological perspective

Chronic residential crowding is associated with difficulties in behavioral adjustment at school, poor academic achievement, heightened vulnerability to the induction of learned helplessness, elevated blood pressure, and impaired parent-child interpersonal relationships among a sample of working-class, 10-to 12-year-old children living in urban India. The significant main effects of residential crowding on blood pressure and learned helplessness are moderated by gender. Residential crowding is positively associated with blood pressure only among boys and with helplessness only among girls. All analyses statistically control for household income. We then demonstrate that perceived parent-child conflict functions as an underlying, intervening process that largely accounts for several correlates of household crowding among children.     

Upper airway obstruction induced by warfarin sodium

I report a patient in whom warfarin sodium induced upper airway obstruction secondary to a spontaneous nontraumatic hemorrhage into the sublingual space. Treatment of this obstructive sublingual space hematoma with conservative medical management is reviewed. I discuss the role of warfarin sodium in coagulation and in the production of this pseudo-Ludwig phenomenon.