Crystal Structure of the Human Monoacylglycerol Lipase,a Key Actor in Endocannabinoid Signaling

2‐Arachidonoylglycerol plays a major role in endocannabinoid signaling, and is tightly regulated by the monoacylglycerol lipase (MAGL). Here we report the crystal structure of human MAGL. The protein crystallizes as a dimer, and despite structural homologies to haloperoxidases and esterases, it distinguishes itself by a wide and hydrophobic access to the catalytic site. An apolar helix covering the active site also gives structural insight into the amphitropic character of MAGL, and likely explains how MAGL interacts with membranes to recruit its substrate. Docking of 2‐arachidonoylglycerol highlights a hydrophobic and a hydrophilic cavity that accommodate the lipid into the catalytic site. Moreover, we identified Cys201 as the crucial residue in MAGL inhibition by N‐arachidonylmaleimide, a sulfhydryl‐reactive compound. Beside the advance in the knowledge of endocannabinoids degradation routes, the structure of MAGL paves the way for future medicinal chemistry works aimed at the design of new drugs exploiting 2‐arachidonoylglycerol transmission.     

X-Ray Micro-Calorimeter Based on Si Thermistors for X-Ray Astronomy: Design and First Measurements

X-ray Astronomy provides a unique window on a wide variety of astrophysical phenomena. The currently operating X-ray space observatories perform X-ray spectral imaging with the use of CCDs. When available, cryogenic X-ray microcalorimeter arrays will far outperform CCDs in terms of spectral resolution, energy bandwidth and count rate. Experience has been gained with Infra-Red bolometer arrays at CEA-LETI (Grenoble) in collaboration with the CEA-SAp (Saclay); taking advantage of this background, we are now developing an X-ray spectro-imaging camera for the next generation space astronomy missions, using silicon technology (implanted and high temperature diffused thermistors). Each pixel of this array detector is made of a tantalum absorber bound, by indium bump hybridization, to a silicon thermistor. The absorber array is bound to the thermistor array in a single automatic step. The thermo-mechanical link, provided by hybridization, is being improved in terms of thermal capacitance. Finally, our main effort is in developing arrays of silicon thermistors with negligible excess 1/f noise. The thermistor has been simulated with the 2D simulator ATHENA (SILVACO International). We studied the effects of the implants and their thermal treatment on both vertical and lateral dopant distributions at the edges of the thermistor. Prototypes have been created following the procedure optimized by the ATHENA simulation. We present the status of the development and results of measurements performed on these four main building blocks required to create a detector array up to 32×32 pixels in size.      

Ultrasound contribution in the analysis of the newborn and infant normal and clubfoot: a preliminary study

This study examined the effects of coder gender on Potential for Hostility ratings. Six trained coders (3 men and 3 women) who were unaware of the coder gender effect hypothesis coded 30 male and 30 female undergraduates for Potential for Hostility. Although reliability estimates as calculated by Cronbach's alpha suggested that all coders were consistent, an analysis of variance revealed a significant main effect for coder gender, wherein female coders rated participants as displaying significantly less Potential for Hostility than did male coders. This significant difference was also meaningful, as coder gender accounted for 32% of the variance in Potential for Hostility scores. Thus, future Potential for Hostility investigations need to consider the gender of those coding, as this factor both significantly and substantially influences reported Potential for Hostility ratings.     

Designing highly flexible virtual machines: the JnJVM experience

Dynamic flexibility is a major challenge in modern system design to react to context or applicative requirements evolutions. Adapting behaviors may impose substantial code modification across the whole system, in the field, without service interruption and without state loss. This paper presents the JnJVM, a full Java virtual machine (JVM) that satisfies these needs by using dynamic aspect weaving techniques and a component architecture. It supports adding or replacing its own code, while it is running, with no overhead on unmodified code execution. Our measurements reveal similar performance when compared with the monolithic JVM Kaffe. Three illustrative examples show different extension scenarios: (i) modifying the JVMs behavior; (ii) adding capabilities to the JVM; and (iii) modifying applications behavior. Copyright © 2008 John Wiley & Sons, Ltd.     

Ocular involvement in Epstein-Barr virus-associated T-cell lymphoma

PURPOSE: To determine if serous retinal detachment may occur in a case of Epstein-Barr virus-associated T-cell lymphoma. METHODS: We examined a 51-year-old man who had recent loss of vision and poor general health. RESULTS: Ocular involvement consisted of bilateral serous retinal detachment and choroidal infiltrates. The diagnosis of lymphoma was made by liver biopsy. The course of the disease was fulminant. Postmortem histologic examination disclosed a massive infiltration of the choroid and hematopoietic organs by pleomorphic large T cells. Epstein-Barr virus was detected by in situ hybridization. CONCLUSION: Ocular involvement, including choroidal infiltrates and serous retinal detachment, may occur in Epstein-Barr virus-associated T-cell lymphoma.     

CAY10499, a novel monoglyceride lipase inhibitor evidenced by an expeditious MGL assay

Monoglyceride lipase (MGL) plays a major role in the metabolism of the lipid transmitter 2-arachidonoylglycerol (2-AG). This endocannabinoid is known to mediate a large number of physiological processes, and its regulation is thought to be of great therapeutic potential. However, the number of available monoglyceride lipase inhibitors is limited, mostly due to the lack of rapid and accurate pharmacological assays for the enzyme. We have developed a 96-well-format assay for MGL using a nonradiolabeled substrate, 4-nitrophenylacetate. The IC(50) values that were obtained for known inhibitors of MGL using 4-nitrophenylacetate were similar to those reported by using the radiolabeled form of an endogenous substrate, 2-oleoylglycerol. In a first small-scale screening, we identified CAY10499 as a novel monoglyceride lipase inhibitor. Thus, we report here the characterization of this submicromolar inhibitor, which acts on MGL through an unprecedented mechanism for inhibitors of this enzyme.     

Disulfiram is an inhibitor of human purified monoacylglycerol lipase, the enzyme regulating 2-arachidonoylglycerol signaling

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the termination of endocannabinoid signaling. Its crucial role in 2-arachidonoylglycerol (2-AG) metabolism, together with the numerous pharmacological properties mediated by this endocannabinoid, emphasize the interest in MAGL as therapeutic target, along with the need to design potent and selective inhibitors. Meanwhile, the complexity of 2-AG degradation pathways underscores the need to use a purified source of enzyme in evaluation studies of new inhibitors. We report here the first heterologous expression and purification of human MAGL. A highly pure protein was obtained and allowed us to measure the affinity of several MAGL inhibitors for the human enzyme. Importantly, disulfiram (tetraethylthiuram disulfide), a compound used to treat alcoholism, and other disulfide-containing compounds were shown to inhibit MAGL with good potency, likely through an interaction with cysteine residues.     

Detection of Morphological Abnormalities in Schizophrenia: An Important Step to Identify Associated Genetic Disorders or Etiologic Subtypes

Current research suggests that alterations in neurodevelopmental processes, involving gene X environment interactions during key stages of brain development (prenatal period and adolescence), are a major risk for schizophrenia. First, epidemiological studies supporting a genetic contribution to schizophrenia are presented in this article, including family, twin, and adoption studies. Then, an extensive literature review on genetic disorders associated with schizophrenia is reviewed. These epidemiological findings and clinical observations led researchers to conduct studies on genetic associations in schizophrenia, and more specifically on genomics (CNV: copy-number variant, and SNP: single nucleotide polymorphism). The main structural (CNV) and sequence (SNP) variants found in individuals with schizophrenia are reported here. Evidence of genetic contributions to schizophrenia and current knowledge on genetic syndromes associated with this psychiatric disorder highlight the importance of a clinical genetic examination to detect minor physical anomalies in individuals with ultra-high risk of schizophrenia. Several dysmorphic features have been described in schizophrenia, especially in early onset schizophrenia, and can be viewed as neurodevelopmental markers of vulnerability. Early detection of individuals with neurodevelopmental abnormalities is a fundamental issue to develop prevention and diagnostic strategies, therapeutic intervention and follow-up, and to ascertain better the underlying mechanisms involved in the pathophysiology of schizophrenia.