CHEMICAL PACEMAKERS : III. ACTIVATION ENERGIES OF SOME RATE-LIMITING COMPONENTS OF RESPIRATORY SYSTEMS

1. In a previous paper it was found that 11,200 calories is obtained for the energy of activation in the oxidation of succinate to fumarate in the presence of crude beef heart extract when succino-dehydrogenase was made the limiting factor. 16,000 calories was obtained with this preparation when cytochrome-cytochrome oxidase was made the limiting factor. In the present paper activation energies of the components of this enzyme system are further studied. 2. Oxidation of p-phenylenediamine catalyzed by the extract and known not to involve the dehydrogenase component yields Arrhenius equation plots indicating a pacemaker reaction with a µ of 9,500 calories. 3. An activation energy of 17,500 calories is obtained for the oxidation of succinate to fumarate in the presence of the beef heart extract partially poisoned by pyrophosphate. Evidence is presented that this value corresponds to a link in the respiratory chain other than that of succino-dehydrogenase or cytochrome c-cytochrome oxidase. 4. Addition of a suitable amount of cresyl blue to a beef heart extract reaction mixture, completely inhibited by cyanide, restores the oxidation of succinate to normal in the presence of pure oxygen. In this system, in which the dye is substituted for the oxidase, when the enzyme extract (dehydrogenase) is made the limiting factor, a µ of 18,500 calories is obtained; when cresyl blue is made the limiting factor, the µ value is 22,000 calories. 5. Results of these experiments indicate that energies of activation are associated not with the enzyme as such, but with the particular reaction steps involving them as catalysts.     

Expression of the human alpha1,2-fucosyltransferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum-mediated cytolysis.

Hyperacute rejection (HAR) is the first critical immunological hurdle that must be addressed in order to develop xenogeneic organs for human transplantation. In the area of cell-based xenotransplant therapies, natural antibodies (XNA) and complement have also been considered barriers to successful engraftment. Transgenic expression of human complement inhibitors in donor cells and organs has significantly prolonged the survival of xenografts. However, expression of complement inhibitors without eliminating xenogeneic natural antibody (XNA) reactivity may provide insufficient protection for clinical application. An approach designed to prevent XNA reactivity during HAR is the expression of human alpha1, 2-fucosyltransferase (H-transferase, HT). H-transferase expression modifies the cell surface carbohydrate phenotype of the xenogeneic cell, resulting in the expression of the universal donor O antigen and a concomitant reduction in the expression of the antigenic Galalpha1,3-Gal epitope. We have engineered various transgenic pig lines that express HT in different cells and tissues, including the vascular endothelium. We demonstrate that in two different HT transgenic lines containing two different HT promoter constructs, expression can be differentially regulated in a constitutive and cytokine-inducible manner. The transgenic expression of HT results in a significant reduction in the expression of the Galalpha1,3-Gal epitope, reduced XNA reactivity, and an increased resistance to human serum-mediated cytolysis. Transgenic pigs that express H-transferase promise to become key components for the development of xenogeneic cells and organs for human transplantation.     

Mikrozephaliesyndrome und geistige Behinderung

Clarification of the cause of mental retardation, which has a prevalence of 2–3%, is a common reason for genetic consultation. On the basis of the cardinal sign of microcephaly, which also has a prevalence of 2–3%, an overview on different conditions with developmental delay/mental retardation is given according to the mode of inheritance. The current version of the Winter–Baraitser Dysmorphology Database lists 558 conditions with the combination of microcephaly and developmental delay/mental retardation. This makes clear that the following overview gives only a limited look at the comprehensive field of clinical genetics/dysmorphology.     

Acidocalcisomen,Mitosomen und Apicoplasten. Neu entdeckte Zellorganellen

Three new, membrane‐bounded organelles were detected in the last decade. Acidocalcisomes which occur in pro‐ and eukaryotes are acidic and store calcium, and further also phosphate, oxygen, magnesium, zink, sodium, potassium, and iron. Furthermore, they are engaged in osmoregulation, pH‐ and Ca²⁺‐homeostasis. Mitosomes are strongly reduced mitochondria of different parasitic protists, which were previously grouped as primarily mitochondria‐free organisms. Apicoplasts are the strongly reduced plastids of the parasitic apicomplexans (formerly sporozoa). They are a target for the development of new drugs, e.g. against the cause of malaria, Plasmodium.     

Personalisierte Medizin – Vision oder Fiktion? Beispiel: Altersdiabetes

Typical civilization diseases, such as type II diabetes, are common, complex in the underlying pathogenic mechanisms, heterogenous in the phenotype and multifactorial due to a wide variety of possible combinations of disease susceptibility or protective genes in different relevant tissues and negative or positive environmental factors. This is in sharp contrast to classical inherited diseases, such as Chorea Huntington, which are often caused by complete loss‐ or gain‐of‐function mutations in a single gene. The causative polymorphisms of susceptibility genes, however, are characterized by relative subtle alterations in the function of the corresponding gene product, which per se do not support the pathogenesis, by high frequency, high expenditure for their identification and rather low predictive value. Consequently, the reliable and early diagnosis of civilization diseases depends on the individual determination of all (or as many as possible) polymorphisms of each susceptibility gene together with the corresponding gene products and the metabolites emerging thereof.     

CHEMICAL PACEMAKERS : PART I. CATALYTIC BRAIN IRON. PART II. ACTIVATION ENERGIES OF CHEMICAL PACEMAKERS

1. Iron spicules found in the brains of general paretic patients are formed from endogenous brain iron normally present in another form. This supports our earlier view that the µ value of 16,000 obtained in advanced paretics for alpha brain wave frequencies as a measure of cortical respiration comes about from the slowing of an iron catalyzed link in cortical respiration such as would result from the reduction of available cytochrome and its oxidase, thus making this step a chemical pacemaker. 2. To test the basic theory of chemical pacemakers, a study was made of the succinate-fumarate enzyme system containing succino-dehydrogenase and cytochrome-cytochrome oxidase acting sequentially. 3. The µ value for the unpoisoned system is 11,200 ± 200 calories. 4. According to theory, the addition of a critical amount of cyanide known to be a specific poison of the cytochrome-cytochrome oxidase system (and not of the dehydrogenase) should shift the µ cleanly to 16,000 calories, and it does. 5. According to theory, selenite, a specific poison for the dehydrogenase, should stop all respiration without shifting the µ. This also is found to be the case. 6. The theory also predicts that if the µ is shifted from 11,000 ± to 16,000 ± by cyanide, the subsequent addition of a critical amount of selenite should shift the µ back again to 11,000 ± calories, and this is found to occur. 7. It is concluded that approximately 11,000 calories is the energy of activation of the succino-dehydrogenase-catalyzed step and 16,000 calories is that for the cytochrome-cytochrome oxidase-catalyzed step. These two values are encountered more frequently than any others in physiological systems. It is to be recalled that a shift of µ for alpha brain wave frequencies from 11,000 to 16,000 calories occurs in the course of advancing syphilitic brain infection and is accompanied by a change in form of brain iron.