Optimising the management of vaginal discharge syndrome in Bulgaria: cost effectiveness of four clinical algorithms with risk assessment

OBJECTIVES: To evaluate the performance and cost effectiveness of the WHO recommendations of incorporating risk-assessment scores and population prevalence of Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) into vaginal discharge syndrome (VDS) algorithms. METHODS: Non-pregnant women presenting with VDS were recruited at a non-governmental sexual health clinic in Sofia, Bulgaria. NG and CT were diagnosed by PCR and vaginal infections by microscopy. Risk factors for NG/CT were identified in multivariable analysis. Four algorithms based on different combinations of behavioural factors, clinical findings and vaginal microscopy were developed. Performance of each algorithm was evaluated for detecting vaginal and cervical infections separately. Cost effectiveness was based on cost per patient treated and cost per case correctly treated. Sensitivity analysis explored the influence of NG/CT prevalence on cost effectiveness. RESULTS: 60% (252/420) of women had genital infections, with 9.5% (40/423) having NG/CT. Factors associated with NG/CT included new and multiple sexual partners in the past 3 months, symptomatic partner, childlessness and >or=10 polymorphonuclear cells per field on vaginal microscopy. For NG/CT detection, the algorithm that relied solely on behavioural risk factors was less sensitive but more specific than those that included speculum examination or microscopy but had higher correct-treatment rate and lower over-treatment rates. The cost per true case treated using a combination of risk factors, speculum examination and microscopy was euro 24.08. A halving and tripling of NG/CT prevalence would have approximately the inverse impact on the cost-effectiveness estimates. CONCLUSIONS: Management of NG/CT in Bulgaria was improved by the use of a syndromic approach that included risk scores. Approaches that did not rely on microscopy lost sensitivity but were more cost effective

On the equivalence of game and denotational semantics for the probabilistic mu-calculus

The probabilistic (or quantitative) modal mu-calculus is a fixed-point logic de- signed for expressing properties of probabilistic labeled transition systems (PLTS). Two semantics have been studied for this logic, both assigning to every process state a value in the interval [0,1] representing the probability that the property expressed by the formula holds at the state. One semantics is denotational and the other is a game semantics, specified in terms of two-player stochastic games. The two semantics have been proved to coincide on all finite PLTS's, but the equivalence of the two semantics on arbitrary models has been open in literature. In this paper we prove that the equivalence indeed holds for arbitrary infinite models, and thus our result strengthens the fruitful connection between denotational and game semantics. Our proof adapts the unraveling or unfolding method, a general proof technique for proving result of parity games by induction on their complexity

Direct visualization reveals dynamics of a transient intermediate during protein assembly

Interactions between proteins underlie numerous biological functions. Theoretical work suggests that protein interactions initiate with formation of transient intermediates that subsequently relax to specific, stable complexes. However, the nature and roles of these transient intermediates have remained elusive. Here, we characterized the global structure, dynamics, and stability of a transient, on-pathway intermediate during complex assembly between the Signal Recognition Particle (SRP) and its receptor. We show that this intermediate has overlapping but distinct interaction interfaces from that of the final complex, and it is stabilized by long-range electrostatic interactions. A wide distribution of conformations is explored by the intermediate; this distribution becomes more restricted in the final complex and is further regulated by the cargo of SRP. These results suggest a funnel-shaped energy landscape for protein interactions, and they provide a framework for understanding the role of transient intermediates in protein assembly and biological regulation

Steric constraints in model proteins

A simple lattice model for proteins that allows for distinct sizes of the amino acids is presented. The model is found to lead to a significant number of conformations that are the unique ground state of one or more sequences or encodable. Furthermore, several of the encodable structures are highly designable and are the non-degenerate ground state of several sequences. Even though the native state conformations are typically compact, not all compact conformations are encodable. The incorporation of the hydrophobic and polar nature of amino acids further enhances the attractive features of the model.Comment: RevTex, 5 pages, 3 postscript figure

Role of the Subunits Interactions in the Conformational Transitions in Adult Human Hemoglobin: an Explicit Solvent Molecular Dynamics Study

Hemoglobin exhibits allosteric structural changes upon ligand binding due to the dynamic interactions between the ligand binding sites, the amino acids residues and some other solutes present under physiological conditions. In the present study, the dynamical and quaternary structural changes occurring in two unligated (deoxy-) T structures, and two fully ligated (oxy-) R, R2 structures of adult human hemoglobin were investigated with molecular dynamics. It is shown that, in the sub-microsecond time scale, there is no marked difference in the global dynamics of the amino acids residues in both the oxy- and the deoxy- forms of the individual structures. In addition, the R, R2 are relatively stable and do not present quaternary conformational changes within the time scale of our simulations while the T structure is dynamically more flexible and exhibited the T\rightarrow R quaternary conformational transition, which is propagated by the relative rotation of the residues at the {\alpha}1{\beta}2 and {\alpha}2{\beta}1 interface.Comment: Reprinted (adapted) with permission from J. Phys. Chem. B DOI:10.1021/jp3022908. Copyright (2012) American Chemical Societ

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a \u3b2-thalassemia mouse model

Anemia in \u3b2-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired \u3b1-globin chains impose substantial oxidative stress on \u3b2-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for \u3b2-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in \u3b2-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2\u3b1 axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing \u3b2-thalassemia\u2013related liver iron overload. In ex vivo studies on erythroid precursors from patients with \u3b2-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for \u3b2-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials

Theory and simulation of short-range models of globular protein solutions

We report theoretical and simulation studies of phase coexistence in model globular protein solutions, based on short-range, central, pair potential representations of the interaction among macro-particles. After reviewing our previous investigations of hard-core Yukawa and generalised Lennard-Jones potentials, we report more recent results obtained within a DLVO-like description of lysozyme solutions in water and added salt. We show that a one-parameter fit of this model based on Static Light Scattering and Self-Interaction Chromatography data in the dilute protein regime, yields demixing and crystallization curves in good agreement with experimental protein-rich/protein-poor and solubility envelopes. The dependence of cloud and solubility points temperature of the model on the ionic strength is also investigated. Our findings highlight the minimal assumptions on the properties of the microscopic interaction sufficient for a satisfactory reproduction of the phase diagram topology of globular protein solutions.Comment: 17 pages, 8 figures, Proc. of Conference "Structural Arrest Transitions in Colloidal Systems with Short-Range Attractions", Messina (ITALY) 17-20 December 200

Roles of residues in the interface of transient protein-protein complexes before complexation

Transient protein-protein interactions play crucial roles in all facets of cellular physiology. Here, using an analysis on known 3-D structures of transient protein-protein complexes, their corresponding uncomplexed forms and energy calculations we seek to understand the roles of protein-protein interfacial residues in the unbound forms. We show that there are conformationally near invariant and evolutionarily conserved interfacial residues which are rigid and they account for ∼65% of the core interface. Interestingly, some of these residues contribute significantly to the stabilization of the interface structure in the uncomplexed form. Such residues have strong energetic basis to perform dual roles of stabilizing the structure of the uncomplexed form as well as the complex once formed while they maintain their rigid nature throughout. This feature is evolutionarily well conserved at both the structural and sequence levels. We believe this analysis has general bearing in the prediction of interfaces and understanding molecular recognition

Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure

Modeling Atmospheric Lines By the Exoplanet Community (MALBEC) version 1.0: A CUISINES radiative transfer intercomparison project

Radiative transfer (RT) models are critical in the interpretation of exoplanetary spectra, in simulating exoplanet climates and when designing the specifications of future flagship observatories. However, most models differ in methodologies and input data, which can lead to significantly different spectra. In this paper, we present the experimental protocol of the MALBEC (Modeling Atmospheric Lines By the Exoplanet Community) project. MALBEC is an exoplanet model intercomparison project (exoMIP) that belongs to the CUISINES (Climates Using Interactive Suites of Intercomparisons Nested for Exoplanet Studies) framework which aims to provide the exoplanet community with a large and diverse set of comparison and validation of models. The proposed protocol tests include a large set of initial participating RT models, a broad range of atmospheres (from Hot Jupiters to temperate terrestrials) and several observation geometries, which would allow us to quantify and compare the differences between different RT models used by the exoplanetary community. Two types of tests are proposed: transit spectroscopy and direct imaging modeling, with results from the proposed tests to be published in dedicated follow-up papers. To encourage the community to join this comparison effort and as an example, we present simulation results for one specific transit case (GJ-1214 b), in which we find notable differences in how the various codes handle the discretization of the atmospheres (e.g., sub-layering), the treatment of molecular opacities (e.g., correlated-k, line-by-line) and the default spectroscopic repositories generally used by each model (e.g., HITRAN, HITEMP, ExoMol)