Stress at the synapse : signal transduction mechanisms of adrenal steroids at neuronal membranes

As the key neuron-to-neuron interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. However, the signal transduction mechanisms by which stress mediates its lasting effects on synapse transmission and on memory are not fully understood. A key component of the stress response is the increased secretion of adrenal steroids. Adrenal steroids (e.g., cortisol) bind to genomic mineralocorticoid and glucocorticoid receptors (gMRs and gGRs) in the cytosol. In addition, they may act through membrane receptors (mMRs and mGRs), and signal transduction through these receptors may allow for rapid modulation of synaptic transmission as well as modulation of membrane ion currents. mMRs increase synaptic and neuronal excitability; mechanisms include the facilitation of glutamate release through extracellular signal-regulated kinase signal transduction. In contrast, mGRs decrease synaptic and neuronal excitability by reducing calcium currents through N-methyl-D-aspartate receptors and voltage-gated calcium channels by way of protein kinase A- and G protein-dependent mechanisms. This body of functional data complements anatomical evidence localizing GRs to the postsynaptic membrane. Finally, accumulating data also suggest the possibility that mMRs and mGRs may show an inverted U-shaped dose response, whereby glutamatergic synaptic transmission is increased by low doses of corticosterone acting at mMRs and decreased by higher doses acting at mGRs. Thus, synaptic transmission is regulated by mMRs and mGRs, and part of the stress signaling response is a direct and bidirectional modulation of the synapse itself by adrenal steroids.

Cytokine expression and secretion by skeletal muscle cells : regulatory mechanisms and exercise effects

Cytokines are important mediators of various aspects of health and disease, including appetite, glucose and lipid metabolism, insulin sensitivity, skeletal muscle hypertrophy and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in the circulating concentrations of interleukin (IL)-6, IL-8, IL-10, IL-1 receptor antagonist, granulocyte-colony stimulating factor, and smaller increases in tumor necrosis factor-α, monocyte chemotactic protein-1, IL-1β, brain-derived neurotrophic factor, IL-12p35/p40 and IL-15. Although many of these cytokines are also expressed in skeletal muscle, not all are released from skeletal muscle into the circulation during exercise. Conversely, some cytokines that are present in the circulation are not expressed in skeletal muscle after exercise. The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources of circulating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate cytokine synthesis (e.g., RNA-binding proteins, microRNAs, suppressor of cytokine signaling proteins, soluble receptors).

Is climate change litigation an effective strategy for promoting greater action to address climate change? What other legal mechanisms might be appropriate?

In recent times a widespread consensus on the reality and gravity of anthropogenic climate change has emerged. Perceived inadequacies in the Australian government’s legal and policy responses to climate change issues have resulted in environmental activists increasingly turning to the courts as a strategy to promote greater action to address adverse climate impacts. The efficacy of this strategy for achieving climate goals is limited by the time and expense of litigating, the restrictions inherent in environmental law administrative challenges, and the possibility that judicial decisions may be overruled by the legislature. To date, climate change litigation in Australia has met with varied success, yet its significance extends beyond the court room as an important mechanism for raising public, political and commercial awareness about climate change issues. Ultimately, however, the types of far-reaching changes needed to mitigate and manage adverse climate impacts require strong regulatory backing. The most effective approach to addressing the complex challenges posed by climate change is a coordinated suite of regulatory measures spearheaded by the Federal Government.

Computational micromodel for epigenetic mechanisms

Characterization of the epigenetic profile of humans since the initial breakthrough on the human genome project has strongly established the key role of histone modifications and DNA methylation. These dynamic elements interact to determine the normal level of expression or methylation status of the constituent genes in the genome. Recently, considerable evidence has been put forward to demonstrate that environmental stress implicitly alters epigenetic patterns causing imbalance that can lead to cancer initiation. This chain of consequences has motivated attempts to computationally model the influence of histone modification and DNA methylation in gene expression and investigate their intrinsic interdependency. In this paper, we explore the relation between DNA methylation and transcription and characterize in detail the histone modifications for specific DNA methylation levels using a stochastic approach.

In silico biology : making the most of parallel computing

Biological systems are typically complex and adaptive, involving large numbers of entities, or organisms, and many-layered interactions between these. System behaviour evolves over time, and typically benefits from previous experience by retaining memory of previous events. Given the dynamic nature of these phenomena, it is non-trivial to provide a comprehensive description of complex adaptive systems and, in particular, to define the importance and contribution of low-level unsupervised interactions to the overall evolution process. In this chapter, the authors focus on the application of the agent-based paradigm in the context of the immune response to HIV. Explicit implementation of lymph nodes and the associated lymph network, including lymphatic chain structure, is a key objective, and requires parallelisation of the model. Steps taken towards an optimal communication strategy are detailed.

Multi-layered model of individual HIV infection progression and mechanisms of phenotypical expression

Cite as: Perrin, Dimitri (2008) Multi-layered model of individual HIV infection progression and mechanisms of phenotypical expression. PhD thesis, Dublin City University.

A parallel approach to social network generation and agent-based epidemic simulation

Understanding the dynamics of disease spread is essential in contexts such as estimating load on medical services, as well as risk assessment and interven- tion policies against large-scale epidemic outbreaks. However, most of the information is available after the outbreak itself, and preemptive assessment is far from trivial. Here, we report on an agent-based model developed to investigate such epidemic events in a stylised urban environment. For most diseases, infection of a new individual may occur from casual contact in crowds as well as from repeated interactions with social partners such as work colleagues or family members. Our model therefore accounts for these two phenomena. Given the scale of the system, efficient parallel computing is required. In this presentation, we focus on aspects related to paralllelisation for large networks generation and massively multi-agent simulations.

Impact of mobility constraints on epidemic broadcast mechanisms in delay-tolerant networks

In this paper, we investigate the effect of mobility constraints on epidemic broadcast mechanisms in DTNs (Delay-Tolerant Networks). Major factors affecting epidemic broadcast performances are its forwarding algorithm and node mobility. The impact of forwarding algorithm and node mobility on epidemic broadcast mechanisms has been actively studied in the literature, but those studies generally use unconstrained mobility models. The objective of this paper is therefore to quantitatively investigate the effect of mobility constraints on epidemic broadcast mechanisms. We evaluate the performances of three classes of epidemic broadcast mechanisms - P-BCAST (PUSH-based BroadCast), SA-BCAST (Self-Adaptive BroadCast), and HP-BCAST (History-based P-BCAST) - with a random waypoint mobility model with mobility constraints. Our finding includes that the existence of mobility constraints significantly improves the reach ability and dissemination speed of epidemic broadcast mechanisms while degrading their efficiency.

Performance evaluation of cloud-based parallel computing

As computational models in fields such as medicine and engineering get more refined, resource requirements are increased. In a first instance, these needs have been satisfied using parallel computing and HPC clusters. However, such systems are often costly and lack flexibility. HPC users are therefore tempted to move to elastic HPC using cloud services. One difficulty in making this transition is that HPC and cloud systems are different, and performance may vary. The purpose of this study is to evaluate cloud services as a means to minimise both cost and computation time for large-scale simulations, and to identify which system properties have the most significant impact on performance. Our simulation results show that, while the performance of Virtual CPU (VCPU) is satisfactory, network throughput may lead to difficulties.