Does One Size Fit All? Drug Resistance and Standard Treatments: Results of Six Tuberculosis Programmes in Former Soviet Countries.

SETTING: After the collapse of the Soviet Union, countries in the region faced a dramatic increase in tuberculosis cases and the emergence of drug resistance. OBJECTIVE: To discuss the relevance of the DOTS strategy in settings with a high prevalence of drug resistance. DESIGN: Retrospective analysis of one-year treatment outcomes of short-course chemotherapy (SCC) and results of drug susceptibility testing (DST) surveys of six programmes located in the former Soviet Union: Kemerovo prison, Russia; Abkhasia, Georgia; Nagorno-Karabagh, Azerbaijan; Karakalpakstan, Uzbekistan; Dashoguz Velayat, Turkmenistan; and South Kazakhstan Oblast, Kazakhstan. Results are reported for new and previously treated smear-positive patients. RESULTS: Treatment outcomes of 3090 patients and DST results of 1383 patients were collected. Treatment success rates ranged between 87% and 61%, in Nagorno-Karabagh and Kemerovo, respectively, and failure rates between 7% and 23%. Any drug resistance ranged between 66% and 31% in the same programmes. MDR rates ranged between 28% in Karakalpakstan and Kemerovo prison and 4% in Nagorno-Karabagh. CONCLUSION: These results show the limits of SCC in settings with a high prevalence of drug resistance. They demonstrate that adapting treatment according to resistance patterns, access to reliable culture, DST and good quality second-line drugs are necessary

Resampling technique applied to statistics of microsegregation characterization

Characterization of chemical heterogeneities at the dendrite scale is of practical importance for understanding phase transformation either during solidification or during subsequent solid-state treatment. Spot analysis with electron probe is definitely well-suited to investigate such heterogeneities at the micron scale that is relevant for most solidified products. However, very few has been done about the statistics of experimental solute distributions gained from such analyses when they are now more and more used for validating simulation data. There are two main sources generating discrepancies between estimated and actual solute distributions in an alloy: i) data sampling with a limited number of measurements to keep analysis within a reasonable time length; and ii) uncertainty linked to the measurement process, namely the physical noise that accompanies X-ray emission. Focusing on the first of these sources, a few 2-D composition images have been generated by phase field modelling of a Mg-Al alloy. These images were then used to obtain "true" solute distributions to which to compare coarse grid analyses as generally performed with a microanalyser. Resampling, i.e. generating several distributions by grid analyses with limited number of picked-up values, was then used to get statistics of estimates of solute distribution. The discussion of the present results deals first with estimating the average solute content and then focuses on the distribution in the primary phase

Enhanced turbulence driven by mesoscale motions and flow-topography interaction in the Denmark Strait Overflow plume

The Denmark Strait Overflow (DSO) contributes roughly half to the total volume transport of the Nordic overflows. The overflow increases its volume by entraining ambient water as it descends into the subpolar North Atlantic, feeding into the deep branch of the Atlantic Meridional Overturning Circulation. In June 2012, a multiplatform experiment was carried out in the DSO plume on the continental slope off Greenland (180 km downstream of the sill in Denmark Strait), to observe the variability associated with the entrainment of ambient waters into the DSO plume. In this study, we report on two high-dissipation events captured by an autonomous underwater vehicle (AUV) by horizontal profiling in the interfacial layer between the DSO plume and the ambient water. Strong dissipation of turbulent kinetic energy of O( math formula) W kg−1 was associated with enhanced small-scale temperature variance at wavelengths between 0.05 and 500 m as deduced from a fast-response thermistor. Isotherm displacement slope spectra reveal a wave number-dependence characteristic of turbulence in the inertial-convective subrange ( math formula) at wavelengths between 0.14 and 100 m. The first event captured by the AUV was transient, and occurred near the edge of a bottom-intensified energetic eddy. Our observations imply that both horizontal advection of warm water and vertical mixing of it into the plume are eddy-driven and go hand in hand in entraining ambient water into the DSO plume. The second event was found to be a stationary feature on the upstream side of a topographic elevation located in the plume pathway. Flow-topography interaction is suggested to drive the intense mixing at this site

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

Calculations of the binding affinities of protein-protein complexes with the fast multipole method

In this paper, we used a coarse-grained model at the residue level to calculate the binding free energies of three protein-protein complexes. General formulations to calculate the electrostatic binding free energy and the van der Waals free energy are presented by solving linearized Poisson-Boltzmann equations using the boundary element method in combination with the fast multipole method. The residue level model with the fast multipole method allows us to efficiently investigate how the mutations on the active site of the protein-protein interface affect the changes in binding affinities of protein complexes. Good correlations between the calculated results and the experimental ones indicate that our model can capture the dominant contributions to the protein-protein interactions. At the same time, additional effects on protein binding due to atomic details are also discussed in the context of the limitations of such a coarse-grained model

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

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

Walking automata in free inverse monoids

International audienceWalking automata, be they running over words, trees or even graphs, possibly extended with pebbles that can be dropped and lifted on vertices, have long been defined and studied in Computer Science. However, questions concerning walking automata are surprisingly complex to solve. In this paper, we study a generic notion of walking automata over graphs whose semantics naturally lays within inverse semigroup theory. Then, from the simplest notion of walking automata on birooted trees, that is, elements of free inverse monoids, to the more general cases of walking automata on birooted finite subgraphs of Cayley's graphs of groups, that is, elements of free E-unitary inverse monoids, we provide a robust algebraic framework in which various classes of recognizable or regular languages of birooted graphs can uniformly be defined and related one with the other

Automata for true concurrency properties

We present an automata-theoretic framework for the model checking of true concurrency properties. These are specified in a fixpoint logic, corresponding to history-preserving bisimilarity, capable of describing events in computations and their dependencies. The models of the logic are event structures or any formalism which can be given a causal semantics, like Petri nets. Given a formula and an event structure satisfying suitable regularity conditions we show how to construct a parity tree automaton whose language is non-empty if and only if the event structure satisfies the formula. The automaton, due to the nature of event structure models, is usually infinite. We discuss how it can be quotiented to an equivalent finite automaton, where emptiness can be checked effectively. In order to show the applicability of the approach, we discuss how it instantiates to finite safe Petri nets. As a proof of concept we provide a model checking tool implementing the technique