Studies of DNA Structures Linking Sister Chromatids, the Proteins that Regulate them, and their Impact on Segregation During Anaphase

Type IIA topoisomerases have long been attributed the ability to simplify DNA topology – supercoils, knots and catenanes – far beyond their thermodynamic equilibrium. Such activity makes clear biological sense, however topology of a DNA molecule is a global attribute, and type IIA topoisomerases are capable only of recognizing local structures that constitute workable substrates. In the case of type IIA topoisomerases local DNA juxtapositions embody these substrates. To be able to reliably simplify DNA topology, without by chance increasing its complexity, these enzymes would be required to have the ability to discern some aspect of the global topology from the interactions with these local juxtaposed DNA substrates. Previous studies have generated computer simulations of juxtaposed chromatin segments whereby information regarding the global topological state is somehow communicated to the enzyme. These models vary in nature, from protein- centric models involving the forced introduction of ‘kinks’ into the DNA, to DNA-centric models, which suggest alterations in chirality of crosses are suggestive of the topological state of the molecule, and thus all local DNA juxtapositions encode details of higher order structure. For the system to function in this manner, information ‘encoded’ in one DNA juxtaposition would have to become altered when other distinct substrates are acted upon. This study aimed to investigate whether S. cerevisiae topoisomerase II is capable of enforcing directional alteration of the ratio of catenated plasmid dimers to monomers in vivo. Systems that artificially generate increased proximity between plasmids were tested and yielded inconclusive results pertaining to this question. Existing evidence has shown a shift in the supercoiling state from (-) to (+) occurs at the metaphase to anaphase transition, and that this forces Top2 to resolve catenated nodes in favour of relaxing supercoils, however this transition would gain credence in the case that prior to this event Top2 was able to concatenate DNA, and that the probability of this occurring was equal to the likelihood of catenated nodes becoming resolved. Further investigation of this transition has revealed the requirement for Cdc5, and Scc1. Additionally the localization of the Condensin complex was analyzed to gain a better understanding of how transition factors are regulated.Open Acces

Development of the Rural Generalist Program Japan: meeting the needs of Japanese rural communities

Context: There is a worldwide shortage of physicians, which is worse in rural areas, with a large underserved rural and remote population. Most jurisdictions in countries of all income levels report shortages of rural doctors, often exacerbated where primary care is not strong. Japan is not an exception: Japanese specialist-driven approaches in medical education and public health have resulted in disproportionate distribution of medical services in the country. Issue: Rural generalism, or rural generalist medicine, is emerging in many jurisdictions as one approach to training and provision of care for rural communities. While there is considerable variation in titles, the format of the training and models of care, the emphasis is on training a generalist doctor capable of meeting community needs. This usually includes development of appropriate skills in primary care, inpatient care, emergency medicine, public health and one or more extended skills. These models are well established in Australia, particularly in Queensland, which has offered a rural generalist program for over a decade. The Rural Generalist Program Japan (RGPJ) has been developed to meet the needs of Japanese rural communities. Lessons learned: This article outlines development of the RGPJ using the World Federation for Medical Education standards. While early evaluations are positive, there is much more to do to develop a mature program capable of meeting the needs of Japan's rural and remote communities

Adding a Brane to the Brane-Anti-Brane Action in BSFT

We attempt to generalize the effective action for the D-brane-anti-D-brane system obtained from boundary superstring field theory (BSFT) by adding an extra D-brane to it to obtain a covariantized action for 2 D-branes and 1 anti-D-brane. We discuss the approximations made to obtain the effective action in closed form. Among other properties, this effective action admits solitonic solutions of codimension 2 (vortices) when one of the D-brane is far separated from the brane-anti-brane pair.Comment: 23 pages, 2 figures, minor revision

International approaches to rural generalist medicine: a scoping review

Background: Contemporary approaches to rural generalist medicine training and models of care are developing internationally as part of an integrated response to common challenges faced by rural and remote health services and policymakers (addressing health inequities, workforce shortages, service sustainability concerns). The aim of this study was to review the literature relevant to rural generalist medicine. Methods: A scoping review was undertaken to answer the broad question 'What is documented on rural generalist medicine?' Literature from January 1988 to April 2017 was searched and, after final eligibility filtering (according to established inclusion and exclusion criteria), 102 articles in English language were included for final analysis. Results: Included papers were analysed and categorised by geographic region, study design and subject themes. The majority of articles (80%) came from Australia/New Zealand and North America, reflecting the relative maturity of programmes supporting rural generalist medicine in those countries. The most common publication type was descriptive opinion pieces (37%), highlighting both a need and an opportunity to undertake and publish more systematic research in this area. Important themes emerging from the review were: - Definition - Existing pathways and programmes - Scope of practice and service models - Enablers and barriers to recruitment and retention - Reform recommendations There were some variations to, or criticisms of, the definition of rural generalist medicine as applied to this review, although this was only true of a small number of included articles. Across remaining themes, there were many similarities and consistent approaches to rural generalist medicine between countries, with some variations reflecting environmental context and programme maturity. This review identified recent literature from countries with emerging interest in rural generalist medicine in response to problematic rural health service delivery. Conclusions: Supported, coordinated rural generalist medicine programmes are being established or developed in a number of countries as part of an integrated response to rural health and workforce concerns. Findings of this review highlight an opportunity to better share the development and evaluation of best practice models in rural generalist medicine

Brane Interaction as the Origin of Inflation

We reanalyze brane inflation with brane-brane interactions at an angle, which include the special case of brane-anti-brane interaction. If nature is described by a stringy realization of the brane world scenario today (with arbitrary compactification), and if some additional branes were present in the early universe, we find that an inflationary epoch is generically quite natural, ending with a big bang when the last branes collide. In an interesting brane inflationary scenario suggested by generic string model-building, we use the density perturbation observed in the cosmic microwave background and the coupling unification to find that the string scale is comparable to the GUT scale.Comment: 28 pages, 8 figures, 2 tables, JHEP forma

Ion-Exchanged Waveguides in Glass Doped with PbS Quantum Dots

The lowest-loss (≤1 dB/cm) ion-exchanged waveguides in glass doped with PbS quantum dots are presented. Near-field mode profile and refractive index profile using the refracted near-field technique were measured for these waveguides. We demonstrate that the optical properties of this glass unchanged during the ion-exchange process

Artemisinin resistance in Plasmodium falciparum malaria.

BACKGROUND: Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. METHODS: In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. RESULTS: We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. CONCLUSIONS: P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.

R/qtl2: Software for Mapping Quantitative Trait Loci with High-Dimensional Data and Multiparent Populations.

R/qtl2 is an interactive software environment for mapping quantitative trait loci (QTL) in experimental populations. The R/qtl2 software expands the scope of the widely used R/qtl software package to include multiparent populations derived from more than two founder strains, such as the Collaborative Cross and Diversity Outbred mice, heterogeneous stocks, and MAGIC plant populations. R/qtl2 is designed to handle modern high-density genotyping data and high-dimensional molecular phenotypes, including gene expression and proteomics. R/qtl2 includes the ability to perform genome scans using a linear mixed model to account for population structure, and also includes features to impute SNPs based on founder strain genomes and to carry out association mapping. The R/qtl2 software provides all of the basic features needed for QTL mapping, including graphical displays and summary reports, and it can be extended through the creation of add-on packages. R/qtl2, which is free and open source software written in the R and C++ programming languages, comes with a test framework

Tetraphenylpentalenide organolanthanide complexes

The D2h symmetrical 1,3,4,6-tetraphenylpentalenide is an excellent ligand for the stabilisation of strongly coloured bis(pentalenide) LnIII sandwich complexes. These easily accessible compounds complement previously reported lanthanide organometallics and provide new opportunities to understand the roles of the f-orbitals in electronic structure and bonding

Ockham’s Razor for a Retinal Lesion and Acromegaly and Breaking the Vicious Circle

Acromegaly due to ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. Treatment consists of surgical removal of the primary tumor, cytostatic therapy, “cold” or radioactive somatostatin analogue treatment, and medical therapy for acromegaly, if needed. A 53 year-old female had an ocular lesion noted on a routine optician visit, originally considered to be an ocular melanoma. She had a bronchial carcinoid successfully removed 22 years previously. She had acromegalic features with an enlarged pituitary gland on magnetic resonance imaging and, additionally, metastatic lesions in her bones, liver, and thyroid gland. Elevated GHRH levels (&amp;gt;250× upper limit of normal) suggested a metastatic lung neuroendocrine tumor secreting GHRH. Cold and radioactive somatostatin analogue therapy reduced both GHRH and insulin-like growth factor 1 (IGF-1) levels, but normalization of the biochemical markers of acromegaly was only achieved after pegvisomant was introduced. Complete control of IGF-1 was achieved, and this may have hindered the growth of the metastatic lesions as well, as the patient remains well 13 years after the diagnosis of metastatic disease and 35 years after the original lung operation. A gradual rise in prolactin levels over last 4 years was noted, which is likely due to the prolonged effect of GHRH on prolactin-secreting cells. The diagnosis of this case applied the law of parsimony from the Ockham’s razor principle. We consider that breaking the vicious circle of IGF-1 feeding the metastatic tumor was key for the long-term outcome of this case