Synthèse d'inhibiteurs des aminoacyl-ARNt synthétases et des aminoacyl-ARNt amidotransférases

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2011-2012Les aminoacyl-ARNt synthetases (aaRS) sont des enzymes essentielles au processus de traduction des acides nucléiques (ADN) en séquences d'acides aminés (protéines). Elles catalysent l'estérification de chacun des 20 acides aminés à leurs ARN de transfert respectifs. Dans une première étape, l'acide aminé est activé pour donner un intermédiaire instable (aa-AMP), lequel réagit avec l'ARNt correspondant dans une seconde étape pour générer l'ARNt aminoacylé (aa-ARNt). Les inhibiteurs synthétisés dans le cas présent sont des analogues de l'intermédiaire instable (chapitres 2, 3 et 4). Les inhibiteurs des aminoacyl-ARNt synthetases ont plusieurs utilités : faciliter la cristallisation des aaRS en vue de déterminer leurs structures par diffraction des rayons-X, étudier les mécanismes réactionnels des aaRS, et à plus long terme, approfondir la recherche sur de nouvelles thérapies antibiotiques. Les aaRS ont évolué de façon divergente entre les procaryotes et les eucaryotes, ce qui rend possible l'inhibition sélective des aaRS bactériennes. Plusieurs bactéries ne possèdent pas la glutamine-ARNt synthetase et utilisent donc une voie indirecte pour le chargement de l'ARNt correspondant (Gln-ARNtGln). En premier lieu, l'acide glutamique est estérifié avec l'ARNt par une glutamyl-ARNt synthetase non discriminante (ND-GluRS). L'ARNtGln incorrectement apparié (Glu-ARNtGln) est par la suite transformé par une aminoacyl-ARNt amidotransférase (AdT) pour donner l'ARNt correctement apparié (Gln-ARNtGln). Ce type de mécanisme existe aussi pour le chargement de l'ARNt correspondant à l'asparagine (transamidation de l'Asp-ARNtAsn). Très peu d'inhibiteurs des aminoacyl-ARNt amidotransférases ont été rapportés jusqu'à maintenant. Pourtant, l'absence de cette enzyme dans le cytoplasme des cellules eucaryotes en fait une cible intéressante pour le développement d'antibiotiques. Le design et la synthèse de nouveaux inhibiteurs ont été réalisés en se basant sur le mécanisme des aminoacyl-ARNt amidotransférases (chapitre 5, 6 et 7)

La compétence collective mise en oeuvre par les infirmières à l'urgence : une étude de cas

Problématique : La compétence collective (CC), soit la combinaison dynamique des compétences individuelles, amènent des résultats supérieurs. Cette notion, peu étudiée en contexte infirmier, s’avère novatrice afin d’appréhender la performance des équipes soignantes. Objectif : Décrire la mise en œuvre de la CC par les infirmières en contexte d’observation à l’urgence d’un centre hospitalier québécois. Méthode : Étude de cas unique alliant sources documentaires (n = 32), observations (n = 3) et entrevues (n=3) selon la technique par incident critique. Résultats : Un déséquilibre (ex. instabilité, compétences) entraîne la combinaison des compétences individuelles centrée sur sa résolution visant une qualité des soins supérieure. Elle entraîne des résultats secondaires (développement des compétences, collaboration accrue). Différents facteurs individuels (compétence), collectifs (collaboration, relations), organisationnels (gestion, formation) et techniques (matériel, environnement) l’influencent. Conclusion : Les résultats soulignent l’apport significatif de la CC et les pistes d’action permettant d’améliorer la performance des équipes soignantes.Background: Collective competence (CC) is a dynamic combination of individual competence that bring superior results. This notion, little studied in nursing context, proves innovative in order to understand the performance of health care teams. Aim: To describe the implementation of the CC by nurses in a context of observation n a Quebec hospital emergency department. Method: Single study case combining documentary sources (n = 32), observations (n = 3) and interviews (n = 3) according to the critical incident technique. Results: An imbalance (eg instability, competence) leads to the combination of individual competence centered on the resolution to a higher quality of care. It causes secondary outcomes (competence development, increased collaboration). Various individual (competence), collective (collaboration, relationships), organizational (management, training) and technical (equipment, environment) factors influence it. Conclusion: The results highlight the significant contribution of the CC and the courses of action to improve the performance of health care teams

Grenzen und Möglichkeiten argumentativer Auseinandersetzungen und die unterrichtliche Ausbildung argumentativer Metakompetenzen

In dem vorliegenden Beitrag möchte ich an aktuelle argumentationsdidaktische Überlegungen anknüpfen und einen spezifischen Aspekt genauer untersuchen, der von der philosophiedidaktischen Forschung bisher ein Stück weit vernachlässigt worden ist. Dieser Aspekt betrifft die Vermittlung sogenannter argumentativer Metakompetenzen, worunter ich grob gesprochen Fähigkeiten des angemessenen Gebrauchs bzw. der verantwortungsvollen Regulation von argumentativen Kompetenzen verstehe. Die grundlegende Idee ist in diesem Zusammenhang, dass die Ausbildung basaler argumentativer Fähigkeiten zwar grundsätzlich durchaus wichtig und wünschenswert ist, dass aber gleichzeitig ein Einsatz dieser Fähigkeiten in unterschiedlichen Situationen ganz unterschiedliche Funktionen erfüllt. Dementsprechend müssen Lernende nicht nur mit argumentativen Kompetenzen ausgestattet, sondern darüber hinaus auch zu einem reflektierten und situativ angemessenen Gebrauch dieser Kompetenzen befähigt werden

An investigation into the determinants of exchange rate volatility

PhD ThesisExchange rate volatility has significant effects on decisions made by many economic agents who participate in foreign exchange markets, most notably exporters, importers and foreign investors. The literature in the field of international macroeconomics has mainly concentrated on changes in the level of exchange rates rather than exchange rate volatility itself. Since we believe that the second moment of the exchange rate should be given more attention, we directly investigate the relationship between exchange rate volatility and macroeconomic fundamentals in developed as well as developing countries. For this reason, from the traditional exchange rate models which relate exchange rate levels to a set of fundamentals, we derive equations that can be used to examine the determinants of exchange rate volatility. We also investigate the possible impact of different variability measures and data frequencies. Our empirical results are generated from a very recently developed approach to cointegration analysis, namely, the bounds testing method of Pesaran et al., 2001. Using four industrialized countries and four less developed countries over the period 1973 to 1998, we found that the volatility of some macroeconomic fundamentals does indeed have a significant impact on the volatility of exchange rates in both groups of countries. Finally, whilst different variability proxies and data frequencies slightly affect the signs of significant variables, they do highly impact on the significance and weight that should be given to the relevant fundamental.Libyan General People's Committee for Higher Educatio

Transcranial direct current stimulation (a-tCDS) after subacromial injections in patients with subacromial pain syndrome: a randomized controlled pilot study

Background: Subacromial pain syndrome (SAPS) is a common complaint in orthopaedics. Subacromial corticosteroid injections (CSI) can relieve pain in the short term. Anodal transcranial direct current stimulation (a-tDCS) has been used for symptomatic pain relief in a variety of chronic pain conditions. The aim of this pilot study was to assess whether the application a-tDCS could enhance the symptomatic relief provided by CSI in patients affected by SAPS. Methods: Thirty-eight participants (18 to 65-year-old) suffering from SAPS were recruited to have a CSI and randomly allocated to receive, 1 weeks post CSI, real a-tDCS (r-tDCS), sham tDCS (s-tDCS) or no intervention (Control). Upper limb function was measured 1 week prior to the CSI, at the 2- and 4-week follow-ups using self-administered questionnaires and physical measures. Self-reported pain and activity during each day were logged by the participants using visual analog scales (VAS). Differences between groups were tested using repeated-measures ANOVAs. Results: Pain VAS and the Single Assessment Numeric Evaluation scale (SANE) showed significant improvement from baseline 2 weeks and 4 weeks after CSI in all groups (p < 0.05). There were no significant group X time interaction 2 weeks following tDCS treatment in any of the variables. Conclusion: All groups showed significant improvement in pain VAS and SANE scores following the CSI. One session of a-tDCS treatment 2 weeks following CSI did not result in any additive or potentializing effects when compared to a s-tDCS or a control group

The Impact of Superior Labral Anterior to Posterior Lesions on Functional Status in Shoulder Instability: A Multicenter Cohort Study

BACKGROUND: Type IV superior labral anterior to posterior (SLAP) lesions, which are superior labral detachments associated with Bankart tears, are reported to occur in up to 25% of recurrent shoulder instability patients. However, the clinical implications of this finding are debatable. PURPOSE: To determine whether there are any functional differences between anterior instability patients with and without type IV SLAP lesions at the time of presentation and at short-term follow-up after surgical intervention. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A prospective, multicenter database was established to follow the clinical evolution of patients with shoulder instability. Patients were diagnosed as having a type IV SLAP lesion at the time of arthroscopic Bankart surgery (SLAP+). These patients were compared with a group of patients who simply had a Bankart lesion (SLAP-). The 2 groups had their functional outcomes (Western Ontario Shoulder Instability Index [WOSI]; Disability of the Arm, Shoulder, and Hand [QuickDASH]; and Walch-Duplay) compared prior to surgery and 1 year postoperatively. RESULTS: A total of 103 subjects were included in the study; of these, 56 (43 men, 13 women) completed 1-year follow-up. Twenty-three subjects had a type IV SLAP tear, and most had this repaired along with their Bankart lesion. At baseline, SLAP+ subjects had inferior QuickDASH scores compared with SLAP- subjects (37.8 vs 29.0) as well as poorer pain subscores on both the WOSI and QuickDASH. At 1-year follow-up, however, there were no significant differences in any of the outcome measures. CONCLUSION: A type IV SLAP lesion can be expected in 22% of patients with recurrent shoulder instability. This finding implies that at baseline, the patient will have slightly worse functional scores related to pain. However, following surgical management of the labral pathology, these patients will have equivalent functional outcomes at short-term follow-up. CLINICAL RELEVANCE: With surgical management of the superior and anteroinferior labrum, patients with type IV SLAP lesions will do as well as those with only Bankart tears. Thus, the presence of SLAP lesions should not alter the decision to provide surgical management and should not change the prognosis for a specific patient

Unravelling the effect of experimental pain on the corticomotor system using transcranial magnetic stimulation and electroencephalography.

Abstract : The interaction between pain and the motor system is well-known, with past studies showing that pain can alter corticomotor excitability and have deleterious effects on motor learning. The aim of this study was to better understand the cortical mechanisms underlying the interaction between pain and the motor system. Experimental pain was induced on 19 young and healthy participants using capsaicin cream, applied on the middle volar part of the left forearm. The effect of pain on brain activity and on the corticomotor system was assessed with electroencephalography (EEG) and transcranial magnetic stimulation (TMS), respectively. Compared to baseline, resting state brain activity significantly increased after capsaicin application in the central cuneus (theta frequency), left dorsolateral prefrontal cortex (alpha frequency), and left cuneus and right insula (beta frequency). A pain-evoked increase in the right primary motor cortex (M1) activity was also observed (beta frequency), but only among participants who showed a reduction in corticospinal output (as depicted by TMS recruitment curves). These participants further showed greater beta M1-cuneus connectivity than the other participants. These findings indicate that pain-evoked increases in M1 beta power are intimately tied to changes in the corticospinal system, and provide evidence that beta M1-cuneus connectivity is related to the corticomotor alterations induced by pain. The differential pattern of response observed in our participants suggest that the effect of pain on the motor system is variable from on individual to another; an observation that could have important clinical implications for rehabilitation professionals working with pain patients

Gln-tRNAGln synthesis in a dynamic transamidosome from Helicobacter pylori, where GluRS2 hydrolyzes excess Glu-tRNAGln

In many bacteria and archaea, an ancestral pathway is used where asparagine and glutamine are formed from their acidic precursors while covalently linked to tRNAAsn and tRNAGln, respectively. Stable complexes formed by the enzymes of these indirect tRNA aminoacylation pathways are found in several thermophilic organisms, and are called transamidosomes. We describe here a transamidosome forming Gln-tRNAGln in Helicobacter pylori, an ε-proteobacterium pathogenic for humans; this transamidosome displays novel properties that may be characteristic of mesophilic organisms. This ternary complex containing the non-canonical GluRS2 specific for Glu-tRNAGln formation, the tRNA-dependent amidotransferase GatCAB and tRNAGln was characterized by dynamic light scattering. Moreover, we observed by interferometry a weak interaction between GluRS2 and GatCAB (KD = 40 ± 5 µM). The kinetics of Glu-tRNAGln and Gln-tRNAGln formation indicate that conformational shifts inside the transamidosome allow the tRNAGln acceptor stem to interact alternately with GluRS2 and GatCAB despite their common identity elements. The integrity of this dynamic transamidosome depends on a critical concentration of tRNAGln, above which it dissociates into separate GatCAB/tRNAGln and GluRS2/tRNAGln complexes. Ester bond protection assays show that both enzymes display a good affinity for tRNAGln regardless of its aminoacylation state, and support a mechanism where GluRS2 can hydrolyze excess Glu-tRNAGln, ensuring faithful decoding of Gln codons

Treatment of glenohumeral instability in rugby players

Rugby is a high-impact collision sport, with impact forces. Shoulder injuries are common and result in the longest time off sport for any joint injury in rugby. The most common injuries are to the glenohumeral joint with varying degrees of instability. The degree of instability can guide management. The three main types of instability presentations are: (1) frank dislocation, (2) subluxations and (3) subclinical instability with pain and clicking. Understanding the exact mechanism of injury can guide diagnosis with classical patterns of structural injuries. The standard clinical examination in a large, muscular athlete may be normal, so specific tests and techniques are needed to unearth signs of pathology. Taking these factors into consideration, along with the imaging, allows a treatment strategy. However, patient and sport factors need to be also considered, particularly the time of the season and stage of sporting career. Surgery to repair the structural damage should include all lesions found. In chronic, recurrent dislocations with major structural lesions, reconstruction procedures such as the Latarjet procedure yields better outcomes. Rehabilitation should be safe, goal-driven and athlete- specific. Return to sport is dependent on a number of factors, driven by the healing process, sport requirements and extrinsic pressures