519 research outputs found
Ribose supplementation alone or with elevated creatine does not preserve high energy nucleotides or cardiac function in the failing mouse heart
Background: Reduced levels of creatine and total adenine nucleotides (sum of ATP, ADP and AMP) are hallmarks of chronic
heart failure and restoring these pools is predicted to be beneficial by maintaining the diseased heart in a more favourable
energy state. Ribose supplementation is thought to support both salvage and re-synthesis of adenine nucleotides by
bypassing the rate-limiting step. We therefore tested whether ribose would be beneficial in chronic heart failure in control
mice and in mice with elevated myocardial creatine due to overexpression of the creatine transporter (CrT-OE).
Methods and Results: Four groups were studied: sham; myocardial infarction (MI); MI+ribose; MI+CrT-OE+ribose. In a pilot
study, ribose given in drinking water was bioavailable, resulting in a two-fold increase in myocardial ribose-5-phosphate
levels. However, 8 weeks post-surgery, total adenine nucleotide (TAN) pool was decreased to a similar amount (8–14%) in all
infarcted groups irrespective of the treatment received. All infarcted groups also presented with a similar and substantial
degree of left ventricular (LV) dysfunction (3-fold reduction in ejection fraction) and LV hypertrophy (32–47% increased
mass). Ejection fraction closely correlated with infarct size independently of treatment (r2 = 0.63, p<0.0001), but did not
correlate with myocardial creatine or TAN levels.
Conclusion: Elevating myocardial ribose and creatine levels failed to maintain TAN pool or improve post-infarction LV
remodeling and function. This suggests that ribose is not rate-limiting for purine nucleotide biosynthesis in the chronically
failing mouse heart and that alternative strategies to preserve TAN pool should be investigated
Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart
Background: Multiple studies suggest creatine mediates anti-oxidant activity in addition to its established role in cellular
energy metabolism. The functional significance for the heart has yet to be established, but antioxidant activity could
contribute to the cardioprotective effect of creatine in ischaemia/reperfusion injury.
Objectives: To determine whether intracellular creatine levels influence responses to acute reactive oxygen species (ROS)
exposure in the intact beating heart. We hypothesised that mice with elevated creatine due to over-expression of the
creatine transporter (CrT-OE) would be relatively protected, while mice with creatine-deficiency (GAMT KO) would fare
worse.
Methods and Results: CrT-OE mice were pre-selected for creatine levels 20–100% above wild-type using in vivo 1
H–
MRS.
Hearts were perfused in isovolumic Langendorff mode and cardiac function monitored throughout. After 20 min
equilibration, hearts were perfused with either H2O2 0.5 mM (30 min), or the anti-neoplastic drug doxorubicin 15 mM
(100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCd expression were quantified in
perfused hearts as markers of oxidative damage and apoptotic signalling. Wild-type hearts responded to ROS challenge
with a profound decline in contractile function that was ameliorated by co-administration of catalase or dexrazoxane as
positive controls. In contrast, the functional deterioration in CrT-OE and GAMT KO hearts was indistinguishable from wildtype
controls, as was the extent of oxidative damage and apoptosis. Exogenous creatine supplementation also failed to
protect hearts from doxorubicin-induced dysfunction.
Conclusions: Intracellular creatine levels do not influence the response to acute ROS challenge in the intact beating heart,
arguing against creatine exerting (patho-)physiologically relevant anti-oxidant activity
SQCD Inflation & SUSY Breaking
A model of generalised hybrid inflation in a supersymmetric QCD theory is
proposed whose parameters are the gauge coupling and quark masses. Its
gravitational coupling to another SQCD sector induces a metastable
supersymmetry breaking vacuum of the ISS type as ISS quarks become massive at
the end of inflation. Using a known mechanism with a gravitational breaking of
the baryon number and the gauging of flavour symmetries, we find that gauge
mediation of supersymmetry breaking is compatible with the dynamics of the
inflation sector. Reheating proceeds via the thermalization of the ISS
messengers into the standard model states. This setup contains a single
dimensionful parameter in the form of a quark mass term in the inflationary
sector, i.e. all other scales involved are either related to this single mass
parameter or dynamically generated.Comment: 15 pages, typos corrected, references adde
Anisotropic three-dimentional magnetic fluctuations in heavy fermion CeRhIn5
CeRhIn5 is a heavy fermion antiferromagnet that orders at 3.8 K. The
observation of pressure-induced superconductivity in CeRhIn5 at a very high Tc
of 2.1 K for heavy fermion materials has led to speculations regarding to its
magnetic fluctuation spectrum. Using magnetic neutron scattering, we report
anisotropic three-dimensional antiferromagnetic fluctuations with an energy
scale of less than 1.7 meV for temperatures as high as 3Tc. In addition, the
effect of the magnetic fluctuations on electrical resistivity is well described
by the Born approximation.Comment: 4 pages, 4 figure
Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema Attacks : COMPACT subgroup findings
It's not only about technology, it's about people: interpersonal skills as a part of the IT education.
Proceedings of: Second World Summit on the Knowledge Society (WSKS 2009), Chania, Crete, Greece, September 16-18, 2009.The importance of what have been termed the "soft skills" for the professional development of IT professionals is beyond any doubt. Taking account of this circumstance, the objective of the current research may be phrased as two separate questions. In the first place, determining the importance which IT related degree students place on these types of competencies for their professional future. In the second place, the importance which the development of the mentioned competencies has been given during their studies. The realization of an empirical study has fulfilled the two objectives described. The results demonstrate, on the one side, the moderate relevance which students assign to interpersonal competencies, especially emotional competencies, in contrast to the international curricular recommendations and studies concerning labor markets. On the other hand, the results indicate the scarce emphasis which lecturers have placed on the development of such competencies.Publicad
Advances in Distinguishing Groundwater Influenced by Oil Sands Process-Affected Water (OSPW) from Natural Bitumen-Influenced Groundwater
The objective of this study was to advance analytical methods for detecting oil sands process-affected water (OSPW) seepage from mining containments and discriminating any such seepage from the natural bitumen background in groundwaters influenced by the Alberta McMurray formation. Improved sampling methods and quantitative analyses of two groups of monoaromatic acids were employed to analyze OSPW and bitumen-affected natural background groundwaters for source discrimination. Both groups of monoaromatic acids showed significant enrichment in OSPW, while ratios of O /O containing heteroatomic ion classes of acid extractable organics (AEOs) did not exhibit diagnostic differences. Evaluating the monoaromatic acids to track a known plume of OSPW-affected groundwater confirmed their diagnostic abilities. A secondary objective was to assess anthropogenically derived artificial sweeteners and per- and polyfluoroalkyl substances (PFAS) as potential tracers for OSPW. Despite the discovery of acesulfame and PFAS in most OSPW samples, trace levels in groundwaters influenced by general anthropogenic activities preclude them as individual robust tracers. However, their inclusion with the other metrics employed in this study served to augment the tiered, weight of evidence methodology developed. This methodology was then used to confirm earlier findings of OSPW migrations into groundwater reaching the Athabasca River system adjacent to the reclaimed pond at Tar Island Dyke
Dose Precision Using a Pretransplant Test PK of Intravenous Busulfan Prior to BuCyVP-16 Preparative Regimen in Lymphoma
Decreased occurrence of ketoacidosis and preservation of beta cell function in relatives screened and monitored for type 1 diabetes in Australia and New Zealand
Published December 2022Aims: Islet autoantibody screening of infants and young children in the Northern Hemisphere, together with semi-annual metabolic monitoring, is associated with a lower risk of ketoacidosis (DKA) and improved glucose control after diagnosis of clinical (stage 3) type 1 diabetes (T1D). We aimed to determine if similar benefits applied to older Australians and New Zealanders monitored less rigorously. Methods: DKA occurrence and metabolic control were compared between T1D relatives screened and monitored for T1D and unscreened individuals diagnosed in the general population, ascertained from the Australasian Diabetes Data Network. Results: Between 2005 and 2019, 17,105 relatives (mean (SD) age 15.7 (10.8) years; 52% female) were screened for autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2. Of these, 652 screened positive to a single and 306 to multiple autoantibody specificities, of whom 201 and 215, respectively, underwent metabolic monitoring. Of 178 relatives diagnosed with stage 3 T1D, 9 (5%) had DKA, 7 of whom had not undertaken metabolic monitoring. The frequency of DKA in the general population was 31%. After correction for age, sex and T1D family history, the frequency of DKA in screened relatives was >80% lower than in the general population. HbA1c and insulin requirements following diagnosis were also lower in screened relatives, consistent with greater beta cell reserve. Conclusions: T1D autoantibody screening and metabolic monitoring of older children and young adults in Australia and New Zealand, by enabling pre-clinical diagnosis when beta cell reserve is greater, confers protection from DKA. These clinical benefits support ongoing efforts to increase screening activity in the region and should facilitate the application of emerging immunotherapies.John M. Wentworth, Helena Oakey, Maria E. Craig, Jennifer J. Couper, Fergus J. Cameron, Elizabeth A. Davis, Antony R. Lafferty, Mark Harris, Benjamin J. Wheeler, Craig Jefferies, Peter G. Colman, Leonard C. Harriso
Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework
Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency
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