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5 figures, 1 table.-- Supporting information available., Nanoparticles (NPs) of conjugated polymers in intimate contact with sheets of graphene oxide (GO) constitute a promising class of water-dispersible nanohybrid materials of increased interest for the design of sustainable and improved optoelectronic thin-film devices, revealing properties exclusively pre-established upon their liquid-phase synthesis. In this context, we report for the first time the preparation of a P3HTNPs–GO nanohybrid employing a miniemulsion synthesis approach, whereby GO sheets dispersed in the aqueous phase serve as a surfactant. We show that this process uniquely favors a quinoid-like conformation of the P3HT chains of the resulting NPs well located onto individual GO sheets. The accompanied change in the electronic behavior of these P3HTNPs, consistently confirmed by the photoluminescence and Raman response of the hybrid in the liquid and solid states, respectively, as well as by the properties of the surface potential of isolated individual P3HTNPs–GO nano-objects, facilitates unprecedented charge transfer interactions between the two constituents. While the electrochemical performance of nanohybrid films is featured by fast charge transfer processes, compared to those taking place in pure P3HTNPs films, the loss of electrochromic effects in P3HTNPs–GO films additionally indicates the unusual suppression of polaronic charge transport processes typically encountered in P3HT. Thus, the established interface interactions in the P3HTNPs–GO hybrid enable a direct and highly efficient charge extraction channel via GO sheets. These findings are of relevance for the sustainable design of novel high-performance optoelectronic device structures based on water-dispersible conjugated polymer nanoparticles., This work was funded by Spanish MCIN/AEI/10.13039/501100011033 under projects PID2019-104272RB-C51, PID2019-104272RB-C52, PID2019-104272RB-C55, and PID2019-104739GB-I00. Financial support from Gobierno de Aragon (DGA) under project “Grupos Consolidados” T03_20R is acknowledged. E.C. is grateful for PhD grant BES2017-080020 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”. M.N.R.’s work was financed by grant PID2019-104272RB-C52/PRE2020-094503 funded by MCIN/AEI/10.13039/501100011033 and by “‘ESF Investing in your future”’. R.A. acknowledges support from EU H2020 “ESTEEM3” (Grant number 823717) and Graphene Flagship (881603).

A series of relatively small studies collectively suggest that zonisamide may be effective in the treatment of infantile spasms. Using a large single‐center cohort of children with infantile spasms, we set out to evaluate the efficacy and safety of zonisamide. We retrospectively identified all patients with infantile spasms who were treated with zonisamide at our center. For each patient, we recorded dates of birth, infantile spasms onset, response (if any), and most recent follow‐up. To quantify zonisamide exposure, we recorded daily dosage and patient weight at each sequential encounter so as to allow calculation of peak and weighted‐average weight‐based dosage. We identified 87 children who were treated with zonisamide, of whom 78 had previously been treated with hormonal therapy or vigabatrin. Peak and weighted‐average zonisamide dosage were 7.1 (interquartile range 3.6, 10.2) and 5.4 (interquartile range 3.0, 8.9) mg/kg/day, respectively. Whereas five (6%) patients exhibited resolution of epileptic spasms, only two (2%) patients exhibited video‐EEG confirmed resolution of both epileptic spasms and hypsarrhythmia (electroclinical response). Importantly, both electroclinical responders had not previously been treated with hormonal therapy or vigabatrin; in contrast, none of the 78 children with prior failure of hormonal therapy or vigabatrin subsequently responded to zonisamide. Zonisamide was well tolerated, and there were no deaths. This study suggests that zonisamide exhibits favorable tolerability but very limited efficacy among patients who do not respond to first‐line therapy.

BACKGROUND Previous qualitative studies and data science studies using Reddit for tobacco research are limited by the lack of available demographic information. Social media investigations are often limited to manual qualitative coding or machine learning classification in isolation. OBJECTIVE This study combines both machine learning methods and manual qualitative coding to provide contextual age nuance to social media analysis. By being able to predict a Redditor’s age using publicly available data, the most popular posts can be analyzed and qualitatively coded to provide nuanced comparisons on thematic topics by age group. METHODS The current study combines these two methods to 1) predict Reddit users’ age into two categories (13-20, 21-54) and 2) qualitatively code Electronic Nicotine Delivery System [ENDS] related Reddit posts within the two age groups. We identified Reddit posts on three topics: Vaping in General, Tobacco 21 Minimum Age Laws, and Flavor Restriction Policies. An age algorithm was used to predict Reddit users’ ages (13-20 or 21-54 year old users). The 25 posts with the highest karma score (number of upvotes minus number of downvotes) for each query and each predicted age group were qualitatively coded. RESULTS The top three, two of which were part of the query, out of nine, topics that emerged were “Flavor Restriction Policies”, “Tobacco 21 Policies”, and “Use”. Tobacco 21 and Flavor Restriction Policy posts were prominent coding categories. Opposition to flavor restriction policies was a prominent sub-category for both groups, but more common in the 21-54 group. The 13-20 group was more likely to discuss opposition to minimum age laws as well as access to flavored ENDS products. The 21-54 group more commonly mentioned general vaping use behavior. CONCLUSIONS Users predicted to be in the 13-20 age group posted about different ENDS-related topics on Reddit than users predicted to be in the 21-54 age group. Future studies could use these complementary methods with social media data to gain insights from target audiences.

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BACKGROUND Social media are important for monitoring perceptions of public health issues and for educating target audiences about health; however, limited information about the demographics of social media users makes it challenging to identify conversations among target audiences and limits how well social media can be used for public health surveillance and education outreach efforts. Certain social media platforms provide demographic information on followers of a user account, if given, but they are not always disclosed, and researchers have developed machine learning algorithms to predict social media users’ demographic characteristics, mainly for Twitter. To date, there has been limited research on predicting the demographic characteristics of Reddit users. OBJECTIVE We aimed to develop a machine learning algorithm that predicts the age segment of Reddit users, as either adolescents or adults, based on publicly available data. METHODS This study was conducted between January and September 2020 using publicly available Reddit posts as input data. We manually labeled Reddit users’ age by identifying and reviewing public posts in which Reddit users self-reported their age. We then collected sample posts, comments, and metadata for the labeled user accounts and created variables to capture linguistic patterns, posting behavior, and account details that would distinguish the adolescent age group (aged 13 to 20 years) from the adult age group (aged 21 to 54 years). We split the data into training (n=1660) and test sets (n=415) and performed 5-fold cross validation on the training set to select hyperparameters and perform feature selection. We ran multiple classification algorithms and tested the performance of the models (precision, recall, F1 score) in predicting the age segments of the users in the labeled data. To evaluate associations between each feature and the outcome, we calculated means and confidence intervals and compared the two age groups, with 2-sample t tests, for each transformed model feature. RESULTS The gradient boosted trees classifier performed the best, with an F1 score of 0.78. The test set precision and recall scores were 0.79 and 0.89, respectively, for the adolescent group (n=254) and 0.78 and 0.63, respectively, for the adult group (n=161). The most important feature in the model was the number of sentences per comment (permutation score: mean 0.100, SD 0.004). Members of the adolescent age group tended to have created accounts more recently, have higher proportions of submissions and comments in the r/teenagers subreddit, and post more in subreddits with higher subscriber counts than those in the adult group. CONCLUSIONS We created a Reddit age prediction algorithm with competitive accuracy using publicly available data, suggesting machine learning methods can help public health agencies identify age-related target audiences on Reddit. Our results also suggest that there are characteristics of Reddit users’ posting behavior, linguistic patterns, and account features that distinguish adolescents from adults.

Summary: Amyloid β-protein (Aβ) toxicity is hypothesized to play a seminal role in Alzheimer’s disease (AD) pathogenesis. However, it remains unclear how Aβ causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Aβ-induced synaptic injury is related to the cleavage of amyloid β precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide. In organotypic slice cultures derived from mice with a knock-in mutation in the APP gene (APP D664A) to inhibit caspase cleavage, Aβ-induced synaptic injury is markedly reduced in two models of Aβ toxicity. Loss of dendritic spines is also attenuated in mice treated with caspase inhibitors. Importantly, the time-dependent dendritic spine loss is correlated with localized activation of caspase-3 but is absent in APP D664A cultures. We propose that the APP cytosolic domain plays an essential role in Aβ-induced synaptic damage in the injury pathway mediated by localized caspase activation.

Skeletal muscle plays a central role in insulin-controlled glucose homeostasis. The molecular mechanisms related to insulin resistance in this tissue are incompletely understood. Herpud1 is an endoplasmic reticulum membrane protein that maintains intracellular Ca2+ homeostasis under stress conditions. It has recently been reported that Herpud1-knockout mice display intolerance to a glucose load without showing altered insulin secretion. The functions of Herpud1 in skeletal muscle also remain unknown. Based on these findings, we propose that Herpud1 is necessary for insulin-dependent glucose disposal in skeletal muscle. Here we show that Herpud1 silencing decreased insulin-dependent glucose uptake, GLUT4 translocation to the plasma membrane, and Akt Ser473 phosphorylation in cultured L6 myotubes. A decrease in insulin-induced Akt Ser473 phosphorylation was observed in soleus but not in extensor digitorum longus muscle samples from Herpud1-knockout mice. Herpud1 knockdown increased the IP3R-dependent cytosolic Ca2+ response and the activity of Ca2+-dependent serine/threonine phosphatase calcineurin in L6 cells. Calcineurin decreased insulin-dependent Akt phosphorylation and glucose uptake. Moreover, calcineurin inhibition restored the insulin response in Herpud1-depleted L6 cells. Based on these findings, we conclude that Herpud1 is necessary for adequate insulin-induced glucose uptake due to its role in Ca2+/calcineurin regulation in L6 myotubes.

Cardiovascular diseases are the leading cause of death worldwide. Despite preventive efforts, early detection of atherosclerosis, the common pathophysiological mechanism underlying cardiovascular diseases remains elusive, and overt coronary artery disease or myocardial infarction is often the first clinical manifestation. Nanoparticles represent a novel strategy for prevention, diagnosis, and treatment of atherosclerosis, and new multifunctional nanoparticles with combined diagnostic and therapeutic capacities hold the promise for theranostic approaches to this disease. This review focuses on the development of nanosystems for therapy and diagnosis of subclinical atherosclerosis, coronary artery disease, and myocardial infarction and the evolution of nanosystems as theranostic tools. We also discuss the use of nanoparticles in noninvasive imaging, targeted drug delivery, photothermal therapies together with the challenges faced by nanosystems during clinical translation.

Increased inflammation biomarkers plasma levels, including C-reactive protein (CRP), have been associated with the initiation and perpetuation of atrial fibrillation (AF). However, it is not known whether an increased CRP plasma level, without concomitant inflammation, is sufficient to induce AF. We investigated whether higher CRP plasma levels, determined by the presence of +219GA CRP gene polymorphism, is associated with an increased risk of post-operative AF.One hundred and fifteen adult patients submitted to elective coronary surgery were genotyped for the CRP +219GA polymorphism. CRP plasma levels were determined by enzyme-linked immunosorbent assay.CRP plasma levels before surgery were higher in GG than in GA+AA patients (3.4±3.1 vs. 1.7±1.8, p0.015). Thirteen percent of the patients presented post-operative AF. Despite the positive correlation between the polymorphism and CRP levels, there was no significant difference in the occurrence of post-operative AF between the different genotypes.These results suggest that increased CRP plasma levels that are not associated with an inflammatory process are not sufficient to trigger AF after cardiac surgery.

Cardiac hypertrophy is an adaptive response triggered by pathological stimuli. Regulation of the synthesis and the degradation of the Ca2+ channel inositol 1,4,5-trisphosphate receptor (IP3R) affects progression to cardiac hypertrophy. Herpud1, a component of the endoplasmic reticulum-associated degradation (ERAD) complex, participates in IP3R1 degradation and Ca2+ signaling, but the cardiac function of Herpud1 remains unknown. We hypothesize that Herpud1 acts as a negative regulator of cardiac hypertrophy by regulating IP3R protein levels. Our results show that Herpud1-knockout mice exhibit cardiac hypertrophy and dysfunction and that decreased Herpud1 protein levels lead to elevated levels of hypertrophic markers in cultured rat cardiomyocytes. In addition, IP3R levels were elevated both in Herpud1-knockout mice and Herpud1 siRNA-treated rat cardiomyocytes. The latter treatment also led to elevated cytosolic and nuclear Ca2+ levels. In summary, the absence of Herpud1 generates a pathological hypertrophic phenotype by regulating IP3R protein levels. Herpud1 is a novel negative regulator of pathological cardiac hypertrophy.

The aim of this chapter is to explain the emergence and distribution of clitic doubling (CLD) in Romance. On the basis of newly assembled diachronic and synchronic data, the chapter argues that the development can be analysed as a cycle of five different stages. The emergence of the CLD parameter (Fischer and Rinke 2013) is connected to the grammaticalization path of the clitic itself and the verb’s ability to move to the front of the sentence, which in turn affects the A’-positions in front of the verb that are available for the object. CLD in Spanish and Catalan is argued to have taken over partially the information-structural meaning expressed by word order in the Old Romance languages.

Summary The FRAX tool incorporates data on the incidence of fractures and mortality in each country. The epidemiology of fractures changes over time, this makes it necessary to update the specific FRAX model of each population. It is shown that there are differences between old and new FRAX models in older individuals. Purpose A new FRAX® model for Ecuador was released online in April 2019. This paper describes the data used to build the revised model, its characteristics, and how intervention and assessment thresholds were constructed. Methods The national rates of hip fracture incidence standardized by age and sex from the age of 40 years for 2016 were used to synthesize a FRAX model for Ecuador. For other major fractures, Ecuadorian incidence rates were calculated using ratios obtained in Malmö, Sweden, for other major osteoporotic fractures. The new FRAX model was compared with the previous model released in 2012. Assessment and intervention thresholds were based on age-specific probabilities of a major osteoporotic fracture equivalent to women with a previous fracture. Results Fracture incidence rates increase with age. The probability of hip or major fractures at 10 years increased in patients with a clinical risk factor, lower BMI, female sex, a higher age, and a lower BMD T-score. Compared to the previous model, the new FRAX model gave similar 10-year fracture probabilities in men and women age less than70 years but substantially higher above this age. Notwithstanding, there were very close correlations in fracture probabilities between the two models (> 0.99) so that the revision had little impact on the rank order of risk. Conclusions The FRAX tool provides a country-specific fracture prediction model for Ecuador. This update of the model is based on the original FRAX methodology, which has been validated externally in several independent cohorts. The FRAX model is an evolving tool that is being continuously refined, as the databases of each country are updated with more epidemiological information.

Apical caspases initiate and effector caspases execute apoptosis. Reagents that can distinguish between caspases, particularly apical caspases-8, 9, and 10 are scarce and generally nonspecific. Based upon a previously described large-scale screen of peptide-based caspase substrates termed HyCoSuL, we sought to develop reagents to distinguish between apical caspases in order to reveal their function in apoptotic cell death paradigms. To this end, we selected tetrapeptide-based sequences that deliver optimal substrate selectivity and converted them to inhibitors equipped with a detectable tag (activity-based probes-ABPs). We demonstrate a strong relationship between substrate kinetics and ABP kinetics. To evaluate the utility of selective substrates and ABPs, we examined distinct apoptosis pathways in Jurkat T lymphocyte and MDA-MB-231 breast cancer lines triggered to undergo cell death via extrinsic or intrinsic apoptosis. We report the first highly selective substrate appropriate for quantitation of caspase-8 activity during apoptosis. Converting substrates to ABPs promoted loss-of-activity and selectivity, thus we could not define a single ABP capable of detecting individual apical caspases in complex mixtures. To overcome this, we developed a panel strategy utilizing several caspase-selective ABPs to interrogate apoptosis, revealing the first chemistry-based approach to uncover the participation of caspase-8, but not caspase-9 or -10 in TRAIL-induced extrinsic apoptosis. We propose that using select panels of ABPs can provide information regarding caspase-8 apoptotic signaling more faithfully than can single, generally nonspecific reagents

Social media are important for monitoring perceptions of public health issues and for educating target audiences about health; however, limited information about the demographics of social media users makes it challenging to identify conversations among target audiences and limits how well social media can be used for public health surveillance and education outreach efforts. Certain social media platforms provide demographic information on followers of a user account, if given, but they are not always disclosed, and researchers have developed machine learning algorithms to predict social media users' demographic characteristics, mainly for Twitter. To date, there has been limited research on predicting the demographic characteristics of Reddit users.We aimed to develop a machine learning algorithm that predicts the age segment of Reddit users, as either adolescents or adults, based on publicly available data.This study was conducted between January and September 2020 using publicly available Reddit posts as input data. We manually labeled Reddit users' age by identifying and reviewing public posts in which Reddit users self-reported their age. We then collected sample posts, comments, and metadata for the labeled user accounts and created variables to capture linguistic patterns, posting behavior, and account details that would distinguish the adolescent age group (aged 13 to 20 years) from the adult age group (aged 21 to 54 years). We split the data into training (n=1660) and test sets (n=415) and performed 5-fold cross validation on the training set to select hyperparameters and perform feature selection. We ran multiple classification algorithms and tested the performance of the models (precision, recall, F1 score) in predicting the age segments of the users in the labeled data. To evaluate associations between each feature and the outcome, we calculated means and confidence intervals and compared the two age groups, with 2-sample t tests, for each transformed model feature.The gradient boosted trees classifier performed the best, with an F1 score of 0.78. The test set precision and recall scores were 0.79 and 0.89, respectively, for the adolescent group (n=254) and 0.78 and 0.63, respectively, for the adult group (n=161). The most important feature in the model was the number of sentences per comment (permutation score: mean 0.100, SD 0.004). Members of the adolescent age group tended to have created accounts more recently, have higher proportions of submissions and comments in the r/teenagers subreddit, and post more in subreddits with higher subscriber counts than those in the adult group.We created a Reddit age prediction algorithm with competitive accuracy using publicly available data, suggesting machine learning methods can help public health agencies identify age-related target audiences on Reddit. Our results also suggest that there are characteristics of Reddit users' posting behavior, linguistic patterns, and account features that distinguish adolescents from adults.

Several small case series provide conflicting impressions of the efficacy of felbamate for treatment of epileptic spasms. Using a large single-center cohort of children with epileptic spasms, we retrospectively evaluated the efficacy and safety of felbamate. We identified all patients with video-EEG confirmed epileptic spasms who were treated with felbamate at our center. We quantified felbamate exposure by calculating peak and weighted-average weight-based dose. Clinical response was defined as resolution of epileptic spasms for at least 28 days, beginning not more than 3 months after felbamate initiation. Electroclinical response was defined as clinical response accompanied by overnight video-EEG demonstrating freedom from epileptic spasms and hypsarrhythmia. Among a cohort of 476 infants, we identified 62 children who were treated with felbamate, of whom 58 had previously failed treatment with hormonal therapy or vigabatrin. Median peak and weighted-average felbamate dosages were 47 and 40 mg/kg/day, respectively. Five (8%) children were classified as clinical responders and two (3%) children were classified as electroclinical responders. Among 17 patients with latency from epileptic spasms onset to felbamate initiation of less than 12 months, we observed 4 (24%) clinical responders. This study suggests that felbamate may be efficacious for treatment of epileptic spasms and that further rigorous study is warranted.

En este trabajo se presenta el primer mapa geologico digital interactivo de la Faja Volcanica Transmexicana (FVTM). El area cubierta por la cartografia geologica abarca 10° de longitud (106°- 96° W) y 2°45' de latitud (19°-21°45' N). La geologia ha sido compilada en ArcGIS a traves de una interpretacion de toda la informacion disponible en la literatura e integrada con nuestra propia cartografia geologica. Los mapas publicados fueron digitalizados a partir de copias impresas; cuando fue posible se corrigio la ubicacion de los rasgos con una clara expresion morfologica utilizando modelos de elevacion digital en el SIG. El mapa incluye 36 unidades geologicas, fallas, chimeneas volcanicas y calderas. Las unidades geologicas informales utilizadas son cronoestratigraficas y litologicas y estan disenadas para destacar los principales episodios volcanicos que conforman el cinturon volcanico. La asignacion de la edad para cada unidad ha sido cotejada con una base de datos geocronologicos que incluye 2009 edades. La clasificacion litologica de cada poligono ha sido comparada por consistencia con una base de datos geoquimicos recopilados de la literatura.

Close contacts between endoplasmic reticulum and mitochondria enable reciprocal Ca2+ exchange, a key mechanism in the regulation of mitochondrial bioenergetics. During the early phase of endoplasmic reticulum stress, this inter-organellar communication increases as an adaptive mechanism to ensure cell survival. The signalling pathways governing this response, however, have not been characterized. Here we show that caveolin-1 localizes to the endoplasmic reticulum–mitochondria interface, where it impairs the remodelling of endoplasmic reticulum–mitochondria contacts, quenching Ca2+ transfer and rendering mitochondrial bioenergetics unresponsive to endoplasmic reticulum stress. Protein kinase A, in contrast, promotes endoplasmic reticulum and mitochondria remodelling and communication during endoplasmic reticulum stress to promote organelle dynamics and Ca2+ transfer as well as enhance mitochondrial bioenergetics during the adaptive response. Importantly, caveolin-1 expression reduces protein kinase A signalling, as evidenced by impaired phosphorylation and alterations in organelle distribution of the GTPase dynamin-related protein 1, thereby enhancing cell death in response to endoplasmic reticulum stress. In conclusion, caveolin-1 precludes stress-induced protein kinase A-dependent remodelling of endoplasmic reticulum–mitochondria communication.

Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and metabolic abnormalities in the heart. Myocardial energy metabolism depends on mitochondria, which must generate sufficient ATP to meet the high energy demands of the myocardium. Dysfunctional mitochondria are involved in the pathophysiology of diabetic heart disease. A large body of evidence implicates myocardial insulin resistance in the pathogenesis of DCM. Recent studies show that insulin signaling influences myocardial energy metabolism by impacting cardiomyocyte mitochondrial dynamics and function under physiological conditions. However, comprehensive understanding of molecular mechanisms linking insulin signaling and changes in the architecture of the mitochondrial network in diabetic cardiomyopathy is lacking. This review summarizes our current understanding of how defective insulin signaling impacts cardiac function in diabetic cardiomyopathy and discusses the potential role of mitochondrial dynamics.

We present an updated version of the geologic map of Los Humeros Volcanic Complex (LHVC) and geothermal field, based on acomplete revised characterization of the rock units and contacts, structural features, stratigraphy and recent radiometric dating withmodern methods (U/Th, 40Ar/39Ar, Carrasco-Núñez et al., 2017, in press), together with the use of high resolution Digital TerrainModel at 1m resolution and Google Earth optical imagery. Improvements of this version include refined stratigraphic sequence,revised classification of each lithostratigraphic unit, updated structural features and geochronologic data; all together providingconstraints to support a new evolutionary volcanic history for LHVC. Main changes with previous works involve the recently dis-covery of much younger ages for the main caldera-forming eruption. Much younger ages were also obtained for other importantexplosive phases. These findings reveal the existence of a much younger long-lived magmatic system with Holocene activity and ahigh geothermal potential that requires a further assessment for exploration and volcanic hazard purposes.

Skeletal muscle plays a central role in insulin-controlled glucose homeostasis. The molecular mechanisms related to insulin resistance in this tissue are incompletely understood. Herpud1 is an endoplasmic reticulum membrane protein that maintains intracellular Ca

Mifepristone is the only FDA-approved drug for glycaemia control in patients with Cushing's syndrome and type 2 diabetes. Mifepristone also has beneficial effects in animal models of diabetes and patients with antipsychotic treatment-induced obesity. However, the mechanisms through which Mifepristone produces its beneficial effects are not completely elucidated. Purpose To determine the effects of mifepristone on insulin-stimulated glucose uptake on a model of L6 rat-derived skeletal muscle cells. Results Mifepristone enhanced insulin-dependent glucose uptake, GLUT4 translocation to the plasma membrane and Akt Ser 473 phosphorylation in L6 myotubes. In addition, mifepristone reduced oxygen consumption and ATP levels and increased AMPK Thr 172 phosphorylation. The knockdown of AMPK prevented the effects of mifepristone on insulin response. Conclusions Mifepristone enhanced insulin-stimulated glucose uptake through a mechanism that involves a decrease in mitochondrial function and AMPK activation in skeletal muscle cells.

Growth differentiation factor 11 (GDF11) is a novel factor with controversial effects on cardiac hypertrophy both in vivo and in vitro. Although recent evidence has corroborated that GDF11 prevents the development of cardiac hypertrophy, its molecular mechanism remains unclear. In our previous work, we showed that norepinephrine (NE), a physiological pro-hypertrophic agent, increases cytoplasmic Ca2+ levels accompanied by a loss of physical and functional communication between sarcoplasmic reticulum (SR) and mitochondria, with a subsequent reduction in the mitochondrial Ca2+ uptake and mitochondrial metabolism. In order to study the anti-hypertrophic mechanism of GDF11, our aim was to investigate whether GDF11 prevents the loss of SR-mitochondria communication triggered by NE. Our results show that: a) GDF11 prevents hypertrophy in cultured neonatal rat ventricular myocytes treated with NE. b) GDF11 attenuates the NE-induced loss of contact sites between both organelles. c) GDF11 increases oxidative mitochondrial metabolism by stimulating mitochondrial Ca2+ uptake. In conclusion, the GDF11-dependent maintenance of physical and functional communication between SR and mitochondria is critical to allow Ca2+ transfer between both organelles and energy metabolism in the cardiomyocyte and to avoid the activation of Ca2+-dependent pro-hypertrophic signaling pathways.

Following publication of the article, the authors wrote to point out the following mistake

Insulin-like growth factor-1 (IGF-1) signaling is a key pathway in the control of cell growth and survival. Three critical nodes in the IGF-1 signaling pathway have been described in cardiomyocytes: protein kinase Akt/mammalian target of rapamycin (mTOR), Ras/Raf/extracellular signal-regulated kinase (ERK), and phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3 )/Ca(2+) . The Akt/mTOR and Ras/Raf/ERK signaling arms govern survival in the settings of cardiac stress and hypertrophic growth. By contrast, PLC/InsP3 /Ca(2+) functions to regulate metabolic adaptability and gene transcription. Autophagy is a catabolic process involved in protein degradation, organelle turnover, and nonselective breakdown of cytoplasmic components during nutrient starvation or stress. In the heart, autophagy is observed in a variety of human pathologies, where it can be either adaptive or maladaptive, depending on the context. We proposed the hypothesis that IGF-1 protects the heart by rescuing the mitochondrial metabolism and the energetics state, reducing cell death and controls the potentially exacerbate autophagic response to nutritional stress. In light of the importance of IGF-1 and autophagy in the heart, we review here IGF-1 signaling and autophagy regulation in the context of cardiomyocyte nutritional stress.

Lung cancer is one of the most common types of cancer in men and women and a leading cause of death worldwide resulting in more than one million deaths per year. The venom of marine snails Conus contains up to 200 pharmacologically active compounds that target several receptors in the cell membrane. Due to their diversity and specific binding properties, Conus toxins hold great potential as source of new drugs against cancer. We analyzed the cytotoxic effect of a 17-amino acid synthetic peptide (s-cal14.1a) that is based on a native toxin (cal14.1a) isolated from the sea snail Conus californicus. Cytotoxicity studies in four lung cancer cell lines were complemented with measurement of gene expression of apoptosis-related proteins Bcl-2, BAX and the pro-survival proteins NFκB-1 and COX-2, as well as quantification of caspase activity. Our results showed that H1299 and H1437 cell lines treated with s-call4.1a had decreased cell viability, activated caspases, and reduced expression of the pro-survival protein NFκB-1. To our knowledge, this is the first report describing activation of apoptosis in human lung cancer cell lines by s-cal14.1a and we offer insight into the possible mechanism of action.

Systemic endothelial dysfunction and increased oxidative stress have been observed in pulmonary arterial hypertension (PAH). We evaluate whether oxidative stress and endothelial dysfunction are associated with acute pulmonary vascular bed response to an inhaled prostanoid in PAH patients.Fourteen idiopathic PAH patients and 14 controls were included. Oxidative stress was assessed through plasma malondialdehyde (MDA) levels and xanthine oxidase (XO) and endothelial-bound superoxide dismutase (eSOD) activity. Brachial artery endothelial-dependent flow-mediated vasodilation (FMD) was used to evaluate endothelial function. Hemodynamic response to inhaled iloprost was assessed with transthoracic echocardiography.PAH patients showed impaired FMD (2.8 ± 0.6 vs. 10.7 ± 0.6%, P.01), increased MDA levels and XO activity (0.6 ± 0.2 vs. 0.3 ± 0.2 μM, P.01 and 0.04 ± 0.01 vs. 0.03 ± 0.01 U/mL, P = .02, respectively) and decreased eSOD activity (235 ± 23 vs. 461 ± 33 AUC, P.01). Iloprost improved right cardiac output (3.7 ± 0.6 to 4.1 ± 1.2 L/min, P = .02) and decreased pulmonary vascular resistance (4.1 ± 1.1 to 2.9 ± 0.9 Wood U, P = .01). Changes in right cardiac output after prostanoid inhalation correlated significantly with baseline eSOD activity and FMD (Rho: 0.61, P.01 and Rho: 0.63, P = .01, respectively).PAH patients show increased systemic oxidative stress and endothelial dysfunction markers. Response to inhaled prostanoid is inversely related to both parameters.

Increased oxidative stress in heart failure (HF) leads to inflammation and endothelial dysfunction (ED). Both statins and allopurinol have known anti-oxidant properties, but their utility in HF has not been fully assessed.This investigation was a prospective, double-blind, double-dummy study, performed between March 2007 and June 2009. Seventy-four HF patients, with New York Heart Association (NYHA) Class II or III status and left ventricular ejection fraction (LVEF)40%, were included. Patients received placebo during 4 weeks and were then randomized to receive 4 weeks of either atorvastatin 20 mg/day plus placebo (ATV+PLA group) or atorvastatin 20 mg/day orally plus allopurinol 300 mg/day orally (ATV+ALLO group). Malondialdehyde (MDA), extracellular superoxide dismutase (ecSOD) activity and uric acid (UA) levels, among others, were determined at baseline and after 4 weeks of treatment. ED was assessed by flow-dependent endothelial-mediated vasodilation (FDD), and functional capacity by 6-minute walk test (6MWT).Thirty-two patients were randomized to ATV+PLA and 38 to ATV+ALLO. Mean age was 59 ± 2 years, 82% were male, and 22% had an ischemic etiology. Hypertension was present in 60% and diabetes in 15% of those studied. No significant differences were observed between baseline measurements and after placebo. After 4 weeks of treatment, both groups showed a significant decrease on MDA (0.9 ± 0.1 to 0.8 ± 0.1 and 1.0 ± 0.5 to 0.9 ± 0.1 μmol/liter, p = 0.88), UA (7.4 ± 0.4 to 6.8 ± 0.3 and 7.2 ± 0.4 to 5.0 ± 0.3 mg/dl, p0.01) and FDD (3.9 ± 0.2% to 5.6 ± 0.4% and 4.6 ± 0.3% to 7.1 ± 0.5%, p = 0.07) with increased ecSOD activity (109 ± 11 to 173 ± 13 and 98 ± 10 to 202 ± 16, U/ml/min, p = 0.41) and improved 6MWT (447 ± 18 to 487 ± 19 and 438 ± 17 to 481 ± 21 m, p = 0.83), with all values for ATV+PLA and ATV+ALLO, respectively; p-values are for comparison between groups after treatment.Short-term ATV treatment in heart failure (HF) patients reduces oxidative stress and improves FDD and functional capacity. These beneficial effects are not strengthened by the addition of allopurinol.

Background: Pulmonary Arterial Hypertension (PAH) is characterized by endothelial dysfunction and vascular remodeling. Several lines of experimental evidence indícate that oxidative stress plays an important role in the pathogenesis of PAH. The role of oxidative stress and its relation with peripheral endothelial function and pulmonary vascular response to vasodilators remains unknown. Aim: To evalúate whether systemic oxidative stress and endothelial dysfunction markers are associated with the response of the pulmonary vascular bed to inhaled vasodilators in PAH patients. Methods: Cross-sectional study Fourteen patients with PAH and 14 age and gender-matched controls were in-cluded. Systemic oxidative stress was assessed through plasma malondialdehyde (MDA), xanthine oxidase (eXO) levéis and endothelial-bound superoxide dis-mutase (eSOD) activity Brachial artery endothelial-de-pendent flow-mediated vasodilation (FDD) was used to evalúate endothelial function. Right ventricular function and pulmonary vascular bed reactivity to inhaled vasodilators was determined with echocardiography in PAH patients. Results: Compared to controls, PAH patients showed impaired FDD (2.8 ± 0.6 vs 10.7% ± 0.6, p< 0.01), increased MDA and eXO levéis (0.61 ± 0.17 vs 0.34 ± 0.15μM, p

Homocysteine-inducible, endoplasmic reticulum (ER) stress-inducible, ubiquitin-like domain member 1 (HERPUD1), an ER resident protein, is upregulated in response to ER stress and Ca(2+) homeostasis deregulation. HERPUD1 exerts cytoprotective effects in various models, but its role during oxidative insult remains unknown. The aim of this study was to investigate whether HERPUD1 contributes to cytoprotection in response to redox stress and participates in mediating stress-dependent signaling pathways. Our data showed that HERPUD1 protein levels increased in HeLa cells treated for 30 min with H2O2 or angiotensin II and in aortic tissue isolated from mice treated with angiotensin II for 3 weeks. Cell death was higher in HERPUD1 knockdown (sh-HERPUD1) HeLa cells treated with H2O2 in comparison with control (sh-Luc) HeLa cells. This effect was abolished by the intracellular Ca(2+) chelating agent BAPTA-AM or the inositol 1,4,5-trisphosphate receptor (ITPR) antagonist xestospongin B, suggesting that the response to H2O2 was dependent on intracellular Ca(2+) stores and the ITPR. Ca(2+) kinetics showed that sh-HERPUD1 HeLa cells exhibited greater and more sustained cytosolic and mitochondrial Ca(2+) increases than sh-Luc HeLa cells. This higher sensitivity of sh-HERPUD1 HeLa cells to H2O2 was prevented with the mitochondrial permeability transition pore inhibitor cyclosporine A. We concluded that the HERPUD1-mediated cytoprotective effect against oxidative stress depends on the ITPR and Ca(2+) transfer from the ER to mitochondria.

Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant. Deletion of caspase-8 sensitized AML to birinapant, whereas combined loss of caspase-8 and the necroptosis effector MLKL (mixed lineage kinase domain-like) prevented birinapant/IDN-6556-induced death, showing that inhibition of caspase-8 sensitizes AML cells to birinapant-induced necroptosis. However, loss of MLKL alone did not prevent a caspase-dependent birinapant/IDN-6556-induced death, implying that AML will be less likely to acquire resistance to this drug combination. A therapeutic breakthrough in AML has eluded researchers for decades. Demonstrated antileukemic efficacy and safety of the birinapant/emricasan combination in vivo suggest that induction of necroptosis warrants clinical investigation as a therapeutic opportunity in AML.

Insulin is a major regulator of glucose metabolism, stimulating its mitochondrial oxidation in skeletal muscle cells. Mitochondria are dynamic organelles that can undergo structural remodeling in order to cope with these ever-changing metabolic demands. However, the process by which mitochondrial morphology impacts insulin signaling in the skeletal muscle cells remains uncertain. To address this question, we silenced the mitochondrial fusion proteins Mfn2 and Opa1 and assessed insulin-dependent responses in L6 rat skeletal muscle cells. We found that mitochondrial fragmentation attenuates insulin-stimulated Akt phosphorylation, glucose uptake and cell respiratory rate. Importantly, we found that insulin induces a transient rise in mitochondrial Ca2+ uptake, which was attenuated by silencing Opa1 or Mfn2. Moreover, treatment with Ruthenium red, an inhibitor of mitochondrial Ca2+ uptake, impairs Akt signaling without affecting mitochondrial dynamics. All together, these results suggest that control of mitochondrial Ca2+ uptake by mitochondrial morphology is a key event for insulin-induced glucose uptake.

Se estableció la composición química del toronjil (Melissa officinalis L.) cultivado en Coloso, Departamento de Sucre en Colombia, mediante la técnica de cromatografía de gases acoplada a espectrometría de masas. Esto fue realizado para determinar la variabilidad en la composición química producida por las condiciones climáticas que presenta la región. El toronjil se usa en esta comunidad en bebidas aromáticas y como tranquilizante natural considerando sus múltiples propiedades antioxidantes, microbiológicas, conservantes y aromatizantes de alimentos. Se identificó eugenol como el compuesto mayoritario con 45.47%, seguido del cariofileno, α-cariofileno, 3-metil-4-isopropil fenol, germacreno D, con 40.77%, 2.94%, 1.52% y 1.17% respectivamente. De acuerdo a los resultados, el aceite esencial de toronjil está de acuerdo con el quimiotipo eugenol. Chemical composition of Lemon balm (Melissa officinalis L.) grown in Coloso, Department of Sucre in Colombia, using the technique of gas chromatography coupled with mass spectrometry was determined. This was done to establish the variability in the chemical composition caused by weather conditions presented region. Lemon balm is used in this community in aromatic beverages and as a natural tranquilizer, considering its several antioxidant, microbiological, preserving and aromatic properties. eugenol was determined as the major component 45.47%, followed caryophyllene, α-caryophyllene, 3-methyl-4-isopropyl phenol, germacrene D, with 40.77%, 2.94%, 1.52% and 1.17% respectively. According to the results, the essential oil of lemon balm agrees with the eugenol chemotype.