Bayesian calibration of electrophysiology models using restitution curve emulators

Calibration of cardiac electrophysiology models is a fundamental aspect of model personalization for predicting the outcomes of cardiac therapies, simulation testing of device performance for a range of phenotypes, and for fundamental research into cardiac function. Restitution curves provide information on tissue function and can be measured using clinically feasible measurement protocols. We introduce novel “restitution curve emulators” as probabilistic models for performing model exploration, sensitivity analysis, and Bayesian calibration to noisy data. These emulators are built by decomposing restitution curves using principal component analysis and modeling the resulting coordinates with respect to model parameters using Gaussian processes. Restitution curve emulators can be used to study parameter identifiability via sensitivity analysis of restitution curve components and rapid inference of the posterior distribution of model parameters given noisy measurements. Posterior uncertainty about parameters is critical for making predictions from calibrated models, since many parameter settings can be consistent with measured data and yet produce very different model behaviors under conditions not effectively probed by the measurement protocols. Restitution curve emulators are therefore promising probabilistic tools for calibrating electrophysiology models

Calibrating cardiac electrophysiology models using latent Gaussian processes on atrial manifolds

Models of electrical excitation and recovery in the heart have become increasingly detailed, but have yet to be used routinely in the clinical setting to guide personalized intervention in patients. One of the main challenges is calibrating models from the limited measurements that can be made in a patient during a standard clinical procedure. In this work, we propose a novel framework for the probabilistic calibration of electrophysiology parameters on the left atrium of the heart using local measurements of cardiac excitability. Parameter fields are represented as Gaussian processes on manifolds and are linked to measurements via surrogate functions that map from local parameter values to measurements. The posterior distribution of parameter fields is then obtained. We show that our method can recover parameter fields used to generate localised synthetic measurements of effective refractory period. Our methodology is applicable to other measurement types collected with clinical protocols, and more generally for calibration where model parameters vary over a manifold

PARP1 mediated PARylation contributes to myogenic progression and glucocorticoid transcriptional response

Abstract The ADP-ribosyltransferase, PARP1 enzymatically generates and applies the post-translational modification, ADP-Ribose (ADPR). PARP1 roles in genome maintenance are well described, but recent work highlights roles in many fundamental processes including cellular identity and energy homeostasis. Herein, we show in both mouse and human skeletal muscle cells that PARP1-mediated PARylation is a regulator of the myogenic program and the muscle transcriptional response to steroid hormones. Chemical PARP1 modulation impacts the expression of major myocellular proteins, including troponins, key in dictating muscle contractile force. Whilst PARP1 in absence of DNA damage is often assumed to be basally inactive, we show PARylation to be acutely sensitive to extracellular glucose concentrations and the steroid hormone class, glucocorticoids which exert considerable authority over muscle tissue mass. Specifically, we find during myogenesis, a transient and significant rise in PAR. This early-stage differentiation event, if blocked with PARP1 inhibition, reduced the abundance of important muscle proteins in the fully differentiated myotubes. This suggests that PAR targets during early-stage differentiation are central to the proper development of the muscle contractile unit. We also show that reduced PARP1 in myoblasts impacts a variety of metabolic pathways in line with the recorded actions of glucocorticoids. Currently, as both regulators of myogenesis and muscle mass loss, glucocorticoids represent a clinical conundrum. Our work goes on to identify that PARP1 influences transcriptional activation by glucocorticoids of a subset of genes critical to human skeletal muscle pathology. These genes may therefore signify a regulatory battery of targets through which selective glucocorticoid modulation could be achieved. Collectively, our data provide clear links between PARP1-mediated PARylation and skeletal muscle homeostatic mechanisms crucial to tissue mass maintenance and endocrine response

The effect of neonatal leptin treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity, hyperleptinemia, insulin resistance, and type 2 diabetes. Although the mechanisms are unclear, this "programming" has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition (UN) during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Using this model of maternal UN, we have recently shown that neonatal leptin treatment in females reverses the postnatal sequelae induced by developmental programming. To examine possible gender-related effects of neonatal leptin treatment, the present study investigated the effect of neonatal leptin treatment on the metabolic phenotype of adult male offspring. Leptin treatment (recombinant rat leptin, 2.5 microg/g.d, sc) from postnatal d 3-13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring. Neonatal leptin treatment of male offspring from normally nourished mothers caused an increase in diet-induced weight gain and related metabolic sequelae, including hyperinsulinemia and increased total body adiposity compared with saline-treated controls. This occurred without an increase in caloric intake. These effects were specific to offspring of normal pregnancies and were not observed in offspring of mothers after UN during pregnancy. In the latter, neonatal leptin treatment conferred protection against the development of the programmed phenotype, particularly in those fed the chow diet postnatally. These data further reinforce the importance of leptin in determining long-term energy homeostasis, and suggest that leptin's effects are modulated by gender and both prenatal and postnatal nutritional status

Visual Impairment

The past decade has witnessed a considerable upsurge of clinical and research interest in the problems of developmentally and physically the fields of psychology, disabled persons. Indeed, professionals from special education, rehabilitation, psychiatry, and social work have all directed attention to the development and implementation of evaluation and remedial programs. The heightened activity in this area is in part a result of early assessment research with these populations, which provided preliminary evidence of difficulties in social and emotional adjustment in many disabled individuals. In response to these findings, many intervention efforts have been implemented to deal with these issues and improve the life situation of the disabled. Also, there were indications that developmentally and physically disabled children often were deprived of adequate educations. As a result, legal and legislative initiatives have been enacted in recent years to make public education available to all students irrespective of disability. Central to all therapeutic and psychoeducational endeavors with the disabled is psychological evaluation. Only through careful and com­prehensive psychological evaluation can areas of deficit as well as strengths be identified. Once treatment targets and goals have been ascertained, psychological evaluation is needed to determine the efficacy of intervention strategies. However, the field of psychological evalua­tion, in general, and with disabled persons, in particular, has become highly specialized. This is largely a function of the changing roles of psychological evaluators.https://nsuworks.nova.edu/cps_facbooks/1221/thumbnail.jp