Pharmacological management of failure of treatment with antidepressants]

Depression, a chronic disease and a leading cause of disability worldwide, will generate increasing needs in terms of public health in the coming years. Many antidepressants are now available. However, these molecules present real limitations and disadvantages. Thus there are great expectations on the part of the clinicians for more efficient drugs that are better tolerated. How can we satisfy such hopes and innovate in this domain today? One original and most promising strategy for developing new antidepressants that are more efficient and better tolerated involves antagonizing both alpha 2-noradrenergic and 5HT2 and 5HT3 serotonergic receptors, without blocking 5HT1A serotonergic receptors. The technology now available in pharmacological research allows the development of such molecules.     

Constrained RTRL To Reduce Learning Rate and Forgetting Phenomenon

A fully connected continuous time recurrent neural network, trained by means of Real-Time Recurrent Learning, is investigated. A theoretical analysis of the output vector of the network during the training stage is performed. We point out the necessity to apply an additional constraint to the synaptic weight matrix with the intention of reducing the learning time while the forgetting is decreased. This constraint consists of updating the weights of the output cells using the output error gradient into the RTRL and a matrix of learning rates calculated from an average vector computed from the vectors previously memorized. For this first approach of the problem, only fixpoints attractors have been investigated. Some simple computational simulations validate the method.     

cAMP-dependent protein kinase phosphorylates and activates nuclear Ca2+-ATPase

A Ca2+-pump ATPase, similar to that in the endoplasmic reticulum, has been located on the outer membrane of rat liver nuclei. The effect of cAMP-dependent protein kinase (PKA) on nuclear Ca2+-ATPase (NCA) was studied by using purified rat liver nuclei. Treatment of isolated nuclei with the catalytic unit of PKA resulted in the phosphorylation of a 105-kDa band that was recognized by antibodies specific for sarcoplasmic reticulum Ca2+-ATPase type 2b. Partial purification and immunoblotting confirmed that the 105-kDa protein band phosphorylated by PKA is NCA. The stoichiometry of phosphorylation was 0.76 mol of phosphate incorporated/mol of partially purified enzyme. Measurement of ATP-dependent 45Ca2+ uptake into purified nuclei showed that PKA phosphorylation enhanced the Ca2+-pumping activity of NCA. We show that PKA phosphorylation of Ca2+-ATPase enhances the transport of 10-kDa fluorescent-labeled dextrans across the nuclear envelope. The findings reported in this paper are consistent with the notion that the crosstalk between the cAMP/PKA- and Ca2+-dependent signaling pathways identified at the cytoplasmic level extends to the nucleus. Furthermore, these data support a function for crosstalk in the regulation of calcium-dependent transport across the nuclear envelope.