115 research outputs found
The Molecular Basis of Neural Memory. Part 7 Neural Intelligence (NI) versus Artificial Intelligence (AI)
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An improved method for the catalytic preparation of t-butyl esters of carboxylic and fatty acids
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The Calbindin-D28k binding site on inositol monophosphatase may allow inhibition independent of the lithium site of action
Get PDFAmong numerous reported biochemical effects the lithium-inhibitable enzyme inositol-monophosphatase (IMPase) remains a viable target for lithium's therapeutic mechanism of action. Calbindin-D28k (calbindin) interacts with IMPase enhancing its activity. In the present study in silico modeling of IMPase-calbindin binding using the program MolFit indicated that the 55-66 amino acid segment of IMPase anchors calbindin via Lys59 and Lys61 with a glutamate in between (Lys-Glu-Lys motif). The model further suggested that the Lys-Glu-Lys motif interacts with residues Asp24 and Asp26 of calbindin. Indeed, we found that differently from wildtype calbindin, IMPase was not activated by mutated calbindin in which Asp24 and Asp26 were replaced by alanine. Calbindin's effect was significantly reduced by a peptide with the sequence of amino acids 58-63 of IMPase (peptide 1) and by six amino-acid peptides including at least part of the Lys-Glu-Lys motif. The three amino-acid peptide Lys-Glu-Lys or five amino-acid peptides containing this motif were ineffective. Intracerebroventricular administration of peptide 1 resulted in a significant antidepressant-like reduced immobility in the Porsolt forced swim test (FST) compared with mice treated with a scrambled peptide or artificial cerebrospinal fluid. Based on the sequence of peptide 1, and to potentially increase the peptide's stability, cyclic and linear pre-cyclic analog peptides were synthesized. One cyclic and one linear pre-cyclic analog peptides exhibited an inhibitory effect on calbindin-activated brain IMPase activity in vitro. These findings may lead to the development of molecules capable of inhibiting IMPase activity at an alternative site than that of lithium
Systematic Solid Phase Synthesis of Linear Pseudooligolysines Containing Multiple Adjacent CH2NH Amide Bond Surrogates: Potential Agents for Gene Delivery
No full textTyrphostins inhibit the epidermal growth factor receptor-mediated breakdown of phosphoinositides
No full textAbstractIn response to epidermal growth factor (EGF) and the Ca2+ ionophore A23187, the total phosphatidylinositides (IPT) increased in A431 human epidermoid carcinoma cells 1.8- and 2.0-fold and in the EGF-dependent A431/Clone 15-2 cells 3.0- and 8.0-fold, respectively, over basal levels. Both responses were inhibited by the antiproliferative agents tyrphostins, but the EGF-induced increase in IPT was inhibited to a much greater extent than that induced by the ionophore. Tyrphostins which are potent EGF-receptor kinase inhibitors were also potent in blocking the EGF-induced production of phosphoinositides. The less potent tyrphostins were found to inhibit the EGF-dependent IPT formation more weakly. These results support the notion that phospholipase C is activated through its phosphorylation by the EGF receptor. Tyrphostins; Epidermal growth factor; Phospholipase C phosphorylation; Ca2+ ionophore; (A431 cell, A431/Clone 15-2 cell
The Molecular Basis of Memory. Part 3: Tagging with emotive neurotransmitters.
No full textMany neurons of all animals that exhibit memory (snails, worms, flies, vertebrae) present arborized shapes with many varicosities and boutons. These neurons, release neurotransmitters and contain ionotropic receptors that produce and sense electrical signals (ephaptic transmission). The extended shapes maximize neural contact with the surrounding neutrix (neural extracellular matrix (nECM)+ diffusible (neurometals and neurotransmitters) as well as with other neurons. We propose a tripartite mechanism of animal memory based on the dynamic interactions of splayed neurons with the neutrix. Their interactions form cognitive units of information (cuinfo), metal-centered complexes within the nECM around the neuron. Emotive content is provided by NTs, which embody molecular links between physiologic (body) responses and psychic feelings. We propose that neurotransmitters form mixed complexes with cuinfo used for tagging emotive memory.Thus, NTs provide encoding option not available to a Turing, binary-based, device.The neurons employ combinatorially diverse options, with > 10 NMs and > 90 NTs for encoding (flavoring) cuinfo with emotive tags. The neural network efficiently encodes, decodes and consolidates related (entangled) sets of cuinfo into a coherent pattern, the basis for emotionally imbued memory, critical for determining a behavioral choice aimed at survival. The tripartite mechanism with tagging of NTs permits of a causal connection between physiology and psychology.<br/
Synthesis of N′-substituted Ddz-protected hydrazines and their application in solid phase synthesis of aza-peptides
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