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

A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling

The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca2+ signaling leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca2+ uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca2+ dynamics and redox transients in neuronal cytotoxicity

Holes in my memories: A qualitative study of men affected by father absence

This qualitative study explored adult men's experiences of father absence. Interviews with 21 men between the ages of 24 and 70 explored narratives of father absence and how the men perceived this influenced their life trajectory. Thematic analysis revealed that these men experienced a range of difficulties and challenges, including episodes of sadness and depression associated with loss and grief for the paternal relationship, self-esteem issues, feelings of anger and rejection, and difficulty forming trusting relationships particularly with other men. This study contributes to understanding mental health issues that can be associated with paternal absence for men. © 2014 Informa Healthcare USA, Inc

Topiramate Induced Acute Angle Closure Glaucoma

Topiramate is an oral sulphamate medication primarily used for seizure, migraine and neuropathic pain. It has been associated with secondary angle closure, which can mimic acute angle closure glaucoma. Suspicion for medication induced angle closure glaucoma should be higher whenever angle closure presents bilaterally. We present two cases of bilateral angle closure glaucoma secondary to topiramate

Interacting effects of temperature, habitat and phenotype on predator avoidance behaviour in <i>Diadema antillarum</i>: implications for restorative conservation

Caribbean long-spined sea urchin Diadema antillarum populations crashed following a mass mortality event in 1983-1984 with cascading effects on reef health. Population restoration efforts may be hampered by unknown effects of short- and long-term elevated sea surface temperature (SST). We investigated how a key behavioural trait, predator avoidance behaviour (PAB; percentage of long defensive spines that moved in response to shadow stimuli), was affected by elevated SST in 180 individuals from 2 contrasting Honduran reefs: Utila (flattened reef structure, dearth of predation refugia) and Banco Capiro (complex reef structure, abundant refugia). Initiation of PAB is mediated by melanin, which breaks down at elevated water temperatures; thus, as SST rises, D. antillarum may become vulnerable to predation. We compared local current SST (CSST; 29.7°C) with 2 IPCC predicted long-term climate change scenarios under laboratory conditions. PAB decreased by 13.98-15.37% at CSST +1.4°C and 31.67-42.44% at CSST +3.1°C. Trial temperatures were similar to maxima recorded in the Caribbean during the 2016 El Niño, so our results also represent likely responses to worst-case short-term acute temperature anomalies. Juveniles maintained higher PAB than adults, indicating increased reliance on anti-predation behaviours. White-spined phenotypes from Utila’s flattened reef maintained higher PAB than black-spined counterparts, likely due to increased conspicuousness to visual predators. Habitat complexity may mitigate temperature-driven losses in natural behavioural defences. D. antillarum may be resilient to near-term (D. antillarum populations must be coupled to augmented reef complexity to improve future resilience

Plasma Dynamics

Contains reports on four research projects

The influence of left ventricular hypertrophyon survival in patients with coronaryartery disease: do race and gender matter?

AbstractObjectivesWe sought to determine the overall prognostic importance of left ventricular hypertrophy (LVH) among patients with coronary artery disease (CAD), as well as to determine whether this risk varies as a function of race or gender.BackgroundLeft ventricular hypertrophy is more prevalent among blacks and women than their counterparts. Blacks and women also have higher mortality with coronary disease.MethodsWe studied records of 2,461 patients (19% black, 42% women) diagnosed with CAD at cardiac catheterization between 1990 and 1998 from a single academic center. Left ventricular hypertrophy was defined using standard echocardiographic measures. Cox proportional hazards models were used for adjusted survival analyses. Mean patient follow-up was three years.ResultsPatients with LVH were older (68 vs. 65 years, p < 0.01), more often women (54% vs. 36%, p < 0.01), and black (25% vs. 16%, p < 0.01), and had higher unadjusted three-year mortality rates than patients without LVH (42% vs. 34%, p < 0.01). Left ventricular hypertrophy remained an independent predictor of mortality after adjusting for other clinical risk factors (hazard ratio 1.56, 95% confidence interval 1.35 to 1.80) with prognostic importance equivalent to that of left ventricular ejection fraction. Although the relative risk of LVH did not vary by race or gender, the attributable risk of LVH was greater in blacks and women.ConclusionsClinicians should consider the prognostic importance of LVH when assessing risk in patients with CAD. Because LVH is more common among black and women patients with CAD, it partially accounts for racial and gender differences in survival

Substrate utilization during submaximal exercise in children with a severely obese parent

Background We have reported a reduction in fatty acid oxidation (FAO) at the whole-body level and in skeletal muscle in severely obese (BMI ≥ 40 kg/m2) individuals; this defect is retained in cell culture suggesting an inherent component. The purpose of the current study was to determine if an impairment in whole-body fatty acid oxidation (FAO) was also evident in children with a severely obese parent. Methods Substrate utilization during submaximal exercise (cycle ergometer) was determined in children ages 8–12 y with a severely obese parent (OP, n = 13) or two lean/non-obese (BMI range of 18 to 28 kg/m2) parents (LP, n = 13). A subgroup of subjects (n = 3/group) performed 4 weeks of exercise training with substrate utilization measured after the intervention. Results The children did not differ in age (LP vs. OP, respectively) (10.7 ± 0.5 vs. 10.2 ± 0.5 y), BMI percentile (65.3 ± 5.2 vs. 75.9 ± 7), Tanner Stage (1.4 ± 0.2 vs. 1.5 ± 0.2), VO2peak (40.3 ± 2.7 vs. 35.6 ± 2.6 ml/kg/min) or physical activity levels (accelerometer). At the same absolute workload of 15 W (~38% VO2peak), RER was significantly (P ≤ 0.05) lower in LP vs. OP (0.83 ± 0.02 vs. 0.87 ± 0.01) which was reflected in a reduced reliance on FAO for energy production in the OP group (58.6 ± 5.1 vs. 43.1 ± 4.0% of energy needs during exercise from FAO). At a higher exercise intensity (~65% VO2peak) there were no differences in substrate utilization between LP and OP. After exercise training RER tended to decrease (P = 0.06) at the 15 W workload, suggesting an increased reliance on FAO regardless of group. Conclusions These findings suggest that the decrement in FAO with severe obesity has an inherent component that may be overcome with exercise training

The first quadrupole excitations in spherical nuclei and nuclear pairing

Excitation energies and transition probabilities of the first 2+ excitations in even lead, tin and nickel isotopes are calculated within the self-consistent Theory of Finite Fermi Systems based on the Energy Density Functional by Fayans et al. A reasonable agreement with available experimental data is obtained. The effect of the density dependence of the effective pairing interaction is analyzed in detail by comparing results obtained with volume and surface pairing. The effect is found to be noticeable, especially for the 2+ energies which are systematically higher at 200-300 keV for the volume paring as compared with the surface pairing case, the latter being in a better agreement with the data.Comment: Presented at International Conference on Nuclear Structure and Related Topics, Dubna, July 2 - 7, 201

Emergency open cholecystectomy is associated with markedly lower incidence of postoperative nausea and vomiting (PONV) than elective open cholecystectomy: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>During a previous study to define and compare incidence risks of postoperative nausea and vomiting (PONV) for elective laparoscopic and open cholecystectomy at two hospitals in Jamaica, secondary analysis comparing PONV risk in elective open cholecystectomy to that after emergency open cholecystectomy suggested that it was markedly reduced in the latter group. The decision was made to collect data on an adequate sample of emergency open cholecystectomy cases and further explore this unexpected finding in a separate study.</p> <p>Methods</p> <p>Data were collected for 91 emergency open cholecystomy cases identified at the two paricipating hospitals from May 2007 retrograde, as was done for the 175 elective open cholecystectomy cases (from the aforementioned study) with which the emergency cases were to be compared. Variables selected for extraction and statistical analysis included all those known, suspected and plausibly associated with the risk of PONV and with urgency of surgery.</p> <p>Results</p> <p>Emergency open cholecystectomy was associated with a markedly reduced incidence risk of PONV compared to elective open cholecystectomy (6.6% versus 28.6%, P < 0.001). The suppressive effect of emergency increased after adjustment for confounders in a multivariable logistic regression model (odds ratio 0.103, P < 0.001). This finding also identifies, by extrapolation, an association between reduced risk of PONV and preoperative nausea and vomiting, which occurred in 80.2% of emergency cases in the 72 hour period preceding surgery.</p> <p>Conclusions</p> <p>The incidence risk of postoperative nausea and vomiting is markedly decreased after emergency open cholecystectomy compared to elective open cholecystectomy. The study, by extrapolation, also identifies a paradoxical association between pre-operative nausea and vomiting, observed in 80.2% of emergency cases, and suppression of PONV. This association, if confirmed in prospective cohort studies, may have implications for PONV prophylaxis if it can be exploited at a sub-clinical level.</p