The Receptor Tyrosine Kinase Alk Controls Neurofibromin Functions in Drosophila Growth and Learning

Anaplastic Lymphoma Kinase (Alk) is a Receptor Tyrosine Kinase (RTK) activated in several cancers, but with largely unknown physiological functions. We report two unexpected roles for the Drosophila ortholog dAlk, in body size determination and associative learning. Remarkably, reducing neuronal dAlk activity increased body size and enhanced associative learning, suggesting that its activation is inhibitory in both processes. Consistently, dAlk activation reduced body size and caused learning deficits resembling phenotypes of null mutations in dNf1, the Ras GTPase Activating Protein-encoding conserved ortholog of the Neurofibromatosis type 1 (NF1) disease gene. We show that dAlk and dNf1 co-localize extensively and interact functionally in the nervous system. Importantly, genetic or pharmacological inhibition of dAlk rescued the reduced body size, adult learning deficits, and Extracellular-Regulated-Kinase (ERK) overactivation dNf1 mutant phenotypes. These results identify dAlk as an upstream activator of dNf1-regulated Ras signaling responsible for several dNf1 defects, and they implicate human Alk as a potential therapeutic target in NF1

Effect of Ultrasonic-Assisted Blanching on Size Variation, Heat Transfer, and Quality Parameters of Mushrooms

The main aim of this work was to assess the influence of the application of power ultrasound during blanching of mushrooms (60 90 °C) on the shrinkage, heat transfer, and quality parameters. Kinetics of mushroom shrinkage was modeled and coupled to a heat transfer model for conventional (CB) and ultrasonic-assisted blanching (UB). Cooking value and the integrated residual enzymatic activity were obtained through predicted temperatures and related to the hardness and color variations of mushrooms, respectively. The application of ultrasound led to an increase of shrinkage and heat transfer rates, being this increase more intense at low process temperatures. Consequently, processing time was decreased (30.7 46.0 %) and a reduction in hardness (25.2 40.8 %) and lightness (13.8 16.8 %) losses were obtained. The best retention of hardness was obtained by the UB at 60 °C, while to maintain the lightness it was the CB and UB at 90 °C. For enhancing both quality parameters simultaneously, a combined treatment (CT), which consisted of a CB 0.5 min at 90 °C and then an UB 19.9min at 60 °C, was designed. In this manner, compared with the conventional treatment at 60 °C, reductions of 39.1, 27.2, and 65.5 % for the process time, hardness and lightness losses were achieved, respectively. These results suggest that the CT could be considered as an interesting alternative to CB in order to reduce the processing time and improve the overall quality of blanched mushrooms.The authors acknowledge the financial support of Consejo Nacional de Investigaciones Cientificas y Tecnicas and Universidad Nacional de La Plata from Argentina, Erasmus Mundus Action 2-Strand 1 and EuroTango II Researcher Training Program and Ministerio de Economia y Competitividad (SPAIN) and the FEDER (project DPI2012-37466-CO3-03).Lespinard, A.; Bon Corbín, J.; Cárcel Carrión, JA.; Benedito Fort, JJ.; Mascheroni, RH. (2015). 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A., Quintero-Ramos, A., Barnard, J., Balandrán-Quintana, R. R., Talamás-Abbud, R., & Jiménez-Castro, J. (2007). Effect of ultrasound on the mass transfer and physical changes in brine bell pepper at different temperatures. Journal of Food Engineering, 81, 374–379.Gallego-Juárez, J. A., Riera, E., De la Fuente, S., Rodríguez-Corral, G., Acosta-Aparicio, V. M., & Blanco, A. (2007). Application of high-power ultrasound for dehydration of vegetables: processes and devices. Drying Technology, 25, 1893–1901.Gamboa-Santos, J., Montilla, A., Soria, A. C., & Villamiel, M. (2012). Effects of conventional and ultrasound blanching on enzyme inactivation and carbohydrate content of carrots. European Food Research and Technology, 234, 1071–1079.García-Pérez, J. V., Cárcel, J. A., De la Fuente, S., & Riera, E. (2006). Ultrasonic drying of foodstuff in a fluidized bed. Parametric study. Ultrasonics, 44, 539–543.García-Pérez, J. V., Cárcel, J. A., Riera, E., Rosselló, C., & Mulet, A. (2012). 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An Evolutionary Conserved Role for Anaplastic Lymphoma Kinase in Behavioral Responses to Ethanol

Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention

La définition de l’obstruction bronchique par le rapport VEMS/CV : seuil fixe ou limite inférieure de la normale ?

International audienceIntroduction: While the screening of chronic obstructive lung diseases (COPD, asthma, etc.) constitutes a major public health issue in France and worldwide, simple spirometry appears currently as the key to meeting the challenge. Since description of the forced expiratory maneuver by Robert Tiffeneau in 1947, it has been admitted that the FEV1/VC ratio permits diagnosis obstructive pulmonary diseases. However, the diagnostic criteria for this ratio remain uncertain. The long-lasting debate between advocates of a 0.7 “fixed ratio” (FR) of 0.7 and advocates of the “lower limit of normal” (LLN) remains relevant.State of the arts: In this general review, we describe the respective advantages of the FR and LLN criteria according to the most recently published studies, and characterize the conditions associated with discrepancies between these criteria.Perspectives and conclusions: FR and LLN appear not to share similar diagnosis values and the use of both criteria facilitates proposal of an up-to-date interpretation and diagnosis strategy in the context of first-line spirometry, particularly for patients with FEV1/VC ratio in the “grey zone”Alors que le dépistage des maladies respiratoires obstructives chroniques (bronchopneumopathie chronique obstructive [BPCO], asthme, etc.) constitue un enjeu majeur de santé publique en France et dans le monde, la spirométrie simple est l’outil incontournable pour relever ce défi. Alors qu’il est établi depuis Robert Tiffeneau en 1947 que le rapport VEMS/CV permet le diagnostic de ces maladies chroniques obstructives, le critère diagnostique fait l’objet d’intenses débats entre partisans l’utilisation d’un « seuil fixe » de 0,7, et partisans de l’utilisation de la « limite inférieure de la normale ». Nous proposons dans cette revue narrative une présentation des avantages respectifs de ces deux critères diagnostiques, tenant compte des arguments les plus récents de la littérature, mais aussi des situations de discordance entre ces deux critères afin de proposer une stratégie d’interprétation et de diagnostic tenant compte de ces deux critères, dans le contexte d’une spirométrie de dépistage

Impaired training-induced adaptation of blood pressure in COPD patients: implication of the muscle capillary bed

Fares Gouzi,1,2 Jonathan Maury,1,3 François Bughin,1,2 Marine Blaquière,1,2 Bronia Ayoub,1,2 Jacques Mercier,1,2 Antonia Perez-Martin,4,5 Pascal Pomiès,1 Maurice Hayot1,2 1PhyMedExp, INSERM U1046, CNRS UMR 9214, University of Montpellier, 2Department of Clinical Physiology, Montpellier University Hospital, Montpellier, 3Pulmonary Rehabilitation Center “La Solane”, 5 Santé Group, Osséja, 4Dysfunction of Vascular Interfaces Laboratory, EA 2992, University of Montpellier, 5Department of Vascular Medicine and Investigations, Nîmes University Hospital, Nîmes, France Background and aims: Targeting the early mechanisms in exercise-induced arterial hypertension (which precedes resting arterial hypertension in its natural history) may improve cardiovascular morbidity and mortality in COPD patients. Capillary rarefaction, an early event in COPD before vascular remodeling, is a potential mechanism of exercise-induced and resting arterial hypertension. Impaired training-induced capillarization was observed earlier in COPD patients; thus, this study compares the changes in blood pressure (BP) during exercise in COPD patients and matches control subjects (CSs) after a similar exercise training program, in relationship with muscle capillarization. Methods: Resting and maximal exercise diastolic pressure (DP) and systolic pressure (SP) were recorded during a standardized cardiopulmonary exercise test, and a quadriceps muscle biopsy was performed before and after training.Results: A total of 35 CSs and 49 COPD patients (forced expiratory volume in 1 second=54%±22% predicted) completed a 6-week rehabilitation program and improved their symptom-limited maximal oxygen uptake (VO2SL: 25.8±6.1 mL/kg per minute vs 27.9 mL/kg per minute and 17.0±4.7 mL/kg per minute vs 18.3 mL/kg per minute; both P<0.001). The improvement in muscle capillary-to-fiber (C/F) ratio was significantly greater in CSs vs COPD patients (+11%±9% vs +23%±21%; P<0.05). Although maximal exercise BP was reduced in CSs (DP: 89±10 mmHg vs 85±9 mmHg; P<0.001/SP: 204±25 mmHg vs 196±27 mmHg; P<0.05), it did not change in COPD patients (DP: 94±14 mmHg vs 97±16 mmHg; P=0.46/SP: 202±27 mmHg vs 208±24 mmHg; P=0.13). The change in muscle C/F ratio was negatively correlated with maximal exercise SP in CSs and COPD patients (r=-0.41; P=0.02). Conclusion: COPD patients showed impaired training-induced BP adaptation related to a change in muscle capillarization, suggesting the possibility of blunted angiogenesis. Keywords: angiogenesis, hypertension, pulmonary rehabilitatio

Specific muscle functional, morphological and angiogenic responses to exercise training in copd patients

International audienc

Involvement of the FoxO1/MuRF1/Atrogin-1 Signaling Pathway in the Oxidative Stress-Induced Atrophy of Cultured Chronic Obstructive Pulmonary Disease Myotubes

Oxidative stress is thought to be one of the most important mechanisms implicated in the muscle wasting of chronic obstructive pulmonary disease (COPD) patients, but its role has never been demonstrated. We therefore assessed the effects of both pro-oxidant and antioxidant treatments on the oxidative stress levels and atrophic signaling pathway of cultured COPD myotubes. Treatment of cultured COPD myotubes with the pro-oxidant molecule H2O2 resulted in increased ROS production (P = 0.002) and protein carbonylation (P = 0.050), in association with a more pronounced atrophy of the myotubes, as reflected by a reduced diameter (P = 0.003), and the activated expression of atrophic markers MuRF1 and FoxO1 (P = 0.022 and P = 0.030, respectively). Conversely, the antioxidant molecule ascorbic acid induced a reduction in ROS production (P<0.001) and protein carbonylation (P = 0.019), and an increase in the myotube diameter (P<0.001) to a level similar to the diameter of healthy subject myotubes, in association with decreased expression levels of MuRF1, atrogin-1 and FoxO1 (P<0.001, P = 0.002 and P = 0.042, respectively). A significant negative correlation was observed between the variations in myotube diameter and the variations in the expression of MuRF1 after antioxidant treatment (P = 0.047). Moreover, ascorbic acid was able to prevent the H2O2-induced atrophy of COPD myotubes. Last, the proteasome inhibitor MG132 restored the basal atrophy level of the COPD myotubes and also suppressed the H2O2-induced myotube atrophy. These findings demonstrate for the first time the involvement of oxidative stress in the atrophy of COPD peripheral muscle cells in vitro, via the FoxO1/MuRF1/atrogin-1 signaling pathway of the ubiquitin/proteasome system

Skeletal Muscle Phenotype in Patients Undergoing Long-Term Hemodialysis Awaiting Kidney Transplantation

International audienceBackground and objectives Age and comorbidity-related sarcopenia represent a main cause of muscle dysfunction in patients on long-term hemodialysis. However, recent findings suggest muscle abnormalities that are not associated with sarcopenia. The aim of this study was to isolate functional and cellular muscle abnormalities independently of other major confounding factors, including malnutrition, age, comorbidity, or sedentary lifestyle, which are common in patients on maintenance hemodialysis. To overcome these confounding factors, alterations in skeletal muscle were analyzed in highly selected patients on long-term hemodialysis undergoing kidney transplantation. Design, setting, participants, & measurements In total, 22 patients on long-term hemodialysis scheduled for kidney transplantation with few comorbidities, but with a long-term uremic milieu exposure, and 22 age, sex, and physical activity level frequency-matched control participants were recruited. We compared biochemical, functional, and molecular characteristics of the skeletal muscle using maximal voluntary force and endurance of the quadriceps, 6-minute walking test, and muscle biopsy of vastus lateralis . For statistical analysis, mean comparison and multiple regression tests were used. Results In patients on long-term hemodialysis, muscle endurance was lower, whereas maximal voluntary force was not significantly different. We observed a transition from type I (oxidative) to type II (glycolytic) muscle fibers, and an alteration of mitochondrial structure (swelling) without changes in DNA content, genome replication (peroxisome proliferator activator receptor γ coactivator-1 α and mitochondrial transcription factor A), regulation of fusion (mitofusin and optic atrophy 1), or fission (dynamin-related protein 1). Notably, there were autophagosome structures containing glycogen along with mitochondrial debris, with a higher expression of light chain 3 (LC3) protein, indicating phagophore formation. This was associated with a greater conversion of LC3-I to LC3-II and the expression of Gabaralp1 and Bnip3l genes involved in mitophagy. Conclusions In this highly selected long-term hemodialysis population, a low oxidative phenotype could be defined by a poor endurance, a fiber-type switch, and an alteration of mitochondria structure, without evidence of sarcopenia. This phenotype could be related to uremia through the activation of autophagy/mitophagy. Clinical Trial registration numbers: NCT02794142 and NCT02040363