Using an in vitro model to study oxidised protein accumulation in ageing fibroblasts

© 2015 Elsevier B.V. All rights reserved. Background The accumulation of oxidised proteins in ageing cells and tissues results from an increase in oxidant damage coupled with impaired degradation of the damaged proteins. Heat Shock Proteins (HSP) and other chaperones are required to recognise damaged proteins and transport them to the lysosomal and proteasomal degradation pathways. How these systems fail in ageing cells is not clear. Methods We monitor oxidised protein accumulation, the activity of the proteasome and lysosomal proteases, and HSP levels in MRC-5 fibroblasts throughout their mitotic lifespan. We then use a novel in vitro cell culture model to experimentally generate oxidised proteins in young and old MRC-5 fibroblasts and compare their rates of degradation and changes in the key pathways involved in oxidised protein removal. Results We show that the activity of the proteasome and some lysosomal enzymes decreases with ageing in MRC-5 cells as do levels of HSP70 but this is not associated with an accumulation of oxidised proteins which only occurs as cells closely approach post-mitotic senescence. Old cells are unable to degrade experimentally generated oxidised proteins as efficiently as young cells. Exposure to mild heat stress however increases the efficiency of oxidised protein degradation by young cells and increases levels of HSP70. Conclusions Our results highlight the importance of the HSP/chaperone system in oxidised protein metabolism, particularly in ageing cells. General significance These data might have implications for the development of therapies for pathologies associated with protein accumulation and suggest that the HSP/chaperone system would be an important target

A complete sample of quasars from the 7C redshift survey

We present details of a new sample of radio-loud quasars drawn from 0.013 sr of the 7C Redshift Survey. This sample is small (21 quasars) but complete in that every object with an unresolved nucleus and/or broad emission lines with S(151MHz) > 0.5 Jy has been discovered. The dependence of the quasar fraction with redshift and radio luminosity is investigated, providing new evidence supporting the unification of radio-loud quasars and powerful radio galaxies. This 7C sample is compared with optically-selected quasars, in order to determine whether there are systematic biases in the different selection techniques. There are no lightly reddened (Av approx. 1) quasars in our sample amongst the 14 with z < 2. The discovery of a reddened quasar at z = 2.034 and its implications are discussed. A tight correlation between radio luminosity and optical/near infrared continuum luminosity for a subset of the sample is also found.Comment: 6 pages Latex, To appear in the "Cosmology with the New Radio Surveys" Conference - Tenerife 13-15 January 199

Optical alignment and spinning of laser-trapped microscopic particles

Light-induced rotation of absorbing microscopic particles by transfer of angular momentum from light to the material raises the possibility of optically driven micromachines. The phenomenon has been observed using elliptically polarized laser beams or beams with helical phase structure. But it is difficult to develop high power in such experiments because of overheating and unwanted axial forces, limiting the achievable rotation rates to a few hertz. This problem can in principle be overcome by using transparent particles, transferring angular momentum by a mechanism first observed by Beth in 1936, when he reported a tiny torque developed in a quartz waveplate due to the change in polarization of transmitted light. Here we show that an optical torque can be induced on microscopic birefringent particles of calcite held by optical tweezers. Depending on the polarization of the incident beam, the particles either become aligned with the plane of polarization (and thus can be rotated through specified angles) or spin with constant rotation frequency. Because these microscopic particles are transparent, they can be held in three-dimensional optical traps at very high power without heating. We have observed rotation rates in excess of 350 Hz.Comment: 4 pages, 4 figure

The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation

Mechanisms of protein misfolding are of increasing interest in the aetiology of neurodegenerative diseases characterized by protein aggregation and tangles including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body Dementia (LBD), and Progressive Supranuclear Palsy (PSP). Some forms of neurodegenerative illness are associated with mutations in genes which control assembly of disease related proteins. For example, the mouse sticky mutation sti, which results in undetected mischarging of tRNAAla with serine resulting in the substitution of serine for alanine in proteins causes cerebellar Purkinje cell loss and ataxia in laboratory animals. Replacement of serine 422 with glutamic acid in tau increases the propensity of tau aggregation associated with neurodegeneration. However, the possibility that environmental factors can trigger abnormal folding in proteins remains relatively unexplored. We here report that a non-protein amino acid, β-N-methylamino-L-alanine (BMAA), can be misincorporated in place of l-serine into human proteins. We also report that this misincorporation can be inhibited by l-serine. Misincorporation of BMAA into human neuroproteins may shed light on putative associations between human exposure to BMAA produced by cyanobacteria and an increased incidence of ALS. © 2013 Dunlop et al

Extremely red radio galaxies

At least half the radio galaxies at z>1 in the 7C Redshift Survey have extremely red colours (R-K>5), consistent with stellar populations which formed at high redshift (z>5). We discuss the implications of this for the evolution of massive galaxies in general and for the fraction of near-IR-selected EROs which host AGN, a result which is now being tested by deep, hard X-ray surveys. The conclusion is that many massive galaxies undergo at least two active phases: one at z~5 when the black hole and stellar bulge formed and another at z~1-2 when activity is triggered by an event such as an interaction or merger.Comment: 6 pages, 2 figures, to appear in the proceedings of the workshop on "QSO hosts and their environments", IAA, Granada, 10-12 Jan 2001, Ed. I. Marque

Transparency in health economic modeling : options, issues and potential solutions

Economic models are increasingly being used by health economists to assess the value of health technologies and inform healthcare decision making. However, most published economic models represent a kind of black box, with known inputs and outputs but undisclosed internal calculations and assumptions. This lack of transparency makes the evaluation of the model results challenging, complicates comparisons between models, and limits the reproducibility of the models. Here, we aim to provide an overview of the possible steps that could be undertaken to make economic models more transparent and encourage model developers to share more detailed calculations and assumptions with their peers. Scenarios with different levels of transparency (i.e., how much information is disclosed) and reach of transparency (i.e., who has access to the disclosed information) are discussed, and five key concerns (copyrights, model misuse, confidential data, software, and time/resources) pertaining to model transparency are presented, along with possible solutions. While a shift toward open-source models is underway in health economics, as has happened before in other research fields, the challenges ahead should not be underestimated. Importantly, there is a pressing need to find an acceptable trade-off between the added value of model transparency and the time and resources needed to achieve such transparency. To this end, it will be crucial to set incentives at different stakeholder levels. Despite the many challenges, the many benefits of publicly sharing economic models make increased transparency a goal worth pursuing

Use and perceived helpfulness of smoking cessation methods: results from a population survey of recent quitters

<p>Abstract</p> <p>Background</p> <p>Increasing rates of smoking cessation is one of the most effective measures available to improve population health. To advance the goal of increasing successful cessation at the population level, it is imperative that we understand more about smokers' use of cessation methods, as well as the helpfulness of those methods in real-world experiences of quitting. In this survey of recent quitters, we simultaneously examined rates of use and perceived helpfulness of various cessation methods.</p> <p>Methods</p> <p>Recent quitters (within 12 months; n = 1097) completed a telephone survey including questions relating to 13 cessation methods. Indices of use and perceived helpfulness for each method were plotted in a quadrant analysis. Socio-demographic differences were explored using bivariate and multivariate analyses.</p> <p>Results</p> <p>From the quadrant analysis, cold turkey, NRT and gradual reduction before quitting had high use and helpfulness; GP advice had high use and lower helpfulness. Prescribed medication and online programs had low use but high helpfulness. Remaining methods had low use and helpfulness. Younger quitters were more likely to use unassisted methods such as cold turkey; older or less educated quitters were more likely to use assisted methods such as prescribed medication or advice from a general practitioner.</p> <p>Conclusions</p> <p>The majority of recent quitters quit cold turkey or cut down before quitting, and reported that these methods were helpful. Efforts to influence population smoking prevalence should attempt to provide support and motivation for smokers choosing these methods, in addition to assessing the effectiveness and accessibility of other methods for smokers who need or choose them.</p

Comparison of outpatient health care utilization among returning women and men Veterans from Afghanistan and Iraq

<p>Abstract</p> <p>Background</p> <p>The number of women serving in the United States military increased during Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), leading to a subsequent surge in new women Veterans seeking health care services from the Veterans Administration (VA). The objective of this study was to examine gender differences among OEF/OIF Veterans in utilization of VA outpatient health care services.</p> <p>Methods</p> <p>Our retrospective cohort consisted of 1,620 OEF/OIF Veterans (240 women and 1380 men) who enrolled for outpatient healthcare at a single VA facility. We collected demographic data and information on military service and VA utilization from VA electronic medical records. To assess gender differences we used two models: use versus nonuse of services (logistic regression) and intensity of use among users (negative binomial regression).</p> <p>Results</p> <p>In our sample, women were more likely to be younger, single, and non-white than men. Women were more likely to utilize outpatient care services (odds ratio [OR] = 1.47, 95% confidence interval [CI]:1.09, 1.98), but once care was initiated, frequency of visits over time (intensity) did not differ by gender (incident rate ratio [IRR] = 1.07; 95% CI: 0.90, 1.27).</p> <p>Conclusion</p> <p>Recently discharged OEF/OIF women Veterans were more likely to seek VA health care than men Veterans. But the intensity of use was similar between women and men VA care users. As more women use VA health care, prospective studies exploring gender differences in types of services utilized, health outcomes, and factors associated with satisfaction will be required.</p