Neurotrophins and neuronal plasticity in the action of antidepressants and morphine

Neuronal plasticity is a well characterized phenomenon in the developing and adult brain. It refers to capasity of a single neuron to modify morphology, synaptic connections and activity. Neuronal connections and capacity for plastic events are compromised in several pathological disorders, such as major depression. In addition, neuronal atrophy has been reported in depressive patients. Neurotrophins are a group of secretory proteins functionally classified as neuronal survival factors. Neurotrophins, especially brain derived neurotrophic factor (BDNF), have also been associated with promoting neuronal plasticity in dysfunctional neuronal networks. Chronic antidepressant treatment increases plastic events including neurogenesis and arborization and branching of neurites in distinct brain areas, such as the hippocampus. One suggested mode of action is where the antidepressants elevate the synaptic levels of BDNF thus further activating several signaling cascades via trkB-receptor. In our studies we have tried to clarify the mechanisms of action for antidepressants and to resolve the role of BDNF in this process. We found that chronic antidepressant treatment increases amount of markers of neuronal plasticity in both hippocampus and in the medial prefrontal cortex, both of which are closely linked to the etiology of major depression. Secondary actions of antidepressants include rapid activation of the trkB receptor followed by a phosphorylation of transcription factor CREB. In addition, activation of CREB by phosphorylation appears responsible for the regulation of the expression of the BDNF gene. Using transgenic mice we found that BDNF-induced trkB-mediated signaling proved crucial for the behavioral effects of antidepressants in the forced swimming test and for the survival of newly-born neurons in the adult hippocampus. Antidepressants not only increased neurogenesis in the adult hippocampus but also elevated the turnover of hippocampal neurons. During these studies we also discovered that another trkB ligand, NT-4, is involved in morphine-mediated anti-nociception and tolerance. These results present a novel role for trkB-mediated signaling in plastic events present in the opioid system. This thesis evaluates neuronal plasticity and trkB as a target for future antidepressant treatments.

Human action recognition from video sequences

This PhD research has proposed new machine learning techniques to improve human action recognition based on local features. Several novel video representation and classification techniques have been proposed to increase the performance with lower computational complexity. The major contributions are the construction of new feature representation techniques, based on advanced machine learning techniques such as multiple instance dictionary learning, Latent Dirichlet Allocation (LDA) and Sparse coding. A Binary-tree based classification technique was also proposed to deal with large amounts of action categories. These techniques are not only improving the classification accuracy with constrained computational resources but are also robust to challenging environmental conditions. These developed techniques can be easily extended to a wide range of video applications to provide near real-time performance.

Assessing taxpayer response to legislative changes: A case study of ‘in-house’ fringe benefits rules

On 22 October 2012, the Australian Federal Government announced the removal of the $1,000 in-house fringe benefits concession when used as part of a salary packaging arrangement. At the time of the announcement, the Federal Government predicted that the removal of the concession would contribute additional tax revenue of $445 million over the following four years as well as an increase of GST payments to the States and Territories. However, anecdotal evidence at the same time indicated that the Australian employer response was to immediately stop providing employees with such in-house fringe benefits via salary sacrificing arrangements. Data presented in this article, collected from a combination of interviews with tax managers of four Australian entities as well as a review of the published archival data, confirms that the abolition of the $1,000 in-house fringe benefits concession was perceived as a negative change, whereby employees were considered the ‘big losers’ despite assertions by the Federal Government to the contrary. Using a conceptual map of tax rule change developed by Oats and Sadler, this article seeks to understand the reasons for this fringe benefits tax change and taxpayer response. In particular, the economic and political factors, and the responses of the relevant taxpayers (employers) are explored. Drawing on behavioural economic concepts, the actions, attitudes and response of employers to the rule change are also examined. The research findings suggest that the decision by Australian employers to cease providing the in-house fringe benefits as part of a salary-packaging arrangement after the legislative amendment was impacted by more than simple rational behaviour.

Calculating the bound spectrum by path summation in action-angle variables

The density of states n(E) is calculated for a bound system whose classical motion is integrable, starting from an expression in terms of the trace of the time-dependent Green function. The novel feature is the use of action-angle variables. This has the advantages that the trace operation reduces to a trivial multiplication and the dependence of n(E) on all classical closed orbits with different topologies appears naturally. The method is contrasted with another, not applicable to integrable systems except in special cases, in which quantization arises from a single closed orbit which is assumed isolated and the trace taken by the method of stationary phase.

Mechanism of action of selenious acid in the electrodeposition of manganese

The effect of selenious acid as an addition agent in the electrodeposition of manganese was studied by analysing the current-potential curves for manganese deposition. The mechanism of action of this addition agent was found to be essentially similar to that proposed for sulphur dioxide, namely to affect the manganese deposition indirectly by influencing the hydrogen evolution reaction which is a parallel reaction at the electrode surface.

Educational action research in Singapore: To prove or improve?

The rise of educational action research amongst schools in Singapore can be attributed to the government’s belief that educational research and reform can improve school performance and help Singapore keep pace with the impact of globalization. However, against a backdrop of neo-liberal educational reform where efficiency, accountability and demonstrable outcomes are valued, the underlying intent of the action research projects would seem to be inconsistent with the emancipatory intent normally associated with action research. A systematic review was conducted of 71 action research projects submitted to a local educational conference in 2006. Of concern to us is how action research has been narrowly interpreted and recruited simply as an evaluative tool with the emancipatory potential largely ignored. The paper is theoretically framed by governmentality and performativity to explore the embedded power relations that may “fabricate” the action research projects. The findings and discussions suggest a need for the government, schools and teacher-researchers to reflexively question the current expectation of action research and to be clear about its broader purpose

Bustle behind the scenes of action : nemosis as a model for fibroblast inflammatory activation

Wound healing is a complex process that requires an interplay between several cell types. Classically, fibroblasts have been viewed as producers of extracellular matrix, but more recently they have been recognized as orchestrators of the healing response, promoting and directing, inflammation and neovascularization processes. Compared to those from healthy tissue, inflammation-associated fibroblasts display a dramatically altered phenotype and have been described as sentinel cells, able to switch to an immunoregulatory profile on cue. However, the activation mechanism still remains largely uncharacterized. Nemosis is a model for stromal fibroblast activation. When normal human primary fibroblasts are deprived of growth support they cluster, forming multicellular spheroids. Clustering results in upregulation of proinflammatory markers such as cyclooxygenase-2 and secretion of prostaglandins, proteinases, cytokines, and growth factors. Fibroblasts in nemosis induce wound healing and tumorigenic responses in many cell types found in inflammatory and tumor microenvironments. This study investigated the effect of nemotic fibroblasts on two components of the vascular system, leukocytes and endothelium, and characterized the inflammation-promoting responses that arose in these cell types. Fibroblasts in nemosis were found to secrete an array of chemotactic cytokines and attract leukocytes, as well as promote their adhesion to the endothelium. Nuclear factor-kB, the master regulator of many inflammatory responses, is activated in nemotic fibroblasts. Nemotic fibroblasts are known to produce large amounts of hepatocyte growth factor, a motogenic and angiogenic factor. Also, as shown in this study, they produce vascular endothelial growth factor. These two factors induced migratory and sprouting responses in endothelial cells, both required for neovascularization. Nemotic fibroblasts also caused a decrease in the expression of adherens and tight junction components on the surface of endothelial cells. The results allow the conclusion that fibroblasts in nemosis share many similarities with inflammation-associated fibroblasts. Both inflammation and stromal fibroblasts are known to be involved in tumorigenesis and tumor progression. Nemosis may be viewed as a model for stromal fibroblast activation, or it may correlate with cell-cell interactions between adjacent fibroblasts in vivo. Nevertheless, due to nemosis-derived production of proinflammatory cytokines and growth factors, fibroblast nemosis may have therapeutic potential as an inducer of controlled tissue repair. Knowledge of stromal fibroblast activation gained through studies of nemosis, could provide new strategies to control unwanted inflammation and tumor progression.

A Team of Continuous-Action Learning Automata for Noise-Tolerant Learning of Half-Spaces

Learning automata are adaptive decision making devices that are found useful in a variety of machine learning and pattern recognition applications. Although most learning automata methods deal with the case of finitely many actions for the automaton, there are also models of continuous-action-set learning automata (CALA). A team of such CALA can be useful in stochastic optimization problems where one has access only to noise-corrupted values of the objective function. In this paper, we present a novel formulation for noise-tolerant learning of linear classifiers using a CALA team. We consider the general case of nonuniform noise, where the probability that the class label of an example is wrong may be a function of the feature vector of the example. The objective is to learn the underlying separating hyperplane given only such noisy examples. We present an algorithm employing a team of CALA and prove, under some conditions on the class conditional densities, that the algorithm achieves noise-tolerant learning as long as the probability of wrong label for any example is less than 0.5. We also present some empirical results to illustrate the effectiveness of the algorithm.

Cytotoxicity of half sandwich ruthenium(II) complexes with strong hydrogen bond acceptor ligands and their mechanism of action

Neutral and cationic organometallic ruthenium(II) piano stool complexes of the type [(eta(6)-cymene)R-uCl(X)(Y)] (complexes R1-R8) has been synthesized and characterized. In cationic complexes, X, Y is either a eta(2) phosphorus ligand such as 1,1-bis(diphenylphosphino)methane (DPPM) and 1,2-bis(diphenylphosphino)ethane (DPPE) or partially oxidized ligands such as 1,2-bis(diphenylphosphino)methane monooxide (DPPMO) and 1,2-bis(diphenylphosphino)ethane monooxide (DPPEO) which are strong hydrogen bond acceptors. In neutral complexes. X is chloride and Y is a monodentate phosphorous donor. Complexes with DPPM and DPPMO ligands ([(eta(6)-cymene)Ru(eta(2)-DPPM)Cl]PF6 (R2), [(eta(6)-cymene)Ru(eta(2)-DPPMO)Cl]PF6 (R3), [(eta(6)-cymene)Ru(eta(1)-DPPM)Cl-2] (R5) and [(eta(6)-cymene)Ru(eta(1)-DPPMO)Cl-2] (R6) show good cytotoxicity. Growth inhibition study of several human cancer cell lines by these complexes has been carried out. Mechanistic studies for R5 and R6 show that inhibition of cancer cell growth involves both cell cycle arrest and apoptosis induction. Using an apoptosis PCR array, we identified the sets of antiapoptotic genes that were down regulated and pro-apoptotic genes that were up regulated. These complexes were also found to be potent metastasis inhibitors as they prevented cell invasion through matrigel. The complexes were shown to bind DNA in a non intercalative fashion and cause unwinding of plasmid DNA in cell-free medium by competitive ethidium bromide binding, viscosity measurements, thermal denaturation and gel mobility shift assays.

The generalized anomeric effect in the 1,3-thiazolidines: Evidence forboth sulphur and nitrogen as electron donors. Crystal structures of various N-acylthiazolidines including mercury(II) complexes. Possible relevance to penicillin action

Evidence for the generalized anomeric effect (GAE) in the N-acyl-1,3-thiazolidines, an important structural motif in the penicillins, was sought in the crystal structures of N-(4-nitrobenzoyl)-1,3-thiazolidine and its (2:1) complex with mercuric chloride, N-acetyl-2-phenyl-1,3-thiazolidine, and the (2:1) complex of N-benzoyl-1,3-thiazolidine with mercuric bromide. An inverse relationship was generally observed between the. C-2-N and C-2-S bond lengths of the thiazolidine ring, supporting the existence of the GAE. (Maximal bond length changes were similar to 0.04 angstrom for C-2-N-3, S-1-C-2, and similar to 0.08 angstrom for N-3-C-6.) Comparison with N-acylpyrrolidines and tetrahydrothiophenes indicates that both the nitrogen-to-sulphur and sulphur-to-nitrogen GAE's operate simultaneously in the 1,3-thiazolidines, the former being dominant. (This is analogous to the normal and exo-anomeric effects in pyranoses, and also leads to an interesting application of Baldwin's rules.) The nitrogen-to-sulphur GAE is generally enhanced in the mercury(II) complexes (presumably via coordination at the sulphur); a 'competition' between the GAE and the amide resonance of the N-acyl moiety is apparent. There is evidence for a 'push-pull' charge transfer between the thiazolidine moieties in the mercury(II) complexes, and for a 'back-donation' of charge from the bromine atoms to the thiazolidine moieties in the HgBr2 complex. (The sulphur atom appears to be sp(2) hybridised in the mercury(II) complexes, possibly for stereoelectronic reasons.) These results are apparently relevant to the mode of action of the penicillins. (c) 2006 Elsevier B.V. All rights reserved.

Structural plasticity and enzyme action: Crystal structures of Mycobacterium tuberculosis peptidyl-tRNA hydrolase

Peptidyl-tRNA hydrolase cleaves the ester bond between tRNA and the attached peptide in peptidyl-tRNA in order to avoid the toxicity resulting from its accumulation and to free the tRNA available for further rounds in protein synthesis. The structure of the enzyme from Mycobacteritan tuberculosis has been determined in three crystal forms. This structure and the structure of the enzyme frorn Escherichia coli in its crystal differ substantially on account of the binding of the C terminus of the E. coli enzyme to the peptide-binding site of a neighboring molecule in the crystal. A detailed examination of this difference led to an elucidation of the plasticity of the binding site of the enzyme. The peptide-binding site of the enzyme is a cleft between the body, of the molecule and a polypepticle Y stretch involving a loop and a helix. This stretch is in the open conformation when the enzyme is in the free state as in the crystals of M. tuberculosis peptidyl-tRNA hydrolase. Furthermore, there is no physical continuity between the tRNA and the peptide-binding sites. The molecule in the E. coli crystal mimics the peptide-bound enzyme molecule. The peptide stretch referred to earlier now closes on the bound peptide. Concurrently, a channel connecting the tRNA and the peptide-binding site opens primarily through the concerted movement of two residues. Thus, the crystal structure of M. tuberculosis peptidyl-tRNA hydrolase when compared with the crystal structure of the E. coli enzyme, leads to a model of structural changes associated with enzyme action on the basis of the plasticity of the molecule. (c) 2007 Elsevier Ltd. All rights reserved.

Affirmative action and effort choice: An experimental investigation

We study the effect of affirmative action on effort in an experiment conducted in high schools in socioeconomically disadvantaged areas in Queensland, Australia. All participating schools have a large representation of indigenous Australians, a population group that is frequently targeted by affirmative action. Our participants perform a simple real-effort task in a competitive setting. Those ranked in the top third receive a high piece-rate payment and all the others receive a low payment. We introduce affirmative action by providing the lowest (bottom third) performers with a positive handicap increasing their chances to achieve the high payment target. Our findings show that the policy increases effort of those that it aims to favour, without discouraging effort of those who are indirectly penalized by affirmative action.