Cognitive epidemiology of ethnic health and the CHRM2 vagal vigour hypothesis

Ethnic populations representing areas throughout California were compared regarding cognitive ability, socioeconomic position, and mortality. Cognition and socioeconomic position were inversely correlated with mortality. The single nucleotide polymorphism rs8191992 in the M2 muscarinic receptor gene (CHRM2) was previously linked to IQ and modulation of vagal tone. The CHRM2 vagal vigour hypothesis posits that variation at rs8191992 alters the binding site for a brain-expressed microRNA (hsa-mir-383) thereby changing expression of brain M2 muscarinic receptors to cause pleiotropic effects on cognition and vagus nerve signalling which then affects health via the vagal cholinergic anti-inflammatory pathway. This may help explain ethnic health differences, including the Hispanic Health Paradox, since ethnic differences in rs8191992 allele frequencies correspond to ethnic differences in systemic inflammation and mortality. The rs8191992 A-allele may contribute to the clustering of low IQ and low vagal tone with higher substance abuse, externalizing psychopathology, depression, systemic inflammation, metabolic syndrome, and cardiovascular disease

The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase.

The yeast silent information regulator (Sir)2 protein links cellular metabolism and transcriptional silencing through its nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase activity. We report that mitochondria from mammalian cells contain intrinsic NAD-dependent deacetylase activity. This activity is inhibited by the NAD hydrolysis product nicotinamide, but not by trichostatin A, consistent with a class III deacetylase. We identify this deacetylase as the nuclear-encoded human Sir2 homologue hSIRT3, and show that hSIRT3 is located within the mitochondrial matrix. Mitochondrial import of hSIRT3 is dependent on an NH2-terminal amphipathic alpha-helix rich in basic residues. hSIRT3 is proteolytically processed in the mitochondrial matrix to a 28-kD product. This processing can be reconstituted in vitro with recombinant mitochondrial matrix processing peptidase (MPP) and is inhibited by mutation of arginines 99 and 100. The unprocessed form of hSIRT3 is enzymatically inactive and becomes fully activated in vitro after cleavage by MPP. These observations demonstrate the existence of a latent class III deacetylase that becomes catalytically activated upon import into the human mitochondria

Arachidonic Acid Release and Catecholamine Secretion from Digitonin-Treated Chromaffin Cells: Effects of Micromolar Calcium, Phorbol Ester, and Protein Alkylating Agents

The relationship between catecholamine secretion and arachidonic acid release from digitonin-treated chromaffin cells was investigated. Digitonin renders permeable the plasma membranes of bovine adrenal chromaffin cells to Ca 2+ , ATP, and proteins. Digitonin-treated cells undergo exocytosis of catecholamine in response to micromolar Ca 2+ in the medium. The addition of micromolar Ca 2+ to digitonin-treated chromaffin cells that had been prelabeled with [ 3 H]arachidonic acid caused a marked increase in the release of [ 3 H]arachidonic acid. The time course of [ 3 H]arachidonic acid release paralleled catecholamine secretion. Although [ 3 H]arachidonic acid release and exocytosis were both activated by free Ca 2+ in the micromolar range, the activation of [ 3 H]arachidonic acid release occurred at Ca 2+ concentrations slightly lower than those required to activate exocytosis. Pretreatment of the chromaffin cells with N -ethylmaleimide (NEM) or p -bromophenacyl bromide (BPB) resulted in dose-dependent inhibition of 10 Μ M Ca 2+ -stimulated [ 3 H]arachidonic acid release and exocytosis. The IC 50 of NEM for both [ 3 H]arachidonic acid release and exocytosis was 40 Μ M. The IC 50 of BPB for both events was 25 Μ M. High concentrations (5–20 m M ) of Mg 2+ caused inhibition of catecholamine secretion without altering [ 3 H]arachidonic acid release. A phorbol ester that activates protein kinase C, 12- O -tetradecanoylphorbol-13-acetate (TPA), caused enhancement of both [ 3 H]arachidonic acid release and exocytosis. The findings demonstrate that [ 3 H]arachidonic acid release is stimulated during catecholamine secretion from digitonin-treated chromaffin cells and they are consistent with a role for phospholipase A 2 in exocytosis from chromaffin cells. Furthermore the data suggest that protein kinase C can modulate both arachidonic acid release and exocytosis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65534/1/j.1471-4159.1985.tb07140.x.pd

The Relationship Between Arachidonic Acid Release and Catecholamine Secretion from Cultured Bovine Adrenal Chromaffin Cells

Increased arachidonic acid release occurred during activation of catecholamine secretion from cul- tured bovine adrenal medullary chromaffin cells. The nicotinic agonist l,l-dimethyl-4-phenylpiperazinium (DMPP) caused an increased release of prcincubated [ 3 H]arachidonic acid over a time course which corre- sponded to the stimulation of catecholamine secretion. Like catecholamine secretion, the DMPP-induced [ 3 H]arachidonic acid release was calcium-dependent and was blocked by the nicotinic antagonist mecamylamine. Depolarization by elevated K + , which induced catechol amine secretion, also stimulated arachidonic acid release. Because arachidonic acid release from cells probably re- sults from phospholipase A 2 activity, our findings indicate that phospholipase A 2 may be activated in chromaffin cells during secretion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66068/1/j.1471-4159.1984.tb06690.x.pd

Relationship Between Ca 2+ Uptake and Catecholamine Secretion in Primary Dissociated Cultures of Adrenal Medulla

Carbachol or elevated K + stimulated 45 Ca 2+ uptake into chromaffin cells two- to fourfold. The uptake was stimulated by cholinergic drugs with nicotinic activity, but not by those with only muscarinic activity. Ca 2+ uptake and catecholamine secretion induced by the mixed nicotinic-muscarinic agonist carbachol were inhibited by the nicotinic antagonist mecamylamine, but not by the muscarinic antagonist atropine. Significant Ca 2+ uptake occurred within 15 s of stimulation by carbachol or elevated K + at a time before catecholamine secretion was readily detected. At later times the time course of secretion induced by carbachol or elevated K + was similar to that of Ca 2+ uptake. There was a close correlation between Ca 2+ uptake and catecholamine secretion at various concentrations of Ca 2+ . The concentration dependencies for inhibition of both processes by Mg 2+ or Cd 2+ were similar. Ca 2+ uptake saturated with increasing Ca 2+ concentrations, with an apparent K m for both carbachol-induced and elevated K + -induced Ca 2+ uptake of approximately 2 m M . The Ca 2+ dependency, however, was different for the two stimuli. The studies provide strong support for the notion that Ca 2+ entry and a presumed increase in cytosolic Ca 2+ concentration respectively initiates and maintains secretion. They also provide evidence for the existence of saturable, intracellular, Ca 2+ - dependent processes associated with catecholamine secretion. Ca 2+ entry may, in addition, enhance nicotinic receptor desensitization and may cause inactivation of voltage-sensitive Ca 2+ channels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66166/1/j.1471-4159.1982.tb07940.x.pd

Loss of 5-methylcytosine alters the biogenesis of vault-derived small RNAs to coordinate epidermal differentiation.

The presence and absence of RNA modifications regulates RNA metabolism by modulating the binding of writer, reader, and eraser proteins. For 5-methylcytosine (m5C) however, it is largely unknown how it recruits or repels RNA-binding proteins. Here, we decipher the consequences of m5C deposition into the abundant non-coding vault RNA VTRNA1.1. Methylation of cytosine 69 in VTRNA1.1 occurs frequently in human cells, is exclusively mediated by NSUN2, and determines the processing of VTRNA1.1 into small-vault RNAs (svRNAs). We identify the serine/arginine rich splicing factor 2 (SRSF2) as a novel VTRNA1.1-binding protein that counteracts VTRNA1.1 processing by binding the non-methylated form with higher affinity. Both NSUN2 and SRSF2 orchestrate the production of distinct svRNAs. Finally, we discover a functional role of svRNAs in regulating the epidermal differentiation programme. Thus, our data reveal a direct role for m5C in the processing of VTRNA1.1 that involves SRSF2 and is crucial for efficient cellular differentiation.We thank everybody who provided us with reagents, in particular we thank James Stevenin for sending us recombinant SRSF2. We gratefully acknowledge the support of all the WT-MRC Stem Cell Institute core facility managers. This work was funded by Cancer Research UK (CR-630 UK) and the European Research Council (ERC). Parts of this research in Michaela Frye's laboratory was supported by core funding from Wellcome and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. Juri Rappsilber’s laboratory was supported by Wellcome Trust Senior Research Fellowship (084229). Gracjan Michlewski’s laboratory was supported by the MRC Career Development Award (G10000564), Wellcome Trust Seed Award (210144/Z/18/Z) and Wellcome Trust Centre for Cell Biology Core Grants (077707 and 092076). Abdulrahim Sajini was supported by a scholarship from the University of Tabuk and Khalifa University of Science and Technology Faculty start-up award number FSU-2018-01. Rebecca Wagner was supported by the Wellcome Trust PhD Programme in Stem Cell Biology & Medicine

Incidence and trends of blastomycosis-associated hospitalizations in the United States

We used the State Inpatient Databases from the United States Agency for Healthcare Research and Quality to provide state-specific age-adjusted blastomycosis-associated hospitalization incidence throughout the entire United States. Among the 46 states studied, states within the Mississippi and Ohio River valleys had the highest age-adjusted hospitalization incidence. Specifically, Wisconsin had the highest age-adjusted hospitalization incidence (2.9 hospitalizations per 100,000 person-years). Trends were studied in the five highest hospitalization incidence states. From 2000 to 2011, blastomycosis-associated hospitalizations increased significantly in Illinois and Kentucky with an average annual increase of 4.4% and 8.4%, respectively. Trends varied significantly by state. Overall, 64% of blastomycosis-associated hospitalizations were among men and the median age at hospitalization was 53 years. This analysis provides a complete epidemiologic description of blastomycosis-associated hospitalizations throughout the endemic area in the United States

A Full Suite of Histone and Histone Modifying Genes Are Transcribed in the Dinoflagellate Lingulodinium

BACKGROUND: Dinoflagellates typically lack histones and nucleosomes are not observed in DNA spreads. However, recent studies have shown the presence of core histone mRNA sequences scattered among different dinoflagellate species. To date, the presence of all components required for manufacturing and modifying nucleosomes in a single dinoflagellate species has not been confirmed. METHODOLOGY AND RESULTS: Analysis of a Lingulodinium transcriptome obtained by Illumina sequencing of mRNA shows several different copies of each of the four core histones as well as a suite of histone modifying enzymes and histone chaperone proteins. Phylogenetic analysis shows one of each Lingulodinium histone copies belongs to the dinoflagellate clade while the second is more divergent and does not share a common ancestor. All histone mRNAs are in low abundance (roughly 25 times lower than higher plants) and transcript levels do not vary over the cell cycle. We also tested Lingulodinium extracts for histone proteins using immunoblotting and LC-MS/MS, but were unable to confirm histone expression at the protein level. CONCLUSION: We show that all core histone sequences are present in the Lingulodinium transcriptome. The conservation of these sequences, even though histone protein accumulation remains below currently detectable levels, strongly suggests dinoflagellates possess histones

Revascularization for coronary artery disease in diabetes mellitus: Angioplasty, stents and coronary artery bypass grafting

Author Manuscript: 2011 April 14Patients with diabetes mellitus (DM) are prone to a diffuse and rapidly progressive form of atherosclerosis, which increases their likelihood of requiring revascularization. However, the unique pathophysiology of atherosclerosis in patients with DM modifies the response to arterial injury, with profound clinical consequences for patients undergoing percutaneous coronary intervention (PCI). Multiple studies have shown that DM is a strong risk factor for restenosis following successful balloon angioplasty or coronary stenting, with greater need for repeat revascularization and inferior clinical outcomes. Early data suggest that drug eluting stents reduce restenosis rates and the need for repeat revascularization irrespective of the diabetic state and with no significant reduction in hard clinical endpoints such as myocardial infarction and mortality. For many patients with 1- or 2-vessel coronary artery disease, there is little prognostic benefit from any intervention over optimal medical therapy. PCI with drug-eluting or bare metal stents is appropriate for patients who remain symptomatic with medical therapy. However, selection of the optimal myocardial revascularization strategy for patients with DM and multivessel coronary artery disease is crucial. Randomized trials comparing multivessel PCI with balloon angioplasty or bare metal stents to coronary artery bypass grafting (CABG) consistently demonstrated the superiority of CABG in patients with treated DM. In the setting of diabetes CABG had greater survival, fewer recurrent infarctions or need for re-intervention. Limited data suggests that CABG is superior to multivessel PCI even when drug-eluting stents are used. Several ongoing randomized trials are evaluating the long-term comparative efficacy of PCI with drug-eluting stents and CABG in patients with DM. Only further study will continue to unravel the mechanisms at play and optimal therapy in the face of the profoundly virulent atherosclerotic potential that accompanies diabetes mellitus.National Institutes of Health (U.S.) (GM 49039

Inhibitors of trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease.

Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi