177 resultados para 174-1073


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One of the many difficulties associated with the drafting of the Property Agents and Motor Dealers Act 2000 (Qld) (‘the Act’) is the operation of s 365. If the requirements imposed by this section concerning the return of the executed contract are not complied with, the buyer and the seller will not be bound by the relevant contract and the cooling-off period will not commence. In these circumstances, it is clear that a buyer’s offer may be withdrawn. However, the drafting of the Act creates a difficulty in that the ability of the seller to withdraw from the transaction prior to the parties being bound by the contract is not expressly provided by s 365. On one view, if the buyer is able to withdraw an offer at any time before receiving the prescribed contract documentation the seller also should not be bound by the contract until this time, notwithstanding that the seller may have been bound at common law. However, an alternative analysis is that the legislative omission to provide the seller with a right of withdrawal may be deliberate given the statutory focus on buyer protection. If this analysis were correct the seller would be denied the right to withdraw from the transaction after the contract was formed at common law (that is, after the seller had signed and the fact of signing had been communicated to the buyer).

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Lean product design has the potential to reduce the overall product development time and cost and can improve the quality of a product. However, it has been found that no or little work has been carried out to provide an integrated framework of "lean design" and to quantitatively evaluate the effectiveness of lean practices/principles in product development process. This research proposed an integrated framework for lean design process and developed a dynamic decision making tool based on Methods Time Measurement (MTM) approach for assessing the impact of lean design on the assembly process. The proposed integrated lean framework demonstrates the lean processes to be followed in the product design and assembly process in order to achieve overall leanness. The decision tool consists of a central database, the lean design guidelines, and MTM analysis. Microsoft Access and C# are utilized to develop the user interface to use the MTM analysis as decision making tool. MTM based dynamic tool is capable of estimating the assembly time, costs of parts and labour of various alternatives of a design and hence is able to achieve optimum design. A case study is conducted to test and validate the functionality of the MTM Analysis as well as to verify the lean guidelines proposed for product development.

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Bistability arises within a wide range of biological systems from the λ phage switch in bacteria to cellular signal transduction pathways in mammalian cells. Changes in regulatory mechanisms may result in genetic switching in a bistable system. Recently, more and more experimental evidence in the form of bimodal population distributions indicates that noise plays a very important role in the switching of bistable systems. Although deterministic models have been used for studying the existence of bistability properties under various system conditions, these models cannot realize cell-to-cell fluctuations in genetic switching. However, there is a lag in the development of stochastic models for studying the impact of noise in bistable systems because of the lack of detailed knowledge of biochemical reactions, kinetic rates, and molecular numbers. In this work, we develop a previously undescribed general technique for developing quantitative stochastic models for large-scale genetic regulatory networks by introducing Poisson random variables into deterministic models described by ordinary differential equations. Two stochastic models have been proposed for the genetic toggle switch interfaced with either the SOS signaling pathway or a quorum-sensing signaling pathway, and we have successfully realized experimental results showing bimodal population distributions. Because the introduced stochastic models are based on widely used ordinary differential equation models, the success of this work suggests that this approach is a very promising one for studying noise in large-scale genetic regulatory networks.

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Tyrosine trans-phosphorylation is a key event in receptor tyrosine kinase signaling, yet, the structural basis for this process has eluded definition. Here, we present the crystal structure of the FGF receptor 2 kinases caught in the act of trans-phosphorylation of Y769, the major C-terminal phosphorylation site. The structure reveals that enzyme- and substrate-acting kinases engage each other through elaborate and specific interactions not only in the immediate vicinity of Y769 and the enzyme active site, but also in regions that are as much of 18 A away from D626, the catalytic base in the enzyme active site. These interactions lead to an unprecedented level of specificity and precision during the trans-phosphorylation on Y769. Time-resolved mass spectrometry analysis supports the observed mechanism of trans-phosphorylation. Our data provide a molecular framework for understanding the mechanism of action of Kallmann syndrome mutations and the order of trans-phosphorylation reactions in FGFRs. We propose that the salient mechanistic features of Y769 trans-phosphorylation are applicable to trans-phosphorylation of the equivalent major phosphorylation sites in many other RTKs.

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Job dissatisfaction, stress and burnout are linked to high rates of nurses leaving the profession, poor morale and poor patient outcomes. Haemodialysis (HD) nursing is uniquely characterised by the intense-prolonged interaction with patients who require complex technological care. A review of nine papers found that factors affecting job satisfaction were aspects of nursing care, organisational factors and length of time that a nurse has been working in nephrology nursing. Factors affecting job stress and burnout were due to interpersonal relationships with physicians, patient care activities, violence and abuse from patients, organisational factors and a lack of access to ongoing education.

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Land-change science emphasizes the intimate linkages between the human and environmental components of land management systems. Recent theoretical developments in drylands identify a small set of key principles that can guide the understanding of these linkages. Using these principles, a detailed study of seven major degradation episodes over the past century in Australian grazed rangelands was reanalyzed to show a common set of events: (i) good climatic and economic conditions for a period, leading to local and regional social responses of increasing stocking rates, setting the preconditions for rapid environmental collapse, followed by (ii) a major drought coupled with a fall in the market making destocking financially unattractive, further exacerbating the pressure on the environment; then (iii) permanent or temporary declines in grazing productivity, depending on follow-up seasons coupled again with market and social conditions. The analysis supports recent theoretical developments but shows that the establishment of environmental knowledge that is strictly local may be insufficient on its own for sustainable management. Learning systems based in a wider community are needed that combine local knowledge, formal research, and institutional support. It also illustrates how natural variability in the state of both ecological and social systems can interact to precipitate nonequilibrial change in each other, so that planning cannot be based only on average conditions. Indeed, it is this variability in both environment and social subsystems that hinders the local learning required to prevent collapse.

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Abstract Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.

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Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133+ enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

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Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian “ideal observer” analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor binding noise. Second, from this model, we derive an equation predicting how the degree of response of an axon to a gradient should vary with gradient steepness and absolute concentration. Third, we confirm this prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies with both these quantities. These experiments demonstrate a degree of sensitivity much higher than previously reported for any chemotacting system. Together, these results reveal both the quantitative constraints that must be satisfied for effective axonal guidance and the computational principles that may be used by the underlying signal transduction pathways, and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro settings.

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Abstract Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.