PPARβ/δ ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation

We studied whether PPARβ/δ deficiency modifies the effects of high fructose intake (30% fructose in drinking water) on glucose tolerance and adipose tissue dysfunction, focusing on the CD36-dependent pathway that enhances adipose tissue inflammation and impairs insulin signaling. Fructose intake for 8weeks significantly increased body and liver weight, and hepatic triglyceride accumulation in PPARβ/δ-deficient mice but not in wild-type mice. Feeding PPARβ/δ-deficient mice with fructose exacerbated glucose intolerance and led to macrophage infiltration, inflammation, enhanced mRNA and protein levels of CD36, and activation of the JNK pathway in white adipose tissue compared to those of water-fed PPARβ/δ-deficient mice. Cultured adipocytes exposed to fructose also exhibited increased CD36 protein levels and this increase was prevented by the PPARβ/δ activator GW501516. Interestingly, the levels of the nuclear factor E2-related factor 2 (Nrf2), a transcription factor reported to up-regulate Cd36 expression and to impair insulin signaling, were increased in fructose-exposed adipocytes whereas co-incubation with GW501516 abolished this increase. In agreement with Nrf2 playing a role in the fructose-induced CD36 protein level increases, the Nrf2 inhibitor trigonelline prevented the increase and the reduction in insulin-stimulated AKT phosphorylation caused by fructose in adipocytes. Protein levels of the well-known Nrf2 target gene NAD(P)H: quinone oxidoreductase 1 (Nqo1) were increased in water-fed PPARβ/δ-null mice, suggesting that PPARβ/δ deficiency increases Nrf2 activity; and this increase was exacerbated in fructose-fed PPARβ/δ-deficient mice. These findings indicate that the combination of high fructose intake and PPARβ/δ deficiency increases CD36 protein levels via Nrf2, a process that promotes chronic inflammation and insulin resistance in adipose tissue.

Feedback regulation of Gab2-dependent signaling by the Ras/MAPK pathway

La voie de signalisation des Récepteurs Tyrosine Kinase (RTK) occupe un rôle central dans la régulation de la croissance cellulaire, la prolifération, la différentiation et la motilité. Une régulation anormale des RTKs mène à plusieurs maladies humaines telles que le cancer du sein, la seconde cause de mortalité chez les femmes à cause de l’amplification et la mutation fréquente de la protéine tyrosine kinase HER2 (ERBB2). Grb2-associated binder (Gab) 2 est une protéine adaptatrice qui agit en aval de plusieurs RTKs, y compris HER2, pour réguler de multiples voies de signalisation. En réponse à la stimulation par de nombreux facteurs de croissances et cytokines, Gab2 est recruté à la membrane plasmique où il potentialise l’activation des voies de signalisation Ras/mitogen-activated protein kinase (MAPK) et PI3K (phosphatidylinositol-3-kinase)/Akt (protein kinase B). En plus d’occuper un rôle essentiel durant le développement du système hématopoïétique, Gab2 est souvent amplifié dans les cancers, notamment le cancer du sein et les mélanomes. Cependant, les mécanismes moléculaires qui régulent le fonctionnement de Gab2 sont peu connus. Il est établi que lors de l’activation des RTKs, Gab2 est phosphorylé au niveau de plusieurs résidus Tyrosine, menant à l’association de différentes protéines comme p85 et Shp2. En plus de la phosphorylation en Tyrosine, notre laboratoire ainsi que d’autres groupes de recherche avons identifié que Gab2 est aussi phosphorylé au niveau de résidus Ser/Thr suite à l’activation de la voie de signalisation MAPK. Cependant, la régulation des fonctions de Gab2 par ces modifications post-traductionnelles est encore peu connue. Dans le but de comprendre comment Gab2 est régulé par la voie de signalisation MAPK, nous avons utilisé différentes approches. Dans la première partie de ma thèse, nous avons déterminé un nouveau mécanisme démontrant que la voie de signalisation Ras/MAPK, par le biais des protéines kinases RSK (p90 ribosomal S6 kinase), phosphoryle Gab2. Ce phénomène se produit à la fois in vivo et in vitro au niveau de trois résidus Ser/Thr conservés. Des mutations au niveau de ces sites de phosphorylation entrainent le recrutement de Shp2 menant à l’augmentation de la motilité cellulaire, ce qui suggère que les protéines RSK restreignent les fonctions dépendantes de Gab2. Ce phénomène est le résultat de la participation de RSK dans la boucle de rétroaction négative de la voie de signalisation MAPK. Dans la seconde partie de ma thèse, nous avons démontré que les protéines ERK1/2 phosphorylent Gab2 au niveau de plusieurs résidus pS/T-P à la fois in vitro et in vivo, entrainant l’inhibition du recrutement de p85. De plus, nous avons établi pour la première fois que Gab2 interagit physiquement avec ERK1/2 dans des cellules lors de l’activation de la voie de signalisation MAPK. Par ailleurs, nous avons montré un nouveau domaine d’attache du module ERK1/2 sur Gab2. Des mutations sur les résidus essentiels de ce domaine d’attache n’entrainent pas seulement la dissociation de ERK1/2 avec Gab2, mais diminuent également la phosphorylation dépendante de ERK1/2 sur Gab2. Ainsi, nos données montrent que la voie de signalisation MAPK régule les fonctions de la protéine Gab2 par le biais des kinases RSK et ERK1/2. Cette thèse élabore par ailleurs un schéma complet des fonctions de Gab2 dépendantes de la voie de signalisation MAPK dans le développement de nombreux cancers.

Bone marrow cells differentiation to neurons in the rat brain using Serotonin and GABA:Their role on glutamate receptors, IP3, cAMP and cGMP functional regulation in unilateral Parkinsonism induced by 6-hydroxydopamine

Parkinson's disease is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Our findings demonstrated that glutamatergic system is impaired during PD. The evaluations of these damages have important implications in understanding the molecular mechanism underlying motor, cognitive and memory deficits in PD. Our results showed a significant increase of glutamate content in the brain regions of 6- OHDA infused rat compared to control. This increased glutamate content caused an increase in glutamatergic and NMDA receptors function. Glutamate receptor subtypes- NMDAR1, NMDA2B and mGluR5 have differential regulatory role in different brain regions during PD. The second messenger studies confirmed that the changes in the receptor levels alter the IP3, cAMP and cGMP content. The alteration in the second messengers level increased the expression of pro-apoptotic factors - Bax and TNF-α, intercellular protein - α-synuclein and reduced the expression of transcription factor - CREB. These neurofunctional variations are the key contributors to motor and cognitive abnormalities associated with PD. Nestin and GFAP expression study confirmed that 5-HT and GABA induced the differentiation and proliferation of the BMC to neurons and glial cells in the SNpc of rats. We also observed that activated astrocytes are playing a crucial role in the proliferation of transplanted BMC which makes them significant for stem cell-based therapy. Our molecular and behavioural results showed that 5-HT and GABA along with BMC potentiates a restorative effect by reversing the alterations in glutamate receptor binding, gene expression and behaviour abnormality that occur during PD. The therapeutic significance in Parkinson’s disease is of prominence.

On the Tailoring of Magnetic Properties of Fe-Based Alloy Thin Films by Swift Heavy Ion Irradiation and Thermal Annealing

The development of new materials has been the hall mark of human civilization. The quest for making new devices and new materials has prompted humanity to pursue new methods and techniques that eventually has given birth to modern science and technology. With the advent of nanoscience and nanotechnology, scientists are trying hard to tailor materials by varying their size and shape rather than playing with the composition of the material. This, along with the discovery of new and sophisticated imaging tools, has led to the discovery of several new classes of materials like (3D) Graphite, (2D) graphene, (1D) carbon nanotubes, (0D) fullerenes etc. Magnetic materials are in the forefront of applications and have beencontributing their share to remove obsolescence and bring in new devices based on magnetism and magnetic materials. They find applications in various devices such as electromagnets, read heads, sensors, antennas, lubricants etc. Ferromagnetic as well as ferrimagnetic materials have been in use in the form of various devices. Among the ferromagnetic materials iron, cobalt and nickel occupy an important position while various ferrites finds applications in devices ranging from magnetic cores to sensors.

Tailoring Magnetic Properties of Co-Fe Thin Films by Topographical Modifications Using Thermal Annealing and Swift Heavy Ion Irradiation and Fabrication of Magnetoelectric Multilayers for Device Applications

Magnetism and magnetic materials have been playing a lead role in improving the quality of life. They are increasingly being used in a wide variety of applications ranging from compasses to modern technological devices. Metallic glasses occupy an important position among magnetic materials. They assume importance both from a scientific and an application point of view since they represent an amorphous form of condensed matter with significant deviation from thermodynamic equilibrium. Metallic glasses having good soft magnetic properties are widely used in tape recorder heads, cores of high-power transformers and metallic shields. Superconducting metallic glasses are being used to produce high magnetic fields and magnetic levitation effect. Upon heat treatment, they undergo structural relaxation leading to subtle rearrangements of constituent atoms. This leads to densification of amorphous phase and subsequent nanocrystallisation. The short-range structural relaxation phenomenon gives rise to significant variations in physical, mechanical and magnetic properties. Magnetic amorphous alloys of Co-Fe exhibit excellent soft magnetic properties which make them promising candidates for applications as transformer cores, sensors, and actuators. With the advent of microminiaturization and nanotechnology, thin film forms of these alloys are sought after for soft under layers for perpendicular recording media. The thin film forms of these alloys can also be used for fabrication of magnetic micro electro mechanical systems (magnetic MEMS). In bulk, they are drawn in the form of ribbons, often by melt spinning. The main constituents of these alloys are Co, Fe, Ni, Si, Mo and B. Mo acts as the grain growth inhibitor and Si and B facilitate the amorphous nature in the alloy structure. The ferromagnetic phases such as Co-Fe and Fe-Ni in the alloy composition determine the soft magnetic properties. The grain correlation length, a measure of the grain size, often determines the soft magnetic properties of these alloys. Amorphous alloys could be restructured in to their nanocrystalline counterparts by different techniques. The structure of nanocrystalline material consists of nanosized ferromagnetic crystallites embedded in an amorphous matrix. When the amorphous phase is ferromagnetic, they facilitate exchange coupling between nanocrystallites. This exchange coupling results in the vanishing of magnetocrystalline anisotropy which improves the soft magnetic properties. From a fundamental perspective, exchange correlation length and grain size are the deciding factors that determine the magnetic properties of these nanocrystalline materials. In thin films, surfaces and interfaces predominantly decides the bulk property and hence tailoring the surface roughness and morphology of the film could result in modified magnetic properties. Surface modifications can be achieved by thermal annealing at various temperatures. Ion irradiation is an alternative tool to modify the surface/structural properties. The surface evolution of a thin film under swift heavy ion (SHI) irradiation is an outcome of different competing mechanism. It could be sputtering induced by SHI followed by surface roughening process and the material transport induced smoothening process. The impingement of ions with different fluence on the alloy is bound to produce systematic microstructural changes and this could effectively be used for tailoring magnetic parameters namely coercivity, saturation magnetization, magnetic permeability and remanence of these materials. Swift heavy ion irradiation is a novel and an ingenious tool for surface modification which eventually will lead to changes in the bulk as well as surface magnetic property. SHI has been widely used as a method for the creation of latent tracks in thin films. The bombardment of SHI modifies the surfaces or interfaces or creates defects, which induces strain in the film. These changes will have profound influence on the magnetic anisotropy and the magnetisation of the specimen. Thus inducing structural and morphological changes by thermal annealing and swift heavy ion irradiation, which in turn induce changes in the magnetic properties of these alloys, is one of the motivation of this study. Multiferroic and magneto-electrics is a class of functional materials with wide application potential and are of great interest to material scientists and engineers. Magnetoelectric materials combine both magnetic as well as ferroelectric properties in a single specimen. The dielectric properties of such materials can be controlled by the application of an external magnetic field and the magnetic properties by an electric field. Composites with magnetic and piezo/ferroelectric individual phases are found to have strong magnetoelectric (ME) response at room temperature and hence are preferred to single phasic multiferroic materials. Currently research in this class of materials is towards optimization of the ME coupling by tailoring the piezoelectric and magnetostrictive properties of the two individual components of ME composites. The magnetoelectric coupling constant (MECC) (_ ME) is the parameter that decides the extent of interdependence of magnetic and electric response of the composite structure. Extensive investigates have been carried out in bulk composites possessing on giant ME coupling. These materials are fabricated by either gluing the individual components to each other or mixing the magnetic material to a piezoelectric matrix. The most extensively investigated material combinations are Lead Zirconate Titanate (PZT) or Lead Magnesium Niobate-Lead Titanate (PMNPT) as the piezoelectric, and Terfenol-D as the magnetostrictive phase and the coupling is measured in different configurations like transverse, longitudinal and inplane longitudinal. Fabrication of a lead free multiferroic composite with a strong ME response is the need of the hour from a device application point of view. The multilayer structure is expected to be far superior to bulk composites in terms of ME coupling since the piezoelectric (PE) layer can easily be poled electrically to enhance the piezoelectricity and hence the ME effect. The giant magnetostriction reported in the Co-Fe thin films makes it an ideal candidate for the ferromagnetic component and BaTiO3 which is a well known ferroelectric material with improved piezoelectric properties as the ferroelectric component. The multilayer structure of BaTiO3- CoFe- BaTiO3 is an ideal system to understand the underlying fundamental physics behind the ME coupling mechanism. Giant magnetoelectric coupling coefficient is anticipated for these multilayer structures of BaTiO3-CoFe-BaTiO3. This makes it an ideal candidate for cantilever applications in magnetic MEMS/NEMS devices. SrTiO3 is an incipient ferroelectric material which is paraelectric up to 0K in its pure unstressed form. Recently few studies showed that ferroelectricity can be induced by application of stress or by chemical / isotopic substitution. The search for room temperature magnetoelectric coupling in SrTiO3-CoFe-SrTiO3 multilayer structures is of fundamental interest. Yet another motivation of the present work is to fabricate multilayer structures consisting of CoFe/ BaTiO3 and CoFe/ SrTiO3 for possible giant ME coupling coefficient (MECC) values. These are lead free and hence promising candidates for MEMS applications. The elucidation of mechanism for the giant MECC also will be the part of the objective of this investigation.

Conceptualization and therapeutic treatment of a compulsive gambling case by Functional Analysis and Acceptance and Commitment Therapy

A clinical case of compulsive gambling is exposed in this article. The subject’s playing behaviour had both positive and negative consequences. The subject tried to practice control over the urge to play. As shown in the functional analysis, the failure to control the urge despite the best efforts worsened the problem due to its negative consequences. A variation of acceptance and commitment therapy (ACT) was applied in order to break down the fight-surrender vicious circle of the playing behaviour. Two treatment strategies were agreed upon: acceptance of the fact that both playing and not playing had negatives consequences and commitment to one of these options despite its disadvantages. Finally, it is proposed that this acceptance and commitment therapy is a useful therapeutic process as it decreases the suffering subject and eliminates the problem: playing bahaviour.

Perfil epidemiológico de la prevalencia de hipoacusia en un grupo de empleados que trabaja en el ambiente urbano, 2015

El propósito de este estudio es determinar la relación entre la exposición ocupacional y los niveles de audición en trabajadores urbanos en espacio abierto (aseo urbano en general). Se realizó un estudio de corte transversal con 491 personas que incluyen hombres y mujeres, cuyo ambiente laboral es el espacio abierto de la ciudad. Los datos se obtuvieron durante los exámenes médicos periódicos realizados en el año 2014 a los empleados de una empresa cuya actividad económica es el aseo urbano, que incluye recolección de basuras, cuidado forestal y de prados de uso común, y limpieza del borde de los andenes. Se realizó estadística descriptiva para las características demográficas y razón de disparidad u Odds Ratio (OR) para buscar la relación de antecedentes y hábitos personales con el riesgo de desarrollar pérdida auditiva. De las 491 personas expuestas a niveles altos de ruido ocupacional, 62% presentó pérdida auditiva, de los cuales la mayoría se desempeña como guadañadores y cortadores de césped, y son personas que llevan trabajando entre 1-5 años en la empresa. Se encontró un aumento estadísticamente significativo entre la baja escolaridad y el riesgo de sufrir hipoacusia (p=0.0001) y un efecto protector del uso de motocicleta y audífonos. La enfermedad vascular periférica, la práctica de tejo y la diabetes mostraron una fuerte tendencia a aumentar el riesgo. La pérdida auditiva encontrada en este grupo no se puede relacionar directamente con la exposición ocupacional a ruido, a pesar de ser trabajos que se llevan a cabo en el espacio urbano. Sin embargo, la baja escolaridad favorece la lesión auditiva y puede verse acelerada por enfermedades de alta prevalencia como diabetes y practicas recreacionales locales.

El Role-playing com estratègia didàctica en l’atenció sanitària: una experiència educativa als estudis d’infermeria sobre el procés de morir

Per aconseguir un aprenentatge significatiu en el concepte d’atenció sanitària integral sobre el procés de morir ens va semblar interessant utilitzar com estratègia didàctica el role-playing. Aquesta metodologia afavoreix que els estudiants escenifiquin entrant empàticament al paper de qualsevol dels personatges simbòlics que es troben en la situació del procés de morir: afectat, cuidador/s, professional sanitari. En aquest marc permet que els estudiants a partir d’una dinàmica de grup identifiquin conceptes, procediments, actituds, valors i normes a partir de la vivenciació difícilment assolibles amb d’altres metodologies. En aquesta línia coneixen a fons l’impacte multidimensional que genera una situació de malaltia crònica irreversible i la repercussió en les vides de les persones implicades en el procés. Aquesta experiència didàctica, provoca un canvi d’actitud en les components cognitives, emocionals o afectives i conductuals. La tècnica del role-playing és una via ideal per incidir en la component afectiva i emocional que en la sessió magistral mostra una enorme complexitat d’identificar i retroalimentar. Aquesta intervenció repercuteix directament en l’aprenentatge i modificació de la conducta i en l’adquisició d’uns continguts apresos des d’una experiència vivencial i grupal. El procés d’estructuració racional de la vivència transfereix a un ensenyament-aprenentatge significatiu

Variables that influence the real-ear response of the TDH-49 earphone

This paper discusses a study performed to determine whether anatomical features of the outer ear affect the sound stimulus delivered by earphone to the tympanic membrane.

The use of otoscopy and middle-ear measurement as screening procedures

This paper is a review of a study to determine whether the use of otoscopic examination and middle ear impedance measurement are feasible tools for use by an audiologist during a screening program.

Uneven playing field or falling standards? Chinese students' competence in English.

This paper explores student and teacher perspectives of challenges relating to the levels of competence in English of Chinese students studying overseas from the perspective of critical pedagogy. It draws on two complementary studies undertaken by colleagues at the University of Reading. The first—a research seminar attended by representatives from a wide range of UK universities—presents the views of teachers and administrators; the second draws on four case studies of the language learning of Chinese postgraduate students during their first year of study in the UK, and offers the student voice. Interview and focus group data highlight the limitations of current tests of English used as part of the requirements for university admission. In particular, university teachers expressed uncertainty about whether the acceptance of levels of written English which fall far short of native-speaker competence is an ill-advised lowering of standards or a necessary and pragmatic response to the realities of an otherwise uneven playing field. In spite of this ambivalence, there is evidence of a growing willingness on the part of university teachers and support staff to find solutions to the language issues facing Chinese students, some of which require a more strategic institutional approach, while others rely on greater flexibility on the part of individuals. Although the studies reported in this paper were based on British universities, the findings will also be of interest to those involved in tertiary education in other English-speaking countries which are currently attracting large numbers of Chinese students.

A left-ear disadvantage for the presentation of irrelevant sound: manipulations of task requirements and changing state

Three experiments attempted to clarify the effect of altering the spatial presentation of irrelevant auditory information. Previous research using serial recall tasks demonstrated a left-ear disadvantage for the presentation of irrelevant sounds (Hadlington, Bridges, & Darby, 2004). Experiments 1 and 2 examined the effects of manipulating the location of irrelevant sound on either a mental arithmetic task (Banbury & Berry, 1998) or a missing-item task (Jones & Macken, 1993; Experiment 4). Experiment 3 altered the amount of change in the irrelevant stream to assess how this affected the level of interference elicited. Two prerequisites appear necessary to produce the left-ear disadvantage; the presence of ordered structural changes in the irrelevant sound and the requirement for serial order processing of the attended information. The existence of a left-ear disadvantage highlights the role of the right hemisphere in the obligatory processing of auditory information. (c) 2006 Published by Elsevier Inc.

Children playing branded video games: The impact of interactivity on product placement effectiveness

This study extends product placement research by testing the impact of interactivity on product placement effectiveness. The results suggest that when children cannot interact with the placements in video games, perceptual fluency is the underlying mechanism leading to positive affect. Therefore, the effects are only evident in a stimulus-based choice where the same stimulus is provided as a cue. However, when children have the opportunity to interact with the placements in video games, they may be influenced by conceptual fluency. Thus, placements are still effective in a memory-based choice where no stimulus is provided as a cue. Keywords: Perceptual fluency; Conceptual fluency; Video games; Interactivity; Children; Product placement

Parenting by anxious mothers: effects of disorder subtype, context and child characteristics

Background:  There has been increasing research interest in parenting by anxious adults; however, little is known about anxiety-subtype effects, or effects of the context in which parenting is assessed. Methods:  Two groups of anxious mothers, social phobia (N = 50), generalised anxiety disorder (N = 38), and nonanxious controls (N = 62) were assessed with their 4.9-year-old children in three tasks: two presented threat specifically relevant to each maternal disorder, namely, a social threat task where the child had to give a speech, and a nonsocial threat task where the child had to explore potentially scary objects; the third was a nonthreat task (playing with play dough). Seven parenting dimensions were scored. Effects on parenting of maternal anxiety subgroup and task, and their interactions, were examined, as were effects of earlier child behavioural inhibition and currently manifest anxiety. Results:  There were no parenting differences between maternal groups in the nonthreat play-dough task; parenting difficulties in the two anxious groups were principally evident in the disorder-specific challenge. Parenting differences between nonanxious and anxious mothers occurred independently of child characteristics. There was little evidence for particular forms of parenting difficulty being unique to maternal disorder. Conclusions:  Anxious mothers’ parenting difficulties emerge when occurring under challenge, especially when this is disorder-specific. These effects should be considered in research and clinical practice.

Distribution of esterase activity in porcine ear skin, and the effects of freezing and heat separation

Porcine ear skin is widely used to study skin permeation and absorption of ester compounds, whose permeation and absorption profiles may be directly influenced by in situ skin esterase activity. Importantly, esterase distribution and activity in porcine ear skin following common protocols of skin handling and storage have not been characterised. Thus, we have compared the distribution and hydrolytic activity of esterases in freshly excised, frozen, heated and explanted porcine ear skin. Using an esterase staining kit, esterase activity was found to be localised in the stratum corneum and viable epidermis. Under frozen storage and a common heating protocol of epidermal sheet separation, esterase staining in the skin visibly diminished. This was confirmed by a quantitative assay using HPLC to monitor the hydrolysis of aspirin, in freshly excised, frozen or heated porcine ear skin. Compared to vehicle-only control, the rate of aspirin hydrolysis was approximately three-fold higher in the presence of freshly excised skin, but no different in the presence of frozen or heated skin. Therefore, frozen and heat-separated porcine ear skin should not be used to study the permeation of ester-containing permeants, in particular co-drugs and pro-drugs, whose hydrolysis or degradation can be modulated by skin esterases.