100 research outputs found

    Analytic Solution for the Ground State Energy of the Extensive Many-Body Problem

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    A closed form expression for the ground state energy density of the general extensive many-body problem is given in terms of the Lanczos tri-diagonal form of the Hamiltonian. Given the general expressions of the diagonal and off-diagonal elements of the Hamiltonian Lanczos matrix, αn(N)\alpha_n(N) and βn(N)\beta_n(N), asymptotic forms α(z)\alpha(z) and β(z)\beta(z) can be defined in terms of a new parameter zn/Nz\equiv n/N (nn is the Lanczos iteration and NN is the size of the system). By application of theorems on the zeros of orthogonal polynomials we find the ground-state energy density in the bulk limit to be given in general by E0=inf[α(z)2β(z)]{\cal E}_0 = {\rm inf}\,\left[\alpha(z) - 2\,\beta(z)\right].Comment: 10 pages REVTex3.0, 3 PS figure

    Association of mutation patterns in gyrA/B genes and ofloxacin resistance levels in Mycobacterium tuberculosis isolates from East China in 2009

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    <p>Abstract</p> <p>Background</p> <p>This study aimed to analyze the association of mutation patterns in <it>gyrA </it>and <it>gyrB </it>genes and the ofloxacin resistance levels in clinical <it>Mycobacterium tuberculosis </it>isolates sampled in 2009 from East China.</p> <p>Methods</p> <p>The quinolone resistance-determining region of <it>gyrA/B </it>were sequenced in 192 <it>M. tuberculosis </it>clinical isolates and the minimal inhibitory concentrations (MICs) of 95 ofloxacin-resistant <it>M. tuberculosis </it>isolates were determined by using microplate nitrate reductase assays.</p> <p>Results</p> <p>Mutations in <it>gyrA </it>(codons 90, 91 and 94) and in <it>gyrB </it>(G551R, D500N, T539N, R485C/L) were observed in 89.5% (85/95) and 11.6% (11/95) of ofloxacin-resistant strains, respectively. The <it>gyrB </it>mutations G551R and G549D were observed in 4.1% (4/97) of ofloxacin-susceptible strains and no mutation was found in <it>gyrA </it>in ofloxacin-susceptible strains. The MICs of all ofloxacin-resistant strains showed no significant difference among strains with mutations at codons 90, 91 or 94 in <it>gyrA </it>(F = 1.268, <it>p </it>= 0.287). No differences were detected among strains with different amino acid mutations in the quinolone resistance-determining region of <it>gyrA </it>(F = 1.877, <it>p </it>= 0.123). The difference in MICs between ofloxacin-resistant strains with mutations in <it>gyrA </it>only and ofloxacin-resistant strains with mutations in both <it>gyrA </it>and <it>gyrB </it>genes was not statistically significant (F = 0.549, <it>p </it>= 0.461).</p> <p>Conclusions</p> <p>Although <it>gyrA/B </it>mutations can lead to ofloxacin resistance in <it>M. tuberculosis</it>, there were no associations of different mutation patterns in <it>gyrA/B </it>and the level of ofloxacin resistance in <it>M. tuberculosis </it>isolates from East China in 2009.</p

    Structural Insights into the Quinolone Resistance Mechanism of Mycobacterium tuberculosis DNA Gyrase

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    Mycobacterium tuberculosis DNA gyrase, an indispensable nanomachine involved in the regulation of DNA topology, is the only type II topoisomerase present in this organism and is hence the sole target for quinolone action, a crucial drug active against multidrug-resistant tuberculosis. To understand at an atomic level the quinolone resistance mechanism, which emerges in extensively drug resistant tuberculosis, we performed combined functional, biophysical and structural studies of the two individual domains constituting the catalytic DNA gyrase reaction core, namely the Toprim and the breakage-reunion domains. This allowed us to produce a model of the catalytic reaction core in complex with DNA and a quinolone molecule, identifying original mechanistic properties of quinolone binding and clarifying the relationships between amino acid mutations and resistance phenotype of M. tuberculosis DNA gyrase. These results are compatible with our previous studies on quinolone resistance. Interestingly, the structure of the entire breakage-reunion domain revealed a new interaction, in which the Quinolone-Binding Pocket (QBP) is blocked by the N-terminal helix of a symmetry-related molecule. This interaction provides useful starting points for designing peptide based inhibitors that target DNA gyrase to prevent its binding to DNA

    Prognostic factors for disability claim duration due to musculoskeletal symptoms among self-employed persons

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    <p>Abstract</p> <p>Background</p> <p>Employees and self-employed persons have, among others, different personal characteristics and different working conditions, which may influence the prognosis of sick leave and the duration of a disability claim. The purpose of the current study is to identify prognostic factors for the duration of a disability claim due to non-specific musculoskeletal disorders (MSD) among self-employed persons in the Netherlands.</p> <p>Methods</p> <p>The study population consisted of 276 self-employed persons, who all had a disability claim episode due to MSD with at least 75% work disability. The study was a cohort study with a follow-up period of 12 months. At baseline, participants filled in a questionnaire with possible individual, work-related and disease-related prognostic factors.</p> <p>Results</p> <p>The following prognostic factors significantly increased claim duration: age > 40 years (Hazard Ratio 0.54), no similar symptoms in the past (HR 0.46), having long-lasting symptoms of more than six months (HR 0.60), self-predicted return to work within more than one month or never (HR 0.24) and job dissatisfaction (HR 0.54).</p> <p>Conclusions</p> <p>The prognostic factors we found indicate that for self-employed persons, the duration of a disability claim not only depends on the (history of) impairment of the insured, but also on age, self-predicted return to work and job satisfaction.</p

    Hepatitis C Virus Antigenic Convergence

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    Vaccine development against hepatitis C virus (HCV) is hindered by poor understanding of factors defining cross-immunoreactivity among heterogeneous epitopes. Using synthetic peptides and mouse immunization as a model, we conducted a quantitative analysis of cross-immunoreactivity among variants of the HCV hypervariable region 1 (HVR1). Analysis of 26,883 immunological reactions among pairs of peptides showed that the distribution of cross-immunoreactivity among HVR1 variants was skewed, with antibodies against a few variants reacting with all tested peptides. The HVR1 cross-immunoreactivity was accurately modeled based on amino acid sequence alone. The tested peptides were mapped in the HVR1 sequence space, which was visualized as a network of 11,319 sequences. The HVR1 variants with a greater network centrality showed a broader cross-immunoreactivity. The entire sequence space is explored by each HCV genotype and subtype. These findings indicate that HVR1 antigenic diversity is extensively convergent and effectively limited, suggesting significant implications for vaccine development

    The Sudden Dominance of blaCTX–M Harbouring Plasmids in Shigella spp. Circulating in Southern Vietnam

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    Shigellosis is a disease caused by bacteria belonging to Shigella spp. and is a leading cause of bacterial gastrointestinal infections in infants in unindustrialized countries. The Shigellae are dynamic and capable of rapid change when placed under selective pressure in a human population. Extended spectrum beta lactamases (ESBLs) are enzymes capable of degrading cephalosporins (a group of antimicrobial agents) and the genes that encode them are common in pathogenic E. coli and other related organisms in industrialized countries. In southern Vietnam, we have isolated multiple cephalosporin-resistant Shigella that express ESBLs. Furthermore, over two years these strains have replaced strains isolated from patients with shigellosis that cannot express ESBLs. Our work describes the genes responsible for this characteristic and we investigate one of the elements carrying one of these genes. These finding have implications for treatment of shigellosis and support the growing necessity for vaccine development. Our findings also may be pertinent for other countries undergoing a similar economic transition to Vietnam's and the corresponding effect on bacterial populations

    Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

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    In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field
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