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

Residual Stress State of X65 Pipeline Girth Welds before and after Local and Furnace Post Weld Heat Treatment

This research investigated the effects of global (in other words, furnace-based) and local post weld heat treatment (PWHT) on residual stress (RS) relaxation in API 5L X65 pipe girth welds. All pipe spools were fabricated using identical pipeline production procedures for manufacturing multipass narrow gap welds. Nondestructive neutron diffraction (ND) strain scanning was carried out on girth welded pipe spools and strain-free comb samples for the determination of the lattice spacing. All residual stress measurements were carried out at the KOWARI strain scanning instrument at the Australian Nuclear Science and Technology Organization (ANSTO). Residual stresses were measured on two pipe spools in as-welded condition and two pipe spools after local and furnace PWHT. Measurements were conducted through the thickness in the weld material and adjacent parent metal starting from the weld toes. Besides, three line-scans along pipe length were made 3 mm below outer surface, at pipe wall midthickness, and 3 mm above the inner surface. PWHT was carried out for stress relief; one pipe was conventionally heat treated entirely in an enclosed furnace, and the other was locally heated by a flexible ceramic heating pad. Residual stresses measured after PWHT were at exactly the same locations as those in as-welded condition. Residual stress states of the pipe spools in as-welded condition and after PWHT were compared, and the results were presented in full stress maps. Additionally, through-thickness residual stress profiles and the results of one line scan (3 mm below outer surface) were compared with the respective residual stress profiles advised in British Standard BS 7910 “Guide to methods for assessing the acceptability of flaws in metallic structures” and the UK nuclear industry's R6 procedure. The residual stress profiles in as-welded condition were similar. With the given parameters, local PWHT has effectively reduced residual stresses in the pipe spool to such a level that it prompted the thought that local PWHT can be considered a substitute for global PWHT.</jats:p

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

Specificity quantification of biomolecular recognition and its implication for drug discovery

Highly efficient and specific biomolecular recognition requires both affinity and specificity. Previous quantitative descriptions of biomolecular recognition were mostly driven by improving the affinity prediction, but lack of quantification of specificity. We developed a novel method SPA (SPecificity and Affinity) based on our funneled energy landscape theory. The strategy is to simultaneously optimize the quantified specificity of the “native” protein-ligand complex discriminating against “non-native” binding modes and the affinity prediction. The benchmark testing of SPA shows the best performance against 16 other popular scoring functions in industry and academia on both prediction of binding affinity and “native” binding pose. For the target COX-2 of nonsteroidal anti-inflammatory drugs, SPA successfully discriminates the drugs from the diversity set, and the selective drugs from non-selective drugs. The remarkable performance demonstrates that SPA has significant potential applications in identifying lead compounds for drug discovery

Undiagnosed osteoid osteoma of the spine presenting as painful scoliosis from adolescence to adulthood: a case report

Presented here is a case of a young woman, with an undiagnosed osteoid osteoma of the spine, which presented with painful scoliosis in adolescence and was treated by bracing until her accession to adulthood. A more thorough investigation, years after the initial one, revealed the tumor. Surgical excision and stabilization offered the long-awaited cure. Misdiagnosis resulted in intractable pain for years, deformity, the discomfort of brace therapy, and the frustration of a prolonged yet ineffective treatment

ConPlex: a server for the evolutionary conservation analysis of protein complex structures

Evolutionary conservation analyses are important for the identification of protein–protein interactions. For protein complex structures, sequence conservation has been applied to determine protein oligomerization states, to characterize native interfaces from non-specific crystal contacts, and to discriminate near-native structures from docking artifacts. However, a user-friendly web-based service for evolutionary conservation analysis of protein complexes has not been available. Therefore, we developed ConPlex (http://sbi.postech.ac.kr/ConPlex/) a web application that enables evolutionary conservation analyses of protein interactions within protein quaternary structures. Users provide protein complex structures; ConPlex automatically identifies protein interfaces and carries out evolutionary conservation analyses for the interface regions. Moreover, ConPlex allows the results of the residue-specific conservation analysis to be displayed on the protein complex structure and provides several options to customize the display output to fit each user’s needs. We believe that ConPlex offers a convenient platform to analyze protein complex structures based on evolutionary conservation of protein–protein interface residues

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

Evaluation of multiple protein docking structures using correctly predicted pairwise subunits

<p>Abstract</p> <p>Background</p> <p>Many functionally important proteins in a cell form complexes with multiple chains. Therefore, computational prediction of multiple protein complexes is an important task in bioinformatics. In the development of multiple protein docking methods, it is important to establish a metric for evaluating prediction results in a reasonable and practical fashion. However, since there are only few works done in developing methods for multiple protein docking, there is no study that investigates how accurate structural models of multiple protein complexes should be to allow scientists to gain biological insights.</p> <p>Methods</p> <p>We generated a series of predicted models (decoys) of various accuracies by our multiple protein docking pipeline, Multi-LZerD, for three multi-chain complexes with 3, 4, and 6 chains. We analyzed the decoys in terms of the number of correctly predicted pair conformations in the decoys.</p> <p>Results and conclusion</p> <p>We found that pairs of chains with the correct mutual orientation exist even in the decoys with a large overall root mean square deviation (RMSD) to the native. Therefore, in addition to a global structure similarity measure, such as the global RMSD, the quality of models for multiple chain complexes can be better evaluated by using the local measurement, the number of chain pairs with correct mutual orientation. We termed the fraction of correctly predicted pairs (RMSD at the interface of less than 4.0Å) as <it>fpair </it>and propose to use it for evaluation of the accuracy of multiple protein docking.</p

The eNMR platform for structural biology

The e-NMR project is a European cooperation initiative that aims at providing the bio-NMR user community with a software platform integrating and streamlining the computational approaches necessary for the analysis of bio-NMR data. The e-NMR platform is based on a Grid computational infrastructure. A main focus of the current implementation of the e-NMR platform is on streamlining structure determination protocols. Indeed, to facilitate the use of NMR spectroscopy in the life sciences, the eNMR consortium has set out to provide protocolized services through easy-to-use web interfaces, while still retaining sufficient flexibility to handle specific requests by expert users. Various programs relevant for structural biology applications are already available through the e-NMR portal, including HADDOCK, XPLOR-NIH, CYANA and csRosetta. The implementation of these services, and in particular the distribution of calculations to the GRID infrastructure, has required the development of specific tools. However, the GRID infrastructure is maintained completely transparent to the users. With more than 150 registered users, eNMR is currently the second largest European Virtual Organization in the life sciences