Recent advances on the possible neuroprotective activities of Epstein-Barr virus oncogene BARF1 protein in chronic inflammatory disorders of central nervous system

Multiple sclerosis and neurodegenerative diseases in which cells of the central nervous system (CNS) are lost or damaged are rapidly increasing in frequency, and there is neither effective treatment nor cure to impede or arrest their destructive course. The Epstein-Barr virus is a human gamma-herpesvirus that infects more than 90% of the human population worldwide and persisting for the lifetime of the host. It is associated with numerous epithelial cancers, principally undifferentiated nasopharyngeal carcinoma and gastric carcinoma. Individuals with a history of symptomatic primary EBV infection, called infectious mononucleosis, carry a moderately higher risk of developing multiple sclerosis (MS). It is not known how EBV infection potentially promotes autoimmunity and central nervous system (CNS) tissue damage in MS. Recently it has been found that EBV isolates from different geographic regions have highly conserved BARF1 epitopes. BARF1 protein has the neuroprotective and mitogenic activity, thus may be useful to combat and overcome neurodegenerative disease. BARF1 protein therapy can potentially be used to enhance the neuroprotective activities by combinational treatment with anti-inflammatory antagonists and neuroprotectors in neural disorders.

Ontogeny of putative GABAergic neurons and their receptors in the nervous system of the crayfish Cherax destructor

Inhibitory neurons exert control the expression of many aspects of behaviour by regulating the effectiveness of excitatory neural function. By comparison with excitatory neural systems, relatively little is known about the development of inhibitory neurons and the influence which these neurons exert on the development of other neural systems. Two issues which relate to the development of inhibitory neurons are of particular interest. First, a paradox arises when inhibitory neurons are considered in terms of modern models of synaptic development which involve activity-dependent mechanisms of synaptic plasticity. Second, there is some evidence that inhibitory neurotransmitters may act in a special trophic manner during the early development of nervous systems. Investigations of these issues would be greatly facilitated in a neural system in which it was possible to experimentally control aspects of the development of individual pre- and postsynaptic cells. The aim of the results presented in this thesis was to characterise the normal development of one such system: the GABAergic inhibitory system of the Australian freshwater crayfish, Cherax destructor. The ontogeny of the inhibitory neurotransmitter GABA across the embryonic period of 30% to 100% development was investigated using immunohistochemical techniques. GABA-like immunoreactive cells and fibres were first detected in the embryonic brain region. The expression of GABA-like immunoreactivity progressed along a rostro-caudal gradient, with GABA-like immunoreactive cells being detected in the most anterior thoracic ganglia at 45% development and in all ganglia by 65% development. GABA-like immunoreactive fibres were evident in peripheral nerves as early as 55% development and ramified extensively throughout the neuropil of the nervous system by 65% development. By contrast, immunoreactivity to the primary excitatory neurotransmitter, glutamate, was not detected until 60-65% development. Glutamate-like immunoreactivity at 60-65% development was evident only in the form of punctate staining in the midline of the ventral nerve cord. Cell body staining was observed only at 90% development and was restricted to only a few cells on the periphery of the ventral nerve cord. Radio-labelled ligand binding methods and autoradiography were used to study the expression of putative GABA receptors in the Cherax embryos from 30% to 100% development. Specific binding was evident in the earliest embryos studies at 30% development. There was an initial increase in binding from 30% to 40% development, followed by a dramatic drop to almost zero binding at 50-55% development. This was followed by a gradual increase in binding levels with age, reaching a plateau at 85% development. Preliminary pharmacological evaluation of binding indicated that at least three GABA receptor types were expressed during embryonic development. Methods for culturing, dissociated neural tissues explanted form Cherax embryos at 85% development were established. The success of cultures was demonstrated by neurite extension, and neuronal networks in which neurons appeared to form connections with other neurons and with explanted muscle cells after two days in culture. Immunohistochemical studies demonstrated that some explanted neurons expressed GABA-like immunoreactivity within two days of explanting. These studies have provided a comprehensive description of the development of GABAergic neurons and their receptors in Cherax destructor embryos. The very early expression of GABA-like immunoreactivity, coupled with the early onset of specific GABA binding, strongly indicates that the GABAergic neurons are functional and able to exert an effect on other cells during much of the period of nervous system development in crayfish embryos. These results support the hypothesis that inhibitory neurons may play an important role as regulators of the overall process of assembly and maturation of the nervous system and provide a substantial basis for future experimental studies in which the specific action of inhibitory neurons on the development of discrete components of the crayfish nervous system may be investigated.

New insights into CNS requirements for the copper-ATPase, ATP7A. Focus on "Autonomous requirements of the Menkes disease protein in the nervous system".

COPPER IS INDISPENSABLE for development and function of the central nervous system (CNS). This is dramatically illustrated by the severe neuropathological deficits in Menkes disease, an X-linked copper deficiency disorder resulting from mutation of the gene that encodes an essential copper transporting P1B-type ATPase, ATP7A. Since its discovery over two decades ago, the role of ATP7A in copper transport and homeostasis has been inextricably linked to satisfying systemic and CNS requirements for copper. In a recent issue of American Journal of Physiology-Cell Physiology, Hodgkinson et al. (8) describe an important body of work, which for the first time distinguishes the CNS requirement for ATP7A from the CNS requirement for copper.

Investigating the changes in heart rate asymmetry (HRA) with perturbation of parasympathetic nervous system

The heart rate asymmetry (HRA) is a disproportionate distribution of heart rate signal. The current study was designed to assess the changes in HRA in experimental conditions using Poincaré plot during parasympathetic blockade (atropine infusion) and parasympathetic enhancement (scopolamine administration). After atropine infusion, the heart rate variability in 5 out of 8 subjects was found asymmetric. In contrast, all 8 subjects were found to be asymmetric during scopolamine administration. The physiological relevance of HRA was demonstrated by showing correlation with standard frequency domain parameters during all phases of the experiment. The deviation of asymmetry index (GI ( p )) from symmetric range was further analyzed, which was maximum during scopolamine administration and minimum during atropine infusion. These findings suggest that parasympathetic block reduces the prevalence of HRA, and has significant correlation of GI ( p ) with frequency domain features of HRV analysis.

After three strikes-the continued discriminatory impact of the sentencing system against indigenous Australians: suggested reform

Three strikes laws are discriminatory but not for previously advanced reasons. The three strikes laws are merely an acute example of a fundamentally flawed sentencing system that discriminates against economically and socially disadvantaged people, particularly the group that is the focus of this article – Indigenous Australians. The repeal of the Northern Territory's mandatory sentencing laws has not remedied the unfair manner in which sentencing law and practice operate against Aboriginals; either in the Northern Territory or generally. Criminal punishment systems around the world punish a disproportionate number of socially deprived people. In Australia, Indigenous Australians were grossly over-represented in Australian jails prior to the three strikes laws and will remain so unless steps are taken to address their disadvantage. The obvious solution to redress the over-representation by Indigenous Australians is to provide them with the same social opportunities and resources as the rest of the community. This is overly ambitious – at least in the short term. This article suggests a more attainable change in sentencing law to remedy some of the disadvantages experienced by Aboriginals. It suggests that far less weight should be accorded to prior convictions in the sentencing calculus.

Developing negotiation decision support systems that support mediators : a case study of the Family_Winner system

Negotiation Support Systems have traditionally modelled the process of negotiation. They often rely on mathematical optimisation techniques and ignore heuristics and other methods derived from practice. Our goal is to develop systems capable of decision support to help resolve a given dispute. A system we have constructed, Family_Winner, uses empirical evidence to dynamically modify initial preferences throughout the negotiation process. It sequentially allocates issues using trade-offs and compensation opportunities inherent in the dispute.

Evolution of lactation : ancient origin and extreme adaptations of the lactation system

Lactation, an important characteristic of mammalian reproduction, has evolved by exploiting a diversity of strategies across mammals. Comparative genomics and transcriptomics experiments have now allowed a more in-depth analysis of the molecular evolution of lactation. Milk cell and mammary gland genomic studies have started to reveal conserved milk proteins and other components of the lactation system of monotreme, marsupial, and eutherian lineages. These analyses confirm the ancient origin of the lactation system and provide useful insight into the function of specific milk proteins in the control of lactation. These studies also illuminate the role of milk in the regulation of growth and development of the young beyond simple nutritive aspects.

Construction of the descriptive system for the assessment of quality of life AQoL-6D utility instrument

Background
Multi attribute utility (MAU) instruments are used to include the health related quality of life (HRQoL) in economic evaluations of health programs. Comparative studies suggest different MAU instruments measure related but different constructs. The objective of this paper is to describe the methods employed to achieve content validity in the descriptive system of the Assessment of Quality of Life (AQoL)-6D, MAU instrument.

Methods
The AQoL program introduced the use of psychometric methods in the construction of health related MAU instruments. To develop the AQoL-6D we selected 112 items from previous research, focus groups and expert judgment and administered them to 316 members of the public and 302 hospital patients. The search for content validity across a broad spectrum of health states required both formative and reflective modelling. We employed Exploratory Factor Analysis and Structural Equation Modelling (SEM) to meet these dual requirements.

Results and Discussion
The resulting instrument employs 20 items in a multi-tier descriptive system. Latent dimension variables achieve sensitive descriptions of 6 dimensions which, in turn, combine to form a single latent QoL variable. Diagnostic statistics from the SEM analysis are exceptionally good and confirm the hypothesised structure of the model.

Conclusions
The AQoL-6D descriptive system has good psychometric properties. They imply that the instrument has achieved construct validity and provides a sensitive description of HRQoL. This means that it may be used with confidence for measuring health related quality of life and that it is a suitable basis for modelling utilities for inclusion in the economic evaluation of health programs.

Lipid abundance in zebrafish embryos is regulated by complementary actions of the endocannabinoid system and retinoic acid pathway

The endocannabinoid system (ECS) and retinoic acid (RA) signaling have been associated with influencing lipid metabolism. We hypothesized that modulation of these pathways could modify lipid abundance in developing vertebrates and that these pathways could have a combinatorial effect on lipid levels. Zebrafish embryos were exposed to chemical treatments altering the activity of the ECS and RA pathway. Embryos were stained with the neutral lipid dye Oil-Red-O (ORO) and underwent whole-mount in situ hybridization. Mouse 3T3-L1 fibroblasts were differentiated under exposure to RA modulating chemicals and subsequently stained with ORO and analyzed for gene expression by qRT-PCR. ECS activation and RA exposure increased lipid abundance and the expression of lipoprotein lipase. Additionally, RA treatment increased expression of CCAAT/enhancer binding protein alpha. Both ECS receptors and RA receptor subtypes were separately involved in modulating lipid abundance. Finally, increased ECS or RA activity ameliorated the reduced lipid abundance caused by peroxisome proliferator-activated receptor gamma (PPARγ) inhibition. Therefore, the ECS and RA pathway influence lipid abundance in zebrafish embryos and have an additive effect when treated simultaneously. Furthermore, we demonstrated that these pathways act downstream or independently of PPARγ to influence lipid levels. Our study shows for the first time that the RA and ECS pathways have additive function in lipid abundance during vertebrate development.

Fathers with highly demanding partners and offspring in a semidesert environment: energetic aspects of the breeding system of Monteiro's Hornbills (Tockus monteiri) in Namibia

Molting females of Monteiro's Hornbills (Tockus monteiri) seal themselves in nest cavities to breed until chicks are about half grown. To gain insight into the chronology of energy requirements of the Monteiro's Hornbill family unit in relation to this peculiar breeding strategy, we measured a number of ecological, physiological, and environmental variables during the Monteiro's Hornbill's breeding season. Those measurements included rates of energy expenditure of female Monteiro's Hornbills while in the nest cavity, characterizing their thermal environment, timing of egg laying, molt, hatching and fledging of chicks, as well as measuring clutch size and chick growth. Temperatures within the nest box varied between 12 and 39°C and did not affect the female energy expenditure. Female body mass and energy expenditure averaged 319 g and 5 W, respectively, at the start of concealment and decreased by on average 1.1 g day -1 and 0.05 W day -1 during at least the first 30 days of the 52-58 day concealment period. Clutch size varied between 1 and 8 and averaged 4.1 eggs, with eggs averaging only 66% of the mass predicted for a bird of this size. Over the range of chick ages at which the female might leave the nest, the predicted energy requirements for maintenance and tissue growth for a Monteiro's Hornbill chick increase sharply from 1.2 W at age 8 to 3.0 W at age 25. Reduction of the female energy requirement with time, the relatively low growth rate and therewith low energy requirements of Monteiro's Hornbill chicks, and an appropriate timing of the female's exodus from the nest cavity all aid in containing peak energy demands to levels that are sustainable for the food provisioning male.

Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT) mice and mice with deficient tryptophan hydroxylase 2 (TPH2) function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI) mice. Whereas, maternal separation (MS) stress increased anxiety-and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2, KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A). The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex), will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7-11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7-11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7-11, Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety-and depressive-like behaviors.