Onset, timing, and exposure therapy of stress disorders: mechanistic insight from a mathematical model of oscillating neuroendocrine dynamics

The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates numerous physiological processes. Disruptions in the activity of the HPA axis are correlated with many stress-related diseases such as post-traumatic stress disorder (PTSD) and major depressive disorder. In this paper, we characterize "normal" and "diseased" states of the HPA axis as basins of attraction of a dynamical system describing the inhibition of peptide hormones such as corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by circulating glucocorticoids such as cortisol (CORT). In addition to including key physiological features such as ultradian oscillations in cortisol levels and self-upregulation of CRH neuron activity, our model distinguishes the relatively slow process of cortisol-mediated CRH biosynthesis from rapid trans-synaptic effects that regulate the CRH secretion process. Crucially, we find that the slow regulation mechanism mediates external stress-driven transitions between the stable states in novel, intensity, duration, and timing-dependent ways. These results indicate that the timing of traumatic events may be an important factor in determining if and how patients will exhibit hallmarks of stress disorders. Our model also suggests a mechanism whereby exposure therapy of stress disorders such as PTSD may act to normalize downstream dysregulation of the HPA axis.Comment: 30 pages, 16 figures, submitted to BMC Biology Direc

Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions

Introduction to the R package TDA

We present a short tutorial and introduction to using the R package TDA, which provides some tools for Topological Data Analysis. In particular, it includes implementations of functions that, given some data, provide topological information about the underlying space, such as the distance function, the distance to a measure, the kNN density estimator, the kernel density estimator, and the kernel distance. The salient topological features of the sublevel sets (or superlevel sets) of these functions can be quantified with persistent homology. We provide an R interface for the efficient algorithms of the C++ libraries GUDHI, Dionysus and PHAT, including a function for the persistent homology of the Rips filtration, and one for the persistent homology of sublevel sets (or superlevel sets) of arbitrary functions evaluated over a grid of points. The significance of the features in the resulting persistence diagrams can be analyzed with functions that implement recently developed statistical methods. The R package TDA also includes the implementation of an algorithm for density clustering, which allows us to identify the spatial organization of the probability mass associated to a density function and visualize it by means of a dendrogram, the cluster tree

Ionization cross sections for low energy electron transport

Two models for the calculation of ionization cross sections by electron impact on atoms, the Binary-Encouter-Bethe and the Deutsch-Maerk models, have been implemented; they are intended to extend and improve Geant4 simulation capabilities in the energy range below 1 keV. The physics features of the implementation of the models are described, and their differences with respect to the original formulations are discussed. Results of the verification with respect to the original theoretical sources and of extensive validation with respect to experimental data are reported. The validation process also concerns the ionization cross sections included in the Evaluated Electron Data Library used by Geant4 for low energy electron transport. Among the three cross section options, the Deutsch-Maerk model is identified as the most accurate at reproducing experimental data over the energy range subject to test.Comment: To be published in IEEE Trans. Nucl. Sci., Dec. 201

Gauge coupling Unification and SO(10) in 5D

We analyze the gauge unification in minimal supersymmetric SO(10) grand unified theories in 5 dimensions. The single extra spatial dimension is compactified on the orbifold S^1/(Z_2 x Z_2') reducing the gauge group to that of Pati-Salam SU(4)_c x SU(2)_L x SU(2)_R. The Standard Model gauge group is achieved by the further brane-localized Higgs mechanism on one of the fixed points. There are two main different approaches developed in literature. Higgs mechanism can take place on the Pati Salam brane, or on the SO(10) preserving brane. We show, both analytically and numerically, that in the first case a natural and succesfull gauge coupling unification can be achieved, while the second case is highly disfavoured. For completeness, we consider either the case in which the brane breaking scale is near the cutoff scale or the case in which it is lower than the compactification scale.Comment: 18 Pages and 8 PostScript Figure

PAC Fields over Finitely Generated Fields

We prove the following theorem for a finitely generated field $K$: Let $M$ be a Galois extension of $K$ which is not separably closed. Then $M$ is not PAC over $K$.Comment: 7 pages, Math.

Validation Test of Geant4 Simulation of Electron Backscattering

Backscattering is a sensitive probe of the accuracy of electron scattering algorithms implemented in Monte Carlo codes. The capability of the Geant4 toolkit to describe realistically the fraction of electrons backscattered from a target volume is extensively and quantitatively evaluated in comparison with experimental data retrieved from the literature. The validation test covers the energy range between approximately 100 eV and 20 MeV, and concerns a wide set of target elements. Multiple and single electron scattering models implemented in Geant4, as well as preassembled selections of physics models distributed within Geant4, are analyzed with statistical methods. The evaluations concern Geant4 versions from 9.1 to 10.1. Significant evolutions are observed over the range of Geant4 versions, not always in the direction of better compatibility with experiment. Goodness-of-fit tests complemented by categorical analysis tests identify a configuration based on Geant4 Urban multiple scattering model in Geant4 version 9.1 and a configuration based on single Coulomb scattering in Geant4 10.0 as the physics options best reproducing experimental data above a few tens of keV. At lower energies only single scattering demonstrates some capability to reproduce data down to a few keV. Recommended preassembled physics configurations appear incapable of describing electron backscattering compatible with experiment. With the support of statistical methods, a correlation is established between the validation of Geant4-based simulation of backscattering and of energy deposition