Cyclic Nucleotide Phosphodiesterases and Compartmentation in Normal and Diseased Heart

International audienceCyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cAMP and cGMP, thereby regulating multiple aspects of cardiac function. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families which are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP controlling specific cell functions in response to various neurohormonal stimuli. In myocardium, the PDE3 and PDE4 families are predominant to degrade cAMP and thereby regulate cardiac excitation-contraction coupling. PDE3 inhibitors are positive inotropes and vasodilators in human, but their use is limited to acute heart failure and intermittent claudication. PDE5 is particularly important to degrade cGMP in vascular smooth muscle, and PDE5 inhibitors are used to treat erectile dysfunction and pulmonary hypertension. However, these drugs do not seem efficient in heart failure with preserved ejection fraction. There is experimental evidence that these PDEs as well as other PDE families including PDE1, PDE2 and PDE9 may play important roles in cardiac diseases such as hypertrophy and heart failure. After a brief presentation of the cyclic nucleotide pathways in cardiac cells and the major characteristics of the PDE superfamily, this chapter will present their role in cyclic nucleotide compartmentation and the current use of PDE inhibitors in cardiac diseases together with the recent research progresses that could lead to a better exploitation of the therapeutic potential of these enzymes in the future

Gradient Descent Optimization in Gene Regulatory Pathways

BACKGROUND: Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of which are identification of metabolic pathways, complex genetic diseases, drug discovery and toxicology analysis. High-throughput technologies allow studying various aspects of gene regulatory networks on a genome-wide scale and we will discuss recent advances as well as limitations and future challenges for gene network modeling. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. METHODOLOGY: In the present article, we introduce a new method for identifying a set of optimal gene regulatory pathways by using structural equations as a tool for modeling gene regulatory networks. The method, first of all, generates data on reaction flows in a pathway. A set of constraints is formulated incorporating weighting coefficients. Finally the gene regulatory pathways are obtained through optimization of an objective function with respect to these weighting coefficients. The effectiveness of the present method is successfully tested on ten gene regulatory networks existing in the literature. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. The results compare favorably with earlier experimental results. The validated pathways point to a combination of previously documented and novel findings. CONCLUSIONS: We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. The present method has been successful in deriving the optimal regulatory pathways for all the regulatory networks considered. The biological significance and applicability of the optimal pathways has also been discussed. Finally the usefulness of the present method on genetic engineering is depicted with an example

Conversações sobre a "boa morte": o debate bioético acerca da eutanásia Conversations on the "good death": the bioethical debate on euthanasia

A despeito das grandes discussões hodiernas sobre a eutanásia, permanecem ainda muitos pontos em aberto, aparentemente insolúveis, aguardando que um melhor tratamento conceitual seja desenvolvido. Neste âmbito podem ser incluídos os "preconceitos e fundamentalismos" em relação ao tema — a eutanásia ainda é vista como tabu em boa parte da sociedade, especificamente no caso do Brasil —, as imprecisões semânticas do vocábulo e as acérrimas tensões argumentativas em torno do tema — levando-se em consideração os princípios da sacralidade da vida, da qualidade de vida e da autonomia e o argumento da assim chamada "ladeira escorregadia" ou slippery slope. Compor o horizonte de indagação acerca da eutanásia, partindo dos antecedentes históricos em direção a um melhor equacionamento do problema — e delimitação de perspectivas vindouras necessárias à sua melhor compreensão — é, pois, o objetivo do presente ensaio.<br>Despite extensive current debate on euthanasia, many open and apparently unsolvable issues persist, awaiting a better conceptual treatment. The area includes "prejudices and fundamentalisms" in relation to the theme, still viewed as taboo by a major share of society, specifically in the case of Brazil, while semantic imprecision in the term and argumentative tensions surround the issue, focusing on the principles of sacredness of life, quality of life, and autonomy and the so-called "slippery slope" argument. The purpose of the current essay is thus to serve as a sphere of inquiry concerning euthanasia, moving from historical antecedents towards a better solution to the problem and the demarcation of necessary future perspectives for enhanced understanding of the issue