Structural and functional characterization of Pseudomonas aeruginosa CupB chaperones

Pseudomonas aeruginosa, an important human pathogen, is estimated to be responsible for,10% of nosocomial infections worldwide. The pathogenesis of P. aeruginosa starts from its colonization in the damaged tissue or medical devices (e. g. catheters, prothesis and implanted heart valve etc.) facilitated by several extracellular adhesive factors including fimbrial pili. Several clusters containing fimbrial genes have been previously identified on the P. aeruginosa chromosome and named cup [1]. The assembly of the CupB pili is thought to be coordinated by two chaperones, CupB2 and CupB4. However, due to the lack of structural and biochemical data, their chaperone activities remain speculative. In this study, we report the 2.5 A crystal structure of P. aeruginosa CupB2. Based on the structure, we further tested the binding specificity of CupB2 and CupB4 towards CupB1 (the presumed major pilus subunit) and CupB6 (the putative adhesin) using limited trypsin digestion and strep-tactin pull-down assay. The structural and biochemical data suggest that CupB2 and CupB4 might play different, but not redundant, roles in CupB secretion. CupB2 is likely to be the chaperone of CupB1, and CupB4 could be the chaperone of CupB4:CupB5:CupB6, in which the interaction of CupB4 and CupB6 might be mediated via CupB5

Persistent Tn polyagglutination syndrome during febrile neutropenia: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Tn polyagglutination syndrome is a rare disorder that has been reported on only a few occasions in the literature, and, to the best of our knowledge, never before in the context of febrile neutropenia.</p> <p>Case presentation</p> <p>We report the case of a 26-year-old Caucasian woman who presented to our emergency department complaining of a persistent fever over the previous three days. She had a history of long-standing refractory pancytopenia with multi-lineage dysplasia and severe neutropenia, but she had rarely experienced infection. The results of a physical examination and multiple laboratory tests were unremarkable. While investigating the possible causes of the refractory, long-standing pancytopenia, the possibility of a polyagglutinable state was suggested. Blood samples were sent to the laboratory for an analysis of mixed-field seed lectin agglutination assay. A serum lectin panel confirmed the final diagnosis of Tn-activation.</p> <p>Conclusions</p> <p>We should include Tn-activation in our differential whenever we encounter cases of refractory long-standing idiopathic cytopenias and inconclusive bone marrow results displaying multi-lineage dysplasia. Novel genetic techniques have recently revealed the interesting pathophysiology of this phenomenon. The recognition and inclusion of Tn polyagglutination syndrome in our differential diagnoses has important clinical implications, given its main associated features, such as severe thrombocytopenia and neutropenia, which are usually linked to a benign clinical course and prognosis. Increased awareness of the polyagglutinable disorders will potentially decrease the need for invasive and costly medical interventions and also raises the need for monitoring of this specific sub-set of patients. In addition, the study of the expression and implications of Tn, and other similar antigens, offers a fascinating perspective for the study of its role in the diagnosis, prognosis and immunotherapy of solid tumors and hematological malignancies. The infrequency with which Tn polyagglutination syndrome is encountered, its clinical features and its pathophysiology make it a formidable diagnostic challenge.</p

Quantized reduction as a tensor product

Symplectic reduction is reinterpreted as the composition of arrows in the category of integrable Poisson manifolds, whose arrows are isomorphism classes of dual pairs, with symplectic groupoids as units. Morita equivalence of Poisson manifolds amounts to isomorphism of objects in this category. This description paves the way for the quantization of the classical reduction procedure, which is based on the formal analogy between dual pairs of Poisson manifolds and Hilbert bimodules over C*-algebras, as well as with correspondences between von Neumann algebras. Further analogies are drawn with categories of groupoids (of algebraic, measured, Lie, and symplectic type). In all cases, the arrows are isomorphism classes of appropriate bimodules, and their composition may be seen as a tensor product. Hence in suitable categories reduction is simply composition of arrows, and Morita equivalence is isomorphism of objects.Comment: 44 pages, categorical interpretation adde

The correct prednisone starting dose in polymyalgia rheumatica is related to body weight but not to disease severity

<p>Abstract</p> <p>Background</p> <p>the mainstay of treatment of polymyalgia rheumatica (PMR) is oral glucocorticoids, but randomized controlled trials of treatment are lacking. As a result, there is no evidence from controlled studies on the efficacy of different initial doses or glucocorticoid tapering. The aim of this study is to test if 12.5 mg prednisone/day is an adequate starting dose in PMR and to evaluate clinical predictors of drug response.</p> <p>Methods</p> <p>60 consecutive PMR patients were treated with a starting dose of 12,5 mg/day prednisone. Clinical, laboratory, and, in a subset of 25 patients, ultrasonographic features were recorded as possible predictors of response to prednisone. Remission was defined as disappearance of at least 75% of the signs and symptoms of PMR and normalization of ESR and CRP within the first month, a scenario allowing steroid tapering.</p> <p>Results</p> <p>47/60 (78.3%) patients responded to 12.5 mg of prednisone after a mean interval of 6.6 ± 5.2 days. In univariate analysis, body weight and gender discriminated the two groups. In multivariate analysis, the only factor predicting a good response was low weight (p = 0.004); the higher response rate observed in women was explained by their lower weight. The mean prednisone dose per kg in the responders was 0.19 ± 0.03 mg in comparison with 0.16 ± 0.03 mg for non responders (p = 0.007).</p> <p>Conclusions</p> <p>12.5 mg prednisone is a sufficient starting dose in ¾ of PMR patients. The main factor driving response to prednisone in PMR was weight, a finding that could help in the clinical care of PMR patients and in designing prospective studies of treatment.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01169597">NCT01169597</a></p

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag

The stb Operon Balances the Requirements for Vegetative Stability and Conjugative Transfer of Plasmid R388

The conjugative plasmid R388 and a number of other plasmids carry an operon, stbABC, adjacent to the origin of conjugative transfer. We investigated the role of the stbA, stbB, and stbC genes. Deletion of stbA affected both conjugation and stability. It led to a 50-fold increase in R388 transfer frequency, as well as to high plasmid loss. In contrast, deletion of stbB abolished conjugation but provoked no change in plasmid stability. Deletion of stbC showed no effect, neither in conjugation nor in stability. Deletion of the entire stb operon had no effect on conjugation, which remained as in the wild-type plasmid, but led to a plasmid loss phenotype similar to that of the R388ΔstbA mutant. We concluded that StbA is required for plasmid stability and that StbA and StbB control conjugation. We next observed the intracellular positioning of R388 DNA molecules and showed that they localize as discrete foci evenly distributed in live Escherichia coli cells. Plasmid instability of the R388ΔΔstbA mutant correlated with aberrant localization of the plasmid DNA molecules as clusters, either at one cell pole, at both poles, or at the cell center. In contrast, plasmid molecules in the R388ΔΔstbB mutant were mostly excluded from the cell poles. Thus, results indicate that defects in both plasmid maintenance and transfer are a consequence of variations in the intracellular positioning of plasmid DNA. We propose that StbA and StbB constitute an atypical plasmid stabilization system that reconciles two modes of plasmid R388 physiology: a maintenance mode (replication and segregation) and a propagation mode (conjugation). The consequences of this novel concept in plasmid physiology will be discussed

Economic language and economy change: with implications for cyber-physical systems

The implementation of cyber-physical and similar systems depends on prevailing social and economic conditions. It is here argued that, if the effect of these technologies is to be benign, the current neo-liberal economy must change to a radically more cooperative model. In this paper, economy change means a thorough change to a qualitatively different kind of economy. It is contrasted with economic change, which is the kind of minor change usually considered in mainstream discourse. The importance of language is emphasised, including that of techno-optimism and that of economic conservatism. Problems of injustice, strife, and ecological overload cannot be solved by conventional growth together with technical efficiency gains. Rather, a change is advocated from economics-as-usual to a broader concept, oikonomia (root-household management), which takes into account all that contributes to a good life, including what cannot be represented quantitatively. Some elements of such a broader economy (work; basic income; asset and income limits) are discussed. It is argued that the benefits of technology can be enhanced and the ills reduced in such an economy. This is discussed in the case of cyber-physical systems under the headings employment, security, standards and oligopoly, and energy efficiency. The paper concludes that such systems, and similar technological developments, cannot resolve the problems of sustainability within an economy-as-usual model. If, however, there is the will to create a cooperative and sustainable economy, technology can contribute significantly to the resolution of present problems

First nationwide survey on cardiovascular risk factors in Grand-Duchy of Luxembourg (ORISCAV-LUX)

BACKGROUND: The ORISCAV-LUX study is the first baseline survey of an on-going cardiovascular health monitoring programme in Grand-Duchy of Luxembourg. The main objectives of the present manuscript were 1) to describe the study design and conduct, and 2) to present the salient outcomes of the study, in particular the prevalence of the potentially modifiable and treatable cardiovascular disease risk factors in the adult population residing in Luxembourg. METHOD: ORISCAV-LUX is a cross-sectional study based on a random sample of 4496 subjects, stratified by gender, age categories and district, drawn from the national insurance registry of 18-69 years aged Luxembourg residents, assuming a response rate of 30% and a proportion of 5% of institutionalized subjects in each stratum. The cardiovascular health status was assessed by means of a self-administered questionnaire, clinical and anthropometric measures, as well as by blood, urine and hair examinations. The potentially modifiable and treatable risk factors studied included smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity. Both univariate and multivariate statistical analyses used weighted methods to account for the stratified sampling scheme. RESULTS: A total of 1432 subjects took part in the survey, yielding a participation rate of 32.2%. This figure is higher than the minimal sample size of 1285 subjects as estimated by power calculation. The most predominant cardiovascular risk factors were dyslipidemia (69.9%), hypertension (34.5%), smoking (22.3%), and obesity (20.9%), while diabetes amounted 4.4%. All prevalence rates increased with age (except smoking) with marked gender differences (except diabetes). There was a significant difference in the prevalence of hypertension and of lipid disorders by geographic region of birth. The proportion of subjects cumulating two or more cardiovascular risk factors increased remarkably with age and was more predominant in men than in women (P<0.0001). Only 14.7% of men and 23.1% of women were free of any cardiovascular risk factor. High prevalence of non-treated CVRF, notably for hypertension and dyslipidemia, were observed in the study population. CONCLUSION: The population-based ORISCAV-LUX survey revealed a high prevalence of potentially modifiable and treatable cardiovascular risk factors among apparently healthy subjects; significant gender and age-specific differences were seen not only for single but also for combined risk factors. From a public health perspective, these preliminary findings stress the urgent need for early routine health examinations, preventive interventions and lifestyle behavioural changes, even in young asymptomatic adults, to decrease cardiovascular morbidity and mortality in Luxembourg

Origin and Evolution of GALA-LRR, a New Member of the CC-LRR Subfamily: From Plants to Bacteria?

The phytopathogenic bacterium Ralstonia solanacearum encodes type III effectors, called GALA proteins, which contain F-box and LRR domains. The GALA LRRs do not perfectly fit any of the previously described LRR subfamilies. By applying protein sequence analysis and structural prediction, we clarify this ambiguous case of LRR classification and assign GALA-LRRs to CC-LRR subfamily. We demonstrate that side-by-side packing of LRRs in the 3D structures may control the limits of repeat variability within the LRR subfamilies during evolution. The LRR packing can be used as a criterion, complementing the repeat sequences, to classify newly identified LRR domains. Our phylogenetic analysis of F-box domains proposes the lateral gene transfer of bacterial GALA proteins from host plants. We also present an evolutionary scenario which can explain the transformation of the original plant LRRs into slightly different bacterial LRRs. The examination of the selective evolutionary pressure acting on GALA proteins suggests that the convex side of their horse-shoe shaped LRR domains is more prone to positive selection than the concave side, and we therefore hypothesize that the convex surface might be the site of protein binding relevant to the adaptor function of the F-box GALA proteins. This conclusion provides a strong background for further functional studies aimed at determining the role of these type III effectors in the virulence of R. solanacearum

Prognostic molecular markers in early breast cancer

A multitude of molecules involved in breast cancer biology have been studied as potential prognostic markers. In the present review we discuss the role of established molecular markers, as well as potential applications of emerging new technologies. Those molecules used routinely to make treatment decisions in patients with early-stage breast cancer include markers of proliferation (e.g. Ki-67), hormone receptors, and the human epidermal growth factor receptor 2. Tumor markers shown to have prognostic value but not used routinely include cyclin D(1 )and cyclin E, urokinase-like plasminogen activator/plasminogen activator inhibitor, and cathepsin D. The level of evidence for other molecular markers is lower, in part because most studies were retrospective and not adequately powered, making their findings unsuitable for choosing treatments for individual patients. Gene microarrays have been successfuly used to classify breast cancers into subtypes with specific gene expression profiles and to evaluate prognosis. RT-PCR has also been used to evaluate expression of multiple genes in archival tissue. Proteomics technologies are in development