Phosphorylation of chromosomal proteins as a function of age and its modulation by calcium

$\text{In vitro}$ phosphorylation of histones and non histone chromosomal proteins (NHCP) and its modulation by calcium have been studied using slices of cerebral hemisphere of rats of various ages. Phosphorylation of histones decreases, and that of NHCP increases with increasing age. Calcium inhibits phosphorylation of histones of young and adult rats, but stimulates phosphorylation of NHCP. Phosphorylation of H1 and H4 histones is greater than that of other histones, and calcium inhibits their phosphorylation more markedly than of other histones. The significance of such modifications of chromosomal proteins in the aging process is discussed.     

Potential for Controlling Cholera Using a Ring Vaccination Strategy: Re-analysis of Data from a Cluster-Randomized Clinical Trial

IntroductionVaccinating a buffer of individuals around a case (ring vaccination) has the potential to target those who are at highest risk of infection, reducing the number of doses needed to control a disease. We explored the potential vaccine effectiveness (VE) of oral cholera vaccines (OCVs) for such a strategy.ConclusionsThese findings suggest that high-level protection can be achieved if individuals living close to cholera cases are living in a high coverage ring. Since this was an observational study including participants who had received two doses of vaccine (or placebo) in the clinical trial, further studies are needed to determine whether a ring vaccination strategy, in which vaccine is given quickly to those living close to a case, is feasible and effective.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00289224","term_id":"NCT00289224"}}NCT00289224     

Expression of muscle creatine kinase gene of mice and interaction of nuclear proteins with MEF-2, E boxes and A/T-rich elements during aging

The changes in the expression of muscle creatine kinase (MCK) gene in the heart and skeletal muscle of mice during aging were studied. Its expression declines as a function of age in the heart, however, no age-related change is observed in the skeletal muscle. The cis-acting elements, MEF-2, E boxes and A/T rich elements present in the enhancer region of the mouse MCK gene are known to regulate the expression of the gene. Hence, these elements were subcloned and electrophoretic mobility shift assay was carried out to investigate the changes in the binding of the nuclear trans-acting protein factors of the heart with these elements as a function of age. These factors showed specificity for the respective cis-acting elements. Furthermore, the binding of these factors was found to decrease during aging which may contribute to the age-related decline in the expression of the MCK gene and activity of the heart.     

MEKK4 mediates differentiation in response to retinoic acid via activation of c-Jun N-terminal kinase in rat embryonal carcinoma P19 cells

Differentiation of P19 embryonal carcinoma cells in response to the morphogen retinoic acid is regulated by Galpha(12/13) and is associated with activation of c-Jun N-terminal kinase. The role of MEKK1 and MEKK4 upstream of the c-Jun N-terminal kinase was investigated in P19 cells. P19 clones stably expressing constitutively active and dominant negative mutants of MEKK1 and MEKK4 were created and characterized. Expression of the constitutively active form of either MEKK1 or MEKK4 mimicked the action of retinoic acid, inducing these embryonal carcinoma cells to primitive endoderm. Expression of the dominant negative form of MEKK1 had no influence on the ability of retinoic acid to induce either JNK activation or primitive endoderm formation in P19 stem cells. Expression of the dominant negative form of MEKK4, in contrast, effectively blocks both morphogen-induced activation of JNK and cellular differentiation. These data identify MEKK4 as upstream of c-Jun N-terminal kinase in the pathway mediating differentiation of P19 stem cells to primitive endoderm.     

Calcineurin inhibition enhances motor neuron survival following injury

The immunosuppressive agents cyclosporin A (CsA) and FK‐506 have previously been shown to exhibit neurotrophic and neuroprotective properties in vivo. Given that significant clinical expertise exists for both drugs, they represent an attractive starting point for treatment of acute neural injuries. One putative mechanism for neuroprotection by these drugs relates to inhibition of calcineurin activity. However each drug–immunophilin complex can potentially influence additional signal transduction pathways. Furthermore, several non‐immunosuppressive immunophilin ligands have been described as possessing neuroprotective properties, suggesting that neuroprotection may be separable from calcineurin inhibition. In the present study, we examined the mechanism of this neuroprotection in facial motor neurons following axotomy‐induced injury. Similar to previous studies in rats, CsA and FK‐506 enhanced motor neuron survival in mice following acute injury. To examine the mechanism responsible for neuroprotection by these agents, pharmacologic inhibitors of several potential alternate signalling pathways (17‐(allylamino)‐17‐demethoxygeldanamycin, rapamycin, cypermethrin) were evaluated with respect to neuroprotection. Of these, only cypermethrin, a direct calcineurin inhibitor not previously associated with neuronal survival properties, was observed to significantly enhance motor neuron survival following injury. The results demonstrate for the first time that direct inhibition of calcineurin is neuroprotective in vivo. These data support a model in which calcineurin inhibition promotes neuronal survival, distinct from effects upon neurite outgrowth.     

Transformations of codeine to important semisynthetic opiate derivatives by Pseudomonas putida m10

A biotransformation mixture which contained codeine and washed cells of Pseudomonas putida M10 gave rise to a number of transformation products that are of clinical importance which included hydrocodone, dihydrocodeine and 14beta-hydroxycodeine. Incubations with the same organism and codeinone gave rise to 14beta-hydroxycodeinone and 14beta-hydroxycodeine. Cell-free extracts and membrane fractions of P. putida M10 were shown to catalyse the 14beta-hydroxylation of codeinone. In addition, the potent analgesic oxycodone was shown to be produced from 14beta-hydroxycodeinone.