Synthesis and evaluation of a thio analogue of duocarmycin SA

The design, synthesis, and preliminary evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one-6-carboxylate (CTI) derivatives are detailed representing a single atom change (N to S) embedded in the duocarmycin SA alkylation subunit.     

The biological foundations of culture and morality

Two aspects are discussed: first, the mechanism of learning, and second, the generation of culture and morality. Both aspects are analyzed in relation to the evolution of the mind-brain system. As to the first aspect, I suggest that the use of the concept of innatism requires a re-examination of the genome-dependent effects on the mind-brain system particularly for what concerns the time scale of these effects. The reason is that the information in the genome of the parents is transmitted to the embryo during fertilization of the egg and then into the structures of neuronal cells at the very early stage of ontogenesis, whereas organization of the mind-brain system occurs at a much later time and after an extensive reorganization of the brain structure. The problem is, then, that while during the early stages of the ontogenetic development the neuronal cells maintain their genome determined properties, the full expression of these genome properties within the mind-brain organization undergo fundamental changes which depend not on the properties of the genomic information but rather on the evolution of the operational conditions which are generated in the brain organization and which determine the expression of the genomic potentialities. These operational conditions may become markedly different because of a number of on-going processes due to the formation of new synapses, axons, dendrites and neuronal networks; these phenomena are, to a large extent due to interaction with the environment. Using the Fodor’s language, the effect of the innate properties over the horizontal neuronal networks (the innatism that operates during the whole ontogenesis) assumes a much more important role in the mind-brain than in all other physiological systems. As to the second aspect, I suggest that the development of cultural andmoral worlds are products of the histories of human minds and societies, and depend on the evolutionary nature of these histories.To explain the generation of these worlds I shall discuss a basic problem. How can the neuronal networks of the mind-brain system — usually dealing with phenomena of the natural world and being themselves natural structures obeying the principles and rules of the natural phenomena, where no transition from is to ought or from facts to values is allowed — be able to generate cultural and moral concepts and generate moral behaviours? The solution here proposed is that some sort of modularitydominates in the whole structure of the mind-brain system and that the effect of this modularity is that the neurophysiological processes dealing with the processes of human cultural, moral and social life are structurally associated with emotions, intentions and values. In brief, it is suggested that the mind-brain systems contain, in addition to the division introduced by Fodor, other innate types of neurophysiological processes: some types of processes and of neuronal networks deal with the problems of the natural world and provide answers which are right or wrong, wheras other types of processes and neuronal networks deal with problems of human cultural and social life and provide answers which are adapt on non-adapt.The latter types of neuronal networks are suited to generate the cultural and moral worlds in the course of development and evolution of the Homo sapiens sapiens species and of the single individual. Finally, in view of recent findings on the patterns of mental diseases and the relations of these patterns with alterations of the frontal lobes of the mind brain system, I suggest that the particular types of processes responsible for the moral behaviour of human beings are localized in the frontal lobes. The consequence is that alterations of this type of neurophysiological processes lead to the development of various types of mental diseases.      

Quantification of PRL/Stat5 signaling with a novel pGL4-CISH reporter

Background  

Elevations of serum prolactin (PRL) are associated with an increased risk for breast cancer. PRL signaling through its prolactin receptor (PRLr) involves the Jak2/Stat5 pathway. Luciferase-based reporter assays have been widely used to evaluate the activity of this pathway. However, the existing reporters are often not sensitive enough to monitor the effect of PRL in this pathway.     

Liver autofluorescence properties in animal model under altered nutritional conditions

Autofluorescence spectroscopy is a promising and powerful approach for an in vivo, real time characterization of liver functional properties. In this work, preliminary results on the dependence of liver autofluorescence parameters on the nutritional status are reported, with particular attention to vitamin A and lipid accumulation in liver tissue. Normally fed and 24 h starving rats were used as animal models. Histochemical and autofluorescence analysis showed that lipids and vitamin A colocalize in the liver parenchyma. Fasting condition results in a parallel increase in both lipids and vitamin A. Autofluorescence imaging and microspectrofluorometric analysis carried out on unfixed, unstained tissue sections under 366 nm excitation, evidenced differences in both spectral shape and response to continuous irradiation between liver biopsies from fed and starving rats. As to photobleaching, in particular, fitting analysis evidenced a reduction of about 85% of the signal attributable solely to vitamin A during the first 10 s of irradiation. The tissue whole emission measured in fed and starving rat livers exhibited reductions of about 35% and 52%, respectively, that are closely related to vitamin A contents. The findings open interesting perspectives for the set up of an in situ, real time diagnostic procedure for the assessment of liver lipid accumulation, exploiting the photophysical properties of vitamin A.     

Internal lipid synthesis and vesicle growth as a step toward self-reproduction of the minimal cell

One of the major properties of the semi-synthetic minimal cell, as a model for early living cells, is the ability to self-reproduce itself, and the reproduction of the boundary layer or vesicle compartment is part of this process. A minimal bio-molecular mechanism based on the activity of one single enzyme, the FAS-B (Fatty Acid Synthase) Type I enzyme from Brevibacterium ammoniagenes, is encapsulated in 1-palmitoyl-2oleoyl-sn-glycero-3-phosphatidylcholine (POPC) liposomes to control lipid synthesis. Consequently molecules of palmitic acid released from the FAS catalysis, within the internal lumen, move toward the membrane compartment and become incorporated into the phospholipid bilayer. As a result the vesicle membranes change in lipid composition and liposome growth can be monitored. Here we report the first experiments showing vesicles growth by catalysis of one enzyme only that produces cell boundary from within. This is the prototype of the simplest autopoietic minimal cell.     

ESBRI: A web server for evaluating salt bridges in proteins

Salt bridges can play important roles in protein structure and function and have stabilizing and destabilizing effects in protein folding. ESBRI is a software available as web tool which analyses the salt bridges in a protein structure, starting from the atomic coordinates. In the case of protein complexes, the salt bridges between protein chains can be evaluated, as well as those among specific charged amino acids and the different protein subunits, in order to obtain useful information regard the protein-protein interaction.