Le phénomène de l'intimidation en milieu scolaire : pistes d'intervention pour le counseling de carrière.

De façon générale, l'école se veut source d'enrichissement, de belles découvertes et de création de nouvelles amitiés. Cependant, pour grand nombre d'élèves qui sont victimes d'intimidation en milieu scolaire, ce parcours scolaire se vit dans la peur, l'anxiété et la solitude. Les conséquences vécues auront aussi un impact sur l'orientation professionnelle de ces jeunes, dont l'altération du concept de soi, qui aurait une influence sur le développement de carrière (Super, 1963, dans Bujold, et Gingras, 2000). On parle aussi de l'anxiété qui occuperait un rôle dans l'indécision vocationnelle (Forner, 2007), ainsi que la destruction de relations sociales essentielles pour l'exploration de soi et l'exploration de son environnement (Bluestein et Felsman, 1999), et l'absence de sentiment de sécurité pouvant influencer la prise de décision (Blusstein, Préziozo et Schultheiss, 1995; Hall, Moradi, Tokar et Withrow, 2003, dans Savard, 2008). Par cette analyse, la question de recherche suivante est formulée : quelles sont les pistes d'intervention possibles pour les conseillères et les conseillers d'orientation qui interviennent auprès des élèves victimes d'intimidation en milieu scolaire? Le deuxième chapitre est consacré à la définition des concepts étudiés pour parvenir à répondre à la question de recherche. Au troisième chapitre, la méthodologie permettant d'effectuer le parallèle entre les concepts étudiés et l'intervention en counseling de carrière est présentée. Au quatrième chapitre, les pistes d'intervention possibles pour les conseillères et les conseillers d'orientation sont identifiées. Finalement, en guise de conclusion, il y a l'identification des limites de cet étude et des éléments qu'éclaire cette recherche sur le plan de l'orientation et de la recherche en général, ainsi que les études pouvant s'ensuivre

A novel method for tissue-specific RNAi rescue in Drosophila

Targeted gene silencing by RNA interference allows the study of gene function in plants and animals. In cell culture and small animal models, genetic screens can be performed—even tissue-specifically in Drosophila—with genome-wide RNAi libraries. However, a major problem with the use of RNAi approaches is the unavoidable false-positive error caused by off-target effects. Until now, this is minimized by computational RNAi design, comparing RNAi to the mutant phenotype if known, and rescue with a presumed ortholog. The ultimate proof of specificity would be to restore expression of the same gene product in vivo. Here, we present a simple and efficient method to rescue the RNAi-mediated knockdown of two independent genes in Drosophila. By exploiting the degenerate genetic code, we generated Drosophila RNAi Escape Strategy Construct (RESC) rescue proteins containing frequent silent mismatches in the complete RNAi target sequence. RESC products were no longer efficiently silenced by RNAi in cell culture and in vivo. As a proof of principle, we rescue the RNAi-induced loss of function phenotype of the eye color gene white and tracheal defects caused by the knockdown of the heparan sulfate proteoglycan syndecan. Our data suggest that RESC is widely applicable to rescue and validate ubiquitous or tissue-specific RNAi and to perform protein structure–function analysis

New hydroxylated metabolites of 4-monochlorobiphenyl in whole poplar plants

Two new monohydroxy metabolites of 4-monochlorobiphenyl (CB3) were positively identified using three newly synthesized monohydroxy compounds of CB3: 2-hydroxy-4-chlorobiphenyl (2OH-CB3), 3-hydroxy-4-chlorobiphenyl (3OH-CB3) and 4-hydroxy-3-chlorobiphenyl (4OH-CB2). New metabolites of CB3, including 2OH-CB3 and 3OH-CB3, were confirmed in whole poplars (Populus deltoides × nigra, DN34), a model plant in the application of phytoremediation. Furthermore, the concentrations and masses of 2OH-CB3 and 3OH-CB3 formed in various tissues of whole poplar plants and controls were measured. Results showed that 2OH-CB3 was the major product in these two OH-CB3s with chlorine and hydroxyl moieties in the same phenyl ring of CB3. Masses of 2OH-CB3 and 3OH-CB3 in tissues of whole poplar plants were much higher than those in the hydroponic solution, strongly indicating that the poplar plant itself metabolizes CB3 to both 2OH-CB3 and 3OH-CB3. The total yield of 2OH-CB3 and 3OH-CB3, with chlorine and hydroxyl in the same phenyl ring of CB3, was less than that of three previously found OH-CB3s with chlorine and hydroxyl in the opposite phenyl rings of CB3 (2'OH-CB3, 3'OH-CB3, and 4'OH-CB3). Finally, these two newly detected OH-CB3s from CB3 in this work also suggests that the metabolic pathway was via epoxide intermediates. These five OH-CB3s clearly showed the complete metabolism profile from CB3 to monohydroxylated CB3. More importantly, it's the first report and confirmation of 2OH-CB3 and 3OH-CB3 (new metabolites of CB3) in a living organism

Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies

Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement.Methods We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms.Results We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%).Conclusions We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim

Statin treatment and mortality in community-dwelling frail older patients with diabetes mellitus

Background: Older adults are often excluded from clinical trials. Decision making for administration of statins to older patients with diabetes mellitus (DM) is under debate, particularly in frail older patients with comorbidity and high mortality risk. We tested the hypothesis that statin treatment in older patients with DM was differentially effective across strata of mortality risk assessed by the Multidimensional Prognostic Index (MPI), based on information collected with the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA). Methods: In this retrospective observational study, we estimated the mortality risk in 1712 community-dwelling subjects with DM ≥ 65 years who underwent a SVaMA evaluation to establish accessibility to homecare services/nursing home admission from 2005 to 2013 in the Padova Health District, Italy. Mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), and high (MPI-SVaMA-3) risk of mortality at baseline and propensity score-adjusted hazard ratios (HR) of three-year mortality were calculated according to statin treatment. Results: Higher MPI-SVaMA scores were associated with lower rates of statin treatment (MPI-SVaMA-1 = 39% vs MPI-SVaMA-2 = 36% vs MPI-SVaMA-3 = 24.9%. p<0.001) and higher three-year mortality (MPI-SVaMA-1 = 12.9% vs MPI-SVaMA-2 = 24% vs MPI-SVaMA-3 = 34.4%, p<0.001). After adjustment for propensity score quintiles, statin treatment was significantly associated with lower three-year mortality irrespective of MPI-SVaMA group (interaction test p = 0.303). HRs [95% confidence interval (CI)] were 0.19 (0.14-0.27), 0.28 (0.21-0.36), and 0.26 (0.20-0.34) in the MPI-SVaMA-1, MPI-SVaMA-2, and MPI-SVaMA-3 groups, respectively. Subgroup analyses showed that statin treatment was also beneficial irrespective of age. HRs (95% CI) were 0.21 (0.15-0.31), 0.26 (0.20-0.33), and 0.26 (0.20-0.35) among patients aged 65-74, 75-84, and ≥ 85 years, respectively (interaction test p=0.812). Conclusions: Statin treatment was significantly associat

The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis

Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors(1). Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2(V617F) (JAK2(VF)) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease(1,2). Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2(VF) selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2(VF) lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2(VF) lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1 beta reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2(VF) macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1 beta or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk

Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 x 10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84 x 10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at similar to 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Rapid sample delivery for megahertz serial crystallography at X-ray FELs

Liquid microjets are a common means of delivering protein crystals to the focus of X-ray free-electron lasers (FELs) for serial femtosecond crystallography measurements. The high X-ray intensity in the focus initiates an explosion of the microjet and sample. With the advent of X-ray FELs with megahertz rates, the typical velocities of these jets must be increased significantly in order to replenish the damaged material in time for the subsequent measurement with the next X-ray pulse. This work reports the results of a megahertz serial diffraction experiment at the FLASH FEL facility using 4.3 nm radiation. The operation of gas-dynamic nozzles that produce liquid microjets with velocities greater than 80 m s-1 was demonstrated. Furthermore, this article provides optical images of X-ray-induced explosions together with Bragg diffraction from protein microcrystals exposed to trains of X-ray pulses repeating at rates of up to 4.5 MHz. The results indicate the feasibility for megahertz serial crystallography measurements with hard X-rays and give guidance for the design of such experiments

Reduced Food Intake and Body Weight in Mice Deficient for the G Protein-Coupled Receptor GPR82

G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments