Control and Regulation of Integrated Mitochondrial Function in Metabolic and Transport Networks

The pattern of flux and concentration control coefficients in an integrated mitochondrial energetics model is examined by applying a generalized matrix method of control analysis to calculate control coefficients, as well as response coefficients The computational model of Cortassa et al. encompasses oxidative phosphorylation, the TCA cycle, and Ca2+ dynamics. Control of ATP synthesis, TCA cycle, and ANT fluxes were found to be distributed among various mitochondrial processes. Control is shared by processes associated with ATP/ADP production and transport, as well as by Ca2+ dynamics. The calculation also analyzed the control of the concentrations of key regulatory ions and metabolites (Ca2+, NADH, ADP). The approach we have used demonstrates how properties of integrated systems may be understood through applications of computational modeling and control analysis

A Computational Model of Reactive Oxygen Species and Redox Balance in Cardiac Mitochondria

AbstractElevated levels of reactive oxygen species (ROS) play a critical role in cardiac myocyte signaling in both healthy and diseased cells. Mitochondria represent the predominant cellular source of ROS, specifically the activity of complexes I and III. The model presented here explores the modulation of electron transport chain ROS production for state 3 and state 4 respiration and the role of substrates and respiratory inhibitors. Model simulations show that ROS production from complex III increases exponentially with membrane potential (ΔΨm) when in state 4. Complex I ROS release in the model can occur in the presence of NADH and succinate (reverse electron flow), leading to a highly reduced ubiquinone pool, displaying the highest ROS production flux in state 4. In the presence of ample ROS scavenging, total ROS production is moderate in state 3 and increases substantially under state 4 conditions. The ROS production model was extended by combining it with a minimal model of ROS scavenging. When the mitochondrial redox status was oxidized by increasing the proton permeability of the inner mitochondrial membrane, simulations with the combined model show that ROS levels initially decline as production drops off with decreasing ΔΨm and then increase as scavenging capacity is exhausted. Hence, this mechanistic model of ROS production demonstrates how ROS levels are controlled by mitochondrial redox balance

Simulation studies of a phenomenological model for elongated virus capsid formation

We study a phenomenological model in which the simulated packing of hard, attractive spheres on a prolate spheroid surface with convexity constraints produces structures identical to those of prolate virus capsid structures. Our simulation approach combines the traditional Monte Carlo method with a modified method of random sampling on an ellipsoidal surface and a convex hull searching algorithm. Using this approach we identify the minimum physical requirements for non-icosahedral, elongated virus capsids, such as two aberrant flock house virus (FHV) particles and the prolate prohead of bacteriophage $\phi_{29}$, and discuss the implication of our simulation results in the context of recent experimental findings. Our predicted structures may also be experimentally realized by evaporation-driven assembly of colloidal spheres

A Novel Approach for Ellipsoidal Outer-Approximation of the Intersection Region of Ellipses in the Plane

In this paper, a novel technique for tight outer-approximation of the intersection region of a finite number of ellipses in 2-dimensional (2D) space is proposed. First, the vertices of a tight polygon that contains the convex intersection of the ellipses are found in an efficient manner. To do so, the intersection points of the ellipses that fall on the boundary of the intersection region are determined, and a set of points is generated on the elliptic arcs connecting every two neighbouring intersection points. By finding the tangent lines to the ellipses at the extended set of points, a set of half-planes is obtained, whose intersection forms a polygon. To find the polygon more efficiently, the points are given an order and the intersection of the half-planes corresponding to every two neighbouring points is calculated. If the polygon is convex and bounded, these calculated points together with the initially obtained intersection points will form its vertices. If the polygon is non-convex or unbounded, we can detect this situation and then generate additional discrete points only on the elliptical arc segment causing the issue, and restart the algorithm to obtain a bounded and convex polygon. Finally, the smallest area ellipse that contains the vertices of the polygon is obtained by solving a convex optimization problem. Through numerical experiments, it is illustrated that the proposed technique returns a tighter outer-approximation of the intersection of multiple ellipses, compared to conventional techniques, with only slightly higher computational cost

On reconfiguration of disks in the plane and related problems

We revisit two natural reconfiguration models for systems of disjoint objects in the plane: translation and sliding. Consider a set of n pairwise interior-disjoint objects in the plane that need to be brought from a given start (initial) configuration S into a desired goal (target) configuration T, without causing collisions. In the translation model, in one move an object is translated along a fixed direction to another position in the plane. In the sliding model, one move is sliding an object to another location in the plane by means of an arbitrarily complex continuous motion (that could involve rotations). We obtain various combinatorial and computational results for these two models: (I) For systems of n congruent disks in the translation model, Abellanas et al. showed that 2n − 1 moves always suffice and ⌊8n/5 ⌋ moves are sometimes necessary for transforming the start configuration into the target configuration. Here we further improve the lower bound to ⌊5n/3 ⌋ − 1, and thereby give a partial answer to one of their open problems. (II) We show that the reconfiguration problem with congruent disks in the translation model is NPhard, in both the labeled and unlabeled variants. This answers another open problem of Abellanas et al. (III) We also show that the reconfiguration problem with congruent disks in the sliding model is NP-hard, in both the labeled and unlabeled variants. (IV) For the reconfiguration with translations of n arbitrary convex bodies in the plane, 2n moves are always sufficient and sometimes necessary

Rates of convergence for empirical spectral measures: a soft approach

Understanding the limiting behavior of eigenvalues of random matrices is the central problem of random matrix theory. Classical limit results are known for many models, and there has been significant recent progress in obtaining more quantitative, non-asymptotic results. In this paper, we describe a systematic approach to bounding rates of convergence and proving tail inequalities for the empirical spectral measures of a wide variety of random matrix ensembles. We illustrate the approach by proving asymptotically almost sure rates of convergence of the empirical spectral measure in the following ensembles: Wigner matrices, Wishart matrices, Haar-distributed matrices from the compact classical groups, powers of Haar matrices, randomized sums and random compressions of Hermitian matrices, a random matrix model for the Hamiltonians of quantum spin glasses, and finally the complex Ginibre ensemble. Many of the results appeared previously and are being collected and described here as illustrations of the general method; however, some details (particularly in the Wigner and Wishart cases) are new. Our approach makes use of techniques from probability in Banach spaces, in particular concentration of measure and bounds for suprema of stochastic processes, in combination with more classical tools from matrix analysis, approximation theory, and Fourier analysis. It is highly flexible, as evidenced by the broad list of examples. It is moreover based largely on "soft" methods, and involves little hard analysis

Casting Light Upon The Great Endarkenment

While the Enlightenment promoted thinking for oneself independent of religious authority, the ‘Endarkenment’ (Millgram 2015) concerns deference to a new authority: the specialist, a hyperspecializer. Non-specialists need to defer to such authorities as they are unable to understand their reasoning. Millgram describes how humans are capable of being serial hyperspecializers, able to move from one specialism to another. We support the basic thrust of Millgram’s position, and seek to articulate how the core idea is deployed in very different ways in relation to extremely different philosophical areas. We attend to the issue of the degree of isolation of different specialists and we urge greater emphasis on parallel hyperspecialization, which describes how different specialisms can be embodied in one person at one time

Universal microscopic correlation functions for products of independent Ginibre matrices

We consider the product of n complex non-Hermitian, independent random matrices, each of size NxN with independent identically distributed Gaussian entries (Ginibre matrices). The joint probability distribution of the complex eigenvalues of the product matrix is found to be given by a determinantal point process as in the case of a single Ginibre matrix, but with a more complicated weight given by a Meijer G-function depending on n. Using the method of orthogonal polynomials we compute all eigenvalue density correlation functions exactly for finite N and fixed n. They are given by the determinant of the corresponding kernel which we construct explicitly. In the large-N limit at fixed n we first determine the microscopic correlation functions in the bulk and at the edge of the spectrum. After unfolding they are identical to that of the Ginibre ensemble with n=1 and thus universal. In contrast the microscopic correlations we find at the origin differ for each n>1 and generalise the known Bessel-law in the complex plane for n=2 to a new hypergeometric kernel 0_F_n-1.Comment: 20 pages, v2 published version: typos corrected and references adde

Guarding art galleries by guarding witnesses

Let P be a simple polygon. We de ne a witness set W to be a set of points su h that if any (prospective) guard set G guards W, then it is guaranteed that G guards P . We show that not all polygons admit a nite witness set. If a fi nite minimal witness set exists, then it cannot contain any witness in the interior of P ; all witnesses must lie on the boundary of P , and there an be at most one witness in the interior of any edge. We give an algorithm to compute a minimal witness set for P in O(n2 log n) time, if such a set exists, or to report the non-existence within the same time bounds. We also outline an algorithm that uses a witness set for P to test whether a (prospective) guard set sees all points in P

Characterization of Intracellular and Extracellular Saxitoxin Levels in Both Field and Cultured Alexandrium spp. Samples from Sequim Bay, Washington

Traditionally, harmful algal bloom studies have primarily focused on quantifying toxin levels contained within the phytoplankton cells of interest. In the case of paralytic shellfish poisoning toxins (PSTs), intracellular toxin levels and the effects of dietary consumption of toxic cells by planktivores have been well documented. However, little information is available regarding the levels of extracellular PSTs that may leak or be released into seawater from toxic cells during blooms. In order to fully evaluate the risks of harmful algal bloom toxins in the marine food web, it is necessary to understand all potential routes of exposure. In the present study, extracellular and intracellular PST levels were measured in field seawater samples (collected weekly from June to October 2004–2007) and in Alexandrium spp. culture samples isolated from Sequim Bay, Washington. Measurable levels of intra- and extra-cellular toxins were detected in both field and culture samples via receptor binding assay (RBA) and an enzyme-linked immunosorbent assay (ELISA). Characterization of the PST toxin profile in the Sequim Bay isolates by pre-column oxidation and HPLC-fluorescence detection revealed that gonyautoxin 1 and 4 made up 65 ± 9.7 % of the total PSTs present. Collectively, these data confirm that extracellular PSTs are present during blooms of Alexandrium spp. in the Sequim Bay region