Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic beta-cells.

OBJECTIVE: Pancreatic beta-cells exposed to proinflammatory cytokines display alterations in gene expression resulting in defective insulin secretion and apoptosis. MicroRNAs are small noncoding RNAs emerging as key regulators of gene expression. Here, we evaluated the contribution of microRNAs to cytokine-mediated beta-cell cytotoxicity. RESEARCH DESIGN AND METHODS: We used global microarray profiling and real-time PCR analysis to detect changes in microRNA expression in beta-cells exposed to cytokines and in islets of pre-diabetic NOD mice. We assessed the involvement of the microRNAs affected in cytokine-mediated beta-cell failure by modifying their expression in insulin-secreting MIN6 cells. RESULTS: We found that IL-1beta and TNF-alpha induce the expression of miR-21, miR-34a, and miR-146a both in MIN6 cells and human pancreatic islets. We further show an increase of these microRNAs in islets of NOD mice during development of pre-diabetic insulitis. Blocking miR-21, miR-34a, or miR-146a function using antisense molecules did not restore insulin-promoter activity but prevented the reduction in glucose-induced insulin secretion observed upon IL-1beta exposure. Moreover, anti-miR-34a and anti-miR-146a treatment protected MIN6 cells from cytokine-triggered cell death. CONCLUSIONS: Our data identify miR-21, miR-34a, and miR-146a as novel players in beta-cell failure elicited in vitro and in vivo by proinflammatory cytokines, notably during the development of peri-insulitis that precedes overt diabetes in NOD mice.

A two-week workshop to promote cardiovascular disease prevention programs in countries with limited resources.

Training is a crucial tool for building the capacity necessary for prevention and control of cardiovascular diseases (CVDs) in developing countries. This paper summarizes some features of a 2-week workshop aimed at enabling local health professionals to initiate a comprehensive CVD prevention and control program in a context of limited resources. The workshops have been organized in the regions where CVD prevention programs are being contemplated, in cooperation with health authorities of the concerned regions. The workshop's content includes a broad variety of issues related to CVD prevention and control, and to program development. Strong emphasis is placed on "learning by doing," and groups of 5-6 participants conduct a small-scale epidemiological study during the first week; during the second week, they draft a virtual program of CVD prevention and control adapted to the local situation. This practice-oriented workshop focuses on building expertise among anticipated key players, strengthening networks among relevant health professionals, and advocating the urgent need to tackle the emerging CVD epidemic in developing countries.

On the use of mobile inflatable hypoxic marquees for sport-specific altitude training in team sports.

BACKGROUND/AIM: With the evolving boundaries of sports science and greater understanding of the driving factors in the human performance physiology, one of the limiting factors has now become the technology. The growing scientific interest on the practical application of hypoxic training for intermittent activities such as team and racket sports legitimises the development of innovative technologies serving athletes in a sport-specific setting. METHODS: Description of a new mobile inflatable simulated hypoxic equipment. RESULTS: The system comprises two inflatable units-that is, a tunnel and a rectangular design, each with a 215 m(3) volume and a hypoxic trailer generating over 3000 Lpm of hypoxic air with FiO₂ between 0.21 and 0.10 (a simulated altitude up to 5100 m). The inflatable units offer a 45 m running lane (width=1.8 m and height=2.5 m) as well as a 8 m × 10 m dome tent. FiO₂ is stable within a range of 0.1% in normal conditions inside the tunnel. The air supplied is very dry-typically 10-15% relative humidity. CONCLUSIONS: This mobile inflatable simulated hypoxic equipment is a promising technological advance within sport sciences. It offers an opportunity for team-sport players to train under hypoxic conditions, both for repeating sprints (tunnel configuration) or small-side games (rectangular configuration).

Role of the serine protease CAP1/Prss8 and its inhibitor in the skin

The skin is the largest organ of the human body and protects it from water loss and mechanical damage. This barrier function is mainly provided by the epidermis, the outermost layer of the skin. This balance is regulated by several factors, including serine proteases, serine protease inhibitors and protease target substrates, such as receptors. Any mutations or alterations in the expression of these factors can lead to skin diseases. One of the players in this skin balance is the serine protease CAP1/Prss8, whose over-expression causes ichthyosis, hyperplasia and inflammation. This phenotype can be completely restored in the absence of PAR2 (protease-activated receptor 2) (Frateschi et al., 2011). During my thesis, I demonstrated that CAP1/Prss8 induces skin disease even if its catalytic triad is mutated. Additionally, I demonstrated an inhibitory effect of the serine protease-inhibitor nexin-1 (also called serpinE2, PN-1) on CAP1/Prss8, since nexin-1 negated the effects of both catalytically active and inactive CAP1/Prss8 over-expression. Indeed, CAP1/Prss8 and nexin-1 interact in vitro, but independent of the catalytic triad of CAP1/Prss8. These results demonstrate a novel mechanism of interaction between CAP1/Prss8 and nexin-1, and indicate that the catalytic triad of CAP1/Prss8 is dispensable for nexin-1 inhibition and PAR2 activation. These observations in vivo and in vitro could be helpful to specifically target drugs to treat ichthyoses-like skin diseases, like e.g. atopic dermatitis. - La peau est l'un des organes les plus importants du corps humain au regard de sa surface et de sa masse. Ses principales fonctions sont de nous protéger contre l'entrée de pathogènes et de former une barrière imperméable qui empêche la déshydratation. Ces fonctions sont principalement assurées par l'épiderme, la couche la plus superficielle de la peau, et garanties par plusieurs "acteurs", comme par exemple les sérine-protéases, les inhibiteurs de sérine- protéases ou les protéases cibles comme les récepteurs. Toute mutation ou altération de l'un de ces "acteurs" peut aboutir au déclanchement de maladies de la peau. Pour mieux comprendre les conséquences biologiques résultant d'une altération d'expression de CAP1/Prss8, une serine-protéase normalement exprimée au niveau de l'épiderme, nous avons généré des souris transgéniques surexprimant CAP1/Prss8 au niveau de la peau. Ces dernières présentent une peau squameuse, un épiderme hypertrophique, des processus inflammatoires et des prurits conséquents. Ces symptômes disparaissent si le gène du récepteur PAR2, qui régule l'activité des cellules de l'épiderme, est inactivé. Dans le but de vérifier si le phénotype observé chez les souris CAP1/Prss8 résulte de l'action du site catalytique de CAP1/Prss8, nous avons généré des souris CAP1/Prss8 chez lesquelles nous avons muté les trois acides aminés du site catalytique en alanine. Etonnement ces souris ont développé les mêmes problèmes de peau que les souris CAP1/Prss8, démontrant que l'effet de CAP1/Prss8, dans ce modèle animal, n'est pas lié à son site catalytique. Nous avons également montré in vivo, que la sérine-protéase nexin-1 (aussi appelée SERPINE2, PN-1) est capable d'exercer un effet inhibiteur sur CAP1/Prss8 indépendamment de l'activité du site catalytique de CAP1/Prss8. De plus, nous avons remarqué in vitro que CAP1/Prss8 et nexin-1 interagissent bien que la triade catalytique de CAP1/Prss8 soit enzymatiquement inactivée. Ces observations, in vivo et in vitro, pourraient être utilisées dans l'élaboration de médicaments contenant nexin-1, pour le traitement de pathologies de la peau telles l'ichthyose et la dermatite atopique.

Distinct effects of inflammation on gliosis, osmohomeostasis, and vascular integrity during amyloid beta-induced retinal degeneration.

In normal retinas, amyloid-β (Aβ) accumulates in the subretinal space, at the interface of the retinal pigment epithelium, and the photoreceptor outer segments. However, the molecular and cellular effects of subretinal Aβ remain inadequately elucidated. We previously showed that subretinal injection of Aβ(1-42) induces retinal inflammation, followed by photoreceptor cell death. The retinal Müller glial (RMG) cells, which are the principal retinal glial cells, are metabolically coupled to photoreceptors. Their role in the maintenance of retinal water/potassium and glutamate homeostasis makes them important players in photoreceptor survival. This study investigated the effects of subretinal Aβ(1-42) on RMG cells and of Aβ(1-42)-induced inflammation on retinal homeostasis. RMG cell gliosis (upregulation of GFAP, vimentin, and nestin) on day 1 postinjection and a proinflammatory phenotype were the first signs of retinal alteration induced by Aβ(1-42). On day 3, we detected modifications in the protein expression patterns of cyclooxygenase 2 (COX-2), glutamine synthetase (GS), Kir4.1 [the inwardly rectifying potassium (Kir) channel], and aquaporin (AQP)-4 water channels in RMG cells and of the photoreceptor-associated AQP-1. The integrity of the blood-retina barrier was compromised and retinal edema developed. Aβ(1-42) induced endoplasmic reticulum stress associated with sustained upregulation of the proapoptotic factors of the unfolded protein response and persistent photoreceptor apoptosis. Indomethacin treatment decreased inflammation and reversed the Aβ(1-42)-induced gliosis and modifications in the expression patterns of COX-2, Kir4.1, and AQP-1, but not of AQP-4 or GS. Nor did it improve edema. Our study pinpoints the adaptive response to Aβ of specific RMG cell functions.

On the coincidence of the Mas-Colell bargaining set and the core

In this paper we prove that the Mas-Colell bargaining set coincides with the core for three-player balanced and superadditive cooperative games. This is no longer true without the superadditivity condition or for games with more than three-players. Furthermore, under the same assumptions, the coincidence between the Mas-Collel and the individual rational bargaining set (Vohra (1991)) is revealed. Keywords: Cooperative game, Mas-Colell bargaining set, balancedness, individual rational bargaining set. JEL classi fication: C71, D63, D71.

EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells

Introduction: Cancer stem cells (CSC) display plasticity and self renewal properties reminiscent of normal tissue stem cells but the events responsible for their emergence remain obscure. We have recently identified CSC in Ewing sarcoma family tumors (ESFT) and shown that they arise from mesenchymal stem cells from the bone marrow. Objective of the study: To analyze the mechanisms underlying cancer stem cell development in ESFT. Methods: Primary human mesenchymal stem cells (MSC) isolation from adult and pediatric bone marrow. Retroviral delivery of fusion protein (EWS-FLI1) to primary MSC, and transcriptional and phenotypical analysis. Results: We show that the EWS-FLI-1 fusion gene, associated wit 85-90% of ESFT and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2 and NANOG in human pediatric MSC (hpMSC) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSC expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWSFLI- 1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Conclusion: Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a cancer stem cell phenotype.

Three essays on major trends in a slow clockspeed industry : the case of industrial automation

The motivation for this research initiated from the abrupt rise and fall of minicomputers which were initially used both for industrial automation and business applications due to their significantly lower cost than their predecessors, the mainframes. Later industrial automation developed its own vertically integrated hardware and software to address the application needs of uninterrupted operations, real-time control and resilience to harsh environmental conditions. This has led to the creation of an independent industry, namely industrial automation used in PLC, DCS, SCADA and robot control systems. This industry employs today over 200'000 people in a profitable slow clockspeed context in contrast to the two mainstream computing industries of information technology (IT) focused on business applications and telecommunications focused on communications networks and hand-held devices. Already in 1990s it was foreseen that IT and communication would merge into one Information and communication industry (ICT). The fundamental question of the thesis is: Could industrial automation leverage a common technology platform with the newly formed ICT industry? Computer systems dominated by complex instruction set computers (CISC) were challenged during 1990s with higher performance reduced instruction set computers (RISC). RISC started to evolve parallel to the constant advancement of Moore's law. These developments created the high performance and low energy consumption System-on-Chip architecture (SoC). Unlike to the CISC processors RISC processor architecture is a separate industry from the RISC chip manufacturing industry. It also has several hardware independent software platforms consisting of integrated operating system, development environment, user interface and application market which enables customers to have more choices due to hardware independent real time capable software applications. An architecture disruption merged and the smartphone and tablet market were formed with new rules and new key players in the ICT industry. Today there are more RISC computer systems running Linux (or other Unix variants) than any other computer system. The astonishing rise of SoC based technologies and related software platforms in smartphones created in unit terms the largest installed base ever seen in the history of computers and is now being further extended by tablets. An underlying additional element of this transition is the increasing role of open source technologies both in software and hardware. This has driven the microprocessor based personal computer industry with few dominating closed operating system platforms into a steep decline. A significant factor in this process has been the separation of processor architecture and processor chip production and operating systems and application development platforms merger into integrated software platforms with proprietary application markets. Furthermore the pay-by-click marketing has changed the way applications development is compensated: Three essays on major trends in a slow clockspeed industry: The case of industrial automation 2014 freeware, ad based or licensed - all at a lower price and used by a wider customer base than ever before. Moreover, the concept of software maintenance contract is very remote in the app world. However, as a slow clockspeed industry, industrial automation has remained intact during the disruptions based on SoC and related software platforms in the ICT industries. Industrial automation incumbents continue to supply systems based on vertically integrated systems consisting of proprietary software and proprietary mainly microprocessor based hardware. They enjoy admirable profitability levels on a very narrow customer base due to strong technology-enabled customer lock-in and customers' high risk leverage as their production is dependent on fault-free operation of the industrial automation systems. When will this balance of power be disrupted? The thesis suggests how industrial automation could join the mainstream ICT industry and create an information, communication and automation (ICAT) industry. Lately the Internet of Things (loT) and weightless networks, a new standard leveraging frequency channels earlier occupied by TV broadcasting, have gradually started to change the rigid world of Machine to Machine (M2M) interaction. It is foreseeable that enough momentum will be created that the industrial automation market will in due course face an architecture disruption empowered by these new trends. This thesis examines the current state of industrial automation subject to the competition between the incumbents firstly through a research on cost competitiveness efforts in captive outsourcing of engineering, research and development and secondly researching process re- engineering in the case of complex system global software support. Thirdly we investigate the industry actors', namely customers, incumbents and newcomers, views on the future direction of industrial automation and conclude with our assessments of the possible routes industrial automation could advance taking into account the looming rise of the Internet of Things (loT) and weightless networks. Industrial automation is an industry dominated by a handful of global players each of them focusing on maintaining their own proprietary solutions. The rise of de facto standards like IBM PC, Unix and Linux and SoC leveraged by IBM, Compaq, Dell, HP, ARM, Apple, Google, Samsung and others have created new markets of personal computers, smartphone and tablets and will eventually also impact industrial automation through game changing commoditization and related control point and business model changes. This trend will inevitably continue, but the transition to a commoditized industrial automation will not happen in the near future.

Estudi de la zona de finalització més eficaç per guanyar el punt mitjançant l'atac de dreta en el tennis de taula

L’objectiu d’aquest estudi és determinar la zona més efectiva per guanyar el punt mitjançant l’atac de dreta en el tennis de taula. S’utilitza una adaptació del sistema d’anàlisi dels tres nivells d’habilitat, proposat pels acadèmics xinesos Wu i Li (1990) per tal de classificar els punts de la forma que ens permetin analitzar les zones de finalització i les formes com s’obtenen els punts. L’estudi analitza cinc partits dels sis millors jugadors del rànquing mundial de la ITTF. El resultat de l’estudi és que la zona de finalització més eficaç per obtenir el punt mitjançant l’atac de dreta és la zona 1 de la taula del rival.

Utilització de la variabilitat de la freqüència cardíaca (VFC) per a la valoració de l'estat de recuperació-estrès en l'entrenament del judo

Usually, competitive stress, work life or just the training load in athletes can cause a phenomenon called overtraining syndrome. It is described as imbalance between stimulus and recovery in which decreases performance of athletes without being apparently immersed in a frame of injury or disease. That prolonged fatigue may affect the ability to adapt and thus severely reduce performance. This situation can be prolonged in time despite the existence of weekly or monthly periods of recovery. We want to see if the parameters of HRV, RESTQ-Sport questionnaire and strength values vary significantly in front 2 types of training (an intensive two daily sessions, large volume of work and little rest between the sessions; and another with 4 weekly workouts, with longer recovery time and less volume of work), in national judo players (n=14) to study the relationship between VFC and the imbalance of stress-recovery. METHODOLOGY: We performed a longitudinal and experimental study of HRV in 14 subjects, judo players at the national, randomly divided into 2 groups. One of these was conducted intensive training (high volume and low recovery) and another who made a smoother workout (less volume and less recovery) during a period of 4 weeks. CONCLUTIONS: The correct interpretation of the fluctuation parameters of HRV during the training judo players, may be a good indicator of stress levels, the recovery workload and therefore the observation of VFC is becomes an economic and noninvasive method of monitoring training in judo.

Planificació i gestió esportiva en equips base de clubs de futbol amateur. Factors determinants en l'elecció d'un club de tipus lúdic o competitiu

L’etapa d’iniciació a l’esport té una importància majúscula en el procés d’aprenentatge dels jugadors, i per això també podem trobar dos tipus de clubs: els competitius, els quals estan influïts bàsicament pels resultats obtinguts; i els lúdics, on preval la diversió i el joc sobre l’especialització a l’esport. El que es pretén amb aquesta investigació és descobrir quins factors són més determinants per fer que les famílies escullin un tipus de club o un altre. Per tant, basant-nos amb el que diuen autors com Pacheco (2007), Wein (2004), Frattarola i Sans (2006) i Lasierra i Lavega (1993), s’han concretat una sèrie de factors determinants per l’elecció de cada tipus de club, així com d’altres que seran significatius per les famílies a l’hora de decantar-se per un o per l’altre. Pel que fa a la part metodològica, dir que és una investigació descriptiva transversal. A més, s’ha utilitzat l’estratègia de l’enquesta amb l’instrument del qüestionari, el qual s’ha basat en una mostra formada per 60 pares i mares de nens i nenes d’iniciació en l’esport, i 20 pares i mares de nens d’escoleta, previ a la iniciació esportiva. Pel que fa als resultats obtinguts, aquests mostren que al club lúdic es compleixen els tres factors d’aquest àmbit, mentre que al club competitiu es compleixen els dos mateixos factors lúdics de l’altre club i només un factor competitiu. D’altra banda, cal tenir present la importància que tenen els factors contaminadors en els resultats obtinguts degut a la significativitat d’aquests.

El futbol femení a Osona: desigualtats, necessitats, demanda i potencialitat d'un campus de futbol per a noies de la comarca

L’objectiu d’aquest treball és determinar si existeix una desigualtat entre el futbol femení i el masculí en esdeveniments esportius i en el seu cas realitzar propostes ajustades a les necessitats actuals. D’una banda, les dades cedides per la Federació Catalana de Futbol permeten comparar l’evolució de futbolistes federats i federades i certifiquen que hi ha un canvi de socialització de la dona dins de l’esport, concretament, del futbol osonenc. D’altra banda, de la literatura es desprèn que és possible detectar que la progressió de la dona en l’esport no va d’acord amb les necessitats d’aquest gènere. És per això, que mitjançant la tècnica de treball dels grups de discussió, integrats per jugadores, entrenadors i pares i mares, ens acostarem a la realitat per tal d’esbrinar la demanda d’un possible campus de futbol femení; els seus objectius i les preferències d’aquest col·lectiu per aconseguir satisfer les seves necessitats.

La motivació com estratègia psicològica en la interacció d'entrenadors i esportistes en iniciació esportiva

Un dels aspectes més importants en iniciació esportiva és la motivació. Si aconseguim que els nostres jugadors estiguin motivats per realitzar la pràctica esportiva obtindrem per part seva una major implicació per les tasques d’entrenament i evitarem l’abandonament prematur de la pràctica esportiva per falta de motivació. Els jugadors en les seves primeres etapes s’inicien en l’esport per motius intrínsecs i hem d’esbrinar que és el que vol el nostre grup al principi de temporada. El qüestionari de motius de pràctica esportiva ens servirà per saber que és el que volen els nostres jugadors i com hem de plantejar les tasques d’entrenament per adequar-les a les seves motivacions. La interacció entrenador – jugadors és l’altre punt a tractar en aquest treball ja que la motivació extrínseca produïda per l’entrenador durant els partits i els entrenaments tindrà una repercussió en la motivació intrínseca del nen. El CBAS és un mètode adequat per identificar les conductes de l’entrenador quan interactua amb els seus jugadors durant els partits i quins aspectes s’han de millorar. L’objectiu d’aquest treball és plantejar estratègies per conèixer i millorar la motivació dels jugadors incidint sobre la motivació intrínseca i extrínseca d’aquests mitjançant la interacció que tenen l’entrenador i els jugadors.

Estudi de l'efectivitat del remat al primer toc dins la zona de finalització

L’objectiu principal d’aquest estudi ha estat comprovar quin nombre de contactes amb la pilota és més efectiu a l’hora d’executar l’acció del remat dins la zona de finalització. S’ha utilitzat la metodologia observacional, investigant en un context d’elit com són els partits realitzats per les quatre seleccions millor classificades a l’Eurocopa 2012. La investigació ha tingut en compte diferents variables del remat com el gol, el nombre de contactes amb la pilota abans del remat, l’orientació corporal del jugador que remata i la última acció abans que la pilota entri dins la zona de finalització per ser rematada. Els resultats obtinguts ens donen informació sobre com les seleccions de Portugal, Alemanya, Itàlia i Espanya finalitzaren les seves accions ofensives i permeten al lector fer-se una idea general de com hauria de realitzar-se un remat en la zona de finalització.

Storage and uptake of D-serine into astrocytic synaptic-like vesicles specify gliotransmission.

Glial cells are increasingly recognized as active players that profoundly influence neuronal synaptic transmission by specialized signaling pathways. In particular, astrocytes have been shown recently to release small molecules, such as the amino acids l-glutamate and d-serine as "gliotransmitters," which directly control the efficacy of adjacent synapses. However, it is still controversial whether gliotransmitters are released from a cytosolic pool or by Ca(2+)-dependent exocytosis from secretory vesicles, i.e., by a mechanism similar to the release of synaptic vesicles in synapses. Here we report that rat cortical astrocytes contain storage vesicles that display morphological and biochemical features similar to neuronal synaptic vesicles. These vesicles share some, but not all, membrane proteins with synaptic vesicles, including the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) synaptobrevin 2, and contain both l-glutamate and d-serine. Furthermore, they show uptake of l-glutamate and d-serine that is driven by a proton electrochemical gradient. d-Serine uptake is associated with vesicle acidification and is dependent on chloride. Whereas l-serine is not transported, serine racemase, the synthesizing enzyme for d-serine, is anchored to the membrane of the vesicles, allowing local generation of d-serine. Finally, we reveal a previously unexpected mutual vesicular synergy between d-serine and l-glutamate filling in glia vesicles. We conclude that astrocytes contain vesicles capable of storing and releasing d-serine, l-glutamate, and most likely other neuromodulators in an activity-dependent manner.