A novel task to evaluate irony comprehension and its essential elements in Spanish speakers.

An ironic statement transmits the opposite meaning to its literal counterpart and is one of the most complex communicative acts. Thus, it has been proposed to be a good indicator of social communication ability. Prosody and facial expression are two crucial paralinguistic cues that can facilitate the understanding of ironic statements. The primary aim of this study was to create and evaluate a task of irony identification that could be used in neuroimaging studies. We independently evaluated three cues, contextual discrepancy, prosody and facial expression, and selected the best cue that would lead participants in fMRI studies to identify a stimulus as ironic in a reliable way. This process included the design, selection, and comparison of the three cues, all of which have been previously associated with irony detection. The secondary aim was to correlate irony comprehension with specific cognitive functions. Results showed that psycholinguistic properties could differentiate irony from other communicative acts. The contextual discrepancy, prosody, and facial expression were relevant cues that helped detect ironic statements; with contextual discrepancy being the cue that produced the highest classification accuracy and classification time. This task can be used successfully to test irony comprehension in Spanish speakers using the cue of interest. The correlation of irony comprehension with cognitive functions did not yield consistent results. A more heterogeneous sample of participants and a broader battery of tests may be needed to find reliable cognitive correlates of irony comprehension.

Valoración de la severidad en enfermedades degenerativas articulares temporomandibulares mediante tomografía computarizada Cone Beam / Assessment of the severity of temporomandibular articular degenerative diseases through Cone Beam imaging

RESUMEN: Introducción: Muchos estudios han demostrado que las enfermedades degenerativas articulares Temporomandibulares (EDATM) provocan dolor, alteran la función modificando las estructuras esqueletales que se traducen en asimetrías faciales. La valoración imagenológica contribuye a un adecuado diagnóstico con el objetivo de optimizar la evaluación morfológica de las articulaciones temporomandibulares. Metodología: Se realizó una búsqueda electrónica en las bases de datos de PubMed, Google Scholar y SciELO. La estrategia de búsqueda se realizó utilizando una combinación de términos con el objetivo de analizar la valoración de las características imagenológicas y de volumen condilar. Resultados y Discusión: De un total de 9807 artículos se seleccionaron 18 que cumplían con los requisitos. Se han propuesto muchas categorías para clasificar la severidad imagenológica de la EDATM sumado al advenimiento de softwares y reconstrucciones tridimensionales que han propuesto categorías a través de algoritmos matemáticos y de superposición de imagen que son un gran aporte para el diagnóstico, la toma decisiones en la elección del plan de tratamiento y en el seguimiento. Conclusiones: La valoración de la severidad de las EDATM son claves para que la investigación clínica permita esclarecer los procesos que se relacionan con el objeto de valorar la progresión de esta enfermedad.

ABSTRACT: Introduction: Many studies have shown that Temporomandibular degenerative joint diseases (TMDJD) cause pain, alter function by modifying skeletal structures that result in facial asymmetries. Imaging evaluation contributes to an adequate diagnosis with the aim of optimizing the morphological evaluation of the temporomandibular joints. Methodology: An electronic search was performed in the PubMed, Google Scholar and SciELO databases. The search strategy was performed using a combination of terms in order to analyze the assessment of imaging characteristics and condylar volume. Results and Discussion: From a total of 9807 articles, 18 were selected that met the requirements. Many categories have been proposed to classify the imaging severity of the TMDJD added to the advent of software and three-dimensional reconstructions that have proposed categories through mathematical algorithms and image superposition that are a great contribution to diagnosis, decision-making and choice of the treatment plan and follow-up. Conclusions: The assessment of the severity of TMDJD is key for clinical research in order to clarify the processes that are related to assessing the progression of this disease.

Ca2+/Calmodulin-Dependent Protein Kinase II and Androgen Signaling Pathways Modulate MEF2 Activity in Testosterone-Induced Cardiac Myocyte Hypertrophy.

Testosterone is known to induce cardiac hypertrophy through androgen receptor (AR)-dependent and -independent pathways, but the molecular underpinnings of the androgen action remain poorly understood. Previous work has shown that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and myocyte-enhancer factor 2 (MEF2) play key roles in promoting cardiac myocyte growth. In order to gain mechanistic insights into the action of androgens on the heart, we investigated how testosterone affects CaMKII and MEF2 in cardiac myocyte hypertrophy by performing studies on cultured rat cardiac myocytes and hearts obtained from adult male orchiectomized (ORX) rats. In cardiac myocytes, MEF2 activity was monitored using a luciferase reporter plasmid, and the effects of CaMKII and AR signaling pathways on MEF2C were examined by using siRNAs and pharmacological inhibitors targeting these two pathways. In the in vivo studies, ORX rats were randomly assigned to groups that were administered vehicle or testosterone (125 mg⋅kg-1⋅week-1) for 5 weeks, and plasma testosterone concentrations were determined using ELISA. Cardiac hypertrophy was evaluated by measuring well-characterized hypertrophy markers. Moreover, western blotting was used to assess CaMKII and phospholamban (PLN) phosphorylation, and MEF2C and AR protein levels in extracts of left-ventricle tissue from control and testosterone-treated ORX rats. Whereas testosterone treatment increased the phosphorylation levels of CaMKII (Thr286) and phospholambam (PLN) (Thr17) in cardiac myocytes in a time- and concentration-dependent manner, testosterone-induced MEF2 activity and cardiac myocyte hypertrophy were prevented upon inhibition of CaMKII, MEF2C, and AR signaling pathways. Notably, in the hypertrophied hearts obtained from testosterone-administered ORX rats, both CaMKII and PLN phosphorylation levels and AR and MEF2 protein levels were increased. Thus, this study presents the first evidence indicating that testosterone activates MEF2 through CaMKII and AR signaling. Our findings suggest that an orchestrated mechanism of action involving signal transduction and transcription pathways underlies testosterone-induced cardiac myocyte hypertrophy.

GSK-3ß/NFAT Signaling Is Involved in Testosterone-Induced Cardiac Myocyte Hypertrophy.

Testosterone induces cardiac hypertrophy through a mechanism that involves a concerted crosstalk between cytosolic and nuclear signaling pathways. Nuclear factor of activated T-cells (NFAT) is associated with the promotion of cardiac hypertrophy, glycogen synthase kinase-3ß (GSK-3ß) is considered to function as a negative regulator, mainly by modulating NFAT activity. However, the role played by calcineurin-NFAT and GSK-3ß signaling in testosterone-induced cardiac hypertrophy has remained unknown. Here, we determined that testosterone stimulates cardiac myocyte hypertrophy through NFAT activation and GSK-3ß inhibition. Testosterone increased the activity of NFAT-luciferase (NFAT-Luc) in a time- and dose-dependent manner, with the activity peaking after 24 h of stimulation with 100 nM testosterone. NFAT-Luc activity induced by testosterone was blocked by the calcineurin inhibitors FK506 and cyclosporine A and by 11R-VIVIT, a specific peptide inhibitor of NFAT. Conversely, testosterone inhibited GSK-3ß activity as determined by increased GSK-3ß phosphorylation at Ser9 and ß-catenin protein accumulation, and also by reduction in ß-catenin phosphorylation at residues Ser33, Ser37, and Thr41. GSK-3ß inhibition with 1-azakenpaullone or a GSK-3ß-targeting siRNA increased NFAT-Luc activity, whereas overexpression of a constitutively active GSK-3ß mutant (GSK-3ßS9A) inhibited NFAT-Luc activation mediated by testosterone. Testosterone-induced cardiac myocyte hypertrophy was established by increased cardiac myocyte size and [3H]-leucine incorporation (as a measurement of cellular protein synthesis). Calcineurin-NFAT inhibition abolished and GSK-3ß inhibition promoted the hypertrophy stimulated by testosterone. GSK-3ß activation by GSK-3ßS9A blocked the increase of hypertrophic markers induced by testosterone. Moreover, inhibition of intracellular androgen receptor prevented testosterone-induced NFAT-Luc activation. Collectively, these results suggest that cardiac myocyte hypertrophy induced by testosterone involves a cooperative mechanism that links androgen signaling with the recruitment of NFAT through calcineurin activation and GSK-3ß inhibition.

New insights into IGF-1 signaling in the heart.

Insulin-like growth factor 1 (IGF-1) signaling regulates contractility, metabolism, hypertrophy, autophagy, senescence, and apoptosis in the heart. IGF-1 deficiency is associated with an increased risk of cardiovascular disease, whereas cardiac activation of IGF-1 receptor (IGF-1R) protects from the detrimental effects of a high-fat diet and myocardial infarction. IGF-1R activates multiple pathways through its intrinsic tyrosine kinase activity and through coupling to heterotrimeric G protein. These pathways involve classic second messengers, phosphorylation cascades, lipid signaling, Ca(2+) transients, and gene expression. In addition, IGF-1R triggers signaling in different subcellular locations including the plasma membrane, perinuclear T tubules, and also in internalized vesicles. In this review, we provide a fresh and updated view of the complex IGF-1 scenario in the heart, including a critical focus on therapeutic strategies.

Role of heterotrimeric G protein and calcium in cardiomyocyte hypertrophy induced by IGF-1.

In the heart, insulin-like growth factor-1 (IGF-1) is a peptide with pro-hypertrophic and anti-apoptotic actions. The pro-hypertrophic properties of IGF-1 have been attributed to the extracellular regulated kinase (ERK) pathway. Recently, we reported that IGF-1 also increases intracellular Ca(2+) levels through a pertussis toxin (PTX)-sensitive G protein. Here we investigate whether this Ca(2+) signal is involved in IGF-1-induced cardiomyocyte hypertrophy. Our results show that the IGF-1-induced increase in Ca(2+) level is abolished by the IGF-1 receptor tyrosine kinase inhibitor AG538, PTX and the peptide inhibitor of Gßγ signaling, ßARKct. Increases in the activities of Ca(2+) -dependent enzymes calcineurin, calmodulin kinase II (CaMKII), and protein kinase Cα (PKCα) were observed at 5 min after IGF-1 exposure. AG538, PTX, ßARKct, and the dominant negative PKCα prevented the IGF-1-dependent phosphorylation of ERK1/2. Participation of calcineurin and CaMKII in ERK phosphorylation was discounted. IGF-1-induced cardiomyocyte hypertrophy, determined by cell size and ß-myosin heavy chain (ß-MHC), was prevented by AG538, PTX, ßARKct, dominant negative PKCα, and the MEK1/2 inhibitor PD98059. Inhibition of calcineurin with CAIN did not abolish IGF-1-induced cardiac hypertrophy. We conclude that IGF-1 induces hypertrophy in cultured cardiomyocytes by activation of the receptor tyrosine kinase activity/ßγ-subunits of a PTX-sensitive G protein/Ca(2+) /PKCα/ERK pathway without the participation of calcineurin.

Local control of nuclear calcium signaling in cardiac myocytes by perinuclear microdomains of sarcolemmal insulin-like growth factor 1 receptors.

RATIONALE: The ability of a cell to independently regulate nuclear and cytosolic Ca(2+) signaling is currently attributed to the differential distribution of inositol 1,4,5-trisphosphate receptor channel isoforms in the nucleoplasmic versus the endoplasmic reticulum. In cardiac myocytes, T-tubules confer the necessary compartmentation of Ca(2+) signals, which allows sarcomere contraction in response to plasma membrane depolarization, but whether there is a similar structure tunneling extracellular stimulation to control nuclear Ca(2+) signals locally has not been explored. OBJECTIVE: To study the role of perinuclear sarcolemma in selective nuclear Ca(2+) signaling. METHODS AND RESULTS: We report here that insulin-like growth factor 1 triggers a fast and independent nuclear Ca(2+) signal in neonatal rat cardiac myocytes, human embryonic cardiac myocytes, and adult rat cardiac myocytes. This fast and localized response is achieved by activation of insulin-like growth factor 1 receptor signaling complexes present in perinuclear invaginations of the plasma membrane. The perinuclear insulin-like growth factor 1 receptor pool connects extracellular stimulation to local activation of nuclear Ca(2+) signaling and transcriptional upregulation through the perinuclear hydrolysis of phosphatidylinositol 4,5-biphosphate inositol 1,4,5-trisphosphate production, nuclear Ca(2+) release, and activation of the transcription factor myocyte-enhancing factor 2C. Genetically engineered Ca(2+) buffers--parvalbumin--with cytosolic or nuclear localization demonstrated that the nuclear Ca(2+) handling system is physically and functionally segregated from the cytosolic Ca(2+) signaling machinery. CONCLUSIONS: These data reveal the existence of an inositol 1,4,5-trisphosphate-dependent nuclear Ca(2+) toolkit located in direct apposition to the cell surface, which allows the local control of rapid and independent activation of nuclear Ca(2+) signaling in response to an extracellular ligand.

IGF-1: un factor de crecimiento con acciones cardiovasculares pleiotrópicas / IGF-1: a growth factor with pleiotropic cardiovascular actions

El factor de crecimiento análogo a insulina tipo 1 (IGF-1) es un péptido relacionado estructural y funcionalmente con insulina que posee efectos mitogénicos y citoprotectores. Sus efectos biológicos dependen de la activación del receptor de IGF- 1 (IGF-1R), perteneciente a la familia de receptores con actividad tirosina kinasa intrínseca y que se localiza en la superficie celular. IGF-1 es el principal mediador fisiológico de la hormona del crecimiento y dado que su gen se expresa en múltiplestejidos, este factor es clave en la comunicación endocrina, paracrina y autocrina. Recientes evidencias muestran que IGF- 1 ejerce variadas acciones pleiotrópicas en el sistema cardiovascular, destacándose sus efectos en la hipertrofia, muerte y regeneración celular. En el corazón, IGF-1 promueve su crecimiento, mejora su contractibilidad, facilita el metabolismode la glucosa, disminuye el nivel de insulina circulante, aumenta la sensibilidad a esta hormona, estabiliza el perfil lipídico y estimula la regeneración del músculo cardíaco. Evidencias clínicas y experimentales han mostrado que el deterioro de la función cardíaca se asocia a bajos niveles circulantes de IGF-1. Alteraciones tanto en los niveles de IGF-1 como en su sistema transduccional se consideran factores de riesgo para el desarrollo de distintas patologías cardíacas. Todosestos antecedentes destacan el papel del IGF-1 en cardioprotección y su potencialidad para el tratamiento de diversas patologías cardiovasculares. Sin embargo, los mecanismos moleculares implicados en estos efectos prácticamente se desconocen. En esta revisión, junto con entregar antecedentes actualizados y críticos de las acciones cardiovasculares del IGF-1, se proyectan sus aplicaciones terapéuticas.

Testosterone induces an intracellular calcium increase by a nongenomic mechanism in cultured rat cardiac myocytes.

Androgens are associated with important effects on the heart, such as hypertrophy or apoptosis. These responses involve the intracellular androgen receptor. However, the mechanisms of how androgens activate several membrane signaling pathways are not fully elucidated. We have investigated the effect of testosterone on intracellular calcium in cultured rat cardiac myocytes. Using fluo3-AM and epifluorescence microscopy, we found that exposure to testosterone rapidly (1-7 min) led to an increase of intracellular Ca2+, an effect that persisted in the absence of external Ca2+. Immunocytochemical analysis showed that these effects occurred before translocation of the intracellular androgen receptor to the perinuclear zone. Pretreatment of the cells with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethylester and thapsigargin blocked this response, suggesting the involvement of internal Ca2+ stores. U-73122, an inhibitor of phospholipase C, and xestospongin C, an inhibitor of inositol 1,4,5-trisphosphate receptor, abolished the Ca2+ signal. The rise in intracellular Ca2+ was not inhibited by cyproterone, an antagonist of intracellular androgen receptor. Moreover, the cell impermeant testosterone-BSA complex also produced the Ca2+ signal, indicating its origin in the plasma membrane. This effect was observed in cultured neonatal and adult rat cardiac myocytes. Pertussis toxin and the adenoviral transduction of beta- adrenergic receptor kinase carboxy terminal peptide, a peptide inhibitor of betagamma-subunits of G protein, abolished the testosterone-induced Ca2+ release. In summary, this is the first study of rapid, nongenomic intracellular Ca2+ signaling of testosterone in cardiac myocytes. Using various inhibitors and testosterone-BSA complex, the mechanism for the rapid, testosterone-induced increase in intracellular Ca2+ is through activation of a plasma membrane receptor associated with a Pertussis toxin-sensitive G protein-phospholipase C/inositol 1,4,5-trisphosphate signaling pathway.

Sistemas de transducción de señales en la hipertrofia cardíaca / Signaling mechanisms in cardiac hypertrophy

Los cardiomiocitos son células terminalmente diferenciadas que cesan de dividirse inmediatamente después del nacimiento. Esto hace del corazón un órgano muy vulnerable a eventos isquémicos, tóxicos e inflamatorios. La sobrecarga hemodinámica induce hipertrofia cardíaca, produciendo un aumento de sarcómeros y del volumen celular. Aunque la hipertrofia es inicialmente beneficiosa, aumentando el gasto cardíaco, finalmente es deletérea, generando cardiomiopatía, insuficiencia cardíaca y muerte súbita. El estiramiento mecánico de los cardiomiocitos activa la expresión de genes hipertróficos y de factores de crecimiento cardíacos (agonistas adrenérgicos, Ang II, ET-1, IGF-1, CT-1, FGF-2, TGF-ß, hormonas tiroideas, TNF-alfa, LIF). Estos factores humorales activan diversas vías transduccionales responsables de la expresión de genes hipertróficos. Estas vías son: proteínas kinasas activadas por mitógenos (MAP kinasas), proteína kinasa C (PKC), proteína kinasa dependiente de calcio/calmodulina (CaMK) y calcineurina. Las MAPKs (ERK, JNK y p38-MAPK) se activan por fosforilación secuencial en cascada. La PKC se activa por receptores acoplados a la proteína Gq. Ambas vías se interrelacionan y controlan factores transcripcionales responsables de la hipertrofia. La calcineurina es una fosfatasa dependiente de CA2+ y CaM que desfosforila y activa a NFAT3. La CaMK activa a MEF2 al disociarlo de una desacetilasa de historia tipo II. MEF2 y NFAT3 son factores transcripcionales que controlan la expresión de genes hipertróficos. El uso combinado de la manipulación mecánica/quirúrgica, animales transgénicos, adenovirus modificados genéticamente e inhibidores químicos farmacológicos, han contribuido a dilucidar las vías transduccionales involucradas en el desarrollo de la hipertrofia cardíaca. Sin embargo, recién se están empezando a vislumbrar los mecanismos por los cuales las distintas vías conversan entre sí. Sólo entendiendo la compleja interrelación de las múltiples vías transduccionales se podrán diseñar fármacos que permitan controlar el proceso hipertrófico