Targeting endocannabinoid signaling: FAAH and MAG lipase inhibitors

Inspired by the medicinal properties of the plant Cannabis sativa and its principal component (−)-trans-Δ9-tetrahydrocannabinol (THC), researchers have developed a variety of compounds to modulate the endocannabinoid system in the human brain. Inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are the enzymes responsible for the inactivation of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, respectively, may exert therapeutic effects without inducing the adverse side effects associated with direct cannabinoid CB1 receptor stimulation by THC. Here we review the FAAH and MAGL inhibitors that have reached clinical trials, discuss potential caveats, and provide an outlook on where the field is headed.NWOMolecular Physiolog

Cronin effect and energy conservation constraints in high energy proton-nucleus collisions

We estimate the Cronin effect in pA collisions at the CERN LHC and at RHIC, using a Glauber-Eikonal model of initial state multiparton interactions. For a correct determination of the initial parton flux, we upgrade the model cross section, taking carefully into account all kinematical constraints of each multi-parton interaction process. As compared with previous results, derived with approximate kinematics, we obtain a softer spectrum of produced partons, while improving the agreement of the model with the recent measurements of neutral pions production in d+Au collisions at sqrt(s)=200 AGeV.Comment: Accepted by Phys.Rev.

B-decay CP-asymmetries in SUSY with a U(2)^3 flavour symmetry

We study CP asymmetries in rare B decays within supersymmetry with a U(2)^3 flavour symmetry, motivated by the SUSY flavour and CP problems, the hierarchies in the Yukawa couplings and the absence so far of any direct evidence for SUSY. Even in the absence of flavour-blind phases, we find potentially sizable CP violating contributions to b -> s decay amplitudes. The effects in the mixing-induced CP asymmetries in B ->phi K(S) and B -> eta' K(S), angular CP asymmetries in B -> K* mu+ mu- and the direct CP asymmetry in B -> X(s) gamma can be in the region to be probed by LHCb and next generation B factories. At the same time, these effects in B decays are compatible with CP violating contributions to meson mixing, including a non-standard B(s) mixing phase hinted by current tensions in the CKM fit mostly between S(psi K(S)), epsilon(K) and Delta M(B(s))/Delta M(B(d)).Comment: 13 pages, 3 figure

Chemical proteomics reveals antibiotic targets of oxadiazolones in MRSA

Molecular PhysiologyBio-organic Synthesi

Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

The TREAT-NMD DMD Global Database: Analysis of more than 7,000 Duchenne Muscular Dystrophy mutations

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations)

Efeito do dimetildioctadecilamônio na resposta imune humoral e celular de cobaios inoculados com o herpesvírus bovino-1 inativado Effect of dimethyl dioctadecyl ammonium chloride on the humoral and cellular response to inactivated bovine herpesvirus-1 in guinea pigs

Avaliou-se o potencial adjuvante do cloreto de dimetildioctadecilamônio (DDA cloreto) em estimular as respostas imune humoral e celular, do tipo hipersensibilidade cutânea tardia (DTH), em cobaios que receberam preparações de antígeno contendo o herpesvírus bovino tipo 1 (BHV-1) inativado. Os animais foram vacinados com o BHV-1 em cinco diferentes formulações, representadas pelos grupos: A- adjuvante completo / incompleto de Freund, B- hidróxido de alumínio (Al(OH)3), C- DDA cloreto, D- associação Al(OH)3 / DDA cloreto e E- BHV-1 em solução aquosa sem adjuvante. Os animais do grupo F, grupo-controle negativo, foram inoculados apenas com meio de cultivo celular. Os maiores títulos de anticorpos neutralizantes do BHV-1, expressos em log2, foram obtidos nos grupos D, A e C, com títulos de 6,25, 6,0 e 5,25, respectivamente. Na avaliação da DTH, os maiores aumentos na espessura da dobra da pele foram observados nos grupos A (2,4mm), C (1,8mm) e D (1,1mm). O DDA cloreto, utilizado tanto de forma isolada quanto em associação, determinou a potencialização das respostas imunológicas humoral e celular de cobaios imunizados com o BHV-1 inativado.<br>The adjuvanticity of dimethyl dioctadecyl ammonium chloride (DDA chloride) to induce humoral and cell mediated (delayed type hypersensitivity - DTH -) immune responses was assessed in guinea pigs that received antigen preparations containing inactivated bovine herpesvirus type 1 (BHV-1). The animals were vaccinated with five different formulations, containing BHV-1 represented by groups: A- complete/incomplete Freund adjuvant, B- aluminum hydroxide (Al(OH)3), C- DDA chloride, D- association Al(OH)3/DDA and E- BHV-1 in aqueous solution without adjuvant. Group F was the negative control group and the animals received only cell culture medium. The higher titers of BHV-1 neutralizing antibodies, expressed in log2, were obtained in groups D, A and C with values of 6.25, 6.0 and 5.25, respectively. In the DTH assessment, the higher increase in skin thickness was observed in group A (2.4mm), C (1.8mm) and D (1.1mm). These results showed that DDA chloride used alone or in association to other substance boosted the humoral and cell mediated immune responses in guinea pigs immunized with inactivated BHV-1

Theoretical investigation of free-standing CoPd nanoclusters as a function of cluster size and stoichiometry in the Pd-rich phase: Geometry, chemical order, magnetism, and metallic behavior

We report on a study of the geometrical structure, magnetic properties, and metallic behavior of free-standing CoPd nanoclusters with N=7, 13, 19, 23, and 26 atoms, as a function of cluster size and stoichiometry, in the Pd-rich phase. The investigated structures were obtained using a Gupta potential in combination with a genetic algorithm energy minimization. The electronic properties of the ground state geometrical structures were determined by solving a self-consistent spd tight-binding Hamiltonian. The metallic behavior was studied using Kubo's criterion. We tested our approach against benchmark SIESTA calculations for some of the small clusters investigated in the present work. We discuss the competition between segregation and mixing effects by means of an order parameter. The magnetic moments are analyzed in the context of the local chemical and atomic environments and we propose a simple empirical expression for the average magnetic moment per atom of these binary clusters. ©

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

These authors contributed equally: Gail Davies, Max Lam. These authors jointly supervised this work: Todd Lencz, Ian J. Deary