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PLENARY LECTURE L1. PHYSIOLOGY OF THE CELL STRESS AND ITS ROLE IN MALIGNANT DISEASES.

Juan Lucio Iovanna. Centre de Recherche en Cancérologie de Marseille (CRCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1068, Centre National de la Recherche Scientifique (CNRS) Unit 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.

SYMPOSIA Symposium 1. HIDRATATION.

Chair: Emilio Martínez de Victoria, Catedrático de Fisiología. Departamento de Fisiología, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Granada. España.

S1. SLIGHT OR MODERATE DEHYDRATION AND COGNITIVE PERFORMANCE. A NON-NEGLIGIBLE RELATIONSHIP. Ana Adán Puig. Profesora titular Departamento de Psiquiatría y Psicobiología Clínica. Universidad de Barcelona. España.

S2. HYDRIC REQUIREMENTA AND PHYSICAL ACTIVITY. Pilar Sánchez Collado, Profesora Titular de Universidad, Departamento de Ciencias Biomédicas, Área de Fisiología. Universidad de León, España.

S3. FLUIDS REPLACEMENT IN EXTREME SITUATIONS. Raquel Blasco Redondo. Profesora Asociada de la Facultad de Medicina de la Universidad de Valladolid. Unidad de Medicina Interna del Centro Regional de Medicina Deportiva de la Junta de Castilla y León. Valladolid, España.

Symposium 2. CORTICAL CEREBRAL STATES AND COGNITIVE FUNCTIONS.

Chair: Agnès Gruart i Massó. Catedrática de Fisiología, Departamento de Fisiología. Universidad Pablo de Olavide de Sevilla. España.

S4. I OSCILLATE THEREFORE I EXIST: BRAIN RHYTHMS AND CONSCIOUSNESS. Mavi Sánchez-Vives. Investigadora ICREA, IDIBAPS (Institut d'Investigacions Biomediques August Pi i Sunyer). Barcelona, España.

S5. CIRCUITS FOR REMEMBERING. Agnès Gruart i Massó. Catedrática de Fisiología, Departamento de Fisiología. Universidad Pablo de Olavide de Sevilla. España

S6. INFORMATION TO BE REMEMBERED AND FORGOTTEN: TO HIPPOCAMPUS AND BEYOND. Santiago Canals, Científico Titular, CSIC, Instituto de Neurociencias de Alicante. España.

Symposium 3. ION CHANNELS AND VASCULAR PATHOPHYSIOLOGY.

Chair: Guillermo Álvarez de Toledo Naranjo, Catedrático de Fisiología. Departamento de Fisiología, Universidad de Sevilla. España.

S7. REDISCOVERING THE INTERPLAY BETWEEN K+ AND Ca2+ CHANNELS IN ESSENTIAL HYPERTENSION. José Ramón López López. Profesor Titular del Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid. España.

S8. DESIGN AND FUNCTION OF NEGATIVE-GATING MODULATORS OF VASCULAR KCA2/3 CHANNELS AND POTENTIAL THERAPEUTIC UTILITIES. Ralf Köhler. Hospital Miguel Servet de Zaragoza. España.

S9. L-TYPE CA2+ CHANNELS AND RHOA/RHO KINASE ACTIVATION: A NEW FUNCTIONAL ROLE OF CA2+ CHANNELS IN THE MAINTENANCE OF ARTERIAL CONTRACTION. Juan Ureña López, Catedrático del Departamento de Fisiología Médica y Biofísica. Facultad de Medicina, Universidad de Sevilla. España.

Symposium 4. MITOCHONDRIA, NEURODEGENERATION AND AGING.

Chair: Darío Acuña Castroviejo. Catedrático de Fisiología. Departamento de Fisiología, Universidad de Granada. España.

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S10. NEUROPROTECTIVE EFFECTS OF GROWTH HORMONE (GH). Jesús Devesa Múgica. Fundación Foltra. España.

S11. STEM CELLS IN THE BRAIN OF MAMMALS: NEUROGENESIS, TUMORS AND AGING. José Manuel García Verdugo, Catedrático del Departamento de Biología Celular y Parasitología, Universidad de Valencia. España.

S12. MNGIE: FROM MECHANSIMS TO TREATMENT. Dr. Ramón Martí, Vall d'Hebron. Institut de Recerca. España.

Symposium 5. SURVIVAL MECHANISMS AND HEPATOCELLULAR DEATH.

Chair: Emilio Martínez de Victoria, Catedrático de Fisiología. Departamento de Fisiología, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Granada. España.

S13. MECHANISM OF CELL DEATH SIGNALING IN HEPATOCYTES. Jordi Muntané. Hospital Universitario Reina Sofía de Córdoba, España.

S14. ROLE OF PLASMA MEMBRANE TRANSPORTERS IN LIVER CELL CHEMOPROTECTION. José Juan García Marín, Catedrático del Departamento de Fisiología y Farmacología, Facultad de Farmacia, Universidad de Salamanca. España.

S15. DUAL EFFECT OF MELATONIN ON APOPTOTIC MECHANISMS IN HEPATIC CELLS. Javier González Gallego. Catedrático del Departamento de Ciencias Biomédicas, Instituto de Biomedicina (IBIOMED), Universidad de León. España.

Symposium 6. TRANSIENT RECEPTOR POTENTIAL CHANNELS IN HEALTH AND DISEASE.

Chair: Ginés M. Salido Ruiz, Catedrático de Fisiología. Departamento de Fisiología, Universidad de Extremadura. España.

S16. MOLECULAR MECHANISM OF TRPV1 INFLAMMATORY SENSITIZATION. Antonio Ferrer-Montiel. Catedrático del Departamento de Bioquímica y Biología Molecular, Instituto de Biología Molecular y Celular, Universidad Miguel Hernández. Elche. España.

S17. EMERGING ROLE OF TRP AND STORE OPERATED CHANNELS IN THE CARDIOVASCULAR SYSTEM. Tarik Smani. Instituto de Biomedicina de Sevilla/Hospital, Universitario Virgen del Rocío de Sevilla. España.

S18. TRP CHANNELS AND THE CALCIUM ENTRY SIGNALPLEX. Juan A. Rosado. Profesor Titular del Departamento de Fisiología, Ficell Research Group. Universidad de Extremadura. Cáceres. España.

Symposium 7. PROGRESS IN THE PATHOPHYSIOLOGY OF OBESITY.

Chair: Concepción María Aguilera García, Prof. Titular de Bioquímica y Biología Molecular, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Granada. Granada, España.

S19. GENETIC AND EPIGENETIC MARKERS OF OBESITY: LESSONS FROM INTERVENTION STUDIES. Amelia Martí del Moral. Profesora Titular de Fisiología. Dpto. Ciencias de la Alimentación y Fisiología, Facultad de Farmacia. Pamplona, Navarra. España.

S20. ROLE OF BROWN ADIPOSE TISSUE IN OBESITY PATHOPHYSIOLOGY. Ángel Gil, Catedrático de Bioquímica y Biología Molecular, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Granada. Granada, España.

S21. UNDERSTANDING THE ROLE OF THE GUT MICROBIOME IN OBESITY: The European Project MyNewGut. Yolanda Sanz, Investigadora Titular del Instituto de Agroquímica y Tecnología de Alimentos (IATA). CSIC. Valencia. España.

Symposium 8. EXTREME EXERCISE AND ENVIRONMENTS: NEW CHALLENGES FOR THE PHYSIOLOGIST.

Chair: Jesús Rodríguez Huertas, Catedrático de Fisiología. Departamento de Fisiología, Director del Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Granada. Granada, España.

S22. FUNCTIONAL RESPONSE OF MITOCHONDRIA TO EXERCISE AND EXTREME ENVIRONMENTS. Robert Boushel, D.Sc.Professor and Chair in Physiology Åstrand Laboratory. The Swedish School of Sport and Health Sciences. Sweden.

S23. SAVING MUSCLE MASS DURING VERY SEVERE ENERGY DEFICIT: LESSONS FROM EXTREME EXERCISE IN HUMANS. Prof. Jose A L Calbet, Department of Physical Education. University of Las Palmas de Gran Canaria. España.

S24. HUMAN PHYSIOLOGY IN SPACE, A CHALLENGE FOR FUTURE EXPLORATION. Dr. Victor Demaria-Pesce, Director de Recherches à l’Institut National de la Santé et de la Recherche Médicale (Inserm), Paris y Senior Scientific Adviser en el European Astrounaut Centre (EAC) de la European Space Agency (ESA), Köln, Germany.

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Symposium 9. TEACHING IN PHYSIOLOGY.

Chair: María López-Jurado Romero de la Cruz, Catedrática de Fisiología. Departamento de Fisiología, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Granada. Granada, España.

S25. COMPREHENSIVE LEARNING AND THE MULTIMEDIA TOOLS. Prof. Alejandro Esteller, Catedrático de Fisiología. Departamento de Fisiología y Farmacología. Universidad de Salamanca. aep@usal.es Salamanca, España.

S26. TEACHING PHYSIOLOGY AND THE CHALLENGE OF BOLOGNA. Mª Luisa Ojeda Murillo, Profesora Titular Fisiología, Universidad Sevilla.ojedamuri11@us.es España.

S27. DAILY REVIEW OF PHYSIOLOGY IN THE LIFE OF STUDENTS AND HEALTH PROFESSIONALS. Manuel Castillo Garzón, Catedrático de Fisiología. Departamento de Fisiología, Universidad de Granada. mcgarzon@ugr.es. Granada, España.

Symposium 10. NEW MOLECULAR BASIS OF THE AGING AND NEURODEGENERATIVE DISEASES.

Chair: Juan Sastre Belloch, Catedrático de Fisiología. Departamento de Fisiología, Universidad de Valencia. Valencia, España.

S28. LIPIDOMICS OF LONGEVITY AND HEALTHY AGING. Reinald Pamplona Gras. Catedrático de Fisiología. Universidad de Lleida. Lleida, España.

S29. PHYSIOLOGY OF EXCEPTIONAL LONGEVITY. REGULATION OF RNA EXPRESSION IN CENTENARIANS. José Viña, Catedrático de Fisiología. Departamento de Fisiología, Universidad de Valencia. Valencia, España.

S30. METABOLIC-REDOX LINK BETWEEN NEURONA AND GLIA. Juan Pedro Bolaños, Catedrático de Universidad, Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Salamanca. España.

Symposium 11. HYPOTHALAMIC AND EXTRA-HYPOTHALAMIC ROLES OF LEPTIN THROUGHOUT DEVELOPMENT.

Chair: María Paz Viveros Hernando, Catedrática de Fisiología, Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid. España.

S31. LEPTIN MODULATION OF HYPOTHALAMIC ASTROCYTES: A POSSIBLE MECHANISM OF SYSTEMIC METABOLIC CONTROL. Julie A Chowen, Investigadora, Departamento de Endocrinología, Hospital Infantil Universitario Niño Jesús de Madrid, España.

S32. LEPTIN AND NEURONAL DEVELOPMENT. G. Bouret, Profesor e investigador, Inserm U837, Neurobese Lab, University of Lille, Lille, France &2 Childrens Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA.

S33. HYPOTHALAMIC AND EXTRA-HYPOTHALAMIC LEPTIN ACTIONS: NEW INSIGHTS FROM ANIMAL MODELS. María Paz Viveros, Catedrática de Fisiología, Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid. España.

Symposium 12. LEGAL FRAMEWORK AND WELFARE IN EXPERIMENTAL ANIMALS.

Chair: Mariano Mañas Almendros, Catedrático de Fisiología. Departamento de Fisiología, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Granada. Granada, España.

S34. LEGISLATION ON ANIMAL WELFARE: POINT OF VIEW OF NATIONAL GOVERNMENT. Dra. Pilar León Arnaiz. Jefe de Servicio en Administración General del Estado. Ministerio de Medio Ambiente y Medio Rural y Marino. Dirección General de Recursos Agrícolas y Ganaderos., España.

S35. ENABLED ORGANS FOR THE EVALUATION OF EXPERIMENTATION PROJECTS IN THE CONTEXT OF THE RD 53/2013. Dr. Carlos Costela Villodres. Director del Servicio Central de Experimentación y Producción Animal. Universidad de Cádiz, España.

S36. WELFARE ASSESSMENT IN LABORATORY ANIMAL RESEARCH: REFINEMENT. Dra. Ana Nieto Ruiz de Zárate. Responsable del Control Sanitario del Servicio de Experimentación Animal. Universidad de Granada, España.

Symposium 13. CHRONOBIOLOGY. PHYSIOLOGY OF CIRCADIAN SYSTEM.

Chair: Juan Antonio Madrid Pérez, Catedrático de Fisiología, Director del Laboratorio de Cronobiología. Universidad de Murcia. España.

S37. BIOLOGICAL CLOCKS IN THE LAB AND IN THE CLINIC. Dr. Diego Golombek. Investigador CONICEF, Profesor y Director del Laboratorio de Cronobiología de la Universidad Nacional de Quilmes, Argentina.

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S38. CIRCADIAN FUNCTIONS OF THE RETINAL GANGLION CELLS. Dr. José Manuel García Fernández, Catedrático de Biología Celular. Departamento de Morfología y Biología Celular de la Universidad de Oviedo. España.

S39. CIRCADIAN PHYSIOLOGY OF A DUAL-PHASING RODENT, THE OCTODON DEGUS. Beatriz Baño Otálora. Postdoctoral Fellow. Faculty of Life Sciences. University of Manchester, UK.

Symposium 14. HAEMOSTASIS PHYSIOLOGY: FROM MOLECULAR AND CELLULAR TO PATHOPHYSIOLOGY.

Chair: Antonio Liras, Profesor de Fisiología. Facultad Biología. Universidad Complutense de Madrid. España.

S40. CELLULAR MODELS OF HAEMOSTASIS. Francisco Velasco, Profesor T.U. Hematología. Facultad de Medicina. Universidad de Córdoba. Servicio de Hematología del Hospital Universitario "Reina Sofía", Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba. España.Tfo. 957010202. E-mail: francisco.velasco.sspa@juntadeandalucia.es.

S41. EXPANDING THE CURRENT KNOWLEDGE IN FIBRINOLYSIS. José Antonio Páramo, Profesor C.U. Hematología. Facultad de Medicina. Universidad de Navarra. Co-director del Departamento de Hematología y Hemoterapia. Clínica Universidad de Navarra. España. Tfo. 948296397. E-mail: jparamo@unav.es.

S42. ADVANCED THERAPIES AND HEMOSTASIS. Antonio Liras, Profesor C.D. Fisiología. Facultad Biología. Universidad Complutense de Madrid. Coordinador del Grupo UCM de Investigación sobre Terapias Avanzadas, terapia génica y celular. España. Tfo. 649907879. E-mail: aliras@hotmail.com.UCM de investigación sobre Terapias Avanzadas, terapia génica y celular. España.

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PLENARY LECTURE

L1 PHYSIOLOGY OF THE CELL STRESS AND ITS ROLE IN MALIGNANT DISEASES

Juan Iovanna Centre de Recherche en Cancérologie de Marseille (CRCM), France.

The role of Kras as an initiating cancer mutation is one of the best established pathobiological mechanisms required for the development of Pancreatic ductal adenocarcinoma (PDAC) and other cancers. Noteworthy, during the initiation stage, pancreatic cells do not only trigger pro-tumoral processes, but also cellular events which aimed at counteracting transformation. One of these tumor suppressive processes, elicited by Kras activation is cellular senescence (oncogene-induced senescence or OIS). In the pancreas, the induction of senescence underlies the resistance of exocrine cells to oncogenic Kras-mediated transformation so as to prevent tumor promotion which is often supported by common diseases such as pancreatitis. The Nupr1 gene is strongly induced by pancreatitis. The role that Nupr1 plays in pancreatic tumorigenesis is underscored by recent results from our laboratory showing that the oncogenic form of KrasG12D is unable to promote PanINs in its absence. We find that genetic inactivation of Nupr1 in mice impairs Kras-induced PanIN leading to an increase in b-galactosidase positive cells (specific of OIS). More importantly, both of these cellular and molecular changes are recapitulated by the results of mechanistic experiments using RNAi-based inactivation of Nupr1 in human PDAC cell models. Finally, activation of the oncogenic Kras into the lung induces formation of adenomas in Nupr1 wild-type mice whereas induces OIS in Nupr1-deficient mice. In summary, expression of the stress protein Nupr1 switches OIS to transformation induced by oncogenes.

SYMPOSIA

S3 FLUIDS REPLACEMENT IN EXTREME SITUATIONS

Blasco R Specialist of internal medicine and expert in sport medicine. Medicine Regional Center of Castilla y León. Valladolid. Spain. Humans are homeothermic; we are able to regulate our body temperature although within very narrow margins, (34ºC-45ºC). Homeostasis systems are intensely altered in extreme thermal conditions. When the heat is generated by physical activity, we are able to maintain homeothermy by activating the heat loss mechanisms. However, from 37°C of dry temperature or 29°C of wet one, the subject has difficulties and maintaining a physiological and prolonged physical activity results in a decreased performance and occasionally this endangers the health of the athlete. Factors influencing thermoregulation during physical exercise in extreme situations: Heat, Cold, State of fitness, State of hydration. Training to hydration: During prolonged exercise in heat stress, athletes incur in dehydration mainly by sweating losts. The ideal fluid replacement during exercise in heat is the one in which it is fully replaced the water loss caused by sweating (and in long events, diuresis). However, from a competitive point of view, the intake of large volumes of fluid forces to reduce the running speed of the race and causes gastrointestinal disorders. To avoid this, athletes should train their ability of hydration, by drinking during their

trainings, especially in the season of acclimatization. Digestive –emptying and hydration: The water balance during exercise is not always possible because the maximal sweat rates exceed the maximal gastric emptying rates, which limits the absorption of fluid. However, fluid intake during exercise can be done in small quantities that can be emptied from the stomach and absorbed in the intestine. Fluids containing 4-8% carbohydrate (CHO) can be emptied within 1L/hour rates when gastric volume is maintained above 600 ml. Hypo hydration combined with hyperthermia and intense exercise slows gastric emptying and increases the risk of gastrointestinal discomfort, therefore, it is important to begin the fluid intake in the early stages of the exercise to minimize the hypo hydration and to improve the bioavailability of fluids. Composition of the drink: The formula of the drink must avoid the limitations imposed by the voluntary intake, gastric emptying and intestinal absorption. It has to provide fluid, carbohydrate and electrolytes in sufficient quantity and speed to cause positive physiological responses which will improve as well the performance The exercise carried out under extreme temperatures increases the demands of CHO up to 76%. The balance between CHO and electrolyte keeps low the heart rate. It is imperative to constantly replace them during the hydration process The effectiveness of the drink in heat stress situations is largely determined by the amount and type of CHO. In addition to conferring the sweetness that enhances the palatability, the correct amount of CHO, promote gastric emptying and

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stimulates water and electrolyte absorption in the small intestine. They should have a mixture of CHO at a concentration of 60-70 g / L (6-7%) In the thermal stress, the lost of electrolytes (sweat and urine) is higher by almost 30% to less extreme situations, even in individuals acclimatized (having less concentration of electrolytes in sweat). Electrolytes play a key role in maintaining fluid intake and promote hydration. This intake is made with a small amount of salt. Salt absorption into the blood stream prevents early fall of plasma osmolality below the thirst threshold, and helps keep the desire to drink. Drinks should be 110-125 ml sodium /250 mgrs. Occasionally environmental conditions are not known until the day of the competition, therefore, the athlete should carry a variety of products to make drinks with higher and lower concentration of solutes and to administrate himself the fluids according to his needs. Finally, it is important to take into account that there are extreme environmental conditions in which it is not possible, even for well trained and acclimatized to heat athletes, to maintain a constant level of body functions despite being well hydrated. In such conditions, in which the evaporation rate necessary to maintain a thermal balance exceeds the maximum evaporation capacity of the environment, a rapid increase of the body temperature is produced –hyperthermia-, and the only option to safeguard the health of the athletes consists on lowering the heat production by decreasing the intensity of exercise. S4 I OSCILLATE THEREFORE I EXIST:

BRAIN RHYTHMS AND CONSCIOUSNESS

Sanchez-Vives MV Systems Neuroscience. ICREA-IDIBAPS, Barcelona, Spain Collective neuronal phenomena emerging from activity reverberation in cortical circuits at different spatio-temporal scales results in a rich variety of dynamical states. The same networks that perform computations of remarkable complexity, accounting for a large variety of behaviours and cognitive states can engage in stereotypical patterns of spatio-temporal activation, such as the ones that can be observed during sleep, anaesthesia and in cortical slice. As a result of reverberation in the cerebral cortex, activity gets often temporally structured into rhythmic activity, either slow (around or below 1 Hz) or fast (15-100 Hz) rhythms. Fast rhythms are associated to cognitive performance and even to consciousness. In this symposium I will present recent results from our group regarding: 1) experimental and theoretical basis of cortical rhythms, 2) their alteration in transgenic models of neurological disease, 3) their modulation by subcortical nuclei and 4) their correlation with brain functional connectivity. S5 CIRCUITS FOR REMEMBERING Gruart A Division of Neurosciences, Pablo de Olavide University, Seville, Spain. Introduction: Learning and memory processes are probably the result of the cooperative activity of many

different cortical and subcortical neuronal circuits. It is also possible that those neuronal circuits are not only modified by the cues involved in the acquisition process, but also by the context related to the learning situation. In particular, although the hippocampus is involved in associative learning, the specific contribution of its different synapses is poorly defined. Here, we have studied the activity-dependent changes in synaptic strength of hippocampal synapses during the acquisition of a classical eyeblink conditioning. Methods: The experimental subjects were chronically implanted with stimulating and recording electrodes in selected sites of the intrinsic hippocampal circuit and/or in its main inputs and outputs. Animals were trained with a classical eyeblink conditioning. Eyelid responses were determined from the EMG activity of the orbicularis oculi muscle. We also recorded field excitatory post-synaptic potentials (fEPSPs) evoked at the selected synapses during training. Results and Discussion: Results confirm that the acquisition of an eyeblink conditioning is a multisynaptic process in which the contribution of each synaptic contact is different in strength, and takes place at different moments across learning. Eyeblink conditioning evokes a specific, dynamic map of functional synaptic states in that circuit, unique for this particular learning. Both context and pseudoconditioning training also evoked lasting changes in synaptic strength, suggesting that hippocampal circuits are involved in the identification of both context and cues. S6 INFORMATION TO BE

REMEMBERED AND FORGOTTEN: TO HIPPOCAMPUS AND BEYOND

Canals S Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d’Alacant 03550, Spain The hippocampus is a fundamental structure involved in spatial navigation, learning and memory. Information from primary and association cortices is combined in the hippocampal formation to build multimodal representations of the environment. In order to be successfully stored in memory buffers, this information requires further long-range interactions between the hippocampus and a distributed network of neocortical structures. The neurobiological processes governing information channeling in such complex system is far from being understood. In our group, we investigate the dynamics of activity propagation in brain-wide neuronal networks combining electrophysiological recordings, electrical microstimulation and fMRI in rats. We have previously shown that synaptic plasticity in the dentate gyrus drives the reorganization of functional networks supporting memory. We have further demonstrated that such phenomenon involves an inhibitory gating of activity propagation in the hilus. This mechanism is operated by synaptic plasticity and facilitates hippocampal-cortical interactions. Now, by using a localized depolarization of CA3 neurons in dorsal hippocampus we investigate the next relay in the circuit and demonstrate a frequency-dependent pattern of activity propagation. While activation

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within the hippocampal formation increased monotonically with stimulation frequencies from 5 to 40Hz, robust extra-hippocampal propagation was seen specifically at beta frequencies (10-20 Hz), reaching a network of neocortical and mesolimbic structures. Furthermore, experimentally induced synaptic potentiation at CA3-CA1 synapses modulated the gating of activity propagation to the neocortex. These results identify frequency-dependent information channels in brain-wide networks that appear to fulfill the needs for local independency and global integration through segregating activity propagation in the frequency domain. S10 NEUROPROTECTIVE EFFECTS OF

GROWTH HORMONE (GH) Devesa J1,2, Devesa P1, Almengló C1, Arce V2. 1 Centro Sanitario Fundación Foltra, 15886 Teo; 2 Departamento de Fisiología, Facultad de Medicina, Universidad de Santiago de Compostela. Introduction: GH seems to play a major role in the regulation of postnatal neurogenesis and cell survival, therefore it may be also involved in promoting brain repair after brain injury. Methods: By using specific chemical inhibitors we have investigated the pathways signaling the effect of GH treatment on the proliferation and survival of hippocampal subgranular zone (SGZ)-derived neurospheres obtained from neonatal mice. Results: Our results demonstrate that GH treatment promotes both proliferation and survival of SGZ neurospheres. GH treatment promotes the activation of both Akt-mTOR and JNK signaling pathways; while blockade of these pathways either reduces or abolishes the GH effects. In contrast, no effect of GH on the activation of the Ras-ERK pathway was observed after GH treatment, despite blockade of this signaling path also resulted in a significant reduction of GH effects. Interestingly, SGZ cells were also capable of producing GH, and blockade of endogenous GH also resulted in a decrease in the proliferation and survival of SGZ neurospheres. Conclusions: Altogether, our findings suggest that GH treatment may promote the proliferation and survival of neural progenitors. This effect may be elicited by cooperating with locally-produced GH in order to increase the response of neural progenitors to adequate stimuli. For the first time we demonstrate that pJNK is a key component of the GH-signaling pathways for neural precursors proliferation and survival. On this view, the possibility of using GH treatment to promote neurogenesis and cell survival in some acquired neural injuries may be envisaged. S12 MNGIE: FROM MECHANSIMS TO

TREATMENT Martí R Vall d’Hebron Institut de Recerca, and CIBERER (Barcelona) MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) is a mitochondrial disorder caused by mutations in the nuclear gene TYMP, encoding thymidine phosphorylase (TP). In recent years, knowledge gained

from basic research on the biochemical mechanisms involved in this disorder has allowed us to design plausible therapy approaches. In MNGIE patients, TP dysfunction leads to systemic overload of the nucleosides thymidine and deoxyuridine, which results in alteration of the homeostasis of mitochondrial deoxyribonucleoside triphosphate (dNTP) pool. This imbalance interferes the correct replication of mitochondrial DNA (mtDNA). As a consequence, mtDNA depletion, multiple deletions and somatic point mutations occur in several tissues in patients, ultimately leading to mitochondrial dysfunction. As the clinical phenotype of MNGIE is the result of the toxic accumulation of thymidine and deoxyuridine, therapy approaches have focused on clearing the systemic overload of these nucleosides. First attempts to use hemodialysis failed to reduce nucleoside overload because of the high rate of endogenous production of these compounds by human metabolism. By contrast, hematopoietic stem cell transplantation restored nucleoside homeostasis in patients with successful engraftment, and led to slow clinical improvement. However, the high morbidity and mortality rates associated to the procedure encouraged us to find alternatives, and the most obvious one, gene therapy, has given very promising results in a murine model of the disease. MNGIE is a good example demonstrating how basic research on molecular and biochemical pathomechanisms of the diseases is needed in order to facilitate plausible therapy approaches for patients. S13 MECHANISM OF CELL DEATH

SIGNALING IN HEPATOCYTES Muntané J Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío-Virgen Macarena/IBiS/Universidad de Sevilla/CSIC. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREH o Ciberehd). Hepatocytes have developed cell death and survival programs to regulate cellular and tissue homeostasis. The autophagy allows cells to adapt metabolic pattern and cell signaling to new physiological environment. The profound alteration of homeostasis o pathological conditions (toxic, immunological, metabolic or viral infection) may establish a situation incompatible with cell viability which imply the activation of cell death program such as apoptosis and necrosis. Apoptosis is regulated genetically and allow elimination of compromised cells without causing inflammatory local response. Apoptosis may be induced through cell death receptors (TNF-R1, CD95 and TRAIL-R1 (extrinsic pathway, type I cells) or mitochondrial-dependent pathway (intrinsic pathway, type II cells). Normal hepatocytes belong to type II cells. However, according to the de-differentiation stage of malignant liver cancer cells, hepatocytes acquire characteristics of type I cells. In extreme noxious conditions, with alteration of cellular ionic balance, hepatocytes may activate a necrotic-related cell death program which is generally associated with cell content degradation, uncontrolled release and induction of inflammatory response. Different markers of cell death transition with observation of biochemical and morphological markers of apoptosis and necrosis pathways

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may be observed in specific settings. All three cell pathways (autophagy, apoptosis and necrosis) are intimately regulated with extensively crosstalk among them. S14 ROLE OF PLASMA MEMBRANE

TRANSPORTERS IN LIVER CELL CHEMOPROTECTION

Marin JJG Experimental Hepatology and Drug Targeting (HEVEFARM) IBSAL, CIBERehd, University of Salamanca. The liver is frequently exposed to potentially toxic substances, which include endogenous compounds and toxins or drugs. However, this organ is equiped with effective protective mechanisms, such as plasma membrane transporters that limit the uptake of toxic compounds or enhance their export from the cells. The same mechanisms are also present in cancer cells and limit the antitumour efficacy of chemotherapy. FXR nuclear receptor, whose natural ligands are bile acids, are involved in the regulation of chemoprotection in tissues of the enterohepatic circulation. Thus, Fxr-/- mice spontaneously develop liver and colon tumours. The analysis of biopsies collected from hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma and colon adenocarcinoma has revealed a marked decrease in FXR expression in these tumours. However, when chemoresistance was induced in tumour cells by prolonged exposure to pharmacological stress, this was characterized by up-regulation of FXR together with enhanced expression of drug export pumps, such as BCRP and MRP2. Transfection of chemosensitive cells with FXR has the same effect. Furthermore, the chemoresistance can be due to reduced drug uptake. This is the case of sorafenib, an anticancer drug able of inhibiting receptor tyrosine kinase activity once taken up by the target cells. In this process the organic cation transporter OCT1 plays an important role. The development of liver tumours is accompanied by a fall in the expression of OCT1, together with the appearance of aberrant gene variants of this transporter, which, overall, significantly reduces the ability of tumour cells to take up, and therefore respond to treatment with sorafenib. S15 DUAL EFFECT OF MELATONIN ON

APOPTOTIC MECHANISMS IN HEPATIC CELLS

González-Gallego J Institute of Biomedicine (IBIOMED) and CIBERehd, University of León, Spain Melatonin is a hormone synthetized by the pineal gland that regulates circadian rhythms and has a wide range of proben biological functions, including an antioxidant action. Melatonin plays a role in the prevention of apoptosis in non-tumor cells, exerting an antiapoptotic effect in neurodegenerative diseases through mechanisms which involve a control of the mitochondrial flux of reactive oxygen species (ROS). However, in the last few

years it has been documented that melatonin may also elicit an antitumoral effect partly related to death of tumor cells through the induction of apoptosis. This paradoxical action on apoptotic mechanisms also occurs in liver tissue. We have shown that melatonin exerts antiapoptotic effects on non-tumor liver cells both in aging tissue and in different liver diseases, including fulminant hepatic failure. On the contrary, in tumor HepG2 cells our data indicate that high melatonin doses induce a cell cycle arrest in the G2/M phase and stimulate apoptotic mechanisms. Such actions, mainly mediated through the TM1 receptor, associate to changes in the expression of MAPKs or p53 and in the activation of transcription factors from the FoxO family. These melatonin effects are attributable to different processes, including an increase in ROS generation, changes in the interaction with melatonin receptors or alterations in the control of circadian rhythms. S16 MOLECULAR MECHANISMS OF

TRPV1 INFLAMMATORY SENSITIZATION

Devesa I, Ferrandiz-Huertas C, Mathivanan S, Wolf C and Ferrer-Montiel A Instituto de Biología Molecular y Celular. Universidad Miguel Hernández, Elche, Spain. Introduction Sensitization of sensory neurons upon tissue or nerve damage induces a drastic increase of their excitability, leading to the sensory hypersensitivity that underlies thermal hyperalgesia and allodynia. A major player in the onset and maintenance of nociceptor sensitization is the Transient Receptor Potential Vanilloid 1 (TRPV1), a thermoTRP receptor expressed by peptidergic and non-peptidergic sensory neurons whose activity is highly potentiated by pro-inflammatory agents. TRPV1 is a polymodal channel that can be activated by noxious heat (>42ºC), acidic pH (pH<5.9), voltage and numerous chemical ligands. TRPV1 is a non-selective cation channel with moderate permeability for divalent cations. TRPV1 is subjected to complex regulation, from gene expression to post-translational modification as well as subcellular compartmentalization and association with regulatory proteins. Cumulative evidence suggests that pro-inflammatory agents may additionally regulate TRPV1 activity by increasing the expression and delivery of new channels to the neuronal surface. Results and discussion: We have investigated this hypothesis and found that TRPV1 is rapidly inserted, through an SNARE-dependent exocytotic process, into the plasma membrane of nociceptors upon exposure to pro-algesic compounds such as ATP and NGF. Furthermore, analysis of channel sensitization in both nociceptor subpopulations demonstrate that inflammation-dependent insertion of TRPV1 channels in the cell surface is a mechanism specifically occurring in peptidergic nociceptors. Notably, blockers of neuronal regulated exocytosis reduce the pro-algesic neuronal mobilization of TRPV1 and exhibit long lasting in vivo anti-nociceptive activity. Together, these findings demonstrate that recruitment of TRPV1 channels by algogens is a pivotal mechanism underlying nociceptor

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sensitization under pathological conditions. Funded by: MINECO, CONSOLIDER-INGENIO 2010 and GVA. S17 EMERGING ROLE OF TRP AND

STORE OPERATED CHANNELS IN THE CARDIOVASCULAR SYSTEM.

Smani T Departamento de Fisiología Médica y Biofisica, Instituto de Biomedicina de Sevilla/Hospital, Universitario Virgen del Rocío de Sevilla. España. Transient receptor potential (TRP) channels are known to encode a wide variety of cation channels, some of them are related to store operated calcium entry, with diverse biophysical properties, activation mechanisms, and physiological functions. The mammalian TRP family consists of structurally related ion channels, the majority of which are permeable to both monovalent and divalent cations. The 28 mammalian TRP channels have been subclassified into six main subfamilies TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin). In the last two decades several works have determined the emerging role of TRP channels in the cardiovascular system function in health and disease. This talk will focus on some aspects of TRP channels role in cardiac myocytes, smooth muscle and endothelial cells, and in their impact on the pathogenesis of several cardiovascular diseases such as cardiac hypertrophy, heart failure, arrhythmia, hypertension, or vascular remodelling. S18 TRP CHANNELS AND THE CALCIUM

ENTRY SIGNALPLEX Rosado JA Department of Physiology, University of Extremadura, Av. Universidad s/n, 10003-Cáceres, Spain Store-operated Ca2+ entry (SOCE) is a major process for Ca2+ influx regulated by the filling state of the intracellular Ca2+ pools. The question concerning the mechanism that communicates the information of the filling state of the Ca2+ stores to the store-operated channels was solved after the identification of STIM1 as an ER-resident, Ca2+ binding protein, that gates the Ca2+ channels in the plasma membrane. Two types of store-operated channels and currents have been proposed: the Ca2+ release-activated Ca2+-selective (CRAC) channels, which mediate the non-voltage activated, inwardly rectifying, and Ca2+-selective ICRAC current, and the SOC channels, which conduct the non-voltage activated, non Ca2+-selective ISOC current. Orai channels were identified in 2006 as the subunits of the CRAC channels [1] and The mammalian homologues of the Drosophila Transient Receptor Potential (TRP) channels have been presented as potential SOC channels [2]. Both Orai and TRPC channels have been found to be activated by STIM1 upon depletion of the intracellular Ca2+ stores. The STIM1 cytosolic region named SOAR is sufficient to activate Orai and TRPC channels. In addition, STIM1 activates TRPC channels by electrostatic interaction. Orai and TRPC subunits contribute to conduct SOCE in different cell types, play

relevant cellular functions and even interfere with each other´s functional role. [1] Vig et al. Science. 2006;312:1220–3. [2] Rosado and Sage. Biochem J. 2000;350:631-5. S19 GENETIC AND EPIGENETIC

MARKERS OF OBESITY: LESSONS FROM INTERVENTION STUDIES

Marti A Departamento de Ciencias de la Alimentación y Fisiología, Facultad de Farmacia, Universidad de Navarra, Pamplona (España). Advances in genetics, such as sequencing of the human genome, have contributed to identification of susceptible genetic loci for obesity. These efforts have resulted in the identification of about 30 loci related to human obesity. Of those, a FTO gene variant was the most replicated and showed the highest statistical significance. However, despite these advances, the combined effect of all loci identified so far account for about 5 % of the inherited contribution to obesity risk (40-70%). These humbling statistics confirm the complex nature of obesity and the need to examine additional factors including epigenetics markers. Perhaps the component, (epi)genome–environment interaction, is the most important regulator, in susceptibility to obesity. Epigenetics offers an important window to understand the role of the environment's interactions with the genome in causing disease, and in modulating those interactions to improve human health. Specifically, methylation is the only flexible genomic alteration which can change the way the genome functions under exogenous influence. It is also well known that telomere attrition is a modifiable factor, because it there is some variability independent of chronological age. In this sense lifestyle habits can modify telomere length: tobacco or a high fat diet may lead to shortening the telomere. Here I will present evidence of the role of obesity-related genetic and epigenetic markers in two nutritional interventions in human subjects: the PREDIMED project (a Mediterranean diet intervention study in high cardiovascular risk subjects), and the EVASYON study (a weight loss program for Spanish obese adolescents). S20 ROLE OF BROWN ADIPOSE TISSUE

IN OBESITY PATHOPHYSIOLOGY Gil A Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, Centre of Biomedical Research, University of Granada, Granada, Spain Brown adipose tissue (BAT) is the main tissue regulating thermogenesis in response to food intake and cold. Brown adipocytes arise from a myocyte progenitor, whereas white fat cells arise from a distinct cell lineage. Brown adipocytes have a primary function in heat generation as they uniquely express the uncoupling protein 1 (UCP1) and were considered to be at most a minor component of human adipose tissue. However, over the past five years, there has been an explosion of knowledge about BAT, both

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at the cell biological level and at the clinical level as it has been demonstrated to be present in significant amounts in humans. Recent findings indicate that brown adipocyte progenitor cells, and possibly differentiated brown adipocytes, exist as scattered individual cells and small cell clusters distributed diffusely within skeletal muscle tissue as “beige adipose tissue”. This opens the possibility of a therapeutic approach for obesity based on brown adipocyte-mediated energy expenditure. In fact, exercise appears to mediate the induction of BAT through the action of the muscle hormone irisin and the activation of some transcription factors, namely peroxisome proliferator activator gamma coactivator 1 (PGC-1). In addition, there is now mounting evidence that mature white adipocytes, including human fat cells, can be converted into brown fat-like adipocytes, and that the typical fatty acid storage phenotype of white adipocyte can be altered towards a fat utilization phenotype. These data open up new opportunities for the development of drugs for obesity and its metabolic and cardiovascular complications. S21 UNDERSTANDING THE ROLE OF

THE GUT MICROBIOME IN OBESITY: The European Project MyNewGut.

Sanz Y Microbial Ecology, Nutrition & Health Research Group. Institute of Agrochemistry and Food Technology. National Research Council (IATA-CSIC).Valencia, Spain. Obesity and its associated co-morbidities constitute a major health concern among diet-related diseases since their prevalence is steadily increasing worldwide. Gut microbiota structure and function result from interactions with lifestyle and host factors, which jointly influence the gut, brain and peripheral tissue axes and thereby our disease risk. Diet-induced microbiota modifications seem to contribute to energy balance by influencing extraction of energy form the diet and adiposity according to studies in murine models. Gut microbiota and its genome (microbiome) provide the host with additional metabolic capacities and regulate diverse aspects of cellular differentiation and gene expression involved in energy metabolism and neuroendocrine function. Gut microbiota also contribute to inflammation associated with obesity, leading to chronic metabolic dysfunction; however, specific gut-microbiota modifications may re-program the host's immune response to obesogenic diets, reducing translocation of pro-inflammatory components and inducing anti-inflammatory responses. To progress beyond the state of the art, the 7th FP EU project entitled MyNewGut will develop a multidisciplinary research approach, using functional omics-technologies and systems biology in well-controlled human studies. The aim is to understand the role played by specific components of the human gut microbiota in nutrient metabolism and energy balance as well as in behavioural phenotypes associated with obesity. This information will be used to design new dietary recommendations, food prototypes and intervention strategies, targeting the gut ecosystem, which will

ultimately help to reduce the socioeconomic burden of behavioural and diet-related disorders in the EU. S22 FUNCTIONAL RESPONSE OF

MITOCHONDRIA TO EXERCISE AND EXTREME ENVIRONMENTS

Boushel R Åstrand Laboratory, The Swedish School of Sport and Health Sciences, Stockholm, Sweden. During whole body exercise in humans, oxygen delivery to muscle is the dominant factor defining maximal oxygen consumption (VO2 max). Excess capacity of muscle mitochondrial respiration is an essential feature in the oxygen cascade to support VO2 max by maintaining PO2 in muscle at a level low enough to allow a steep diffusion gradient for oxygen from hemoglobin to mitochondria. The oxygen tension in muscle is a direct function of oxygen delivery, mitochondrial p50 (O2 affinity) and mitochondrial flux capacity which conforms to a hyperbolic decline below a critical PO2. In normoxia, mitochondrial respiration at VO2 max requires ~88% of respiratory capacity if O2 supply is not limiting. VO2 max is reduced upon acute exposure to high altitude and after acclimatization due to limitations in O2 transport and transfer to muscle. Integrating Fick convective and diffusive O2 delivery components with functional measures of mitochondrial respiratory capacity indicates that excess capacity of muscle mitochondria is substantially greater at altitude, posing no limitation to VO2 max. Excess capacity of mitochondria is also revealed after exposure to extreme latitude in the arctic cold, where VO2 max is maintained by a similar O2 delivery to muscle despite a substantial downregulation of mitochondrial respiratory capacity and higher p50, while biochemical coupling efficiency in enhanced. Excess capacity of mitochondria is a salient feature in the O2 cascade in healthy humans, conferring bioenergetic flexibility in the adaptive responses to exercise and extreme environments. At sea level mitochondria respire at ~77% of maximal O2 flux capacity at VO2 max, while at the altitude of 4559 m, VO2 max is achieved at a mitochondrial respiratory rate of 60% of maximum capacity. The concept of a lower activation of mitochondria is illustrated in Figure 3, showing the relative difference in cellular ADP concentration-dependent stimulation of mitochondrial respiration. Thus, an aspect of the comparison of mitochondrial respiration at sea level and altitude is the degree of activation by ADP in-vivo relative to the maximal O2 flux capacity measured ex-vivo with ADP saturation and no O2 supply limitation. Accordingly, mitochondrial respiration in-vivo is regulated both by [ADP] (and Pi, NADH) and O2 supply. The effect of changes in mitochondrial volume is two-fold; first, a high mitochondrial capacity in relation to oxygen delivery will lower p50 and at the same time individual mitochondria will be exposed to a slightly lower ADP concentration further reducing p50. Enhanced muscle mitochondrial capacity is thought to contribute to the training-induced increase in VO2 max, yet there is no evidence for this effect in the absence of improved muscle O2 supply and/or capillary density for O2 diffusion in

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healthy humans. Owing to excess capacity of mitochondria, peak limb VO2 can be increased without change in muscle mitochondrial volume, peak leg and whole body VO2 can be sustained with a substantial (25%) reduction in leg muscle mitochondrial capacity, and the reduction in mitochondrial capacity at high altitude is actually beneficial for maximizing muscle VO2 and ATP production through a lowering of mitochondrial p50, LEAK respiration and ADP-activation of respiration. S23 SAVING MUSCLE MASS DURING

VERY SEVERE ENERGY DEFICIT: LESSONS FROM EXTREME EXERCISE IN HUMANS.

Calbet JAJ Department of Physical Education, Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Canary Islands, Spain. Loss of free fat mass (FFM) is a common consequence of prolonged negative energy balance, observed in healthy human undergoing low calorie diet and patients with conditions causing hypercatabolism and or reduced energy intake. Excessive loss of FFM may be detrimental, since lean tissues and, in particular skeletal muscle, account for most resting metabolism and is essential for the preservation of bone mass and exercise capacity. Moreover, loss of lean mass is negatively associated with survival in intensive care, cancer and other emaciating conditions. Exercising while following low-calorie diets attenuates the loss of FFM. The lean mass-saving effect of exercise can be achieved with strength training, but also with low-intensity exercise such as walking or arm cranking. In humans under very low calorie diets this effect depends on the amount of exercise. Although increasing the ratio of protein to carbohydrate and the total amount of protein ingested may reduce the loss of lean mass, the potential anticatabolic effect of hyperproteic diets remains unclear. Exercise seems to attenuate protein breakdown. The neuroendocrine and molecular signaling events by which exercise and protein ingestion may exert a protective effect on muscle mass even in the most adverse conditions will be examined. S24 HUMAN PHYSIOLOGY IN SPACE, A

CHALLENGE FOR FUTURE EXPLORATION

Demaria-Pesce V Institut National de la Santé et de la Recherche Médicale (Inserm), Paris & European Astronaut Centre (EAC), European Space Agency (ESA), Köln, Germany. More than 50 years after the first human spaceflight, the present continuous occupation of the International Space Station (ISS) in low Earth orbit (LEO) have demonstrated that human being may live and work in space for quite long durations (up to about six months…). Research and finding have also revealed that spaceflight has a dramatic impact on almost all physiological systems : altered sensory control, cardiovascular deconditioning, immune function impairment, nutrition problems, muscle atrophy,

bone demineralisation, vision impairment, and impact on behavioural health and cognitive processes. These physiological responses to space would potentially affect long-term crew health and performance in space and upon return to Earth. Next step of space exploration will be the missions beyond low Earth orbit (LEO), towards the Moon or in the deeper space to Mars. These long-duration exploration spaceflights will require the crewmembers to stay in space for a year or more and could expose them to a level of risk beyond of which may be ethically acceptable. Thus, the next significant challenge for physiology and space medicine is to increase knowledge and better understand the effects of long-duration spaceflight on crew health and performance, and readaptation to the terrestrial environment. To rise this challenge demands a multidisciplinary work with life scientist and engineers in order to support the future space exploration. S25 COMPREHENSIVE LEARNING AND

THE MULTIMEDIA TOOLS Esteller A Department of Physiology and Pharmacology. Salamanca University A professor, who is concerned with teaching and learning, often wonders about the efficacy and productivity of his teaching responsibilities and thinks about the problems of the learning process and its potential solutions. One of the problems, which started in the late 90s, was created by the increase relevance of computers and other teaching possibilities associated with technological changes, which allow the use of large amounts of information in a brief period of time. This new technology is partially responsible of the changes that are taking place in academia, which are conceptual, strategic and methodological. In this talk we analyse the change in the classical teaching-learning paradigm, which requires, for a successful implantation, a selection in advance of the important and necessary information and the use of all the technological resources available that facilitates learning. Multimedia techniques uses multiple channels to deliver the information and allow feed back, interaction and integration, which are required to improve learning. This new educational stage is especially important for those branches of knowledge like biomedical science, which are based in the conglomerate of different bit of information from different scientific disciplines. In academic degrees where physiology is required, comprehensive education is especially important. It is fundamental to explain a physiological phenomenon from the different points of view of all disciplines that had described it. This kind of teaching is very difficult to achieve with the traditional educational systems. S26 TEACHING PHYSIOLOGY AND THE

CHALLENGE OF BOLOGNA Ojeda ML Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla. C/ Profesor García González nº 2, 41012, Sevilla, España.

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In order to deepen into the European integration process for the daily life of European citizens, I and my colleagues of the Physiology Department from Seville University have tried to accomplish the Bologna Declaration helping the student to be "an active agent in the learning process". Taking into account that European evaluation criteria assess not only the acquisition of cognitive skills, but also specific responsibilities for the development of the professional profile, this Department has been including new evaluation systems and innovation activities every year since the Course 2006-07 in different subjects related to Physiology. The Physiology is a basic science with great theoretical content divided into different Systems which are deeply correlated; therefore the different subjects comprising this area often have a very tight time dedicated to their content. This fact coupled with the great amount of students enrolled in each group clearly difficult the correct development of the new evaluation systems and the innovation activities. After eight years of “trial and error” in different subjects related to Physiology in the Degree and Master Courses, from my point of view the main activity where the students can acquire transversals skills and where the feed-back process between students and professor works better is during the time dedicated to the laboratory practices, because the number of students is lower and they can "touch" the subject. On the other side, innovation activities are very helpful in Master Courses, where once again the number of students is reduced, and their motivation for the subject is increased. S28 LIPIDOMICS OF LONGEVITY AND

HEALTHY AGING Pamplona R Dept. of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida, 25198 Lleida, Spain The role of ‘classical’ lipids in aging and human longevity has been widely acknowledged. The emergency of lipidomics as a branch of metabolomics has provided an additional layer of accuracy to identify specific lipid species and its association with aging and longevity. The molecular composition and concentration of lipid species determine their cellular localization, metabolism, and consequently, their impact in health and disease. Moreover, the identification of specific lipid species in aging and longevity would aid to clarify how these lipids alter health and influence longevity. Available evidences demonstrate that membrane lipid composition is an important correlate of the rate of aging of animals and, therefore, the determination of their longevity. However, a minor fraction of the human plasma lipidome has been associated to healthy aging and longevity. The use of high-throughput technologies allowed us to determine the plasma lipidomic profile of mammalian species ranging in maximum longevity from 3.5 to 120 years (including human), as well as in human with extreme longevity (centenarians). The non-targeted approach revealed a specie-specific lipidomic profile that accurately predicts the human longevity. In addition, the results demonstrate that the longer the longevity of a species, the higher is its plasma resistance to lipid peroxidation, analogously to

cellular membranes. These results indicate that the lipidomic signature is an optimized feature associated with animal longevity, emerging specific lipid species as a potential biomarker of longevity. S29 PHYSIOLOGY OF EXCEPTIONAL

LONGEVITY. REGULATION OF RNA EXPRESSION IN CENTENARIANS

Viña J1, Borras C1, Serna E1, Gambini J1, Mohammed K1,

Avellana JA2, Belenguer A2 1Departament de Fisiologia, Universitat de Valencia and INCLIVA, Valencia, Spain 2 Servicio de Geriatría. Hospital de la Ribera. Alzira, Spain Centenarians not only have an extraordinary longevity, but also show a compression of morbidity. They preserve the capacity of maintaining homeostasis, and this is the reason for them to reach such a long life. We hypothesized that centenarians should be extremely well regulated at molecular level, and thus studied their microRNA expression profile. We compared microRNA expression profiles of centenarians, octogenarians and young individuals, by analysing the expression of 15,644 mature microRNAs and, 2,334 snoRNAs and scaRNAs in peripheral blood mononuclear cells. Principal component analysis showed that centenarian microRNA expression profile was similar to that of the young individuals, but different from octogenarians. Moreover, centenarians show an up-regulation of the expression of 102 microRNAs when compared to octogenarians and only one down-regulated, and even when compared to young individuals, 7 microRNAs are up-regulated and none down-regulated. Of these seven only one is also up- regulated in octogenarians. Thus the reamaing six that are specific for centenarians are miR21, miR130a, miR494, miR1975, miR1979 and SCARNA17. We conclude that centenarians up-regulate the expression of small non-coding RNAs like microRNAs and scaRNAs.. This may explain their exceptional ability to maintain homeostasis even in extreme aging. For full description of these ideas see www.nature.com/scientific reports 12- 02982-T. KEY WORDS: Micro RNA, Aging, Genomics S31 LEPTIN MODULATION OF

HYPOTHALAMIC ASTROCYTES: A POSSIBLE MECHANISM OF SYSTEMIC METABOLIC CONTROL

Chowen JA Hospital Infantil Universitario Niño Jesús. CIBER de obesidad y nutrición, Instituto Carlos III, Madrid, Spain Leptin, a hormone produced mainly by adipose tissue, modulates hypothalamic neuronal circuits to reduce food intake. Recently the role of glial cells in mediating the anorexigenic effects of leptin at the hypothalamic level has received much attention. Astrocytes express receptors for diverse metabolic signals, including various forms of the leptin receptor. Leptin stimulates morphological changes in these glial cells and modification of synaptic organization of metabolic circuits. The capacity of astrocytes to

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transport glucose and glutamate is modified by leptin, indicating an additional mechanism by which this hormone can affect neuronal metabolism and synaptic transmission. Indeed, loss of the leptin receptor specifically in astrocytes modifies the metabolic response to this hormone. The role of glial cells in obesity-induced hypothalamic inflammation and development of secondary complications has also received increasing attention during recent years. Leptin induces cytokine production by astrocytes, which could be one mechanism by which obesity associated hyperleptinemia is involved in hypothalamic inflammation and gliosis. The aim of this talk will be to present our current understanding of how leptin signaling in astrocytes affects both physiological and pathophysiological metabolic control. S32 LEPTIN AND NEURONAL

DEVELOPMENT Bouret S Profesor e investigador, Inserm U837, Neurobese Lab, University of Lille, Lille, France &2 Childrens Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA. Leptin is well known as an important hormone in the central control of feeding behavior. During development, fetuses and newborns are exposed to leptin and recent evidence has shown that leptin receptors are widespread throughout the developing brain. This lecture will summarize recent findings concerning the developmental effects of leptin on brain circuits involved in feeding regulation. It will show that the actions of leptin in the developing brain are generally permanent and range from neurogenesis in the embryonic neuroepithelium to axon growth in the postnatal hypothalamus. Nutritional manipulation of leptin secretion during perinatal life has generated considerable concern. This lecture will also provide an overview of recent evidence concerning the role of leptin in the nutritional programming of appetite. S33 HYPOTHALAMIC AND EXTRA-

HYPOTHALAMIC LEPTIN ACTIONS: NEW INSIGHTS FROM ANIMAL MODELS

Viveros MP Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense, Madrid, Spain The hypothalamus has traditionally been the focus of studies for central nervous system leptin actions. However it is known that leptin receptor is highly expressed in rodents and humans not only in hypothalamic nuclei but also in other brain regions including the cortex and the hippocampus. Moreover, recent studies suggest that leptin might act as a cognitive enhancer as it modulates the cellular processes underlying hippocampal-dependent learning and memory. In the neonatal period there is a leptin surge with a peak at postnatal days (PND) 9-10 during which leptin exerts a neurotrophic role in the hypothalamic development of mice. By using two different

animal models (environmental and pharmacological manipulation of postnatal leptin), we have further investigated the role of this leptin surge in the development of extra-hypothalamic brain areas and addressed the long term physiological impact of disrupting the full expression of these developmental leptin actions. The rat maternal deprivation model (maternal separation at PND 9-10) that results in a persistent leptin deficient state, alters the development of hypothalamus, cerebral cortex, hippocampus and cerebellum, provokes long-term behavioral alterations and compromises metabolic and endocrine homeostasis. In turn, neonatal exposure to a leptin receptor antagonist during the critical period of neonatal leptin surge also disrupts the development of hypothalamic and extra-hypothalamic brain areas inducing marked neuronal, glial and synaptic plasticity alterations. Moreover, both treatments resulted in long term immunological impairment. These results highlight the important programming effects of neonatal leptin and encourage the investigation of its neurodevelopmental role in humans. Acknowledgements: BFU2009-10109; BFU2012-38144. S34 LEGISLATION ON ANIMAL

WELFARE: POINT OF VIEW OF NATIONAL GOVERNMENT

León P Servicio de bienestar animal, SG de Productos Ganaderos, DG de Producciones y Mercados Agrarios. Ministerio de Agricultura, Alimentación y Medio Ambiente. Madrid, Spain. Directive 2010/63/EU of the European Parliament and of the Council of 22 September on the protection of animals used for scientific purposes is the framework that establishes the main obligations for respecting animals needs when used for scientific purposes. This legislation has been transposed into our national legislation through Law 32/2007 for the care of animals in their exploitation, transport, experimentation and slaughter, and Royal Decree 53/2013 laying down the basic standards for the protection of animals used for experimental and other scientific purposes, including teaching. The most important points are: a) Scope, including fetal forms, cephalopods, animals used only as suppliers of organs or tissues. b) Principle of the "three R´s, (reduce, refinement and replacement of animals). c) Registration and control of breeders, users and suppliers of animals . d) Transparency of actions, through the publication of non-technical summaries that provides information to interested citizens about the characteristics of projects, especially about how and why those animals are used. e) Training of the staff involved to ensure responsible treatment of animals. f) Authorization (after a free of conflicts evaluation) of all projects (including teachers) using animals for scientific purposes. g) Severity classification of procedures (depending on the degree of pain suffering, distress or lasting harm expected). h) Animal-welfare bodies with different task as giving advice on animal welfare issues or follow the projects. i) Reports,

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from users to administration, and between administrations (nationals and internationals). S35 ENABLED ORGANS FOR THE

EVALUATION OF EXPERIMENTATION PROJECTS IN THE CONTEXT OF THE RD 53/2013

Costela C Central service of Animal Experimentation and Production. University of Cadiz, Spain. Until the publication of the RD 53/2013, which establishes the basic rules concerning animal protection used on experimentation and other scientific purposes, including teaching, several institutional committees of ethics on animal experimentation were created in the Universities and Research Centers of Spain. These committees were organized in a Net of Committees of Ethics from Universities and Public Research Organisms, making agreements on proceedings, action protocols and evaluation mechanisms of research projects. The switch to the regulations of the Directive 2010/63/EU of the European Parliament and of the Council about the protection of animals used for scientific purposes, through the RD 53/2013, established in 2013 that the Competent Organs (entities, authorities or administrative unities of the Spanish autonomous communities) are the ones that must allow research projects that include animals. To make this evaluation possible, the Competent Organs ought to design Enabled Organs for the evaluation. In the region of Andalusia, most of the committees of ethics on animal experimentation that existed before the RD 53/2013 have been labeled as Enabled Organs. The evaluation of the projects established in the Royal Decree also involves the classification of the category of severity (without recuperation, slight, moderated or severe) of every procedure included in a project, and the assignation of the projects to a determinate type depending on the severity of the procedures that it includes (type I, II and III). Also, every project type III and some of the ones type II will need a retrospective evaluation made by the Enabled Organ. S36 WELFARE ASSESSMENT IN

LABORATORY ANIMAL RESEARCH: REFINEMENT

Nieto-Ruiz de Zárate AI Unidad de Experimentación Animal (Centro de Instrumentación Científica). Universidad de Granada Refinement of husbandry in vivo procedures is essential to reducing animal suffering and improves welfare. It is also a specific requirement of the legislation. Successful refinement involves pain and distress control that depends upon the ability to assess animal well-being. It is also necessary to establish a system for recording indicators to detect any sign of discomfort. Then, a wide range of different techniques for pain alleviation can be employed. There are a number of indicators published in different guides that can be objectively measured providing

information about the presence and severity of pain in order to clearly define intervention points of each project. The welfare indicators have to include the minimum number of parameters, the most relevant but also easily identified. The list includes physical, physiological, behavioral and some biochemical parameters. Ideally, the indicators are able to give themselves an objective measurement interpretation and analysis, avoiding variations between observers. The researchers should be taken into account that unwanted variables from the pain induced by procedures could modify the homeostatic mechanisms and affect the animal model. Like it is unheard of to allow surgical procedures without anesthesia, the use of painkiller will be universally achieved in animal research. All of these will refine the use of animals in studies, their number and elevate the standards of laboratory animal care according with both the legislation and society demand. Total alleviated laboratory animal pain could be achieved in the near future or to abandon other type of animal studies.

S37 BIOLOGICAL CLOCKS IN THE LAB AND IN THE CLINIC

Golombek DA Universidad Nacional de Quilmes / CONICET, Buenos Aires, Argentina. Biological timing encompasses several orders of magnitude, ranging from the microsecond to the year. Among these frequencies, circadian (i.e., about 24 h) rhythms and interval timing (i.e., in the second-to-minute range) have been thoroughly studied in several organisms. In mammals, circadian rhythms are generated in the main biological clock located in the hypothalamic suprachiasmatic nuclei (SCN) which are entrained by environmental signals such as the light-dark cycle through a dedicated retinohypothalamic tract. Most, if not all, physiological and behavioral variables exhibit such circadian variations, which resonate throughout the body not only by means of the central SCN clock but also due to peripheral oscillators. Here we will focus on the signal transduction mechanisms responsible for mammalian entrainment, specifically involving the cGMP/nitric oxide pathway. In addition, as an example of circadian control, we have demonstrated diurnal changes in immune parameters which, in turn, feedback into the SCN in order to fine-tune the biological clock. Experimental models of circadian desynchronization result in severe metabolic disruption, which might represent a window into human situations which compromise entrainment, such as chronic jetlag or shiftwork. Indeed, in recent years, the importance of an adequate internal (i.e., among organs) and external (i.e., between the body and the environmental) synchronization has been accepted. Diverse diseases involve a varying degree of circadian disruption which, when adequately targeted, might improve the outcome and quality of life of human patients.

XXXVII CONGRESS OF THE SPANISH SOCIETY OF PHYSIOLOGICAL SCIENCES (SECF)

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S38 CIRCADIAN FUNCTIONS OF THE RETINAL GANGLION CELLS

García-Fernández JM Department of Morphology and Cell Biology. University of Oviedo

Light is the main synchroniser (also known as ‘zeitgeber’) of the central biological clock, the hypothalamic suprachiasmatic nucleus (SCN), which is considered as the circadian pacemaker. In mammals, only the eye contains photoreceptive cells. Such cells are capable of transforming the light they perceive into electrical impulses. In the retina, apart from rods and cones, which are mainly responsible for vision, a third kind of photoreceptors among the retinal ganglion cells (RGCs) has been discovered over a decade ago. Such RGCs express the photopigment melanopsin and are intrinsically photosensitive (ip). Irradiance changes mainly occurring at dawn or dusk are perceived by both ipRGCs and rods/cones. The contribution of the latter reach the ipRGCs through bipolar cells. The irradiance signals are driven by the ipRGCs axons (constituting the retinohypothalamic tract, RHT) and most of them reach the SCN in order to adjust endogenous circadian rhythms with the external day-night cycle, a process called photoentrainment. But light signals transmitted through the ipRGCs also regulate melatonin secretion and have other functions. The discovery of the ipRGCs was achieved in the context of chronobiology in an attempt to elucidate how endogenous rhythms are regulated by light. This constitutes the adaptive circadian system, which is capable of preparing the organism by predicting the daily alternation of light and dark, a consequence of the Earth’s rotation. Changes in the photoperiod caused by the movement around the sun are also detected by this system and regulate different aspects of the reproductive physiology. Hence, irradiance perception constitutes an important evolutive acquisition, because it allows the organism to anticipate predictable changes of the environment. The mammalian melanopsin gene produces two isoforms of the photopigment by alternative splicing. Both isoforms are expressed by the M1 subpopulation of the ipRGCs. The M1 cells have their dentrites in the off sublayer of the inner plexiform layer (IPL) and their axons mostly reach the SCN. The remaining ipRGC subpopulations (M2 to M5) only express one isoform and their axons reach different brain regions. Altogether, the functions of the ipRGCs include the above mentioned circadian photoentrainment and regulation of melatonin secretion, and also regulation of pupillary response to light or activation of hypothalamic regions involved in sleep and arousal. Also, some ipRGC axons reach some visual centers, such as the dorsal lateral geniculate nucleus (dNGL) or the superior colliculus (SC), the latter involved in contrast sensitivity. S39 CIRCADIAN PHYSIOLOGY OF A

DUAL-PHASING RODENT, THE OCTODON DEGUS

Otalora BB1,2 1 Chronobiology Laboratory, Department of Physiology, Faculty of Biology, University of Murcia, Spain

2 Faculty of Life Sciences, University of Manchester, UK Unlike most animal species used in chronobiology, as humans, the Octodon degus is primarily diurnal. Therefore, studying the degu can provide significant insight into the human’s circadian system functionality. Interestingly, under certain conditions some degus have the ability to shift their activity-phase preference from the day to the dark phase. This chronotype heterogeneity (from diurnal to nocturnal) makes the degu an excellent animal model in which to (i) study the mechanisms underlying activity-phase preferences in mammals; (ii) better understand the health consequences associated with conditions that cause phase reversal of activity pattern in humans, such as night-shift work, and (iii) test the potential therapeutic role of chronobiotics in strengthening the circadian rhythmicity. Here, we explore how shifts in activity pattern affect the internal temporal organization of the circadian system in the degu. To do this, we used different approaches, ranging from measurement of clock gene expression in the brain to biochemical, physiological and behavioural analyses. Our results reveal that when diurnal degus become night-active, a complete inversion in the temporal order of their physiology, haematology, and biochemistry does not occur in parallel with the shift seen in their wheel-running activity and body temperature patterns. We also establish that a shifting light:dark schedule that mimics lighting conditions experienced by humans during shift work is an experimental condition which causes disruption in the degu’s circadian system. Finally, we show that exogenous melatonin can cushion the disruptive physiological effects of shift work in this animal model. Supported by Fundación Séneca (12005/PI/09, 19125/PD/13), RETICEF (RD12/0043/0011), MEC and MINECO (AP2006-04117, BFU2010-21945-C02-01, IPT-2011-0833-900000) co-financed by the FEDER Funds. S40 CELLULAR MODELS OF

HAEMOSTASIS Velasco F, Marí P Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) During the 60’s Davie EW and MacFarlanr RG made an important contribution to the coagulation field: a coagulation model in “cascade”. Fibrin formation was the result of a series of proteolytic reactions similar to a waterfall. They explained the interactions between procoagulant plasma proteins, and set the basis for current biological model of coagulation. This model recognized that anionic phospholipids on cell surfaces provided the basis for enzyme/cofactor complex assembly and its interaction with substrates to form the fibrin clot. Discovery of coagulation/fibrinolysis cell receptors changed completely this concept. Cell surfaces provide substrate for zymogenos/serine proteases, becoming authentic coagulation mechanisms regulators. In this dynamic interaction between proteins and cells, a powerful amplification mechanism is generated, whilst regulatory mechanisms start functioning to generate the fibrin clot and stop blood extravasation. Tissue Factor (TF) is a

ACTA PHYSIOLOGICA

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notable cell receptor: involved in the initiation of coagulation, facilitating amplification and propagation, also a mediator of intracellular signaling involved in inflammatory response and tumor development. This phenomenon is possible through activation of protease-activated receptors (PAR). Protein disulfide isomerase (PDI), regulates induction of coagulation, catalyzing the passage of encrypted TF to decrypted (active) and vice versa. Role of PDI in activating TF is not clear, recent data shows that PDI exposure to endothelial damage contributes to stimulate the first step of blood coagulation. Ahamed and Col proposed two functional states of TF: when disulfide bridges between molecules Cys186-Cys209 are formed, TF would join clotting factors and activate PAR-1 and PAR-2, causing blood clotting. If disulfide bridges are broken TF would form a no-coagulant version. Studies made by our medical team have observed that the expression of the TF is also related to mitochondrial dysfunction. Cell surfaces receptors are also essential in regulatory mechanisms of coagulation. Most representative is the anticoagulant protein C system; together with antithrombin regulates excessive thrombin formation and prevents thrombotic complications. Consisting in two vitamin K-dependent proteins: Protein C (PC) and Protein S (PS) that inactivate factors V and VIII. The mechanisms that occur in cell surfaces, through interactions with PAR-1, are able to develop a cytoprotective action. Latest biological findings show factor XII has little involvement in bleeding, but plays a decisive role in thrombotic complications. PolyP, linear anionic polymers synthesized by ATP, are clot activators that could be used as pro-coagulant drugs. Finally, discovery of NETS composed of chromatin fibers released from neutrophils undergoing cell death, capture platelets and increase fibrin deposition. In the last years, coagulation Physiology has experienced a breakthrough. With the incorporation of new biological techniques and the study of microcirculation in real time, this knowledge will be increased and more accurate treatments could appear. S41 EXPANDING THE CURRENT

KNOWLEDGE IN FIBRINOLYSIS Páramo JA Servicio de Hematología. Clínica Universidad de Navarra. Pamplona. The fibrinolytic or plasminogen activator (PA) system, which controls the formation and activity of plasmin, plays a key role in modulating hemostasis, thrombosis and several other biological processes. The central reaction of the PA system is the conversion of plasminogen to plasmin by PAs. Fibrinolysis emanates from an ordered enzymatic process triggered by PAs, such as tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). When mediated by t-PA released from injured

vascular endothelial cells, plasmin is largely involved in fibrin degradation; when mediated by u-PA, plasmin usually participates in pericellular processes, such as cell migration and tumor invasion. Endogenous inhibitory proteins can hamper fibrinolysis either through inhibition of plasmin (e.g. a 2-antiplasmin,a 2-macroglobulin), through inhibition of PAs by plasminogen activator inhibitos (e.g. PAI-1 and PA-2) and through modification of the fibrin surface (e.g. thrombin activatable fibrinolysis inhibitor, TAFI). Besides fibrinolysis, this system plays an important role in other processes such as inflammation and tumour growth. In the last years most genes that regulate fibrinolysis proteins have been characterised, the role of cellular receptors and cofactors has been established, a role of fibrinolysis in acquired coagulopathies, such as cancer, trauma and major surgery has been described and new functions of the fibrinolytic system beyond hemostasis have been unravelled. S42 ADVANCED THERAPIES AND

HEMOSTASIS Liras A Department of Physiology. Biological Sciences School. Complutense University of Madrid Advanced therapies, cell- and gene therapy research group.Campus of International Excellence Monogenic diseases which affect to hemostasis, as congenital bleeding disorders, are ideal candidates for treatment by the emerging advanced therapies, which are capable of correcting alterations in gene expression that result from genetic mutation. Many of these pathologies have altered the activity of a coagulation factor, i.e. factor VIII in hemophilia A, factor IX in hemophilia B and another factor as in factor V deficiency. Advanced therapies, cell- and gene therapy may involve the replacement of a deficient gene by a healthy gene so that it generates a certain functional protein (gene therapy) or the incorporation of a full array of healthy genes and proteins through perfusion of healthy cells (cell therapy). For their part, induced pluripotent stem cells have recently been shown to also play a significant role as another feasible alternative. Hemophilia and other congenital bleeding disorders as like factor V deficiency, are optimally suited for advanced therapies owing to the fact that, it does not require very high expression levels of a coagulation factor to reach moderate or mild disease status. As a result, significant progress has been possible with respect to these kinds of strategies, especially in the fields of gene therapy by using viral (adeno-associated and lentiviral vectors) or non-viral vectors (nucleofection), and cell therapy by means of several types of target stem cells. More recently, antisense-based RNA treatment may be another very good alternative.