PMI: A Delta Psi(m) Independent Pharmacological Regulator of Mitophagy

Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨm and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨm by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy

The Global Epidemiological Transition in Cardiovascular Diseases:Unrecognised Impact of Endemic Infections on Peripheral Artery Disease

An epidemiological transition in the prevalence of peripheral artery disease (PAD) is taking place especially in low- and middle-income countries (LMICs) where an ageing population and adoption of western lifestyles are associated with an increase in PAD. We discuss the limited evidence which suggests that infection, potentially mediated by inflammation, may be a risk factor for PAD, and show by means of an ecological analysis that country-level prevalence of the major endemic infections of HIV, tuberculosis and malaria are associated with the prevalence of PAD. While further research is required, we propose that scientists and health authorities pay more attention to the interplay between communicable and non-communicable diseases, and we suggest that limiting the occurrence of endemic infections might have some effect on slowing the epidemiological transition in PAD

Chemical characterization of the surface sites of coal

We propose to do experimental studies in four related areas concerning the acid-base properties of coal surfaces; (1) develop high precision flow microcalorimetric methods for determining the concentrations and strengths of the acidic and basic surface sites of coal powders; (2) develop photo-acoustic FTIR and solid-state NMR spectral shift techniques for determination of the concentrations and strengths of acidic and basic surface sites of coal powders; (3) determine the concentrations and strengths of the acidic and basic surface sites of some of the well-characterized coal samples from Argonne National Labs, comparing the coal samples before and after demineralization treatments with HCl and HF; (4) study the effects of surface acidity and basicity on the coal/water interface, with emphasis on the role of interfacial acid-base interactions in the adsorption of ions, surfactants and coal/water slurry stabilizers. One of the major goals of this research effort is to identify and characterize acidic and basic molecules which have NMR active nuclei such that through measurements of NMR chemical shifts one can deduce the surface acidity or basicity of solids such as coals. This quarter, triphenylsilanol was investigated as an NMR chemical shift probe molecule. 2 figs., 1 tab

Wetting and bonding characteristics of selected liquid-metals with a high power diode laser treated alumina bioceramic

Changes in the wettability characteristics of an alumina bioceramic occasioned by high power diode laser (HPDL) surface treatment were apparent from the observed reduction in the contact angle. Such changes were due to the HPDL bringing about reductions the surface roughness, increases in the surface O2 content and increases in the polar component of the surface energy. Additionally, HPDL treatment of the alumina bioceramic surface was found to effect an improvement in the bonding characteristics by increasing the work of adhesion. An electronic approach was used to elucidate the bonding characteristics of the alumina bioceramic before and after HPDL treatment. It is postulated that HPDL induced changes to the alumina bioceramic produced a surface with a reduced bandgap energy which consequently increased the work of adhesion by increasing the electron transfer at the metal/oxide interface and thus the metal-oxide interactions. Furthermore, it is suggested that the increase in the work of adhesion of the alumina bioceramic after HPDL treatment was due to a correlation existing between the wettability and ionicity of the alumina bioceramic; for it is believed that the HPDL treated surface is less ionic in nature than the untreated surface and therefore exhibits better wettability characteristics

Low dose aspirin and cognitive function in middle aged to elderly adults: randomised controlled trial

Objective To determine the effects of low dose aspirin on cognitive function in middle aged to elderly men and women at moderately increased cardiovascular risk

Effect of Impurities in Description of Surface Nanobubbles

Surface nanobubbles emerging at solid-liquid interfaces of submerged hydrophobic surfaces show extreme stability and very small (gas-side) contact angles. In a recent study Ducker (W. A. Ducker, Langmuir 25, 8907 (2009).) conjectured that these effects may arise from the presence of impurities at the air-water interface of the nanobubbles. In this paper we present a quantitative analysis of this hypothesis by estimating the dependence of the contact angle and the Laplace pressure on the fraction of impurity coverage at the liquid-gas interface. We first develop a general analytical framework to estimate the effect of impurities (ionic or non-ionic) in lowering the surface tension of a given air-water interface. We then employ this model to show that the (gas-side) contact angle and the Laplace pressure across the nanobubbles indeed decrease considerably with an increase in the fractional coverage of the impurities, though still not sufficiently small to account for the observed surface nanobubble stability. The proposed model also suggests the dependencies of the Laplace pressure and the contact angle on the type of impurity

Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Wettability characteristics of an Al2O3/SiO2-based ceramic modified with CO2, Nd:YAG, excimer and high-power diode lasers

Interaction of CO2, Nd:YAG, excimer and high power diode laser (HPDL) radiation with the surface of an Al2O3/SiO2 based ceramic was found to effect significant changes in the wettability characteristics of the material. It was observed that interaction with CO2, Nd:YAG and HPDL radiation reduced the enamel contact angle from 1180 to 310, 340 and 330 respectively. In contrast, interaction with excimer laser radiation resulted an increase in the contact angle to 1210. Such changes were identified as being due to: (i) the melting and partial vitrification of the Al2O3/SiO2 based ceramic surface as a result of interaction with CO2, Nd:YAG HPDL radiation. (ii) the surface roughness of the Al2O3/SiO2 based ceramic increasing after interaction with excimer laser radiation. (iii) the surface oxygen content of the Al2O3/SiO2 based ceramic increasing after interaction with CO2, Nd:YAG and HPDL radiation. The work has shown that the wettability characteristics of the Al2O3/SiO2 based ceramic could be controlled and/or modified with laser surface treatment. In particular, whether the laser radiation had the propensity to cause surface melting. However, a wavelength dependance of the change of the wetting properties could not be deduced from the findings of this work

Individual variation in levels of haptoglobin-related protein in children from Gabon

Background: Haptoglobin related protein (Hpr) is a key component of trypanosome lytic factors (TLF), a subset of highdensity lipoproteins (HDL) that form the first line of human defence against African trypanosomes. Hpr, like haptoglobin (Hp) can bind to hemoglobin (Hb) and it is the Hpr-Hb complexes which bind to these parasites allowing uptake of TLF. This unique form of innate immunity is primate-specific. To date, there have been no population studies of plasma levels of Hpr, particularly in relation to hemolysis and a high prevalence of ahaptoglobinemia as found in malaria endemic areas. Methods and Principal Findings: We developed a specific enzyme-linked immunosorbent assay to measure levels of plasma Hpr in Gabonese children sampled during a period of seasonal malaria transmission when acute phase responses (APR), malaria infection and associated hemolysis were prevalent. Median Hpr concentration was 0.28 mg/ml (range 0.03-1.1). This was 5-fold higher than that found in Caucasian children (0.049 mg/ml, range 0.002-0.26) with no evidence of an APR. A general linear model was used to investigate associations between Hpr levels, host polymorphisms, parasitological factors and the acute phase proteins, Hp, C-reactive protein (CRP) and albumin. Levels of Hpr were associated with Hp genotype, decreased with age and were higher in females. Hpr concentration was strongly correlated with that of Hp, but not CRP

Prevention is better than cure, but...: Preventive medication as a risk to ordinariness?

Preventive health remains at the forefront of public health concerns; recent initiatives, such as the NHS health check, may lead to recommendations for medication in response to the identification of 'at risk' individuals. Little is known about lay views of preventive medication. This paper uses the case of aspirin as a prophylactic against heart disease to explore views among people invited to screening for a trial investigating the efficacy of such an approach. Qualitative interviews (N=46) and focus groups (N=5, participants 31) revealed dilemmas about preventive medication in the form of clashes between norms: first, in general terms, assumptions about the benefit of prevention were complicated by dislike of medication; second, the individual duty to engage in prevention was complicated by the need not to be over involved with one's own health; third, the potential appeal of this alternative approach to health promotion was complicated by unease about the implications of encouraging irresponsible behaviour among others. Though respondents made different decisions about using the drug, they reported very similar ways of trying to resolve these conflicts, drawing upon concepts of necessity and legitimisation and the special ordinariness of the particular dru