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Mapping the entire frequency bandwidth of brain electrophysiological signals is of paramount importance for understanding physiological and pathological states. The ability to record simultaneously DC-shifts, infraslow oscillations (<0.1 Hz), typical local field potentials (0.1–80 Hz) and higher frequencies (80–600 Hz) using the same recording site would particularly benefit preclinical epilepsy research and could provide clinical biomarkers for improved seizure onset zone delineation. However, commonly used metal microelectrode technology suffers from instabilities that hamper the high fidelity of DC-coupled recordings, which are needed to access signals of very low frequency. In this study we used flexible graphene depth neural probes (gDNPs), consisting of a linear array of graphene microtransistors, to concurrently record DC-shifts and high-frequency neuronal activity in awake rodents. We show here that gDNPs can reliably record and map with high spatial resolution seizures, pre-ictal DC-shifts and seizure-associated spreading depolarizations together with higher frequencies through the cortical laminae to the hippocampus in a mouse model of chemically induced seizures. Moreover, we demonstrate the functionality of chronically implanted devices over 10 weeks by recording with high fidelity spontaneous spike-wave discharges and associated infraslow oscillations in a rat model of absence epilepsy. Altogether, our work highlights the suitability of this technology for in vivo electrophysiology research, and in particular epilepsy research, by allowing stable and chronic DC-coupled recordings.

Data and python code for reproducing the main results of the paper "Full bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene micro-transistor depth neural probes."

Corea del Norte es uno de los estados más herméticos del planeta. Su capital, Pyongyang, casi imposible de visitar, es una de las ciudades con menor afluencia de turistas. Pyongyang fue construido desde cero después de la Guerra de Corea (1950-53). Esto, junto con la relativa estabilidad política del país desde entonces, significa que la capital es un registro bien conservado de la historia moderna de Corea del Norte. En los años 50 y con la ayuda de las dos grandes potencias comunistas, China y la URSS, se diseñó un plan de reconstrucción de Pyongyang para convertirla en capital del nuevo estado de Corea del Norte. En esta primera etapa la construcción se vio influenciada por la arquitectura socialista de posguerra que se estaba dando en los demás países comunistas de Europa del Este. Pronto, el partido de Trabajadores de Corea liderado por Kim Il Sung empezó a obsesionarse con la independencia en todos los aspectos del país, incluida la arquitectura. A partir ese momento y potenciada por la introducción de la nueva ideología Juche, se emprendió la búsqueda de una forma de hacer arquitectura propia norcoreana. North Korea is one of the most hermetic states on the planet. Its capital, Pyongyang, almost impossible to visit, is one of the cities with the least influx of tourists. Pyongyang was rebuilt from scratch after the Korean War (1950- 53). This, along with the relative political stability of the country ever since, means that the capital is a well-preserved record of the modern history of North Korea. In that decade, with help of the two great communist powers, China and the USSR, a plan for the reconstruction of Pyongyang, which was to be the capital of this new state, North Korea, was designed. In this first stage, the construction was very influenced by post-war socialist architecture that was being developed in the rest of communist countries in Eastern Europe. Soon, the Workers’ Party of Korea led by Kim Il Sung became obsessed over the independence in all

El presente trabajo constituye una investigación de carácter teórico-práctico que pretende sistematizar el “proceso de creación dramatúrgica del actor”, término acuñado por la autora desde 2003 en investigaciones anteriores, no habiendo sido utilizado por ningún otro investigador hasta el momento con el mismo enfoque. Se refiere a procesos de creación donde el actor actúa también como autor, interfiriendo en la creación dramatúrgica de la obra. La formalización teórica y metodológica del estudio se realiza a partir de actividades complementarias. La investigación empírica fundamental consiste en un experimento para crear y escenificar una dramaturgia inédita, que enfoca lo sagrado y lo profano en la figura femenina a partir del personaje bíblico de María Magdalena. Puesto que el trabajo del actor es eminentemente práctico, el experimento se presenta como algo fundamental en el estudio, que propone la interrelación entre práctica y teoría, de forma que la práctica contribuya a la producción de conocimientos en el campo del espectáculo. Por tanto, la autora se inspira en la teoría y práctica de profesionales del teatro de reconocido prestigio como Eugenio Barba, Jerzy Grotowiski, Roberta Carreri y Renato Ferracini, entre otros creadores contemporáneos (actores, directores, actores/dramaturgos, directores/dramaturgos e investigadores), teniendo por base su propio trabajo como actriz/dramaturga, mezcla distintas metodologías de praxis escénica, para estructurar una propuesta metodológica del proceso de creación dramatúrgica del actor, y luego realiza el experimento que lleva a cabo todas las etapas del proceso. La originalidad de esta tesis reside en el hecho de que se agregan diferentes teorías surgidas en torno a procesos de creación donde el actor actúa también como autor y se unen a la praxis escénica, sistematizando una metodología del proceso. El trabajo se ilustra con numerosas fotos y los enfoques metodológicos se documentan mediante abundante bibliografía espec, This work is an investigation of theoretical and practical nature which tries to systematize the "process of dramaturgical creation of the actor", a term which was coined by the author in previous research in 2003, and which has not been used by any other researcher so far with the same approach. This term refers to the processes of creation in which the actor also acts as an author, interfering with the dramaturgical creation of the work. The theoretical and methodological formalization of the study is carried out through complementary activities. The fundamental empirical investigation consists in an experiment to create and perform an original dramaturgy, which focuses the sacred and the profane on the female figure arising from the biblical character of Mary Magdalene. Since the actor's work is eminently practical, the experiment presents itself as fundamental in the study, which proposes the interrelation between practice and theory, so that the practice can contribute to the production of knowledge in the field of theater. Therefore, the author draws on the theory and practice of renowned theatrical professionals such as Eugenio Barba, Jerzy Grotowiski, Roberta Carreri and Renato Ferracini, among other contemporary creators (actors, directors, actors / playwrights, directors / playwrights and researchers). Based on her own work as actress / playwright, the author mixes different methodologies of scenic praxis to structure a methodological proposal of the process of dramaturgical creation of the actor, and then performs the experiment that carries out all the stages of the process. The originality of this thesis lies on the fact that it combines different theories around the process of creation, in which the actor also acts as author, which are added to the scenic praxis, thus a methodology of the process is systematized. The work is profusely illustrated and all the methodological approaches have been duly documented by abundant specialized bibliography.

[Background] The leading cause of death among the obese population is heart failure and stroke prompted by structural and functional changes in the heart. The molecular mechanisms that underlie obesity-related cardiac remodeling are complex, and include hemodynamic and metabolic alterations that ultimately affect the functionality of the myocardium. G protein-coupled receptor kinase 2 (GRK2) is an ubiquitous kinase able to desensitize the active form of several G protein-coupled receptors (GPCR) and is known to play an important role in cardiac GPCR modulation. GRK2 has also been recently identified as a negative modulator of insulin signaling and systemic insulin resistance., [Methods] We investigated the effects elicited by GRK2 downregulation in obesity-related cardiac remodeling. For this aim, we used 9 month-old wild type (WT) and GRK2+/− mice, which display circa 50% lower levels of this kinase, fed with either a standard or a high fat diet (HFD) for 30 weeks. In these mice we studied different parameters related to cardiac growth and lipid accumulation., [Results] We find that GRK2+/− mice are protected from obesity-promoted cardiac and cardiomyocyte hypertrophy and fibrosis. Moreover, the marked intracellular lipid accumulation caused by a HFD in the heart is not observed in these mice. Interestingly, HFD significantly increases cardiac GRK2 levels in WT but not in GRK2+/− mice, suggesting that the beneficial phenotype observed in hemizygous animals correlates with the maintenance of GRK2 levels below a pathological threshold. Low GRK2 protein levels are able to keep the PKA/CREB pathway active and to prevent HFD-induced downregulation of key fatty acid metabolism modulators such as Peroxisome proliferator-activated receptor gamma co-activators (PGC1), thus preserving the expression of cardioprotective proteins such as mitochondrial fusion markers mitofusin MFN1 and OPA1., [Conclusions] Our data further define the cellular processes and molecular mechanisms by which GRK2 down-regulation is cardioprotective during diet-induced obesity, reinforcing the protective effect of maintaining low levels of GRK2 under nutritional stress, and showing a role for this kinase in obesity-induced cardiac remodeling and steatosis.

Obesity is a worldwide problem that has reached epidemic proportions both in developed and developing countries. The excessive accumulation of fat poses a risk to health since it favours the development of metabolic alterations including insulin resistance and tissue inflammation, which further contribute to the progress of the complex pathological scenario observed in the obese. In this review we put together the different outcomes of fat accumulation and insulin resistance in the main insulin-responsive tissues, and discuss the role of some of the key molecular routes that control disease progression both in an organ-specific and also in a more systemic manner. Particularly, we focus on the importance of studying the integrated regulation of different organs and pathways that contribute to the global pathophysiology of this condition with a specific emphasis on the role of emerging key molecular nodes such as the G protein-coupled receptor kinase 2 (GRK2) signalling hub

Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet– dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity.

© 2014 Elsevier B.V. G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signaling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance. Cardiac GRK2 levels are increased in human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore, we have explored the interconnections among a systemic insulin resistant status, GRK2 dosage and cardiac insulin sensitivity in adult (9month-old) animals. GRK2+/- mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function. Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy, while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find that cardiac GRK2 levels increase in situations where insulin resistance develops, such as in ob/ob mice or after high fat diet feeding. Our data suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as insulin resistance, diabetes or obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection.

G protein–coupled receptor kinase 2 (GRK2) is a ubiquitous serine/threonine protein kinase able to phosphorylate and desensitize the active form of several G protein–coupled receptors. Given the lack of selective inhibitors for GRK2, we investigated the effects elicited by GRK2 inhibition in vascular responses using global adult hemizygous mice (GRK2+/−). The vasodilator responses to acetylcholine or isoproterenol were increased in aortas and mesenteric resistance arteries from GRK2+/− mice compared with wild-type (WT) littermates. After angiotensin II (AngII) infusion, GRK2+/− mice were partially protected against hypertension, vascular remodeling, and mechanical alterations, even when resting basal blood pressures were not significantly different. AngII infusion also (1) increased GRK2 levels in WT but not in GRK2+/− vessels; (2) increased vasoconstrictor responses to phenylephrine in WT but not in GRK2+/− mice; and (3) decreased vasodilator responses to acetylcholine and vascular pAkt and eNOS levels more in WT than in GRK2+/− animals. Vascular NO production and the modulation of vasoconstrictor responses by endothelial-derived NO remained enhanced in GRK2+/− mice infused with AngII. Thus, GRK2+/− mice are resistant to the development of vascular remodeling and mechanical alterations, endothelial dysfunction, increased vasoconstrictor responses, and hypertension induced by AngII at least partially through the preservation of NO bioavailability. In conclusion, our results describe an important role for GRK2 in systemic hypertension and further establish that an inhibition of GRK2 could be a beneficial treatment for this condition.

G protein–coupled receptor kinase 2 (GR K2) is a ubiquitous, essential protein kinase that is emerging as an integrative node in many signaling networks. Moreover, changes in GR K2 abundance and activity have been identified in several inflammatory, cardiovascular disease, and tumor contexts, suggesting that those alterations may contribute to the initiation or development of pathologies. GR Ks were initially identified as key players in the desensitization and internalization of multiple G protein– coupled receptors (GPCR s), but GR K2 also phosphorylates several non-GPCR substrates and dynamically associates with a variety of proteins related to signal transduction. Ongoing research in our laboratory is aimed at understanding how specific GR K2 interactomes are orchestrated in a stimulus-, context-, or cell type– specific manner. We have recently identified an interaction between GR K2 and histone deacetylase 6 (HDAC 6) that modulates cell spreading and motility. HDAC 6 is a major cytoplasmic a-tubulin deacetylase that is involved in cell motility and adhesion. GR K2 dynamically and directly associates with and phosphorylates HDAC 6 to stimulate its a-tubulin deacetylase activity at specific cellular localizations, such as the leading edge of migrating cells, thus promoting local tubulin deacetylation and enhanced motility. GR K2-HDAC 6–mediated regulation of tubulin acetylation also modulates cellular spreading. This GR K2-HDAC 6 functional interaction may have important implications in pathological contexts related to epithelial cell migration

G protein-coupled receptor kinase 2 (GRK2) is emerging as a key, integrative node in many signalling pathways. Besides its canonical role in the modulation of the signalling mediated by many G protein-coupled receptors (GPCR), this protein can display a very complex network of functional interactions with a variety of signal transduction partners, in a stimulus, cell type, or context-specific way. We review herein recent data showing that GRK2 can regulate insulin-triggered transduction cascades at different levels and that this protein plays a relevant role in insulin resistance and obesity in vivo, what uncovers GRK2 as a potential therapeutic target in the treatment of these disorders.

Grb7 and their related family members Grb10 and Grb14 are adaptor proteins, which participate in the functionality of multiple signal transduction pathways under the control of a variety of activated tyrosine kinase receptors and other tyrosine-phosphorylated proteins. They are involved in the modulation of important cellular and organismal functions such as cell migration, cell proliferation, apoptosis, gene expression, protein degradation, protein phosphorylation, angiogenesis, embryonic development and metabolic control. In this short review we shall describe the organization of the genes encoding the Grb7 protein family, their transcriptional products and the regulatory mechanisms implicated in the control of their expression. Finally, the alterations found in these genes and the mechanisms affecting their expression under pathological conditions such as cancer, diabetes and some congenital disorders will be highlighted. © 2008 Bentham Science Publishers Ltd.