Influence of husbandry procedures on mouse locomotor activity

The currently used raL models of obesity and diabetes are derived from either Zucker or from Koletsky rats. Recently, we identified a spontaneous obese rat from out Wistar colony which is maintained as an inbred stock for the past 75 years. Initially, one of the male progeny in a litter was observed to have abnormal body weight for its age. The parents of this ral were identified, the progeny selectively bred, and a colony has been developed. This is designated as WNIN-0b. The colony is maintained by mating heterozygous animals (+/ob), as the homozygous (ob/ob) were found to be infertile. The trait is carried as an autosomal recessive mutation and the colony is currenfly in F7 generation.Obesity is visible in these mutants around 35 days of age. They are hyperphagic and reach a body weight of 500—600 g by 105 days of age. “Kinky” tail is characteristic of this mutant and this is visible around 50-60 days. Sexual maturity is delayed in female obese mutants, as judged by the day of vaginal opening. The animals are cuglyccmic and show hyperinsulinaemia, hypertriglyceridaemia, arid hypercholesterolemia. Another mutant showing hyperglycemia is also obtained fromthe obese colony. Unlike earlier models which are essentially derived from a randomAbred stock, this is the first report of a rat obese model, developed spontaneously from an inbred strain

Identifying key denning habitat to conserve brown bear (Ursus arctos) in Croatia

CONTEXT: The preservation of denning habitat is paramount to the recovery of threatened bear populations because of the effect that den site disturbance can have on cub mortality. Understanding habitat suitability for denning can allow management efforts to be directed towards the regions where conservation interventions would be most effective. AIM: We sought to identify the environmental and anthropogenic habitat variables associated with the presence of Eurasian brown bear (Ursus arctos) den sites in Croatia. Based on these associations, in order to inform future conservation decisions, we also sought to identify regions of high suitability for denning across Croatia. METHODS: Using the locations of 91 dens inhabited by bears between 1982 and 2011, we opted for the presence-only modelling option in software Maxent to determine the most important predictors of den presence, and thus predict the distribution of high-value denning habitat across Croatia. KEY RESULTS: We found that structural elements were the most important predictors, with ruggedness and elevation both relating positively to den presence. However, distance to nearest settlement was also positively associated with den presence. CONCLUSION: We determine that there is considerable denning habitat value in areas with high and rugged terrain as well as areas with limited human activity. We suspect that high and rugged terrain contains a greater concentration of the karstic formations used for denning than lower-lying regions. IMPLICATIONS: Our study presents the first habitat suitability model for brown bears in Croatia, and identifies core areas suitable for denning both within and outside the species’ current range. As such, it provides useful evidence for conservation decision making and the development of scientifically-based management plans. Our results also support the need for finer spatial scale studies that can reveal specific denning preferences of subpopulations

Immune-Complex Mimics as a Molecular Platform for Adjuvant-Free Vaccine Delivery

Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen-presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-γ secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role

Mucosal Therapy of Multi-Drug Resistant Tuberculosis With IgA and Interferon-γ

New evidence has been emerging that antibodies can be protective in various experimental models of tuberculosis. Here, we report on protection against multidrug-resistant Mycobacterium tuberculosis (MDR-TB) infection using a combination of the human monoclonal IgA 2E9 antibody against the alpha-crystallin (Acr, HspX) antigen and mouse interferon-gamma in mice transgenic for the human IgA receptor, CD89. The effect of the combined mucosal IgA and IFN-γ; treatment was strongest (50-fold reduction) when therapy was applied at the time of infection, but a statistically significant reduction of lung bacterial load was observed even when the therapy was initiated once the infection had already been established. The protection involving enhanced phagocytosis and then neutrophil mediated killing of infected cells was IgA isotype mediated, because treatment with an IgG version of 2E9 antibody was not effective in human IgG receptor CD64 transgenic mice. The Acr antigen specificity of IgA antibodies for protection in humans has been indicated by their elevated serum levels in latent tuberculosis unlike the lack of IgA antibodies against the virulence-associated MPT64 antigen. Our results represent the first evidence for potential translation of mucosal immunotherapy for the management of MDR-TB

Structured decision-making drives guidelines panels’ recommendations ‘for’ but not ‘against’ health interventions

Background: The determinants of guideline panels’ recommendations remain uncertain. Objective: To investigate factors considered by members of 8 panels convened by the American Society of Hematology (ASH) to develop guidelines using GRADE system. Study Design and Setting: web-based survey of the participants in the ASH guidelines panels. Analysis: two level hierarchical, random-effect, multivariable regression analysis to explore the relation between GRADE and non-GRADE factors and strength of recommendations (SOR). Results: In the primary analysis, certainty in evidence [OR=1.83; (95CI% 1.45 to 2.31)], balance of benefits and harms [OR=1.49 (95CI% 1.30 to 1.69)] and variability in patients’ values and preferences [OR=1.47 (95CI% 1.15 to 1.88)] proved the strongest predictors of SOR. In a secondary analysis, certainty of evidence was associated with a strong recommendation [OR=3.60 (95% CI 2.16 to 6.00)] when panel members recommended “for” interventions but not when they made recommendations “against” [OR=0.98 (95%CI: 0.57 to 1.8)] consistent with “yes” bias. Agreement between individual members and the group in rating SOR varied (kappa ranged from -0.01 to 0.64). Conclusion: GRADE’s conceptual framework proved, in general, highly associated with SOR. Failure of certainty of evidence to be associated with SOR against an intervention, suggest the need for improvements in the process

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

Gastrointestinal complaints in runners are not due to small intestinal bacterial overgrowth

<p>Abstract</p> <p>Background</p> <p>Gastrointestinal complaints are common among long distance runners. We hypothesised that small intestinal bacterial overgrowth (SIBO) is present in long distance runners frequently afflicted with gastrointestinal complaints.</p> <p>Findings</p> <p>Seven long distance runners (5 female, mean age 29.1 years) with gastrointestinal complaints during and immediately after exercise without known gastrointestinal diseases performed Glucose hydrogen breath tests for detection of SIBO one week after a lactose hydrogen breath test checking for lactose intolerance. The most frequent symptoms were diarrhea (5/7, 71%) and flatulence (6/7, 86%). The study was conducted at a laboratory.</p> <p>In none of the subjects a pathological hydrogen production was observed after the intake of glucose. Only in one athlete a pathological hydrogen production was measured after the intake of lactose suggesting lactose intolerance.</p> <p>Conclusions</p> <p>Gastrointestinal disorders in the examined long distance runners were not associated with small intestinal bacterial overgrowth.</p

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction