1,053 research outputs found

    Superhelical Duplex Destabilization and the Recombination Position Effect

    Get PDF
    The susceptibility to recombination of a plasmid inserted into a chromosome varies with its genomic position. This recombination position effect is known to correlate with the average G+C content of the flanking sequences. Here we propose that this effect could be mediated by changes in the susceptibility to superhelical duplex destabilization that would occur. We use standard nonparametric statistical tests, regression analysis and principal component analysis to identify statistically significant differences in the destabilization profiles calculated for the plasmid in different contexts, and correlate the results with their measured recombination rates. We show that the flanking sequences significantly affect the free energy of denaturation at specific sites interior to the plasmid. These changes correlate well with experimentally measured variations of the recombination rates within the plasmid. This correlation of recombination rate with superhelical destabilization properties of the inserted plasmid DNA is stronger than that with average G+C content of the flanking sequences. This model suggests a possible mechanism by which flanking sequence base composition, which is not itself a context-dependent attribute, can affect recombination rates at positions within the plasmid

    Minerals information GIS for regional development and inward investment in Northern Highlands of Scotland

    Get PDF
    The principal aim of this project, funded by the Department of Trade and Industry (DTI), is to stimulate exploration for metalliferous minerals in the Northern Highlands of Scotland, thereby promoting inward investment, job creation and the development of infrastructure in the region. The Northern Highlands study area occupies about 27,000 km2 located to the north and west of the Great Glen, including the Hebrides, Orkney and Shetland. The regional geology is highly varied, comprising mainly Archaean and Proterozoic metamorphic rocks and Palaeozoic sedimentary rocks. Intrusive igneous rocks are also widely developed. This geological diversity enhances the potential of the region for the occurrence of a wide range of mineral deposit types. The Northern Highlands are under-explored, relative to other parts of Scotland; nevertheless, this study has documented more than 350 recorded mineral occurrences

    Real-world questions and concerns about disease-modifying antirheumatic drugs (DMARDs): A retrospective analysis of questions to a medicine call center

    Get PDF
    Background: Disease-modifying antirheumatic drugs (DMARDs) have transformed the treatment of numerous autoimmune and inflammatory diseases but their perceived risk of harm may be a barrier to use. Methods: In a retrospective mixed-methods study, we analysed conventional (c) and biologic (b) DMARDs-related calls and compared them with rest of calls (ROC) from consumers to an Australian national medicine call center operated by clinical pharmacists from September 2002 to June 2010. This includes the period where bDMARDs became available on the Pharmaceutical Benefits Scheme, the government-subsidized prescription medicines formulary. We compared caller and patient demographics, enquiry types and motivation to information-seek for both cDMARDs and bDMARDs with ROC, using a t-test for continuous data and a chi-square test for categorical data. We explored call narratives to identify common themes. Results: There were 1547 calls involving at least one DMARD. The top three cDMARD enquiry types were side effects (27.2%), interactions (21.9%), and risk versus benefit (11.7%). For bDMARDs, the most common queries involved availability and subsidized access (18%), mechanism and profile (15.8%), and side effects (15.1%). The main consumer motivations to information-seek were largely independent of medicines type and included: inadequate information (44%), wanting a second opinion (23.6%), concern about a worrying symptom (18.8%), conflicting information (6.9%), or information overload (2.3%). Question themes common to conventional and biological DMARDs were caller overemphasis on medication risk and the need for reassurance. Callers seeking information about bDMARDs generally overestimated effectiveness and focused their attention on availability, cost, storage, and medicine handling. Conclusion: Consumers have considerable uncertainty regarding DMARDs and may overemphasise risk. Patients cautiously assess the benefits and risks of their DMARDs but when new treatments emerge, they tend to overestimate their effectivenes

    A stitch in time: Efficient computation of genomic DNA melting bubbles

    Get PDF
    Background: It is of biological interest to make genome-wide predictions of the locations of DNA melting bubbles using statistical mechanics models. Computationally, this poses the challenge that a generic search through all combinations of bubble starts and ends is quadratic. Results: An efficient algorithm is described, which shows that the time complexity of the task is O(NlogN) rather than quadratic. The algorithm exploits that bubble lengths may be limited, but without a prior assumption of a maximal bubble length. No approximations, such as windowing, have been introduced to reduce the time complexity. More than just finding the bubbles, the algorithm produces a stitch profile, which is a probabilistic graphical model of bubbles and helical regions. The algorithm applies a probability peak finding method based on a hierarchical analysis of the energy barriers in the Poland-Scheraga model. Conclusions: Exact and fast computation of genomic stitch profiles is thus feasible. Sequences of several megabases have been computed, only limited by computer memory. Possible applications are the genome-wide comparisons of bubbles with promotors, TSS, viral integration sites, and other melting-related regions.Comment: 16 pages, 10 figure

    A developmentally regulated chaperone complex for the endoplasmic reticulum of male haploid germ cells

    Get PDF
    Glycoprotein folding is mediated by lectin-like chaperones and protein disulfide isomerases (PDIs) in the endoplasmic reticulum (ER). Calnexin and the PDI homologue ERp57 work together to help fold nascent polypeptides with glycans located toward the N-terminus of a protein, whereas PDI and BiP may engage proteins that lack glycans or have sugars toward the C-terminus. In this study, we show that the PDI homologue PDILT is expressed exclusively in post-meiotic male germ cells, in contrast to the ubiquitous expression of many other PDI family members in the testis. PDILT is induced during puberty and represents the first example of a PDI family member under developmental control. We find that PDILT is not active as an oxido-reductase, but interacts with the model peptide -somatostatin and nonnative BPTI in vitro, indicative of chaperone activity. In vivo, PDILT forms a tissue-specific chaperone complex with the calnexin homologue calmegin. The identification of a redox-inactive chaperone partnership defines a new system of testis-specific protein folding with implications for male fertility

    Patient-based benefit-risk assessment of medicines: development, refinement, and validation of a content search strategy to retrieve relevant studies

    Get PDF
    INTRODUCTION: Poor indexing and inconsistent use of terms and keywords may prevent efficient retrieval of studies on the patient-based benefit-risk assessment (BRA) of medicines. We aimed to develop and validate an objectively derived content search strategy containing generic search terms that can be adapted for any search for evidence on patient-based BRA of medicines for any therapeutic area. METHODS: We used a robust multistep process to develop and validate the content search strategy: (1) we developed a bank of search terms derived from screening studies on patient-based BRA of medicines in various therapeutic areas, (2) we refined the proposed content search strategy through an iterative process of testing sensitivity and precision of search terms, and (3) we validated the final search strategy in PubMed by firstly using multiple sclerosis as a case condition and secondly computing its relative performance versus a published systematic review on patient-based BRA of medicines in rheumatoid arthritis. RESULTS: We conceptualized a final search strategy to retrieve studies on patient-based BRA containing generic search terms grouped into two domains, namely the patient and the BRA of medicines (sensitivity 84%, specificity 99.4%, precision 20.7%). The relative performance of the content search strategy was 85.7% compared with a search from a published systematic review of patient preferences in the treatment of rheumatoid arthritis. We also developed a more extended filter, with a relative performance of 93.3% when compared with a search from a published systematic review of patient preferences in lung cancer

    Layer Analysis of the Structure of Water Confined in Vycor Glass

    Full text link
    A Molecular Dynamics simulation of the microscopic structure of water confined in a silica pore is presented. A single cavity in the silica glass has been modeled as to reproduce the main features of the pores of real Vycor glass. A layer analysis of the site-site radial distribution functions evidence the presence in the pore of two subsets of water molecules with different microscopic structure. Molecules which reside in the inner layer, close to the center of the pore, have the same structure as bulk water but at a temperature of 30 K higher. On the contrary the structure of the water molecules in the outer layer, close to the substrate, is strongly influenced by the water-substrate hydrophilic interaction and sensible distortions of the H-bond network and of the orientational correlations between neighboring molecules show up. Lowering the hydration has little effect on the structure of water in the outer layer. The consequences on experimental determinations of the structural properties of water in confinement are discussed.Comment: 6 pages, 8 figures included in the text, one figure added, changes in the tex

    Salerno's model of DNA reanalysed: could solitons have biological significance?

    Full text link
    We investigate the sequence-dependent behaviour of localised excitations in a toy, nonlinear model of DNA base-pair opening originally proposed by Salerno. Specifically we ask whether ``breather'' solitons could play a role in the facilitated location of promoters by RNA polymerase. In an effective potential formalism, we find excellent correlation between potential minima and {\em Escherichia coli} promoter recognition sites in the T7 bacteriophage genome. Evidence for a similar relationship between phage promoters and downstream coding regions is found and alternative reasons for links between AT richness and transcriptionally-significant sites are discussed. Consideration of the soliton energy of translocation provides a novel dynamical picture of sliding: steep potential gradients correspond to deterministic motion, while ``flat'' regions, corresponding to homogeneous AT or GC content, are governed by random, thermal motion. Finally we demonstrate an interesting equivalence between planar, breather solitons and the helical motion of a sliding protein ``particle'' about a bent DNA axis.Comment: Latex file 20 pages, 5 figures. Manuscript of paper to appear in J. Biol. Phys., accepted 02/09/0

    Experimental study exploring the interaction of structural and leakage dynamics

    Get PDF
    Strategies for managing leakage from water distribution systems require the ability to effectively evaluate such real losses through the understanding of the behavior of individual leaks, including their response to changes in pressure regime due to demand or management strategies. This paper presents the results from an innovative experimental investigation aimed at understanding the response of longitudinal slits in pressurized viscoelastic pipes, specifically considering the interaction between the structural and leakage dynamics. For the first time, leakage flow rate, pressure, leak area, and material strain were recorded simultaneously, providing new knowledge of the complex interaction of these factors. The paper shows that strain and area are directly related, hence it is possible to employ strain as a predictor of leak area, calculated using a calibrated viscoelastic model. Using such an approach, the leakage flow rates under a range of quasi-static pressures were accurately predicted and validated. Overall the paper demonstrates that the orifice equation, with a constant coefficient of discharge, is suitable for accurately estimating dynamic leakage flow rates from longitudinal slits, provided that the leak area is suitably incorporated
    • …
    corecore