Population of human ventricular cell models calibrated with in vivo measurements unravels ionic mechanisms of cardiac alternans

Cardiac alternansis an important risk factor in cardiac physiology, and is related to the initiation of many pathophysiological conditions. However, the mechanisms underlying the generation of alternans remain unclear. In this study, we used a population of computational human ventricle models based onthe O’Hara model [1] to explore the effect of 11 key factors experimentally reported to be related to alternans. In vivo experimental datasets coming from patients undergoing cardiac surgery were used in the calibration of our in silico population of models. The calibrated models in the population were divided into two groups (Normal and Alternans) depending on alternans occurrence. Our results showed that there were significant differences in the following 5 ionic currents between the two groups: fast sodium current, sodium calcium exchanger current, sodium potassium pump current, sarcoplasmic reticulum (SR) calcium release flux and SR calcium reuptake flux. Further analysis indicated that fast sodium current and SR calcium uptake were the two most significant currents that contributed to voltage and calcium alternans generation, respectively

Effects and underlying mechanisms of refractory period pacing on repolarization dynamics in the human heart

Repolarization alternans is related to the initiation of life threatening cardiac arrhythmias. Experimental and computational studies suggest that the abolishment of alternans using dynamic pacing protocols may prevent abnormal heart rhythms. In a recent animal study, refractory period pacing (RPP) on every other beat has shown promising results in alternans reduction. However, the cellular mechanisms underlying this therapy and its efficiency in human patients remain unclear. In this study, in vivo unipolar electrograms acquired during RPP from 240 epicardial sites from one patient were analysed. Current clamp of 18 channels was performed in silico to elucidate the ionic mechanisms underlying action potential modulation by RPP. Its efficacy with positive and negative polarities was tested on a population of 87 calibrated human ventricular models exhibiting alternans. In vivo electrograms showed significant changes in T-wave alternans when applying RPP. In silico, results showed APD shortening for RPP with positive polarity and APD prolongation with RPP negative. Under current clamp protocols, voltage rectification of L-type Ca(2)+ (ICaL) and inward rectifier K+ (IK1) currents were identified as the key determinants for the observed changes. RPP pacing successfully reduced alternans on the in silico models using a negative polarity stimulus in the short beat

Initial/boundary-value problems of tumor growth within a host tissue

This paper concerns multiphase models of tumor growth in interaction with a surrounding tissue, taking into account also the interplay with diffusible nutrients feeding the cells. Models specialize in nonlinear systems of possibly degenerate parabolic equations, which include phenomenological terms related to specific cell functions. The paper discusses general modeling guidelines for such terms, as well as for initial and boundary conditions, aiming at both biological consistency and mathematical robustness of the resulting problems. Particularly, it addresses some qualitative properties such as a priori nonnegativity, boundedness, and uniqueness of the solutions. Existence of the solutions is studied in the one-dimensional time-independent case.Comment: 30 pages, 5 figure

Endometrial carcinoma: molecular alterations involved in tumor development and progression

In the western world, endometrial carcinoma (EC) is the most common cancer of the female genital tract. The annual incidence has been estimated at 10-20 per 100 000 women. Two clinicopathological variants are recognized: the estrogen related (type I, endometrioid) and the non-estrogen related (type II, non-endometrioid).The clinicopathological differences are paralleled by specific genetic alterations, with type I showing microsatellite instability and mutations in phosphatase and tensin homologue deleted on chromosome 70, PIK3CA, K-RAS and CTNNB1 (beta-catenin), and type II exhibiting TP53 mutations and chromosomal instability. Some non-endometrioid carcinomas probably arise from pre-existing endometrioid carcinomas as a result of tumor progression and, not surprisingly, some tumors exhibit combined or mixed features at the clinical, pathological and molecular levels. In EC, apoptosis resistance may have a role in tumor progression. Understanding pathogenesis at the molecular level is essential in identifying biomarkers for successful targeted therapies. In this review, the genetic changes of endometrial carcinogenesis are discussed in the light of the morphological features of the tumors and their precursors

Targeted classification of metal–organic frameworks in the Cambridge structural database (CSD)

Large-scale targeted exploration of metal–organic frameworks (MOFs) with characteristics such as specific surface chemistry or metal-cluster family has not been investigated so far. These definitions are particularly important because they can define the way MOFs interact with specific molecules (e.g. their hydrophilic/phobic character) or their physicochemical stability. We report here the development of algorithms to break down the overarching family of MOFs into a number of subgroups according to some of their key chemical and physical features. Available within the Cambridge Crystallographic Data Centre's (CCDC) software, we introduce new approaches to allow researchers to browse and efficiently look for targeted MOF families based on some of the most well-known secondary building units. We then classify them in terms of their crystalline properties: metal-cluster, network and pore dimensionality, surface chemistry (i.e. functional groups) and chirality. This dynamic database and family of algorithms allow experimentalists and computational users to benefit from the developed criteria to look for specific classes of MOFs but also enable users – and encourage them – to develop additional MOF queries based on desired chemistries. These tools are backed-up by an interactive web-based data explorer containing all the data obtained. We also demonstrate the usefulness of these tools with a high-throughput screening for hydrogen storage at room temperature. This toolbox, integrated in the CCDC software, will guide future exploration of MOFs and similar materials, as well as their design and development for an ever-increasing range of potential applications

Global governance approaches to addressing illegal logging: Uptake and lessons learned

One of the most challenging tasks facing development agencies, trade ministries, environmental groups, social activists and forest-focused business interests seeking to ameliorate illegal logging and related timber trade is to identify and nurture promising global governance interventions capable of helping improve compliance to governmental policies and laws at national, subnational and local levels. This question is especially acute for developing countries constrained by capacity challenges and “weak states” (Risse, 2011). This chapter seeks to shed light on this task by asking four related questions: How do we understand the emergence of illegal logging as a matter of global interest? What are the types of global interventions designed to improve domestic legal compliance? How have individual states responded to these global efforts? What are the prospects for future impacts and evolution? We proceed in the following steps. Following this introduction, step two reviews how the problem of “illegal logging” emerged on the international agenda. Step three reviews leading policy interventions that resulted from this policy framing. Step four reviews developments in selected countries/regions around the world according to their place on the global forest products supply chain: consumers (United States, Europe and Australia); middle of supply chain manufacturers (China and South Korea) and producers (Russia; Indonesia; Brazil and Peru; Ghana, Cameroon and the Republic of Congo). We conclude by reflecting on key trends that emerge from this review relevant for understanding the conditions through which legality might make a difference in addressing critical challenges

Nernst branes from special geometry

We construct new black brane solutions in $U(1)$ gauged ${\cal N}=2$ supergravity with a general cubic prepotential, which have entropy density $s\sim T^{1/3}$ as $T \rightarrow 0$ and thus satisfy the Nernst Law. By using the real formulation of special geometry, we are able to obtain analytical solutions in closed form as functions of two parameters, the temperature $T$ and the chemical potential $\mu$. Our solutions interpolate between hyperscaling violating Lifshitz geometries with $(z,\theta)=(0,2)$ at the horizon and $(z,\theta)=(1,-1)$ at infinity. In the zero temperature limit, where the entropy density goes to zero, we recover the extremal Nernst branes of Barisch et al, and the parameters of the near horizon geometry change to $(z,\theta)=(3,1)$.Comment: 37 pages. v2: numerical pre-factors of scalar fields q_A corrected in Section 3. No changes to conclusions. References adde

Impact of frailty on mortality and hospitalization in chronic heart failure: A systematic review and meta-analysis

© 2018 The Authors. Background-—Although frailty has been associated with increased risks for hospitalization and mortality in chronic heart failure, the precise average effect remains uncertain. We performed a systematic review and meta-analysis to summarize the hazards for mortality and incident hospitalization in patients with heart failure and frailty compared with those without frailty and explored the heterogeneity underlying the effect size estimates. Methods and Results-—MEDLINE, EMBASE, and Cochrane databases were queried for articles published between January 1966 and March 2018. Predefined selection criteria were used. Hazard ratios (HRs) were pooled for meta-analyses, and where odds ratios were used previously, original data were recalculated for HR. Overlapping data were consolidated, and only unique data points were used. Study quality and bias were assessed. Eight studies were included for mortality (2645 patients), and 6 studies were included for incident hospitalization (2541 patients) during a median follow-up of 1.82 and 1.12 years, respectively. Frailty was significantly associated with an increased hazard for mortality (HR, 1.54; 95% confidence interval, 1.34–1.75; P<0.001) and incident hospitalization (HR, 1.56; 95% confidence interval, 1.36–1.78; P<0.001) in chronic heart failure. The Fried phenotype estimated a 16.9% larger effect size than the combined Fried/non-Fried frailty assessment for the end point of mortality (HR, 1.80; 95% confidence interval, 1.41–2.28; P<0.001), but not for hospitalization (HR, 1.57; 95% confidence interval, 1.30–1.89; P<0.001). Study heterogeneity was found to be low (I 2 =0%), and high quality of studies was verified by the Newcastle-Ottawa scale. Conclusions-—Overall, the presence of frailty in chronic heart failure is associated with an increased hazard for death and hospitalization by ≈1.5-fold

BINGO: A code for the efficient computation of the scalar bi-spectrum

We present a new and accurate Fortran code, the BI-spectra and Non-Gaussianity Operator (BINGO), for the efficient numerical computation of the scalar bi-spectrum and the non-Gaussianity parameter f_{NL} in single field inflationary models involving the canonical scalar field. The code can calculate all the different contributions to the bi-spectrum and the parameter f_{NL} for an arbitrary triangular configuration of the wavevectors. Focusing firstly on the equilateral limit, we illustrate the accuracy of BINGO by comparing the results from the code with the spectral dependence of the bi-spectrum expected in power law inflation. Then, considering an arbitrary triangular configuration, we contrast the numerical results with the analytical expression available in the slow roll limit, for, say, the case of the conventional quadratic potential. Considering a non-trivial scenario involving deviations from slow roll, we compare the results from the code with the analytical results that have recently been obtained in the case of the Starobinsky model in the equilateral limit. As an immediate application, we utilize BINGO to examine of the power of the non-Gaussianity parameter f_{NL} to discriminate between various inflationary models that admit departures from slow roll and lead to similar features in the scalar power spectrum. We close with a summary and discussion on the implications of the results we obtain.Comment: v1: 5 pages, 5 figures; v2: 35 pages, 11 figures, title changed, extensively revised; v3: 36 pages, 11 figures, to appear in JCAP. The BINGO code is available online at http://www.physics.iitm.ac.in/~sriram/bingo/bingo.htm

Corner contributions to holographic entanglement entropy

The entanglement entropy of three-dimensional conformal field theories contains a universal contribution coming from corners in the entangling surface. We study these contributions in a holographic framework and, in particular, we consider the effects of higher curvature interactions in the bulk gravity theory. We find that for all of our holographic models, the corner contribution is only modified by an overall factor but the functional dependence on the opening angle is not modified by the new gravitational interactions. We also compare the dependence of the corner term on the new gravitational couplings to that for a number of other physical quantities, and we show that the ratio of the corner contribution over the central charge appearing in the two-point function of the stress tensor is a universal function for all of the holographic theories studied here. Comparing this holographic result to the analogous functions for free CFT's, we find fairly good agreement across the full range of the opening angle. However, there is a precise match in the limit where the entangling surface becomes smooth, i.e., the angle approaches $\pi$, and we conjecture the corresponding ratio is a universal constant for all three-dimensional conformal field theories. In this paper, we expand on the holographic calculations in our previous letter arXiv:1505.04804, where this conjecture was first introduced.Comment: 62 pages, 6 figures, 1 table; v2: minor modifications to match published version, typos fixe