Properties of thiamine transport in isolated perfused hearts of chronically alcoholic guinea pigs

The aim of this study was to determine the mechanism of transport of (14)C-thiamine in the hearts of healthy (nonalcoholic) and chronically alcoholic guinea pigs. We used the single-pass, paired-tracer dilution method on isolated and retrogradely perfused guinea pig hearts. The maximal cellular uptake (U(max)) and total cellular uptake (U(tot)) of (14)C-thiamine were determined under control conditions and under influence of possible modifiers. We tested how the presence of unlabeled thiamine, metabolic inhibitors, or absence of sodium ions influence the transport of (14)C-thiamine. The results of our experiments show that the transport of (14)C-thiamine is specific and energy-dependent and that its properties are significantly changed under the influence of chronic alcoholism. The latter effect occurs by increase in both U(max) and U(tot), as a manifestation of a compensatory mechanism in thiamine deficiency.     

Effects of Obesity on the Conversion from Normal Glucose Tolerance to Diabetes in Hong Kong Chinese

Objective: To assess the effects of BMI on progression to diabetes in Hong Kong Chinese and to analyze the optimal cutoff for overweight and obesity in Hong Kong Chinese. Research Methods and Procedures: This is a prospective study with a mean follow‐up of 2.1 years (median 1.4 years, range 0.9 to 8.4 years). We recruited 172 nondiabetic high‐risk subjects, of whom 115 had normal glucose tolerance (NGT) and 57 had impaired glucose tolerance (IGT). BMI and 75‐gram oral glucose tolerance tests were assessed at baseline and then at yearly intervals Results: The crude rates of progression to diabetes for subjects with NGT or IGT were 8.4% and 11.5% per year, respectively. For subjects with NGT, the progression rate to diabetes differed with different BMI ranges. For subjects with NGT and BMI ≥ 25 kg/m², the crude rates of progression to diabetes or glucose intolerance (diabetes or IGT) were 12.5% per year and 14.6% per year, respectively. The corresponding rates for subjects with NGT and BMI ≥ 28 kg/m² were 14.6% and 18.9% per year, respectively. Among subjects with NGT, those with BMI between 25 and 28 kg/m² had the highest Youden index and likelihood ratio to predict the conversion to diabetes or glucose intolerance. Discussion: Obese subjects with NGT had higher rates of progression to diabetes than nonobese subjects. We recommend redefining BMI cutoffs, with 23 kg/m² for overweight and 28 kg/m² for obesity. This definition may be more sensitive to identify at‐risk subjects and more specific to identify “patients” for therapeutic management.     

Patch dynamics in a landscape modified by ecosystem engineers

Ecosystem engineers, organisms that modify the environment, have the potential to dramatically alter ecosystem structure and function at large spatial scales. The degree to which ecosystem engineering produces large-scale effects is, in part, dependent on the dynamics of the patches that engineers create. Here we develop a set of models that links the population dynamics of ecosystem engineers to the dynamics of the patches that they create. We show that the relative abundance of different patch types in an engineered landscape is dependent upon the production of successful colonists from engineered patches and the rate at which critical resources are depleted by engineers and then renewed. We also consider the effects of immigration from either outside the system or from engineers that are present in non-engineered patches, and the effects of engineers that can recolonize patches before they are fully recovered on the steady state distribution of different patch types. We use data collected on the population dynamics of a model engineer, the beaver, to estimate the per-patch production rate of new colonists, the decay rate of engineered patches, and the recovery rate of abandoned patches. We use these estimated parameters as a baseline to determine the effects of varying parameters on the distribution of different patch types. We suggest a number of hypotheses that derive from model predictions and that could serve as tests of the model.     

Ryanodine receptors, voltage-gated calcium channels and their relationship with protein kinase A in the myocardium

We present a review about the relationship between ryanodine receptors and voltage-gated calcium channels in myocardium, and also how both of them are related to protein kinase A. Ryanodine receptors, which have three subtypes (RyR1-3), are located on the membrane of sarcoplasmic reticulum. Different subtypes of voltage-gated calcium channels interact with ryanodine receptors in skeletal and cardiac muscle tissue. The mechanism of excitation-contraction coupling is therefore different in the skeletal and cardiac muscle. However, in both tissues ryanodine receptors and voltage-gated calcium channels seem to be physically connected. FK-506 binding proteins (FKBPs) are bound to ryanodine receptors, thus allowing their concerted activity, called coupled gating. The activity of both ryanodine receptors and voltage-gated calcium channels is positively regulated by protein kinase A. These effects are, therefore, components of the mechanism of sympathetic stimulation of myocytes. The specificity of this enzyme's targeting is achieved by using different A kinase adapting proteins. Different diseases are related to inborn or acquired changes in ryanodine receptor activity in cardiac myocytes. Mutations in the cardiac ryanodine receptor gene can cause catecholamine-provoked ventricular tachycardia. Changes in phosphorylation state of ryanodine receptors can provide a credible explanation for the development of heart failure. The restoration of their normal level of phosphorylation could explain the positive effect of beta-blockers in the treatment of this disease. In conclusion, molecular interactions of ryanodine receptors and voltage-gated calcium channels with PKA have a significant physiological role. However, their defects and alterations can result in serious disturbances.     

Identifying multiscale habitat factors influencing koala (Phascolarctos cinereus) occurrence and management in Ballarat, Victoria, Australia

Summary   Modelling for the conservation of koala ( Phascolarctos cinereus ) populations has primarily focused on natural habitat variables (e.g. tree species, soil types and soil moisture). Until recently, limited consideration has been given to modelling the effects of the landscape context (e.g. habitat area, habitat configuration and roads). Yet, the combined influence of natural habitats and anthropogenic impacts at multiple spatial scales are likely to be important determinants of where koala populations occur and remain viable in human-modified landscapes. The study tested the importance of multiscale habitat variables on koala occurrence in Ballarat, Victoria, Australia. The models focused at three spatial scales: site ( <  1 ha), patch (1–100 ha), and landscape (100–1000 s ha). Logistic regression and hierarchical partitioning analyses were used to rank alternative models and key explanatory variables.
The results showed that an increased likelihood of koala presence in fragmented landscapes in the urban–forest interface (as opposed to larger blocks of forest habitat) can best be explained by the positive effects of soil fertility and the presence of preferred koala tree species in these fragmented areas. If koalas are to be effectively conserved in Ballarat, it is critical to (i) protect remaining core areas of high-quality habitat, including regenerating areas; (ii) protect scattered habitat patches which provide connectivity; and (iii) develop and implement habitat restoration programmes to improve habitat connectivity and enhance opportunities for safe koala movement between habitat patches intersected by main roads.     

Some practical suggestions for improving engagement between researchers and policy‐makers in natural resource management

Summary Policy‐makers and managers in natural resource management (NRM) often complain that researchers are out of touch. Researchers often complain that policy‐makers and managers make poorly informed decisions. In this article, we report on a meeting between researchers, policy‐makers and managers convened to identify practical solutions to improve engagement between these camps. A necessary starting point is that every researcher and policy‐maker should understand, and tap into, the motivations and reward systems of the other when seeking engagement. For example, researchers can be motivated to engage in policy development if there is a promise of outputs that align with their reward systems such as co‐authored publications. Successful research–policy partnerships are built around personal relationships. As a researcher, you cannot therefore expect your results to inform policy by only publishing in journals. As a policy‐maker, you cannot guarantee engagement from researchers by publicly inviting comment on a document. Actively building and maintaining relationships with key individuals through discussions, meetings, workshops or field days will increase the likelihood that research outcomes will inform policy decisions. We identified secondments, sabbaticals, fellowships and ‘buddies’, an annual national NRM conference and ‘contact mapping’ (a Facebook‐type network) as forums that can catalyse new relationships between researchers and policy‐makers. We challenge every researcher, policy‐maker and manager in NRM to build one new cross‐cultural relationship each year.     

Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors

The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. The series was found to have much improved CDK2 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. Control of overall lipophilicity was important to achieve good in vitro potency along with acceptable physiochemical properties and margins against inhibition of both CYP isoforms and the hERG potassium ion channel. A compound with an attractive overall balance of properties was profiled in vivo and possessed suitable physiochemical and pharmacokinetic profiles for oral dosing.     

Differential protein expression in the corpus callosum (genu) of human alcoholics

Ethanol is an addictive drug that deteriorates different neuronal pathways in the CNS, leading to the induction of cognitive dysfunction. Neuroimaging analyses revealed that alcohol-induced brain damage appears to be region-specific and major dysmorphology has been observed in the prefrontal cortex and the white matter (WM) particularly in the corpus callosum (CC). Recent diffusion tensor imaging (DTI) analysis indicated that microstructural degradation was prominent in the genu followed by the body and the splenium of the CC. Molecular mechanisms underlying these structural changes are largely unknown. In this study, using 2D electrophoresis based proteomics approach, protein expression profiles in 25 genus samples (12 controls, 7 uncomplicated alcoholics and 6 complicated alcoholics with hepatic cirrhosis) were analysed and compared. Image analysis showed that 35 protein spots in the uncomplicated alcoholic and 56 in the complicated group were differentially altered compared to the control (P<0.05; ANOVA). In total of 91 spots, 25 spots were overlapped between two alcoholic groups. When protein expression profile of the genu was compared with those in other WMs [BA9 white matter (WM) and splenium] the highest number of region-specific proteins was identified in the genus indicating that genu might be the most sensitive and/or vulnerable region to chronic alcohol ingestion at least from the aspect of protein expression. Out of total 66 spots (identified as 50 different proteins), 31 spots (identified as 28 different proteins) were expressed only in the complicated group. This result indicates that alcohol-related liver dysfunction has synergetic effects on brain protein expression. It is also interesting to note that abnormality in thiamine-related cascade which was previously found in the BA9 WM was observed in the genu, but not in the splenium. It is therefore suggested that both hepatic and nutritious factors might be underlying the mechanisms of microstructural damage detected by DTI.     

Differential roles of the COOH termini of AAA subunits of PA700 (19 S regulator) in asymmetric assembly and activation of the 26 S proteasome

The 26 S proteasome is an energy-dependent protease that degrades proteins modified with polyubiquitin chains. It is assembled from two multi-protein subcomplexes: a protease (20 S proteasome) and an ATPase regulatory complex (PA700 or 19 S regulatory particle) that contains six different AAA family subunits (Rpt1 to -6). Here we show that binding of PA700 to the 20 S proteasome is mediated by the COOH termini of two (Rpt2 and Rpt5) of the six Rpt subunits that constitute the interaction surface between the subcomplexes. COOH-terminal peptides of either Rpt2 or Rpt5 bind to the 20 S proteasome and activate hydrolysis of short peptide substrates. Simultaneous binding of both COOH-terminal peptides had additive effects on peptide substrate hydrolysis, suggesting that they bind to distinct sites on the proteasome. In contrast, only the Rpt5 peptide activated hydrolysis of protein substrates. Nevertheless, the COOH-terminal peptide of Rpt2 greatly enhanced this effect, suggesting that proteasome activation is a multistate process. Rpt2 and Rpt5 COOH-terminal peptides cross-linked to different but specific subunits of the 20 S proteasome. These results reveal critical roles of COOH termini of Rpt subunits of PA700 in the assembly and activation of eukaryotic 26 S proteasome. Moreover, they support a model in which Rpt subunits bind to dedicated sites on the proteasome and play specific, nonequivalent roles in the asymmetric assembly and activation of the 26 S proteasome.