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Three stage AIDS incubation period: a worst case scenario using addict-needle interaction assumptions.

In this paper we develop and analyse a model for the spread of HIV/AIDS amongst a population of injecting drug users. We start off with a brief literature survey and review; this is followed by the derivation of a model which allows addicts to progress through three distinct stages of variable infectivity prior to the onset of full blown AIDS and where the class of infectious needles is split into three according to the different levels of infectivity in addicts. Given the structure of this model we are required to make assumptions regarding the interaction of addicts and needles of different infectivity levels. We deliberately choose these assumptions so that our model serves as an upper bound for the prevalence of HIV under the assumption of a three stage AIDS incubation period. We then perform an equilibrium and stability analysis on this model. We find that there is a critical threshold parameter R(0) which determines the behaviour of the model. If R(0)< or =1, then irrespective of the initial conditions of the system HIV will die out in all addicts and all needles. If R(0)>1, then there is a unique endemic equilibrium which is locally stable if, as is realistic, the time scale on which addicts inject is much shorter than that of the other epidemiological and demographic processes. Simulations indicate that if R(0)>1, then provided that disease is initially present in at least one addict or needle it will tend to the endemic equilibrium. In addition we derive conditions which guarantee this. We also find that under calibration the long term prevalence of disease in our variable infectivity model is always greater than in an equivalent constant infectivity model. These results are confirmed and explored further by simulation. We conclude with a short discussion.

Acquired Immunodeficiency Syndrome↗

Insect-pathogen dynamics: stage-specific susceptibility and insect density dependence.

The control of insect pests by using insect pathogens as dynamic biological control agents is a recent effort. Model studies on insect-pathogen relations can help in the development of biocontrol programs. Except for the work of Briggs and Godfray [1], insect-pathogen models ignore the stage-specific susceptibility of insects. Moreover most models do not incorporate insect self-regulation. We develop stage-structured models of insect-pathogen relations incorporating insect-density dependence and disease transmitted through direct contact between susceptible and infective individuals. The models are analyzed by using steady-state and stability analysis. Numerical solutions are used as sources of further insight into the dynamics of the insect-pathogen systems. It is shown that there are major differences in the dynamics of adult- and juvenile-infecting diseases. Moreover, the interplay between insect-density dependence and stage-specific susceptibility has important consequences for the dynamics of insect-pathogen systems.

Agriculture↗

Chemotactic signaling, microglia, and Alzheimer's disease senile plaques: is there a connection?

Chemotactic cells known as microglia are involved in the inflammation associated with pathology in Alzheimer's disease (AD). We investigate conditions that lead to aggregation of microglia and formation of local accumulations of chemicals observed in AD senile plaques. We develop a model for chemotaxis in response to a combination of chemoattractant and chemorepellent signaling chemicals. Linear stability analysis and numerical simulations of the model predict that periodic patterns in cell and chemical distributions can evolve under local attraction, long-ranged repulsion, and other constraints on concentrations and diffusion coefficients of the chemotactic signals. Using biological parameters from the literature, we compare and discuss the applicability of this model to actual processes in AD.

Aged↗

Pattern formation in a Turing's type model with minimal reactional complexity

Turing's original reaction network is systematically studied, particularly in what concerns: (a) Its ability to produce patterns in a predictable way. (b) The feasibility of its concentration-independent sink term. Despite the widely accepted view that Turing's original model presents some inherent inability to produce regular structures, the pattern formation properties of this model are found to obey the predictions of the corresponding Linear Stability Analysis in the one-dimension and in 'small' two-dimensional systems. An 'Enzymatic' variation of the original Turing's Model is introduced, where the unrealistic sink term is substituted by an enzymatic degradation. It seems that reaction networks of this type can inspire a promising search for chemical or biochemical experimental systems with pattern formation properties, even in the absence of high non-linearities. It is pointed out that temporal oscillations, impossible for the original Turing's Model, are stable and persistent in its Enzymatic variation.

Journal Article↗

The effect of copper/zinc replacement on the folding free energy of wild type and Cys3Ala/Cys26Ala azurin.

The effect of copper/zinc metal ion replacement on the folding free energy of wild type (w.t.) and disulfide bridge depleted (C3A/C26A) azurin has been investigated by differential scanning calorimetry (DSC) and fluorescence techniques. The denaturation experiments have shown that, in both cases, the thermal transitions of the zinc derivative of azurins can be depicted in terms of the classical Lumry-Eyring model, N if U-->F, thus resembling the unfolding path of the two copper proteins. The thermally induced transition of Zn azurin, monitored by fluorescence occurs at lower temperature than the DSC scans indicating that a local conformational rearrangement of the Trp microenvironment, takes place before protein denaturation. For Zn C3A/C26A azurin, the two techniques reveal the same transition temperature. Comparison of the thermodynamic data shows that the presence of Zn in the active site stabilises the three-dimensional structure of azurin only when the disulfide bridge is present. Compared to the copper form of the protein, the unfolding temperature of Zn azurin has increased by 4 degrees C, while the unfolding free energy, deltaG, is 31 kJ/mol higher. Both enthalpic and entropic factors contribute to the observed DeltaG increase. However, the copper/zinc replacement has no effect on the unfolding free energy of C3A/C26A azurin. Taking Cu azurin w.t. as the reference state, for both Cu and Zn C3A/C26A azurin the unfolding free energy is decreased by about 28 kJ/mol, indicating that metal substitution is not able to compensate the destabilising effect induced by the disulfide bridge depletion. It is noteworthy that the thermal denaturation of the Zn derivative, which thermodynamically is the most stable form of azurin, is also characterized by the highest value of the activation energy, E(a), as derived from the kinetic stability analysis.

Alanine↗

Bacterial and archeal type I topoisomerases.

Bacterial and archeal type I topoisomerases, including topoisomerase I, topoisomerase III and reverse gyrase, have different potential roles in the control of DNA topology including regulation of supercoiling and maintenance of genetic stability. Analysis of their coding sequences in different organisms shows that they belong to the type IA family of DNA topoisomerases, but there is variability in organization of various enzymatic domains necessary for topoisomerase activity. The torus-like structure of the conserved transesterification domain with the active site tyrosine for DNA cleavage/rejoining suggests steps of enzyme conformational change driven by DNA substrate and Mg(II) cofactor binding, that are required for catalysis of change in DNA linking number.

Archaeal Proteins↗

Modeling the interrelations between the calcium oscillations and ER membrane potential oscillations.

A refined electrochemical model accounting for intracellular calcium oscillations and their interrelations with oscillations of the potential difference across the membrane of the endoplasmic reticulum (ER) or other intracellular calcium stores is established. The ATP dependent uptake of Ca2+ from the cytosol into the ER, the Ca2+ release from the ER through channels following a calcium-induced calcium release mechanism, and a potential-dependent Ca2+ leak flux out of the ER are included in the model and described by plausible rate laws. The binding of calcium to specific proteins such as calmodulin is taken into account. The quasi-electroneutrality condition allows us to express the transmembrane potential in terms of the concentrations of cytosolic calcium and free binding sites on proteins, which are the two independent variables of the model. We include monovalent ions in the model, because they make up a considerable portion in the balance of electroneutrality. As the permeability of the endoplasmic membrane for these ions is much higher than that for calcium ions, we assume the former to be in Nernst equilibrium. A stability analysis of the steady-state solutions (which are unique or multiple depending on parameter values) is carried out and the Hopf bifurcation leading from stable steady states to self-sustained oscillations is analysed with the help of appropriate mathematical techniques. The oscillations obtained by numerical integration exhibit the typical spike-like shape found in experiments and reasonable values of frequency and amplitude. The model describes the process of switching between stationary and pulsatile regimes as well as changes in oscillation frequency upon parameter changes. It turns out that calcium oscillations can arise without a permanent influx of calcium into the cell, when a calcium-buffering system such as calmodulin is included.

Animals↗

Unified stabilization approach to principal and minor components extraction algorithms.

Principal component and minor component extractions provide powerful techniques in many information processing fields. There have been proposed a number of algorithms for principal and minor component (or subspace) extraction, which have different dynamical behaviors. In this paper, we give rigorous stability analysis of these algorithms, obtaining a unified insight view on the dynamical behaviors of various algorithms.

Algorithms↗

A comparative study of two modeling approaches in neural networks.

The neuron state modeling and the local field modeling provides two fundamental modeling approaches to neural network research, based on which a neural network system can be called either as a static neural network model or as a local field neural network model. These two models are theoretically compared in terms of their trajectory transformation property, equilibrium correspondence property, nontrivial attractive manifold property, global convergence as well as stability in many different senses. The comparison reveals an important stability invariance property of the two models in the sense that the stability (in any sense) of the static model is equivalent to that of a subsystem deduced from the local field model when restricted to a specific manifold. Such stability invariance property lays a sound theoretical foundation of validity of a useful, cross-fertilization type stability analysis methodology for various neural network models.

Algorithms↗

Pregnancy induces complex changes in the the pattern of mRNA expression in knee ligaments of the adolescent rabbit.

Knee laxity has been shown to increase during human pregnancy, and the laxity of the rabbit medial collateral ligament also increases during pregnancy. To determine whether the changes in tissue function could be related to alterations in the regulation of gene expression for a subset of relevant molecules in ligaments, RNA was isolated from the medial collateral(MCL) and anterior cruciate(ACL) ligaments of first time pregnant adolescent rabbits. Levels of mRNA for matrix molecules (collagen types I and III and the proteoglycans biglycan, decorin, versican and lumican), proteinases and inhibitors (collagenase, urokinase, PAI-1 and TIMP-1, -2 and -3), growth factors (bFGF, IGF-I, TGF-beta1 and ET-1), cytokines (IL-1beta and TNF) and enzymes responsible for important tissue mediators (COX-2 and iNOS) were assessed by semi-quantitative RT-PCR. In the MCL, levels of transcripts for all of the matrix molecules, growth factors and TIMPs 1 and 2 were significantly depressed at 29 days of pregnancy compared to age-matched non-pregnant controls. In contrast, transcripts for PAI-1 were elevated during pregnancy, while those for collagenase (MMP-1), urokinase, TIMP-3, IL-1beta, TNF, COX-2 and iNOS were not statistically altered. mRNA transcript levels rebounded by 7 days post-partum for most genes studied, indicating that the changes were rapidly reversible. For some molecules, transcript levels were again depressed at 18 days post-partum, indicating that regulatory mechanisms were still not stabilized. Analysis of mRNA from the ACL also revealed changes in the pattern of gene expression, with some similarities and differences from the MCL noted. These results indicate that pregnancy induces reversible changes in mRNA for matrix molecules in ligaments, but differences in responsiveness exist between different ligaments. The complexity of the changes observed indicates that there is probably no simple cause and effect relationship between laxity changes and the molecular alterations during pregnancy.

Aging↗

Cell-adhesion-dependent influences on genomic instability and carcinogenesis.

Adhesion-dependent cell signaling is known to be important in carcinogenesis. It is postulated that several types of adhesion molecules act as tumor suppressor genes by enforcing cell-substrate and cell-cell adhesion thereby preventing the migration of cells and their invasion into surrounding tissues. Recent evidence, however, suggests that disruption of adhesion systems can both initiate neoplastic transformation and contribute a rate-limiting step to progression. Adhesion may modulate neoplastic processes by altering pathways that control genomic stability. Analysis of the adhesion-controlled inactivation of the p53 protein and the concomitant relaxation of cell cycle checkpoint control could identify the critical contributions of adhesion-mediated influences to carcinogenesis.

Cell Adhesion↗

Mechanical simulation of composite hip stems.

Calculation of new orthopedic implants prior to manufacturing of prototypes can be economic in the case of complex production processes. The use of composite materials for highly loaded hip stems is one application of the Finite-Element Method. Due to the anisotropic behaviour of composite structures, special routines had to be programmed for element alignment and failure analysis. Stability of carbon fibre-reinforced epoxy hip stems could be confirmed by experimental results. The risk of neck fracture was found to be one of the critical features in the design process.

Anisotropy↗

New insights into the diagnosis and treatment of dry eye.

Over the past decade, numerous advances have been made in relation to dry eye diagnostic markers, technologies, and treatment options. The mainstay of treatment of dry eye is the use of artificial tear solutions and punctum plugs. A goal is the development of agents that provide symptomatic treatment and, at the same time, improve ocular surface keratinization. It is the authors' opinion that the functional visual acuity tester and the new tear stability analysis system will be widely used to improve diagnosis and evaluate treatment outcomes in KCS. Advances in treatment will utilize anti-inflammatory agents, immune suppressants such as Cyclosporin A and FK-506, growth hormones, androgens, topical mucins and ocular surface stimulating drugs, like INS365. Although aqueous-deficient dry eye is most commonly not associated with Sjogren syndrome (SS), aqueous-deficient dry eye is often most severe in patients with SS; thus, this article focuses mainly on SS-associated dry eye.

Journal Article↗

Optical aberrations and visual disturbances associated with dry eye.

Optical aberrations and visual disturbances are associated with dry eye, although visual impairment is often not detected by conventional visual acuity testing. The newly developed functional visual acuity (FVA) device allows continuous dynamic evaluation of distance visual acuity and assessment of the effect of natural tear film status on dynamic visual function. Similarly, to detect corneal surface irregularities during sustained eye opening in dry eye subjects, a new tear stability analysis system (TSAS) has been developed. Both FVA and TSAS measurement systems seem to be effective tools in the assessment of dynamic visual acuity changes in dry eye and normal subjects. Both methods were also found to be helpful in the evaluation of the outcome of management of dry eye disease. FVA testing has been suggested to be an important indication of an individual's performance in relation to certain daily activities, such as driving, reading and working at a video display terminal. This review provides illustrations of results obtained from FVA and TSAS systems.

Astigmatism↗

A multispecies model for the transmission and control of mastitis in dairy cows.

Mastitis in dairy cows is a significant economic and animal welfare issue in the dairy industry. The bacterial pathogens responsible for infection of the mammary gland may be split into two main categories: major and minor pathogens. Infection with major pathogens generally results in clinical illness or strong inflammatory responses and reduced milk yields, whereas minor pathogen infection is usually subclinical. Previous investigations have considered the transmission of these pathogens independently. Experimental evidence has shown cross-protection between species of pathogens. In this study a mathematical model for the coupled transmission of major and minor pathogens along with their interaction via the host was developed in order to consider various methods for controlling the incidence of major pathogen infection. A stability analysis of the model equilibria provides explanations for observed phenomena and previous decoupled modelling results. This multispecies model structure has provided a basis for quantifying the extent of cross-protection between species and assessing possible control strategies against the disease.

Animals↗

Purification of human placental aromatase cytochrome P-450 with monoclonal antibody and its characterization.

A simple and efficient method is described for the purification of microsomal aromatase cytochrome P-450 from human placenta. The enzyme was solubilized with Emulgen 913 and sodium cholate and subjected to chromatography on a column of Sepharose 4B coupled with a specific monoclonal antibody, followed by hydroxyapatite column chromatography. The specific cytochrome P-450 content of purified aromatase was 13.1 (12-14.8) nmol/mg of protein. Aromatase assays were carried out with reconstituted systems of bovine liver P-450 reductase and dilauroyl-L-alpha-phosphatidylcholine with [1 beta-3H,4-14C]-androstenedione as substrate. The specific activity of purified aromatase was 65.0 (50.6-74.3) nmol.min-1.(mg of protein)-1 or a turnover rate of 5.0 (4.3-5.9) min-1. The total recovery of purified aromatase activity was 32.2%, and P-450 recovery was 17.6%. The Km of immunoaffinity-purified aromatase was 12, 210, 41, and 2830 nM for androstenedione, 16 alpha-hydroxyandrostenedione, testosterone, and 16 alpha-hydroxytestosterone, respectively. The very high Km value for 16 alpha-hydroxytestosterone aromatization gives a reasonable indication that estriol is not the directly aromatized product in the fetoplacental unit of human pregnancy. The aromatase P-450 was subjected to SDS-polyacrylamide gel electrophoresis in increasing quantities. Silver stain detection techniques indicated a single band having a molecular mass of 55 kDa with greater than 97% purity. The stability analysis showed a half-life of over 4 years on storage at -80 degrees C.

Animals↗

Thermodynamic stability of chemical species in multiple reaction systems.

A general thermodynamic and stoichiometric method, recently developed by us to study subtle forms of stability/instability relations among chemical species, such as resonance and strain energies (Fishtik, I.; Datta, R. J. Phys. Chem. A 2004, 108, 5727-5739), is extended to stability relations in multiple chemical reaction systems. Namely, a new definition as well as a new algorithm of evaluation of the stabilities of chemical species, referred to as the overall stabilities, is proposed. It is further shown that the overall stabilities may be partitioned into a sum of contributions associated with a complete set of stoichiometrically unique response reactions (RERs). This finding reveals that the conventional stability analysis is stoichiometrically and thermodynamically inconsistent in that it involves only a part of RERs.

Journal Article↗

Kinetic model for the chiral symmetry breaking transition in the growth front of a conglomerate crystal phase.

In its molten phase, 1,1'-binaphthyl is racemic due to its high racemization rate, but it can crystallize as a conglomerate of R and S crystals. Our experiments have indicated that, under some conditions, the crystal growth front of 1,1'-binaphthyl shows many of the characteristics of an open system in which chiral symmetry is broken; i.e., the growing solid phase becomes predominantly R or S. Here we present a kinetic model to explain the observed chiral symmetry breaking. The model is based on growth due to attachment of R or S growth units to a crystal surface in a supercooled melt. Chiral symmetry breaking occurs due to chirally autocatalytic formation of R or S growth units on the growth surface. Unlike the many models suggested and studied in the 1980s, there is no cross-inhibition between R- and S-enantiomer in the model presented here. In our model, asymmetric and symmetric steady-state solutions that do not intersect were found. Through linear stability analysis, the critical point, at which a symmetric solution becomes unstable and makes a transition to an asymmetric solution, is determined.

Journal Article↗