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The GPR17 receptor, expressed on oligodendroglial precursors (OPCs, the myelin producing cells), has emerged as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS). However, the proof-of-concept that selective GPR17 ligands actually exert protective activity in vivo is still missing. Here, we exploited an iterative drug discovery pipeline to prioritize novel and selective GPR17 pro-myelinating agents out of more than 1,000,000 compounds. We first performed an in silico high-throughput screening on GPR17 structural model to identify three chemically-diverse ligand families that were then combinatorially exploded and refined. Top-scoring compounds were sequentially tested on reference pharmacological in vitro assays with increasing complexity, ending with myelinating OPC-neuron co-cultures. Successful ligands were filtered through in silico simulations of metabolism and pharmacokinetics, to select the most promising hits, whose dose and ability to target the central nervous system were then determined in vivo. Finally, we show that, when administered according to a preventive protocol, one of them (named by us as galinex) is able to significantly delay the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. This outcome validates the predictivity of our pipeline to identify novel MS-modifying agents.OBJECTIVE This meta-analysis aimed at critically assessing currently available evidence regarding the overall effectiveness of Piezocision in accelerating orthodontic tooth movement, as well as the adverse effects of this intervention in orthodontic patients. SEARCH METHODS Electronic search of 6 databases and additional manual searches up to April 2019 without restrictions, also update the search was done by 20th November. SELECTION CRITERIA Randomized controlled trials (RCT) and controlled clinical trials (CCT) reporting piezocision-assisted orthodontics versus conventional orthodontics were included in the review. DATA COLLECTION AND ANALYSIS The data are expressed by mean differences (MD), 95% confidence intervals, fixed-effect model or random-effect model in the meta-analysis in regard to statistical heterogeneity analyses (tau2, and I2). Included randomized studies were assessed for risk of bias using the new Cochrane Risk of Bias tool (ROB.2) and the non-randomized studies were assessed using (ROBINS Iappears to be clinically insignificant. SYSTEMATIC REVIEW REGISTRATION CRD42019136303.Typically discretisation procedures are implemented as a part of initial pre-processing of data, before knowledge mining is employed. It means that conclusions and observations are based on reduced data, as usually by discretisation some information is discarded. The paper presents a different approach, with taking advantage of discretisation executed after data mining. In the described study firstly decision rules were induced from real-valued features. Secondly, data sets were discretised. Using categories found for attributes, in the third step conditions included in inferred rules were translated into discrete domain. The properties and performance of rule classifiers were tested in the domain of stylometric analysis of texts, where writing styles were defined through quantitative attributes of continuous nature. TAK-861 nmr The performed experiments show that the proposed processing leads to sets of rules with significantly reduced sizes while maintaining quality of predictions, and allows to test many data discretisation methods at the acceptable computational costs.Many subjects with neuropathologically-confirmed dementia with Lewy bodies (DLB) are never diagnosed during life, instead being categorized as Alzheimer’s disease dementia (ADD) or unspecified dementia. Unrecognized DLB therefore is a critical impediment to clinical studies and treatment trials of both ADD and DLB. There are studies that suggest that olfactory function tests may be able to distinguish DLB from ADD, but few of these had neuropathological confirmation of diagnosis. We compared University of Pennsylvania Smell Identification Test (UPSIT) results in 257 subjects that went on to autopsy and neuropathological examination. Consensus clinicopathological diagnostic criteria were used to define ADD and DLB, as well as Parkinson’s disease with dementia (PDD), with (PDD+AD) or without (PDD-AD) concurrent AD; a group with ADD and Lewy body disease (LBD) not meeting criteria for DLB (ADLB) and a clinically normal control group were also included. The subjects with DLB, PDD+AD and PDD-AD all had lower (one-way ANOVA p less then 0.0001, pairwise Bonferroni p less then 0.05) first and mean UPSIT scores than the ADD, ADLB or control groups. For DLB subjects with first and mean UPSIT scores less than 20 and 17, respectively, Firth logistic regression analysis, adjusted for age, gender and mean MMSE score, conferred statistically significant odds ratios of 17.5 and 18.0 for the diagnosis, vs ADD. For other group comparisons (PDD+AD and PDD-AD vs ADD) and UPSIT cutoffs of 17, the same analyses resulted in odds ratios ranging from 16.3 to 31.6 (p less then 0.0001). To our knowledge, this is the largest study to date comparing olfactory function in subjects with neuropathologically-confirmed LBD and ADD. Olfactory function testing may be a convenient and inexpensive strategy for enriching dementia studies or clinical trials with DLB subjects, or conversely, reducing the inclusion of DLB subjects in ADD studies or trials.INTRODUCTION We sought to estimate the prevalence, severity and identify predictors of violence among adolescent girls and young women (AGYW) in informal settlement areas of Nairobi, Kenya, selected for DREAMS (Determined Resilient Empowered AIDS-free, Mentored and Safe) investment. METHODS Data were collected from 1687 AGYW aged 10-14 years (n = 606) and 15-22 years (n = 1081), randomly selected from a general population census in Korogocho and Viwandani in 2017, as part of an impact evaluation of the “DREAMS” Partnership. For 10-14 year-olds, we measured violence experienced either in the past 6 months or ever using a different set of questions from those used for 15-22 year-olds. Among 15-22 year-olds we measured prevalence of violence, experienced in the past 12 months, using World Health Organization (WHO) definitions for violence typologies. Predictors of violence were identified using multivariable logit models. RESULTS Among 606 girls aged 10-14 years, about 54% and 7% ever experienced psychological and sexual violence, respectively.