Mécanismes et conséquences de l'internalisation du récepteur du "glucose-dependent insulinotropic polypeptide"

L'internalisation et le trafic intracellulaire sont des mécanismes cruciaux dans la régulation de la signalisation des récepteurs couplés aux protéines G (RCPG) dans lesquels les -arrestines jouent un rôle central. Des agonistes biaisés qui sont capables d'activer sélectivement les voies de signalisation dépendantes des protéines G ou dépendantes des -arrestines ont été récemment identifiés. D'autre part, le concept selon lequel la signalisation des RCPG serait limitée à la membrane cellulaire a été contesté sur la base des données qui démontrent que de nombreux RCPG induisent du signal aussi bien à partir d'endosomes qu'au niveau de la surface cellulaire. Le glucose-dependent insulinotropic polypeptide (GIP) est une hormone incrétine essentielle dans l'homéostasie glucidique postprandiale. Elle exerce ses fonctions en se liant à un récepteur couplé aux protéines G, le RGIP qui est impliquée dans divers processus physiologiques et physiopathologiques. À ce jour, l'internalisation et le trafic intracellulaire du RGIP ainsi que leurs mécanismes moléculaires sous-jacents n'ont pas été étudié en détail. Dans ce contexte, le but de notre travail était d'abord d'étudier ces mécanismes et ensuite de caractériser le profil d'internalisation du N-acétyl-GIP, un analogue du GIP connu pour être résistant à la dégradation par le DPP-IV. Enfin, nous avons étudié si, en plus de sa signalisation à la membrane cellulaire, le RGIP est capable d'induire une signalisation à partir d'endosomes. Dans cette étude, nous montrons d'abord que l'internalisation du RGIP est un processus impliquant la clathrine, le complexe AP-2 et la dynamine, mais pas la région C-terminale du récepteur, ni les -arrestines1/2. Nous avons également montré que le N-acétyl-GIP, qui présente une activité agoniste pleine sur la production d'AMPc et sur la sécrétion d'insuline dans les cellules MIN-6-B1, n'est pas capable de stimuler l'internalisation du RGIP. Cela suggère que le N-acétyl-GIP pourrait être un agoniste biaisé du RGIP induisant préférentiellement la voie d'activation de Gs comparativement à un adressage du récepteur vers des puits recouverts de clathrine. Nous avons également réussi à observer une persistance au cours du temps de la production d'AMPc induite par le GIP. Le signal persistant dépend de l'internalisation du RGIP et est irréversible après lavage du GIP de la membrane cellulaire. De plus, nous avons détecté d'une manière directe la forme active de Gs au niveau d'endosomes contenant le RGIP en utilisant des plasmides codant pour des Nanobodies fusionnés à la GFP. Enfin, en utilisant un biosenseur FRET d'AMPc dirigé à la surface des endosomes précoces, nous avons également pu détecter d'une manière directe la production d'AMPc spécifiquement à la surface des endosomes contenant le RGIP internalisé. À notre connaissance, cette dernière observation est la première de ce genre, prouvant le concept de signalisation à partir d'endosomes par une approche de détection directe. Les résultats de cette étude apportent des informations quant à la régulation pharmacologique de l'internalisation et de la signalisation du RGIP, ouvrant des perspectives prometteuses dans le domaine du GIP.Internalization and trafficking are crucial mechanisms regulating G-protein coupled receptors (GPCRs) signaling in which -arrestins play a central role. Biased agonists which selectively activate either G protein or -arrestin signaling pathway were identified. On the other hand, the concept of GPCR signaling being restricted to cell membrane has been contested on the basis of data demonstrating GPCR signaling from endosomes as well as from the cell surface. Glucose insulinotropic polypeptide (GIP) is an incretin hormone essential in post-prandial glucose homeostasis. It exerts its functions through binding to a G protein-coupled receptor, GIPR which is involved in various physiological and pathological processes. To date, GIPR internalization and trafficking and the underlying molecular mechanisms have not been investigated in detail. In this context, the aim of our work was to study these mechanisms and to characterize the internalization profile of N-Acetyl-GIP, a GIP analogue resistant to DPP-IV degradation. Finally, we investigated if GIPR signaling can occur from endosomes alongside its signaling at the cell membrane. In this study, we first report that GIPR internalization involves clatherin, AP-2 and dynamin but not C-terminal region of the GIPR nor -arrestin1/2. Moreover, N-Acetyl-GIP, which fully stimulated cAMP production and insulin secretion from MIN-6-B1 cells, did not stimulate internalization of the GIPR. This suggests that N-Acetyl-GIP could be a biased GIPR agonist preferentially inducing Gs activation pathway over directing the receptor to clathrin-coated pits. We have also succeeded to witness a sustainability in GIP-induced cAMP production. The sustained signal was dependent on GIPR internalization and unreversed by GIP removal from the cell membrane. Moreover, we directly detected the active form of Gas in early endosomes containing GIPR using a genetically encoded GFP tagged nanobody. Finally, using a FRET sensor of cAMP targeted to the surface of early endosomes, we also directly detected cAMP production specifically at the surface of endosomes containing internalized GIPR. The latter observation is the first of this kind, proving the endosomal signaling concept by a direct detection approach. This study brings new insights into the pharmacological regulation of GIPR internalization and signaling, opening promising perspectives in GIP field

Optimal boundary control of dynamics responses of piezo actuating micro-beams

AbstractOptimal control theory is formulated and applied to damp out the vibrations of micro-beams where the control action is implemented using piezoceramic actuators. The use of piezoceramic actuators such as PZT in vibration control is preferable because of their large bandwidth, their mechanical simplicity and their mechanical power to produce controlling forces. The objective function is specified as a weighted quadratic functional of the dynamic responses of the micro-beam which is to be minimized at a specified terminal time using continuous piezoelectric actuators. The expenditure of the control forces is included in the objective function as a penalty term. The optimal control law for the micro-beam is derived using a maximum principle developed by Sloss et al. [J.M. Sloss, J.C. Bruch Jr., I.S. Sadek, S. Adali, Maximum principle for optimal boundary control of vibrating structures with applications to beams, Dynamics and Control: An International Journal 8 (1998) 355–375; J.M. Sloss, I.S. Sadek, J.C. Bruch Jr., S. Adali, Optimal control of structural dynamic systems in one space dimension using a maximum principle, Journal of Vibration and Control 11 (2005) 245–261] for one-dimensional structures where the control functions appear in the boundary conditions in the form of moments. The derived maximum principle involves a Hamiltonian expressed in terms of an adjoint variable as well as admissible control functions. The state and adjoint variables are linked by terminal conditions leading to a boundary-initial-terminal value problem. The explicit solution of the problem is developed for the micro-beam using eigenfunction expansions of the state and adjoint variables. The numerical results are given to assess the effectiveness and the capabilities of piezo actuation by means of moments to damp out the vibration of the micro-beam with a minimum level of voltage applied on the piezo actuators

The reign of al-Hakim Bi Amr Allah, 386/996-411/1021: A political study.

The present thesis is a political study of the reign of al-Hakim Bi Amr Allah the sixth Fatimid Imam-Caliph who ruled between 386-411/996-1021. It consists of a note on the sources and seven chapters. The first chapter is a biographical review of al-Hakim's person. It introduces a history of his birth, childhood, succession to the Caliphate, his education and private life and it examines the contradiction in the sources concerning his character. Chapter II discusses the problems which al-Hakim inherited from the previous rule and examines their impact on the political life of his State. Chapter III introduces the administration of the internal affairs of the State. It examines the struggle for power between the Imam-Caliph and his Wasita and its results on the internal policies of the Imam-Caliph. It also discusses the economic, social, legal and architectural reforms which he introduced throughout his reign. The progress of the Ismaili Daiwa and the problem of Ahl al-Dhimma are also examined in this chapter. Chapter IV is devoted to the external policy of al-Hakim. It studies his policies concerning the maintenance of his suzerainty over the provinces of Damascus, Hijaz and Tripoli and his endeavour to extend it over Aleppo and other parts of the Muslim world. His policy towards the Byzantine and Abbasid Empires is also discussed in this chapter. Chapter V examines the rebellions and uprisings which al-Hakim faced and discusses his methods in dealing with them. Chapter VI introduces the split in the Ismaili Daiwa which resulted in the creation of the Druz Sect. It also examines the causes behind such an important event. Chapter VII is concerned with the death or "disappearance" of al-Hakim and discusses the stories and myths surrounding it

Impact of a Disaster Educational Program on Knowledge and Practices of Teachers among Primary Governmental Schools, Cairo Governorate

Disaster is an extreme event that causes loss of life, property, essential services and means of livelihood. Aim of this study; was to assess the impact of a disaster educational program on knowledge and practices of teachers. Research design; A (pre-post) quasi-experimental design was adopted in this research. Setting; the study was conducted at three primary governmental schools in Cairo governorate. Three educational departments were assigned randomly from total thirty two departments. One school from each educational department was selected randomly (3 schools). These schools were El-Sayida Sakina, Ahmed Lotfy El-Said and El-Kasr Elaini primary governmental schools. The study sample; consisted of 50 teachers were included from three selected school in the research. Teachers number was; 17 teachers in El-Sayida Sakina School, 18 teachers in Ahmed Lotfy El-Said school and 15 in El-Kasr Elaini. Tools for data collection; three tools were used in this study; 1) Demographic characteristics for teachers; 2) Pre/ post knowledge questionnaire sheet. 3) Pre/post observational checklist. Study results; results revealed that, 70 % of teachers were females, 54% aged from 35-55 years.  Nearly all teachers (94%) didn't have any experience in disaster management before the educational program compared to less than half (42%) of the teachers who had unsatisfactory knowledge about disaster management. While 96%, 100% respectively had good knowledge scores about disaster management immediately and 2 months after the educational program. Regarding to teacher's practices, 100% and 84% had good practice scores immediately and 2 months after the educational program respectively while 90% had unsatisfactory practice scores about disaster management before the educational program. A highly statistically significance differences were found between all practice subscales about dealing with injured personnel in disaster among teachers before, immediately and 2 months after the educational program.  The study concluded that, educational program implicated changes in teaches' knowledge, and practices regarding disaster management in primary governmental schools. The study recommended periodic training programs for teachers in primary governmental schools Key words: Teachers, disaster management, primary governmental school

Protective effects of defatted dabai peel extracts in hypercholesterolemic rabbits based on histopathological methods

Defatted dabai peel contains a high amount of anthocyanin. Anthocyanins are known to prevent several types of disease, including cardiovascular-related complications. This study aimed to describe the effects of different doses of defatted dabai peel extract by histopathological analyses on lesions in the liver, kidney, heart and aorta. Histopathology methods were applied to determine the protective effects of defatted dabai peel extracts against hypercholesterolemia-induced oxidative damages to animal organs. Haematoxylin and eosin staining was applied for histopathology examination for liver, kidney, heart and aorta. Data showed that a high dose of defatted dabai extract (3000 mg per day) applied to hypercholesterolemic rabbits for eight weeks had mild protective effect, especially reducing the severity of hepatic fibrosis and steatosis of the renal medulla. The high dose of extract supplementation also reduced inflammation of aorta and formation of atherosclerosis plaque in the cell wall of right ventricle of the heart. The high dose of defatted dabai peel extract could be a protective agent against oxidative stress

Histological study on the protective effect of endogenous stem-cell mobilization in Adriamycin-induced chronic nephropathy in rats

AbstractChronic kidney disease is a global health problem with increasing morbidity and mortality. Therefore, this study was planned to test the protective effect of hematopoietic-stem-cell mobilization by granulocyte colony-stimulating factor (G-CSF) on Adriamycin (ADR)-induced chronic renal disease in rats. Thirty albino rats were equally divided into three groups: control, ADR group [rats received a single intravenous injection of ADR (5mg/kg)], and G-CSF group [rats received ADR by the same route and the same dose as the previous group, and then G-CSF (70μg/kg/d) 2 hours after ADR injection then daily for five consecutive days]. At the time of sacrifice (after 6 weeks), blood samples were taken to estimate the blood urea nitrogen and serum creatinine. Kidney sections were stained with hematoxylin and eosin, toluidine blue, Masson's trichrome, periodic acid–Schiff stains, and immunohistochemical staining against CD34 and caspase-3. The G-CSF group exhibited protection against renal injury manifested by reducing blood urea nitrogen and serum-creatinine levels, improving histological architecture, and increasing the proliferative capacity of renal tubules

Robust Optimal Design of Beams Subject to Uncertain Loads

Optimality conditions are derived for the robust optimal design of beams subject to a combination of uncertain and deterministic transverse and boundary loads using a variational min-max approach. The potential energy of the beam is maximized to compute the worst case loading and minimized to determine the optimal cross-sectional shape which results in coupled nonlinear differential equations for the unknown functions except for the case of a variable width beam. The uncertain component of the transverse load acting on the beam is not known a priori resulting in load uncertainty subject only to an norm constraint. Similarly the optimal area function is subject to a volume constraint leading to an isoperimetric variational problem. The min-max approach leads to robust optimal designs which are not susceptible to unexpected load variations as it occurs under operational conditions. The solution methodology is illustrated for the variable width beam by obtaining analytical results for several cases. The efficiency of the optimal designs is computed with respect to a uniform beam under worst case loading taking the maximum deflection as the quantity for comparison. It is observed that the optimal shapes are more than 70% efficient for the examples given in this study

Variational Principles for Multiwalled Carbon Nanotubes Undergoing Vibrations Based on Nonlocal Timoshenko Beam Theory

Variational principles are derived for multiwalled carbon nanotubes undergoing linear vibrations using the semi-inverse method with the governing equations based on nonlocal Timoshenko beam theory which takes small scale effects and shear deformation into account. Physical models based on the nonlocal theory approximate the nanoscale phenomenon more accurately than the local theories by taking small scale phenomenon into account. Variational formulation is used to derive the natural and geometric boundary conditions which give a set of coupled boundary conditions in the case of free boundaries which become uncoupled in the case of the local theory. Hamilton's principle applicable to this case is also given

COMPUTATIONAL MODEL TO IMPROVE DAIRY ANIMAL FEEDING UNDER MIXED FARMING SYSTEM (CROPS/LIVESTOCK) AS STUDY CASE

Computational model was designed for feeding systems of small dairy farms in Egypt under Mixed Farming System (MFS) (Crops/livestock). The present case study was selected from El-Beheira governorate, where the three common dairy animals (Local cows, Crossbred cows and buffaloes) are available. The main objectives of this study were 1- To find out the optimum combination of inputs from farm green forage and cash crops to minimize animal feeding costs. 2- Asses the possibilities of increasing the farm income by least cost rations formulation using available feed resources for dairy cattle. Technical coefficients of the models were obtained from previous studies under Egyptian condition. The model proposed three scenarios: Scenario I (S I) calculated the actual feeding situation from the case study without any changes as base run, scenario II (S II) proposed to cover animal feeding requirements of the same herd in scenario (S I) from the same available feed resources according to NRC (2001) and scenario III (S III) operating on the available feeding package quantities or reallocated farm feed resources for the same herd. The model used the common feed in summer and winter seasons (300 days) while, two months were considered as transitional period between two seasons, where irregular animal feeding regime is adopted. The results showed that area cultivated with green forages can be reduced by 17% and 25% of total planted area in SII for winter and summer, respectively, compared to base run (SI). Where as in S III, the green forage cultivated areas reduced by 30% and 25% for winter and summer, respectively in comparison with SI, feeding costs in SII were reduced by 51.11% and 38.97% in winter and summer, respectively. Using available feeding packages and reallocated farm resources in SIII reduced feeding costs by 47.78% and 27.67% for winter and summer, respectively. It can be concluded that using available feeding packages or reallocated animal feeding resources either in SII and SIII achieved a considerable reduction on animal feeding costs of small-scale mixed farms compared to base run scenario (SI)