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In this long'awaited follow'up to his 2003 book on Genesis, humanist scholar Leon Kass explores how Exodus raises and then answers the central political questions of what defines a nation and how a nation should govern itself. Considered by some the most important book in the Hebrew Bible, Exodus tells the story of the Jewish people from their enslavement in Egypt through their liberation under Moses's leadership to their covenantal founding at Sinai and the building of the Tabernacle. In Kass's analysis, these events begin the slow process of learning how to stop thinking like slaves and become an independent people. The Israelites ultimately found their nation on three elements: a shared narrative that instills empathy for the poor and the suffering, the uplifting rule of a moral law, and devotion to a higher common purpose. These elements, Kass argues, remain the essential principles for any freedom-loving nation today.

Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by β adrenergic receptor (βAR) activation, which increases the slow outward potassium ion current (IKS). Mutations in two human IKSchannel subunits, hKCNQ1 and hKCNE1, prolong APD and cause inherited cardiac arrhythmias known as LQTS (long QT syndrome). We show that βAR modulation of IKSrequires targeting of adenosine 3′,5′-monophosphate (cAMP)-dependent protein kinase (PKA) and protein phosphatase 1 (PP1) to hKCNQ1 through the targeting protein yotiao. Yotiao binds to hKCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (hKCNQ1-G589D). Identification of the hKCNQ1 macromolecular complex provides a mechanism for SNS modulation of cardiac APD through IKS.

Every year, ~450,000 individuals in the United States die suddenly of cardiac arrhythmia. We identified a variant of the cardiac sodium channel gene SCN5A that is associated with arrhythmia in African Americans (P = 0.000028) and linked with arrhythmia risk in an African-American family (P = 0.005). In transfected cells, the variant allele (Y1102) accelerated channel activation, increasing the likelihood of abnormal cardiac repolarization and arrhythmia. About 13.2% of African Americans carry the Y1102 allele. Because Y1102 has a subtle effect on risk, most carriers will never have an arrhythmia. However, Y1102 may be a useful molecular marker for the prediction of arrhythmia susceptibility in the context of additional acquired risk factors such as the use of certain medications.

We describe a Bayesian method, for fitting curves to data drawn from an exponential family, that uses splines for which the number and locations of knots are free parameters. The method uses reversible‐jump Markov chain Monte Carlo to change the knot configurations and a locality heuristic to speed up mixing. For nonnormal models, we approximate the integrated likelihood ratios needed to compute acceptance probabilities by using the Bayesian information criterion, BIC, under priors that make this approximation accurate. Our technique is based on a marginalised chain on the knot number and locations, but we provide methods for inference about the regression coefficients, and functions of them, in both normal and nonnormal models. Simulation results suggest that the method performs well, and we illustrate the method in two neuroscience applications.

Lithium monoxide anion (LiO⁻) has been generated in the gas phase and is found to be a stronger base than methyl anion (CH[Formula: see text]). This makes LiO⁻ the strongest base currently known, and it will be a challenge to produce a singly charged or multiply charged anion that is more basic. The experimental acidity of lithium hydroxide is ΔH°[Formula: see text] = 425.7 ± 6.1 kcal·mol⁻¹ (1 kcal = 4.184 kJ) and, when combined with results of high-level computations, leads to our best estimate for the acidity of 426 ± 2 kcal·mol⁻¹.

β-Adrenergic receptor stimulation increases heart rate and shortens ventricular action-potential duration, the latter effect due in part to a cAMP-dependent increase in the slow outward potassium current (IKs). Mutations in either KCNQ1 or KCNE1, the IKssubunits, are associated with variants (LQT-1 and LQT-5) of the congenital long QT syndrome. We now show that cAMP-mediated functional regulation of KCNQ1/KCNE1 channels, a consequence of cAMP-dependent protein kinase A phosphorylation of the KCNQ1 N terminus, requires coexpression of KCNQ1 with KCNE1, its auxiliary subunit. Further, at least two KCNE1 mutations linked to LQT-5 (D76N and W87R) cause functional disruption of cAMP-mediated KCNQ1/KCNE1-channel regulation despite the response of the substrate protein (KCNQ1) to protein kinase A phosphorylation. Transduction of protein phosphorylation into physiologically necessary channel function represents a previously uncharacterized role for the KCNE1 auxiliary subunit, which can be disrupted in LQT-5.

Estimation of covariance matrices in small samples has been studied by many authors. Standard estimators, like the unstructured maximum likelihood estimator (ML) or restricted maximum likelihood (REML) estimator, can be very unstable with the smallest estimated eigenvalues being too small and the largest too big. A standard approach to more stably estimating the matrix in small samples is to compute the ML or REML estimator under some simple structure that involves estimation of fewer parameters, such as compound symmetry or independence. However, these estimators will not be consistent unless the hypothesized structure is correct. If interest focuses on estimation of regression coefficients with correlated (or longitudinal) data, a sandwich estimator of the covariance matrix may be used to provide standard errors for the estimated coefficients that are robust in the sense that they remain consistent under misspecification of the covariance structure. With large matrices, however, the inefficiency of the sandwich estimator becomes worrisome. We consider here two general shrinkage approaches to estimating the covariance matrix and regression coefficients. The first involves shrinking the eigenvalues of the unstructured ML or REML estimator. The second involves shrinking an unstructured estimator toward a structured estimator. For both cases, the data determine the amount of shrinkage. These estimators are consistent and give consistent and asymptotically efficient estimates for regression coefficients. Simulations show the improved operating characteristics of the shrinkage estimators of the covariance matrix and the regression coefficients in finite samples. The final estimator chosen includes a combination of both shrinkage approaches, i.e., shrinking the eigenvalues and then shrinking toward structure. We illustrate our approach on a sleep EEG study that requires estimation of a 24 x 24 covariance matrix and for which inferences on mean parameters critically depend on the covariance estimator chosen. We recommend making inference using a particular shrinkage estimator that provides a reasonable compromise between structured and unstructured estimators.

•This study showed that nature exposure decreased levels of perceived stress in 5 out of 6 studies.•This study showed that nature exposure decreased levels of physiologic stress in 7 out of 7 studies.•Nature exposure may have important applications in healthcare and public policy. The purpose of this systematic review is to evaluate the effect nature exposure has on stress as measured by physiologic markers and self-report. Researchers searched PubMed and JSTOR. Randomized control trials and cross-sectional studies were included if they met the following criteria: 1) included a clinical cohort and controls, and the intervention was nature exposure, either real or simulated; (2) utilized measurements of sympathetic activity or perceived stress; (3) study population consisted of greater than thirty male and female volunteers. Twelve studies were included for data extraction and review. Researchers conducted this review at University of South Florida Morsani College of Medicine. Researchers measured perceived stress through the Perceived Stress Scale (PSS) and Depression, Anxiety, and Stress Scale (DASS). Physiologic stress was measured by salivary cortisol, blood pressure (BP), subgenual prefrontal cortex (sgPFC) activation on functional magnetic resonance imaging (fMRI), skin conductance level (SCL), heart rate variability (HRV), muscle tension, heart period, pulse transit time, amygdala and pregenual anterior cingulate cortex (pACC) activation on fMRI, respiratory sinus arrhythmia (RSA), and pre-ejection period (PEP). This review found an inverse relationship between nature exposure and various physiologic markers of stress in all 7 studies measuring physiologic stress. Perceived stress was also affected by higher exposure to nature as indicated by lower self-reports on the PSS and DASS in 5 out of 6 studies measuring perceived stress. Nature exposure has been widely shown to have a positive effect in reducing stress, both perceived and physiologic.

The congenital long QT syndrome is a rare disorder in which mutation carriers are at risk for polymorphic ventricular tachycardia and/or sudden cardiac death. Discovery and analysis of gene mutations associated with variants of this disorder have provided novel insight into mechanisms of cardiac arrhythmia and have raised the possibility of mutation-specific therapeutic intervention.

Ion channels are pore-forming proteins that provide pathways for the controlled movement of ions into or out of cells. Ionic movement across cell membranes is critical for essential and physiological processes ranging from control of the strength and duration of the heartbeat to the regulation of insulin secretion in pancreatic beta cells. Diseases caused by mutations in genes that encode ion channel subunits or regulatory proteins are referred to as channelopathies. As might be expected based on the diverse roles of ion channels, channelopathies range from inherited cardiac arrhythmias, to muscle disorders, to forms of diabetes. This series of reviews examines the roles of ion channels in health and disease.