From mutation to mechanism: deciphering the molecular function of genetic variants linked to human ageing

Many of the leading causes of death in humans, such as cardiovascular disease, type 2 diabetes and Alzheimer’s disease are influenced by biological mechanisms that become dysregulated with increasing age. Hence, by targeting these ageing-related mechanisms, we may be able to improve health in old age. Ageing is partly heritable and genetic studies have been moderately successful in identifying genetic variants associated with ageing-related phenotypes (lifespan, healthspan and longevity). To decipher the mechanisms by which the identified variants influence ageing, studies that focus on their functional validation are vital. In this perspective, we describe the steps that could be taken in the process of functional validation: (1) in silico characterisation using bioinformatic tools; (2) in vitro characterisation using cell lines or organoids; and (3) in vivo characterisation studies using model organisms. For the in vivo characterisation, it is important to focus on translational phenotypes that are indicative of both healthspan and lifespan, such as the frailty index, to inform subsequent intervention studies. The depth of functional validation of a genetic variant depends on its location in the genome and conservation in model organisms. Moreover, some variants may prove to be hard to characterise due to context-dependent effects related to the experimental environment or genetic background. Future efforts to functionally characterise the (newly) identified genetic variants should shed light on the mechanisms underlying ageing and will help in the design of targeted interventions to improve health in old age

Dosage des HAP dans les produits de pêche par GC-MS au niveau des côtes marocaines

Being widespread and highly likely to cause adverse biological effects, PAHs have been the subject of several studies and evaluation. Polycyclic aromatic hydrocarbons (PAHs) are a series of hydrocarbons with the carbon atoms are arranged in benzene cycles united to each other, they pose a significant toxicological risk even at low concentrations, related especially to their carcinogenic and/or mutagenic properties. In addition, PAHs are part of some biodegradable contaminants which makes them persistent in natural environments. Thus, their fate in the environment has become a concern. For humans, the majority source of exposure to PAHs for non-smokers is the ingestion of food (meat, fish, vegetables, etc.). This study is conducted on fishery products collected along the Moroccan coast, landed at the level of the main ports of the Kingdom. Analyses of mean concentrations of PAHs in local products vary significantly according to the sites (p < 0,05). The results show a satisfactory quality of these products for consumption. The sampling sites are selected so as to diagnose the state of organic contamination in various fishing products. The determination of these pollutants is done by gas chromatography coupled to mass spectrometry.Les HAP étant largement répandus et fortement susceptibles d’entraîner des effets biologiques néfastes, ils ont fait l’objet de plusieurs études et évaluations. Les Hydrocarbure Aromatique Polycyclique (HAP) sont une série d'hydrocarbures dont les atomes de carbone sont disposés en cycles benzéniques unis les uns aux autres. Ils présentent un risque toxicologique important même à de faibles concentrations, liés surtout à leurs propriétés cancérigènes et/ou mutagènes. De plus, les HAP font partie des contaminants peu biodégradables ce qui les rend persistants dans les milieux naturels. Ainsi, leur sort dans l'environnement est devenu un sujet préoccupant. Pour l'homme, la source majoritaire d'exposition aux HAP pour les non fumeurs est l'ingestion des denrées alimentaires (viandes, poissons, légumes, etc..). Cette étude est menée sur les produits de pêche prélevés le long  du littoral marocain, débarqués au niveau des principaux ports du royaume. Les analyses des teneurs moyennes des HAP dans les produits locaux variaient significativement selon les sites (p<0,05). Les résultats montrent une qualité satisfaisante de ces  produits pour la consommation. Les sites des prélèvements sont choisis de manière à diagnostiquer l’état de la contamination organique dans les différents produits pêchés. Le dosage de ces polluants est réalisé par chromatographie gazeuse couplée à la spectrométrie de masse

Laser fiber and flexible ureterorenoscopy: the safety distance concept

INTRODUCTION The costs of flexible ureterorenoscopes (fURS) and their repair oblige the surgeon to know the proper handling of instruments. There is a lack of evidence in the literature about the safety distance that the laser fiber should have once out from the scope to avoid instrumental damages. MATERIAL AND METHODS We performed an in-vitro observational study. Seven fURS were tested. The distance from the laser fiber tip and the fURS camera was measured at the first appearance on the endoscopic screen and when the fiber was reaching one fourth of the screen. Secondly, to evaluate the impact of the Holmium laser bubble according to the different fiber distances, an assessment of the size and shape of the bubble created at the tip of the fiber with the laser activated was done recording the images with an High Speed Camera. RESULTS The first appearance on the screen of the laser tip is different in different scopes. In all the scopes when observed that when the laser fiber was at \ubc of the screen the bubble was never touching the fURS tip. CONCLUSION Even if there is a big limitation of this study due the impossibility to measure and to evaluate the damage of the fURS tip surface, we observed that when the laser fiber tip reach \ubc of the screen, the bubble generated by the laser activation is never rebounding on the camera of the scope preserving it from laser damages. We can define this position as the "safety distance"

GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment

The antileukemic agent asparaginase triggers the amino acid response (AAR) in the liver by activating the eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2). To explore the mechanism by which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent liver dysfunction during continued asparaginase treatment, wild-type and Gcn2 null mice were injected once daily with asparaginase or phosphate buffered saline for up to 14 days. Asparaginase induced mRNA expression of multiple AAR genes and greatly increased circulating concentrations of the metabolic hormone fibroblast growth factor 21 (FGF21) independent of food intake. Loss of Gcn2 precluded mRNA expression and circulating levels of FGF21 and blocked mRNA expression of multiple genes regulating lipid synthesis and metabolism including Fas, Ppara, Pparg, Acadm, and Scd1 in both liver and white adipose tissue. Furthermore, rates of triglyceride export and protein expression of apolipoproteinB-100 were significantly reduced in the livers of Gcn2 null mice treated with asparaginase, providing a mechanistic basis for the increase in hepatic lipid content. Loss of AAR-regulated antioxidant defenses in Gcn2 null livers was signified by reduced Gpx1 gene expression alongside increased lipid peroxidation. Substantial reductions in antithrombin III hepatic expression and activity in the blood of asparaginase-treated Gcn2 null mice indicated liver dysfunction. These results suggest that the ability of the liver to adapt to prolonged asparaginase treatment is influenced by GCN2-directed regulation of FGF21 and oxidative defenses, which, when lost, corresponds with maladaptive effects on lipid metabolism and hemostasis

Irreversible Aging Dynamics and Generic Phase Behavior of Aqueous Suspensions of Laponite

In this work we study the aging behavior of aqueous suspension of Laponite having 2.8 weight % concentration using rheological tools. At various salt concentration all the samples demonstrate orientational order when observed using crossed polarizers. In rheological experiments we observe inherent irreversibility in the aging dynamics which forces the system not to rejuvenate to the same state in the shear melting experiment carried out at a later date since preparation. The extensive rheological experiments carried out as a function of time elapsed since preparation demonstrate the self similar trend in the aging behavior irrespective of the concentration of salt. We observe that the exploration of the low energy states as a function of aging time is only kinetically affected by the presence of salt. We estimate that the energy barrier to attain the low energy states decreases linearly with increase in the concentration of salt. The observed superposition of all the elapsed time and the salt concentration dependent data suggests that the aging that occurs in low salt concentration systems over a very long period is qualitatively similar to the aging behavior observed in systems with high salt concentration over a shorter period.Comment: 27 pages, 8 figures. Langmuir, in pres

Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice

Obesity increases risk for liver toxicity by the anti-leukemic agent asparaginase, but the mechanism is unknown. Asparaginase activates the integrated stress response (ISR) via sensing amino acid depletion by the eukaryotic initiation factor 2 (eIF2) kinase GCN2. The goal of this work was to discern the impact of obesity, alone versus alongside genetic disruption of the ISR, on mechanisms of liver protection during chronic asparaginase exposure in mice. Following diet-induced obesity, biochemical analysis of livers revealed that asparaginase provoked hepatic steatosis that coincided with activation of another eIF2 kinase PKR-like endoplasmic reticulum kinase (PERK), a major ISR transducer to ER stress. Genetic loss of Gcn2 intensified hepatic PERK activation to asparaginase, yet surprisingly, mRNA levels of key ISR gene targets such as Atf5 and Trib3 failed to increase. Instead, mechanistic target of rapamycin complex 1 (mTORC1) signal transduction was unleashed, and this coincided with liver dysfunction reflected by a failure to maintain hydrogen sulfide production or apolipoprotein B100 (ApoB100) expression. In contrast, obese mice lacking hepatic activating transcription factor 4 (Atf4) showed an exaggerated ISR and greater loss of endogenous hydrogen sulfide but normal inhibition of mTORC1 and maintenance of ApoB100 during asparaginase exposure. In both genetic mouse models, expression and phosphorylation of Sestrin2, an ATF4 gene target, was increased by asparaginase, suggesting mTORC1 inhibition during asparaginase exposure is not driven via eIF2-ATF4-Sestrin2. In conclusion, obesity promotes a maladaptive ISR during asparaginase exposure. GCN2 functions to repress mTORC1 activity and maintain ApoB100 protein levels independently of Atf4 expression, whereas hydrogen sulfide production is promoted via GCN2-ATF4 pathway

Self-management programmes in temporomandibular disorders: results from an international Delphi process

Self-management (SM) programmes are commonly used for initial treatment of patients with temporomandibular disorders (TMD). The programmes described in the literature, however, vary widely with no consistency in terminology used, components of care or their definitions. The aims of this study were therefore to construct an operationalised definition of self-management appropriate for the treatment of patients with TMD, identify the components of that self-management currently being used and create sufficiently clear and non-overlapping standardised definitions for each of those components. A four-round Delphi process with eleven international experts in the field of TMD was conducted to achieve these aims. In the first round, the participants agreed upon six principal concepts of self-management. In the remaining three rounds, consensus was achieved upon the definition and the six components of self-management. The main components identified and agreed upon by the participants to constitute the core of a SM programme for TMD were as follows: education; jaw exercises; massage; thermal therapy; dietary advice and nutrition; and parafunctional behaviour identification, monitoring and avoidance. This Delphi process has established the principal concepts of self-management, and a standardised definition has been agreed with the following components for use in clinical practice: education; self-exercise; self-massage; thermal therapy; dietary advice and nutrition; and parafunctional behaviour identification, monitoring and avoidance. The consensus-derived concepts, definitions and components of SM offer a starting point for further research to advance the evidence base for, and clinical utility of, TMD SM

Centrifuge modelling of screw piles for offshore wind energy foundations

Screw piles (helical piles) can provide a viable, cost-effective and low-noise installation alternative to increasing the size of existing foundation solutions (e.g. monopiles) to meet the demand for the advancement of offshore wind energy into deeper water. Significant upscaling of widely used onshore screw pile geometries will be required to meet the loading conditions of a jacket supported offshore wind turbine. This increase in size will lead to greater installation force and torque. This paper presents preliminary results from centrifuge tests investigating the requirements to install screw piles designed for an offshore wind energy application using specially developed equipment. Results indicate that the equipment is suitable to investigate these screw pile requirements and that significant force is required for such upscaled screw piles, with 19 MN vertical force and 7 MNm torque for the standard design. Optimisation of the screw pile geometry, reduced these forces by 29 and 11% for the vertical and rotational forces respectively