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The concentration of homocysteine-derived disulfides in human coronary artery
Full text link*Background* 
Based on previous findings, we have estimated that, in injured coronary artery tissue, the low molecular weight disulfides homocystine and cysteine-homocysteine, otherwise identified as oxidized homocysteine equivalents (OHcyE), may achieve a total concentration that is higher than the aqueous solubility of homocystine at room temperature. In order to verify whether or not OHcyE could reach their saturation limit in the vascular tissue, we have measured the solubility of homocystine in physiological-like condition.

*Materials and methods* 
The solubility of homocystine has been measured in aqueous sodium chloride solutions at 37 °C by differential pulse polarography based on the reduction of homocystine to homocysteine.

*Results* 
We have estimated that the concentration achieved by OHcyE in injured coronary artery tissue is at least near-saturating, because the solubility of homocystine in physiological-like condition, above which deposition of homocystine and/or cysteine-homocysteine as solid phase occurs, almost exactly matches its value. Near-saturation levels of OHcyE within the vascular tissue means that significant leakage of intracellular fluid can promote OHcyE crystallization in tissue fluids, which may serve to initiate inflammation. 

*Conclusions* 
We speculate that deposition of OHcyE crystals could damage blood vessels and act as a primer of homocysteine-triggered inflammation, thus being along the causal pathway that leads to vascular dysfunction
Application of the Sensory Contact Model for Pharmacological Studies under Simulated Clinical Conditions
Full text linkThe sensory contact model allows forming different psycho-pathological states (anxious depression, catalepsy, social withdrawal, pathological aggression, cognition disturbances, anhedonia, addictive states etc.) produced by repeated agonistic interactions in male mice and investigating the therapeutic and preventive properties of any drug as well as its efficiency under simulated clinical conditions. This approach can be useful for a better understanding of the drugs’ action in different stages of disease development in individuals. It is suggested that this behavioral approach and pharmacological designs may be applied for the screening of novel psychotropic drugs. 

PharmGKB: Capturing knowledge to catalyze pharmacogenomics research
No full textThis is a powerpoint presentation made initially at the Cold Spring Harbor meeting on Pharmacogenomics, November 2006. It discusses the PharmGKB (http://www.pharmgkb.org/) and how we are building a pipeline for annotation of knowledge. In particular, we are focusing on pathway knowledge, "Very important Pharmacogene" annotations, and curation of the pharmacogenomics literature. We are building an ontology-based system to capture and aggregate knowledge, for use by our curators
INCF -- new capability for global coordination in neuroinformatics
Full text linkThe Global Science Forum (GSF) of the OECD has initiated a new international organization, INCF, to further the development of Neuroinformatics as a global effort with the support of all ministers of research within OECD. This presentation explains the background for the establishment of the INCF, outlines some of the goals, and defines the operations of the INCF Secretariat in relation the INCF National nodes and the general neuroscience community
DARPP-32 is a robust integrator of dopamine and glutamate signals
Full text linkIntegration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA) DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca2+ signals. Dynamic simulations allowed to observe the temporal relationships between cAMP and Ca2+ signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the regulation of PP2A by PKA or by calcium, had little effect on the function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but also a coincidence detector, the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute response on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the coincidence detector function, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca2+ regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons
Open Standards and Resources in Systems Biology: collaborative scale-up toward virtual life
No full textThe practise of Systems Biology relies on interfaces. Interfaces
between the entities we study: the paradigm moved from a physical
object centric view toward a relationship-centric one; interfaces
between tools: From the retrieval of the primary data to the fine
analysis of a model's behaviour, one uses many tools, more or less
well connected; interfaces between individuals: To build any
non-trivial mechanistic model requires to merge existing work and
gather external expertise.

If we want these interfaces to be generic enough to allow for anybody
to leverage on existing toolkits, a fundamental requirement is the
existence of community-developed well supported standards, but also
open resources where to find the "lego" blocks. Over the last
half-decade, several efforts have been launched in that direction,
whether concerning encoding format, ontologies or databases. Some of
them are now well-established in the field and play a significant role
to improve its coherence but also to increase the size and the quality
of quantitative models.