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.     

An explanation for the effect of inoculum size on MIC and the growth/no growth interface

The inoculum effect (IE) is the phenomenon observed where changes in the inoculum size used in an experiment alters the outcome with respect to, for example, the minimum inhibitory concentration of an antimicrobial or the growth/no growth boundary for a given set of environmental conditions. Various hypotheses exist as to the cause of the IE such as population heterogeneity and quorum sensing, as well as the null hypothesis - that it is artefactual. Time to detection experiments (TTD) were carried out on different initial inoculum sizes of several bacterial species (Aeromonas hydrophila, Enterobacter sakazakii, Salmonella Poona, Escherichia coli and Listeria innocua) when challenged with different pH and with combined pH and sodium acetate. Data were modelled using a modification to a Gamma model (Lambert and Bidlas 2007, Int. J. Food Microbiology 115, 204-213), taking into account the inoculum size dependency on the TTD obtained under ideal conditions. The model suggests that changes in minimum inhibitory concentration (MIC) or in the growth-no growth boundary with respect to inoculum size are due to using a smaller or larger inoculum (i.e. is directly related to microbial number) and is not due to other, suggested, phenomena. The model used further suggests that the effect of a changing inoculum size can be modelled independently of any other factor, which implies that a simple 1 to 2-day experiment measuring the TTD of various initial inocula can be used as an adjunct to currently available models.     

Association between cigarette smoking and C-reactive protein in a representative, population-based sample of adolescents.

Although related to inflammatory markers in adults, little is known about the association between cigarette smoking and C-reactive protein (CRP) in adolescent smokers. We examined the association between high-sensitivity CRP (hs-CRP) concentrations and smoking in youth. We used data from a cross-sectional, province-wide survey of a representative sample of youth conducted in Quebec, Canada, in 1999. Data were collected in self-report questionnaires completed by participants and their parents. Participants provided a fasting blood sample, and anthropometric measures were undertaken by trained technicians. The present analysis pertains to 1,501 adolescents aged 13 and 16 years who completed questionnaires and for whom blood samples were available. The independent association between a six-category indicator of smoking status and elevated hs-CRP, defined as a value at least in the 90th percentile of the age- and sex-specific CRP distribution, was assessed in multiple logistic regression analyses controlling for potential confounders. Relative to never-smokers, the odds ratios (95% confidence intervals) for puffers (i.e., never smoked a whole cigarette), those who smoked but not in the past month, light past-month smokers, moderate past-month smokers, and heavy past-month smokers were 1.04 (0.55-1.98), 1.76 (1.06-2.94), 1.39 (0.70-2.76), 2.07 (0.96-4.42), and 2.40 (1.18-4.88), respectively. Our data suggest a positive association between smoking status and elevated CRP in adolescents, and in particular among heavier past-month smokers. Damage related to cigarette smoking may begin soon after tobacco use initiation, reinforcing the preventive message that no level of smoking is safe in youth.     

Effect of solid surface composition on the migration of tributyltin in groundwater

Tributyltin (TBT) is the most important organotin compound that has been introduced into aquatic ecosystems. A better understanding of its interactions with solid surfaces is essential to estimate the possibilities of TBT migration through subsurface environments. For this purpose, TBT sorption onto a porous matrix of natural origin, a quartz sand as an aquifer material, was studied at low concentration levels with a monodirectional model of column type allowing sequential investigation of sorption and desorption processes. Different treatments of the solid phase were performed by injecting alkaline solutions, NaOH at pH 10.8 or NaClO-NaCl at pH 11.5, by decreasing the ionic strength or by adding kaolinite to change the surface composition and properties. The removal of iron and aluminum (hydr)oxides from the sand surface did not affect so much the sorption (decrease in 14% as compared to sorption on the raw sand). The original use of X-ray photoelectron spectroscopy to control treatment efficiency and to characterize sand surface modifications permitted to relate TBT sorption onto the aquifer material to quartz, the main component of the sand, and clay minerals (mainly kaolinite) present at trace levels at the sand surface. A first attempt of transport modeling with these two surface sites showed the consistency of our assumption. Moreover, estimation of Langmuir-type constants showed that TBT sorption affinity for the quartz surface (KL = 26.7 L micromol(-1)) was much greater than for kaolinite (KL = 6.3 L micromol(-1)).     

Bayesian density estimation from grouped continuous data

Grouped data occur frequently in practice, either because of limited resolution of instruments, or because data have been summarized in relatively wide bins. A combination of the composite link model with roughness penalties is proposed to estimate smooth densities from such data in a Bayesian framework. A simulation study is used to evaluate the performances of the strategy in the estimation of a density, of its quantiles and first moments. Two illustrations are presented: the first one involves grouped data of lead concentration in the blood and the second one the number of deaths due to tuberculosis in The Netherlands in wide age classes.     

Amber: the organic gemstone

Resins are produced by woody plants on a worldwide basis. We have found several distinct classes of modern diterpenoid resins based phenomenologically on the solid-state (13)C NMR spectra of the bulk material. Resin fossilizes over millions of years into a robust material sometimes called amber. We have characterized several hundred samples of fossil resin by solid-state (13)C NMR spectroscopy. We can relate one globe-spanning group of fossil resins to the modern genus Agathis, based on spectral evolution over time. A second large group has not been related with certainty to specific modern plants. Fossil resins from Europe fall into two categories, the famous Baltic ambers and another that resembles the Agathis group. Fossil resins from the Americas and Africa are closely related to the modern genus Hymenaea. Based on spectral distinctions, fossil resin found in an archaeological context sometimes can be assigned to a specific geographical origin on the basis of its (13)C NMR spectrum.