The antioxidant action of tamoxifen and its metabolites Inhibition of lipid peroxidation

AbstractThe anti-oestrogen drug tamoxifen is an inhibitor of lipid peroxidation in rat liver microsomes and in phospholipid liposomes. Its cis isomer and N-desmethyl form are weaker inhibitors, but 4-hydroxytamoxifen is much more powerful. It is possible that the antioxidant property of tamoxifen might contribute to its biological actions

Securing Personal Input from Individuals Aging with Intellectual Disability: Do Differing Methodologies Produce Equivalent information?

Research is limited on whether differing methodologies for facilitating personal contributions from individuals aging with intellectual disability produce equivalent knowledge outcomes. Two matched purpose-developed tools examined five quality-of-life domains. Results showed substantial variance between qualitative interview responses and Likert-scale data, and indicate validity concerns for using either methodology in isolation

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Human Skeletal Muscle Mitochondrial Uncoupling Is Associated with Cold Induced Adaptive Thermogenesis

Background: Mild cold exposure and overfeeding are known to elevate energy expenditure in mammals, including humans. This process is called adaptive thermogenesis. In small animals, adaptive thermogenesis is mainly caused by mitochondrial uncoupling in brown adipose tissue and regulated via the sympathetic nervous system. In humans, skeletal muscle is a candidate tissue, known to account for a large part of the epinephrine-induced increase in energy expenditure. However, mitochondrial uncoupling in skeletal muscle has not extensively been studied in relation to adaptive thermogenesis in humans. Therefore we hypothesized that cold-induced adaptive thermogenesis in humans is accompanied by an increase in mitochondrial uncoupling in skeletal muscle. Methodology/Principal Findings: The metabolic response to mild cold exposure in 11 lean, male subjects was measured in a respiration chamber at baseline and mild cold exposure. Skeletal muscle mitochondrial uncoupling (state 4) was measured in muscle biopsies taken at the end of the respiration chamber stays. Mild cold exposure caused a significant increase in 24h energy expenditure of 2.8 % (0.32 MJ/day, range of 20.21 to 1.66 MJ/day, p,0.05). The individual increases in energy expenditure correlated to state 4 respiration (p,0.02, R 2 = 0.50). Conclusions/Significance: This study for the first time shows that in humans, skeletal muscle has the intrinsic capacity for cold induced adaptive thermogenesis via mitochondrial uncoupling under physiological conditions. This opens possibilitie

Perceived ethnic discrimination and persecutory paranoia in individuals at ultra-high risk for psychosis

Despite a consensus that psychosocial adversity plays a role in the onset of psychosis, the nature of this role in relation to persecutory paranoia remains unclear. This study examined the complex relationship between perceived ethnic discrimination and paranoid ideation in individuals at Ultra High Risk (UHR) for psychosis using a virtual reality paradigm to objectively measure paranoia. Data from 64 UHR participants and 43 healthy volunteers were analysed to investigate the relationship between perceived ethnic discrimination and persecutory ideation in a virtual reality environment. Perceived ethnic discrimination was higher in young adults at UHR in comparison to healthy controls. A positive correlation was observed between perceived ethnic discrimination and paranoid persecutory ideation in the whole sample. Perceived ethnic discrimination was not a significant predictor of paranoid persecutory ideation in the VR environment. Elevated levels of perceived ethnic discrimination are present in individuals at UHR and are consistent with current biopsychosocial models in which psychosocial adversity plays a key role in the development of psychosis and attenuated symptomatology

Can multilayer perceptron ensembles model the ecological niche of freshwater fish species?

The potential of Multilayer Perceptron (MLP) Ensembles to explore the ecology of freshwater fish specieswas tested by applying the technique to redfin barbel (Barbus haasi Mertens, 1925), an endemic and mon-tane species that inhabits the North-East quadrant of the Iberian Peninsula. Two different MLP Ensembleswere developed. The physical habitat model considered only abiotic variables, whereas the biotic modelalso included the density of the accompanying fish species and several invertebrate predictors. The results showed that MLP Ensembles may outperform single MLPs. Moreover, active selection of MLP candidatesto create an optimal subset of MLPs can further improve model performance. The physical habitat modelconfirmed the redfin barbel preference for middle-to-upper river segments whereas the importance ofdepth confirms that redfin barbel prefers pool-type habitats. Although the biotic model showed higheruncertainty, it suggested that redfin barbel, European eel and the considered cyprinid species have similarhabitat requirements. Due to its high predictive performance and its ability to deal with model uncertainty, the MLP Ensemble is a promising tool for ecological modelling or habitat suitability prediction in environmental flow assessment.This study was funded by the Spanish Ministry of Economy and Competitiveness with the project SCARCE (Consolider-Ingenio 2010 CSD2009-00065) and the Universitat Politecnica de Valencia, through the project UPPTE/2012/294 (PAID-06-12). Additionally, the authors would like to thank the help of the Conselleria de Territori i Vivenda (Generalitat Valenciana) and the Confederacion Hidrografica del Jucar (Spanish government) which provided environmental data. The authors are indebted to all the colleagues who collaborated in the field data collection and the text adequacy; without their help this paper would have not been possible. Last but not least, the authors would like to specifically thank E. Aparicio and A.J. Cannon, the former because he selflessly provided the bibliography about the redfin barbel and the latter because he patiently explained the 'ins and outs' of the monmlp package.Muñoz Mas, R.; Martinez-Capel, F.; Alcaraz-Hernández, JD.; Mouton, AM. (2015). Can multilayer perceptron ensembles model the ecological niche of freshwater fish species?. Ecological Modelling. 309-310:72-81. https://doi.org/10.1016/j.ecolmodel.2015.04.025S7281309-31

High diversity in neuropeptide immunoreactivity patterns among three closely related species of Dinophilidae (Annelida).

This is the author accepted manuscript.The final version is available from Wiley via the DOI in this record.Neuropeptides are conserved metazoan signaling molecules, and represent useful markers for comparative investigations on the morphology and function of the nervous system. However, little is known about the variation of neuropeptide expression patterns across closely related species in invertebrate groups other than insects. In this study, we compare the immunoreactivity patterns of 14 neuropeptides in three closely related microscopic dinophilid annelids (Dinophilus gyrociliatus, D. taeniatus and Trilobodrilus axi). The brains of all three species were found to consist of around 700 somata, surrounding a central neuropil with 3-5 ventral and 2-5 dorsal commissures. Neuropeptide immunoreactivity was detected in the brain, the ventral cords, stomatogastric nervous system, and additional nerves. Different neuropeptides are expressed in specific, non-overlapping cells in the brain in all three species. FMRFamide, MLD/pedal peptide, allatotropin, RNamide, excitatory peptide, and FVRIamide showed a broad localization within the brain, while calcitonin, SIFamide, vasotocin, RGWamide, DLamide, FLamide, FVamide, MIP, and serotonin were present in fewer cells in demarcated regions. The different markers did not reveal ganglionic subdivisions or physical compartmentalization in any of these microscopic brains. The non-overlapping expression of different neuropeptides may indicate that the regionalization in these uniform, small brains is realized by individual cells, rather than cell clusters, representing an alternative to the lobular organization observed in several macroscopic annelids. Furthermore, despite the similar gross brain morphology, we found an unexpectedly high variation in the expression patterns of neuropeptides across species. This suggests that neuropeptide expression evolves faster than morphology, representing a possible mechanism for the evolutionary divergence of behaviors.Villum Fonde

The 2dF-SDSS LRG and QSO survey: evolution of the clustering of luminous red galaxies since z = 0.6

We present an analysis of the small-to-intermediate scale clustering of samples of Luminous Red Galaxies (LRGs) from the Sloan Digital Sky Survey and the 2dF-SDSS LRG and QSO (2SLAQ) survey carefully matched to have the same rest-frame colours and luminosity. We study the spatial two-point auto-correlation function in both redshift-space and real-space of a combined sample of over 10,000 LRGs, which represent the most massive galaxies in the universe with stellar masses > 10^11 h^-1 M_sun and space densities 10^-4 h^-3 Mpc^-3. We find no significant evolution in the amplitude r_0 of the correlation function with redshift, but do see a slight decrease in the slope with increasing redshift over 0.19 < z < 0.55 and scales of 0.32 < r < 32 h^-1 Mpc. We compare our measurements with the predicted evolution of dark matter clustering and use the halo model to interpret our results. We find that our clustering measurements are inconsistent (>99.9% significance) with a passive model whereby the LRGs do not merge with one another; a model with a merger rate of 7.5 +/- 2.3% from z = 0.55 to z = 0.19 (i.e. an average rate of 2.4% Gyr^-1) provides a better fit to our observations. Our clustering and number density measurements are consistent with the hypothesis that the merged LRGs were originally central galaxies in different haloes which, following the merger of these haloes, merged to create a single Brightest Cluster Galaxy. In addition, we show that the small-scale clustering signal constrains the scatter in halo merger histories. When combined with measurements of the luminosity function, our results suggest that this scatter is sub-Poisson. While this is a generic prediction of hierarchical models, it has not been tested before.Comment: 20 pages, replaced with version accepted for publication in MNRA

The origin of animals: can molecular clocks and the fossil record be reconciled?

The evolutionary emergence of animals is one of the most significant episodes in the history of life, but its timing remains poorly constrained. Molecular clocks estimate that animals originated and began diversifying over 100 million years before the first definitive metazoan fossil evidence in the Cambrian. However, closer inspection reveals that clock estimates and the fossil record are less divergent than is often claimed. Modern clock analyses do not predict the presence of the crown-representatives of most animal phyla in the Neoproterozoic. Furthermore, despite challenges provided by incomplete preservation, a paucity of phylogenetically informative characters, and uncertain expectations of the anatomy of early animals, a number of Neoproterozoic fossils can reasonably be interpreted as metazoans. A considerable discrepancy remains, but much of this can be explained by the limited preservation potential of early metazoans and the difficulties associated with their identification in the fossil record. Critical assessment of both records may permit better resolution of the tempo and mode of early animal evolution.JAC and AGL acknowledge support from Natural Environment Research Council (NERC) Fellowships [grant numbers NE/J018325/1 and NE/L011409/1]. SB and JAC acknowledge funding from the Danish National Research Foundation [DNRF53] and the Swedish Research Council [2013-4290]. PCJD was supported by a Royal Society Wolfson Merit Award, a Leverhulme Trust Research Fellowship and a NERC standard grant [NE/F00348X/1]

Regulation of Brown Fat Adipogenesis by Protein Tyrosine Phosphatase 1B

Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of insulin signaling and energy balance, but its role in brown fat adipogenesis requires additional investigation.To precisely determine the role of PTP1B in adipogenesis, we established preadipocyte cell lines from wild type and PTP1B knockout (KO) mice. In addition, we reconstituted KO cells with wild type, substrate-trapping (D/A) and sumoylation-resistant (K/R) PTP1B mutants, then characterized differentiation and signaling in these cells. KO, D/A- and WT-reconstituted cells fully differentiated into mature adipocytes with KO and D/A cells exhibiting a trend for enhanced differentiation. In contrast, K/R cells exhibited marked attenuation in differentiation and lipid accumulation compared with WT cells. Expression of adipogenic markers PPARγ, C/EBPα, C/EBPδ, and PGC1α mirrored the differentiation pattern. In addition, the differentiation deficit in K/R cells could be reversed completely by the PPARγ activator troglitazone. PTP1B deficiency enhanced insulin receptor (IR) and insulin receptor substrate 1 (IRS1) tyrosyl phosphorylation, while K/R cells exhibited attenuated insulin-induced IR and IRS1 phosphorylation and glucose uptake compared with WT cells. In addition, substrate-trapping studies revealed that IRS1 is a substrate for PTP1B in brown adipocytes. Moreover, KO, D/A and K/R cells exhibited elevated AMPK and ACC phosphorylation compared with WT cells.These data indicate that PTP1B is a modulator of brown fat adipogenesis and suggest that adipocyte differentiation requires regulated expression of PTP1B