Molecular basis of copper transport: cellular and physiological functions of Menkes and Wilson disease proteins (ATP7A and ATPB)

Eukaryotic cells prevent copper-induced, free radical damage to cell components by employing copper-binding proteins and transporters that minimize the likelihood of free copper ions existing in the cell. In the cell, copper is actively transported from the cytoplasm during the biosynthesis of secreted coppercontaining proteins and, as a protective measure, when there is an excess of copper. In humans, this is accomplished by two related copper-transporting ATPases (ATP7A and ATP7B), which are the affected genes in two distinct human genetic disorders of copper transport, Menkes disease (copper deficiency) and Wilson disease (copper toxicosis). The study of these ATPases has revealed their molecular mechanisms of copper transport and their roles in physiological copper homeostasis. Both ATP7A and ATP7B are expressed in specific brain regions and neurological abnormalities are important clinical features in Menkes and Wilson disease.

Metabolism and functions of copper in brain

Copper is an important trace element that is required for essential enzymes. However, due to its redox activity, copper can also lead to the generation of toxic reactive oxygen species. Therefore, cellular uptake, storage as well as export of copper have to be tightly regulated in order to guarantee sufficient copper supply for the synthesis of copper-containing enzymes but also to prevent copper-induced oxidative stress. In brain, copper is of importance for normal development. In addition, both copper deficiency as well as excess of copper can seriously affect brain functions. Therefore, this organ possesses ample mechanisms to regulate its copper metabolism. In brain, astrocytes are considered as important regulators of copper homeostasis. Impairments of homeostatic mechanisms in brain copper metabolism have been associated with neurodegeneration in human disorders such as Menkes disease, Wilson's disease and Alzheimer's disease. This review article will summarize the biological functions of copper in the brain and will describe the current knowledge on the mechanisms involved in copper transport, storage and export of brain cells. The role of copper in diseases that have been connected with disturbances in brain copper homeostasis will also be discussed.

Comparison of Two Methods for Caluculating the Partition Functions of Various Spatial Statistical Models

Likelihood computation in spatial statistics requires accurate and efficient calculation of the normalizing constant (i.e. partition function) of the Gibbs distribution of the model. Two available methods to calculate the normalizing constant by Markov chain Monte Carlo methods are compared by simulation experiments for an Ising model, a Gaussian Markov field model and a pairwise interaction point field model.

Diet, nutrition and the prevention of excess weight gain and obesity

Objective: To review the evidence on the diet and nutrition causes of obesity and to recommend strategies to reduce obesity prevalence.
Design: The evidence for potential aetiological factors and strategies to reduce obesity prevalence was reviewed, and recommendations for public health action, population nutrition goals and further research were made.
Results: Protective factors against obesity were considered to be: regular physical activity (convincing); a high intake of dietary non-starch polysaccharides (NSP)/fibre (convincing); supportive home and school environments for children (probable); and breastfeeding (probable). Risk factors for obesity were considered to be sedentary lifestyles (convincing); a high intake of energy-dense, micronutrient-poor foods (convincing); heavy marketing of energy-dense foods and fast food outlets (probable); sugar-sweetened soft drinks and fruit juices (probable); adverse social and economic conditions—developed countries, especially in women (probable).
A broad range of strategies were recommended to reduce obesity prevalence including: influencing the food supply to make healthy choices easier; reducing the marketing of energy dense foods and beverages to children; influencing urban environments and transport systems to promote physical activity; developing community-wide programmes in multiple settings; increased communications about healthy eating and physical activity; and improved health services to promote breastfeeding and manage currently overweight or obese people.
Conclusions: The increasing prevalence of obesity is a major health threat in both low- and high income countries. Comprehensive programmes will be needed to turn the epidemic around.

Hindu temples in the Sri Lankan ethnic conflict : capture and excess

Developing Deleuze and Guattari's concepts of territorialization and the apparatus of capture, this article explores the role that Sri Lankan Hindu temples have played in the formation of ethnicity and ethnic conflict. Analyzing three contemporary events, the article introduces ways in which many different Sri Lankans (Sinhalese and Tamil) interpret their country's predicament and seek to resolve or prolong it. The events also reveal how scholarship becomes entangled in ethnic nationalism. I then examine in greater detail a village in which temple construction was a critical feature of identity formation during the creation of Sri Lanka as a colonialist and capitalist bureaucratic space. Through this account, I argue that the formation of polarized ethnicity in Sri Lanka is the product of multiple refractive forces, of which temples are one, and not the end result of a singular colonialist bureaucratic agency.

Interpolation of Lipschitz functions

This paper describes a new computational approach to multivariate scattered data interpolation. It is assumed that the data is generated by a Lipschitz continuous function f. The proposed approach uses the central interpolation scheme, which produces an optimal interpolant in the worst case scenario. It provides best uniform error bounds on f, and thus translates into reliable learning of f. This paper develops a computationally efficient algorithm for evaluating the interpolant in the multivariate case. We compare the proposed method with the radial basis functions and natural neighbor interpolation, provide the details of the algorithm and illustrate it on numerical experiments. The efficiency of this method surpasses alternative interpolation methods for scattered data.

A comparison of search functions and other navigational tools provided on government websites

This paper reports the outcomes of a study that evaluated the effectiveness of search functions compared to other navigational tools available on government websites. The study used an observation exercise triangulated with a post observation interview. Results suggest that while there wasn't any significant difference in effectiveness between search functions and other navigational tools, the skill with which the search function is implemented and participants' familiarity with the website, are fundamental determinants of users' opinions. Implications of the findings for research and practice are discussed.

The eight variable homogeneous degree three bent functions

We determine the affine equivalence classes of the eight variable degree three homogeneous bent functions using a new algorithm. Our algorithm applies to general bent functions and can systematically determine the automorphism groups. We provide a partial verification of the computer enumeration of bent functions by Meng et al.

Determination of yield and erosion damage functions using subjectively elicited data: application to small holder tea in Sri Lanka

Tea has been Sri Lanka's major export earner for several decades. However, soil erosion on tea-producing land has had considerable on-site and off-site effects. This study quantifies soil erosion impacts for smallholder tea farms in Sri Lanka by estimating a yield damage function and an erosion damage function using a subjective elicitation technique. The Mitscherlich-Spillman type of function was found to yield acceptable results. The study indicates that high rates of soil erosion require earlier adoption of soil conservation measures than do low rates of erosion. Sensitivity analysis shows the optimum year to change to a conservation practice is very sensitive to the discount rate but less sensitive to the cost of production and price of tea.

Excess and mimesis in organization theory: emancipation from within?

In organizational analysis it can be argued that 'radical separatism'—in the guise of the original 'agenda' for Radical Organization Theory (see Benson, 1977a; Burrell and Morgan, 1979; Clegg and Dunkerley, 1980) or more recently that for Critical Management Studies (see Alvesson and Willmott, 1992; Fournier and Grey, 2000; Casey, 2002; Grey, 2004)—has failed to breach the hegemony of functionalist orthodoxy, and notably so when it comes to practice. Given this failure, we speculate, upon the potential for a different emancipatory approach, one based theoretically on the fluid process of 'undecidability'. Unusually our approach attempts to undermine the conventions of functionalist organization theory from within. In brief, we speculate upon the adoption and enactment of Luce Irigaray's (1985, 1991) strategy of mimicry as a means to illuminate the notion of 'excess' in organization theory. To liberate the feminine, Irigaray mimics the symbolic representation of the female body to excess so as to expose the contradictions of phallocentric discourse. When applied to organization theory, this sees a deliberate mimicking of critiques of radical separatism so as to make explicit the latter's imprisonment within functionalism. Through excessive mimicking of the functionalists' critique, the radical/critical organization theorist may become cognizant of, but perhaps not so subjugated by, the hegemony of functionalist discourse.

Smoothing Lipschitz functions

This paper describes a new approach to multivariate scattered data smoothing. It is assumed that the data are generated by a Lipschitz continuous function f, and include random noise to be filtered out. The proposed approach uses known, or estimated value of the Lipschitz constant of f, and forces the data to be consistent with the Lipschitz properties of f. Depending on the assumptions about the distribution of the random noise, smoothing is reduced to a standard quadratic or a linear programming problem. We discuss an efficient algorithm which eliminates the redundant inequality constraints. Numerical experiments illustrate applicability and efficiency of the method. This approach provides an efficient new tool of multivariate scattered data approximation.

Trafficking of the copper-ATPases, ATP7A and ATP7B: Role in copper homeostasis

Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.