Effects of Spaceflight on Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Structure and Function.

With extended stays aboard the International Space Station (ISS) becoming commonplace, there is a need to better understand the effects of microgravity on cardiac function. We utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study the effects of microgravity on cell-level cardiac function and gene expression. The hiPSC-CMs were cultured aboard the ISS for 5.5 weeks and their gene expression, structure, and functions were compared with ground control hiPSC-CMs. Exposure to microgravity on the ISS caused alterations in hiPSC-CM calcium handling. RNA-sequencing analysis demonstrated that 2,635 genes were differentially expressed among flight, post-flight, and ground control samples, including genes involved in mitochondrial metabolism. This study represents the first use of hiPSC technology to model the effects of spaceflight on human cardiomyocyte structure and function

Rate-dependency of action potential duration and refractoriness in isolated myocytes from the rabbit AV node and atrium

During atrial fibrillation, ventricular rate is determined by atrioventricular nodal (AVN) conduction, which in part is dependent upon the refractoriness of single AVN cells. The aims of this study were to investigate the rate-dependency of the action potential duration (APD) and effective refractory period (ERP) in single myocytes isolated from the AV node and atrium of rabbit hearts, using whole cell patch clamping, and to determine the contribution of the 4-aminopyridine (4-AP)-sensitive current, ITO1to these relationships in the two cell types. AVN cells had a more positive maximum diastolic potential (-60±1 v-71±2 mV), lower Vmax(8±2 v 144±17 V/s) and higher input resistance [420±46 v 65±7 MOHgr (mean±s.eP<0.05n=9–33)], respectively, than atrial myocytes. Stepwise increases in rate from 75 beats/min caused activation failure and Wenckebach periodicity in AVN cells (at around 400 beats/min), but 1:1 activation in atrial cells (at up to 600 beats/min). Rate reduction from 300 to 75 beats/min shortened the ERP in both cell types (from 155±7 to 135±11 ms in AVN cells [P<0.05, n=6] and from 130±8 to 106±7 ms in atrial cells [P<0.05, n=10]). Rate increase from 300 to 480 and 600 beats/min shortened ERP in atrial cells, by 12±4% (n=8) and 26±7% (n=7), respectively (P<0.05). By contrast, AVN ERP did not shorten at rates >300 beats/min. In atrial cells, rate reduction to 75 beats/min caused marked shortening of APD50(from 51±6 to 29±6 ms, P<0.05). 4-AP (1 mm) significantly prolonged atrial APD50at 75 beats/min (P<0.05, n=7), but not at 300 or 400 beats/min. In AVN cells, in contrast, there was less effect of rate change on APD, and 4-AP did not alter APD50at any rate. 4-AP also did not affect APD90or ERP in either cell type. In conclusion, a lack of ERP-shortening at high rates in rabbit single AVN cells may contribute to ventricular rate control. ITO1contributed to the APD50rate relation in atrial, but not AVN cells and did not contribute to the ERP rate relation in either cell type

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p < 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Pointes (TdP) is assessed using an in silico model of the human ventricular action potential (AP) that integrates in vitro pharmacology data from multiple ion channels. Thus, modeling predictions of cardiac risk liability will depend critically on the variability in pharmacology data, and uncertainty quantification (UQ) must comprise an essential component of the in silico assay. This study explores UQ methods that may be incorporated into the CiPA framework. Recently, we proposed a promising in silico TdP risk metric (qNet), which is derived from AP simulations and allows separation of a set of CiPA training compounds into Low, Intermediate, and High TdP risk categories. The purpose of this study was to use UQ to evaluate the robustness of TdP risk separation by qNet. Uncertainty in the model parameters used to describe drug binding and ionic current block was estimated using the non-parametric bootstrap method and a Bayesian inference approach. Uncertainty was then propagated through AP simulations to quantify uncertainty in qNet for each drug. UQ revealed lower uncertainty and more accurate TdP risk stratification by qNet when simulations were run at concentrations below 5× the maximum therapeutic exposure (Cmax). However, when drug effects were extrapolated above 10× Cmax, UQ showed that qNet could no longer clearly separate drugs by TdP risk. This was because for most of the pharmacology data, the amount of current block measured was <60%, preventing reliable estimation of IC50-values. The results of this study demonstrate that the accuracy of TdP risk prediction depends both on the intrinsic variability in ion channel pharmacology data as well as on experimental design considerations that preclude an accurate determination of drug IC50-values in vitro. Thus, we demonstrate that UQ provides valuable information about in silico modeling predictions that can inform future proarrhythmic risk evaluation of drugs under the CiPA paradigm

Alianzas estratégicas: instrumento de negociación y desarrollo sostenible mirado desde la perspectiva de la interculturalidad

Poverty is a phenomenon which is caused by lack of education and no access to adequate social services, malnutrition, no hygienic conditions and sex discrimination. For this reason, in different countries like Peru, a Social Mining Fund has been created. This organization shows a big potential to become a relevant strategic tool to set the bases for a sustainable development, reducing poverty rates and allowing institutional development. Similarly, this Fund has caused the onset of strategic alliances, which have increased the production of resources, the inclusion of new markets, becoming an essential instrument of intercultural negotiation in the mining sector. In this paper, a new development model is presented based on the three strategies in which the Social Mining Fund can be applied, being sustainable development, poverty rate decrease and institutional development, and at the same time focused on a general axis- an intercultural perspective.La pobreza es un fenómeno que se manifiesta en la falta de acceso a la educación y servicios adecuados, la desnutrición, la falta de saneamiento y las desigualdades de género. Frente a ello, en países como el Perú se ha establecido un Fondo Social Minero, el cual tiene el potencial de convertirse en una herramienta estratégica poderosa para sentar las bases del desarrollo sostenible, reducción de la pobreza y para el desarrollo institucional. A su vez el Fondo ha traído como correlato la constitución de alianzas estratégicas, las que han ayudado a aumentar la productividad de los recursos, a abrir nuevos mercados y son un instrumento esencial de negociación entre las diferentes culturas implicadas en la inversión minera. En este artículo, se propone la aplicabilidad de un modelo de desarrollo basado por un lado en las tres estrategias en las que el Fondo Social Minero puede ser utilizado: desarrollo sostenible, reducción de la pobreza y desarrollo institucional; y de otro lado atravesado por un eje fundamental: la perspectiva intercultural

Noa Industrias S.A.: un caso de éxito en el Parque Industrial de Villa El Salvador

The success story about the growth of a small home furniture manufacturing company located in the Industrial Park of Villa El Salvador is shown in this work. In order to ensure customer satisfaction and loyalty models and designs are in continuous innovation.El caso de éxito sobre el crecimiento de una pequeña empresa de fabricación de muebles para el hogar ubicada en Parque Industrial de Villa El Salvador. Donde innovan continuamente modelos y diseños con la finalidad de asegurar la satisfacción y fidelidad de sus clientes

Alianzas estratégicas: instrumento de negociación y desarrollo sostenible mirado desde la perspectiva de la interculturalidad

Poverty is a phenomenon which is caused by lack of education and no access to adequate social services, malnutrition, no hygienic conditions and sex discrimination. For this reason, in different countries like Peru, a Social Mining Fund has been created. This organization shows a big potential to become a relevant strategic tool to set the bases for a sustainable development, reducing poverty rates and allowing institutional development. Similarly, this Fund has caused the onset of strategic alliances, which have increased the production of resources, the inclusion of new markets, becoming an essential instrument of intercultural negotiation in the mining sector. In this paper, a new development model is presented based on the three strategies in which the Social Mining Fund can be applied, being sustainable development, poverty rate decrease and institutional development, and at the same time focused on a general axis- an intercultural perspective.La pobreza es un fenómeno que se manifiesta en la falta de acceso a la educación y servicios adecuados, la desnutrición, la falta de saneamiento y las desigualdades de género. Frente a ello, en países como el Perú se ha establecido un Fondo Social Minero, el cual tiene el potencial de convertirse en una herramienta estratégica poderosa para sentar las bases del desarrollo sostenible, reducción de la pobreza y para el desarrollo institucional. A su vez el Fondo ha traído como correlato la constitución de alianzas estratégicas, las que han ayudado a aumentar la productividad de los recursos, a abrir nuevos mercados y son un instrumento esencial de negociación entre las diferentes culturas implicadas en la inversión minera. En este artículo, se propone la aplicabilidad de un modelo de desarrollo basado por un lado en las tres estrategias en las que el Fondo Social Minero puede ser utilizado: desarrollo sostenible, reducción de la pobreza y desarrollo institucional; y de otro lado atravesado por un eje fundamental: la perspectiva intercultural

Aprendizaje organizacional en organizaciones profesionales

This work examines at the exploratory level formal or informal organizational learning mechanisms that are present in organizations of professionals from the case of studies or law firms. This first approximation results in the identification of six organizational learning mechanisms: reflection on the cases, the revision of the doctrine, the trial and error, the monitoring, the diffusion of knowledge, and the spirit of the body. There is also a tendency to favour the culture of learning through the involvement and empowerment of employees, the transformation of the role of an administrator in the role of teacher and coach and a tendency towards a horizontal and participatory structure.Examina a nivel exploratorio los mecanismos de aprendizaje organizacional formales o informales que están presentes en organizaciones de profesionales a partir del caso de los estudios o bufetes de abogados. Esta primera aproximación da por resultado la identificación de seis mecanismos de aprendizaje organizacional: la reflexión sobre los casos la revisión de la doctrina el ensayo y error el monitoreo la difusión del conocimiento y el espíritu de cuerpo. Se encuentra también una tendencia a favorecer la cultura de aprendizaje a través del involucramiento y empoderamiento de los empleados la transformación del rol de administrador en rol de maestro y entrenador y una tendencia hacia la estructura horizontal y participativa

Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics

Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterisation of ion channel kinetics - the voltage-dependent rates of transition between open, closed and inactivated channel states. We present a new method for rapidly exploring and characterising ion channel kinetics, applying it to the hERG potassium channel as an example, with the aim of generating a quantitatively predictive representation of the ion current. We fit a mathematical model to currents evoked by a novel 8 second sinusoidal voltage clamp in CHO cells over-expressing hERG1a. The model is then used to predict over 5 minutes of recordings in the same cell in response to further protocols: a series of traditional square step voltage clamps, and also a novel voltage clamp comprised of a collection of physiologically-relevant action potentials. We demonstrate that we can make predictive cell-specific models that outperform the use of averaged data from a number of different cells, and thereby examine which changes in gating are responsible for cell-cell variability in current kinetics. Our technique allows rapid collection of consistent and high quality data, from single cells, and produces more predictive mathematical ion channel models than traditional approaches