The Resolved Outer Population of NGC6822 with WFPC2

We present F336W (U), F439W (B), F555W (V), and F675W (R) Wide Field Planetary Camera 2 (WFPC2) photometry of two outer regions of the Local Group dwarf irregular galaxy NGC6822. The NE region is ~13 arcmin from the galaxy centre, while the W region lies 10 arcmin out, and within the wispy low surface brightness outer regions of the galaxy. The fields are not crowded and contain few NGC 6822 stars. We discuss errors and uncertainties and find that the W region contains a main sequence that extends to stars of about 2 solar masses, with an age of about 200 Myr. The NE region has no main sequence or stars younger than 1 Gyr, but does contain some luminous red stars that are not matched in the W field. These stars are not clumped in the field. The results suggest that the W region may be a trace of a tidal event that triggered the current star-formation in this isolated galaxy.Comment: 12 pages including 2 tables, plus 4 figures (#1 omitted) To appear in PAS

Modeling the UBVRI time delays in Mrk 335

We develop a model of time delays between the continuum bands in the Narrow Line Seyfert 1 galaxy Mrk 335 to explain the observed delays measured in this source. We consider two geometries: an accretion disk with fully ionized warm absorber of considerable optical depth, located close to the symmetry axis, and an accretion disk with a hot corona. Both media lead to significant disk irradiation but the disk/corona geometry gives lower values of the time delays. Only the disk/corona models give results consistent with measurements of Sergeev et al., and a low value of the disk inclination is favored. The presence of an optically thick, fully ionized outflow is ruled out at the 2-sigma level.Comment: MNRAS (in press

Young and Intermediate-age Distance Indicators

Distance measurements beyond geometrical and semi-geometrical methods, rely mainly on standard candles. As the name suggests, these objects have known luminosities by virtue of their intrinsic proprieties and play a major role in our understanding of modern cosmology. The main caveats associated with standard candles are their absolute calibration, contamination of the sample from other sources and systematic uncertainties. The absolute calibration mainly depends on their chemical composition and age. To understand the impact of these effects on the distance scale, it is essential to develop methods based on different sample of standard candles. Here we review the fundamental properties of young and intermediate-age distance indicators such as Cepheids, Mira variables and Red Clump stars and the recent developments in their application as distance indicators.Comment: Review article, 63 pages (28 figures), Accepted for publication in Space Science Reviews (Chapter 3 of a special collection resulting from the May 2016 ISSI-BJ workshop on Astronomical Distance Determination in the Space Age

Challenging the holy grail of hospital accreditation: A cross sectional study of inpatient satisfaction in the field of cardiology

Extent: 7p.Background: Subjective parameters such as quality of life or patient satisfaction gain importance as outcome parameters and benchmarks in health care. In many countries hospitals are now undergoing accreditation as mandatory or voluntary measures. It is believed but unproven that accreditations positively influence quality of care and patient satisfaction. The present study aims to assess in a defined specialty (cardiology) the relationship between patient satisfaction (as measured by the recommendation rate) and accreditation status. Methods: Consecutive patients discharged from 25 cardiology units received a validated patient satisfaction questionnaire. Data from 3,037 patients (response rate > 55%) became available for analysis. Recommendation rate was used as primary endpoint. Different control variables such as staffing level were considered. Results: The 15 accredited units did not differ significantly from the 10 non-accredited units regarding main hospital (i.e. staffing levels, no. of beds) and patient (age, gender) characteristics. The primary endpoint "recommendation rate of a given hospital" for accredited hospitals (65.6%, 95% Confidence Interval (CI) 63.4 - 67.8%) and hospitals without accreditation (65.8%, 95% CI 63.1 - 68.5%) was not significantly different. Conclusion: Our results support the notion that - at least in the field of cardiology - successful accreditation is not linked with measurable better quality of care as perceived by the patient and reflected by the recommendation rate of a given institution. Hospital accreditation may represent a step towards quality management, but does not seem to improve overall patient satisfaction.Cornelia Sack, Peter Lütkes, Wolfram Günther, Raimund Erbel, Karl-Heinz Jöckel and Gerald J Holtman

Binarity and multiperiodicity in high-amplitude delta Scuti stars

We have carried out a photometric and spectroscopic survey of bright high-amplitude delta Scuti (HADS) stars. The aim was to detect binarity and multiperiodicity (or both) in order to explore the possibility of combining binary star astrophysics with stellar oscillations. Here we present the first results for ten, predominantly southern, HADS variables. We detected the orbital motion of RS Gru with a semi-amplitude of ~6.5 km/s and 11.5 days period. The companion is inferred to be a low-mass dwarf star in a close orbit around RS Gru. We found multiperiodicity in RY Lep both from photometric and radial velocity data and detected orbital motion in the radial velocities with hints of a possible period of 500--700 days. The data also revealed that the amplitude of the secondary frequency is variable on the time-scale of a few years, whereas the dominant mode is stable. Radial velocities of AD CMi revealed cycle-to-cycle variations which might be due to non-radial pulsations. We confirmed the multiperiodic nature of BQ Ind, while we obtained the first radial velocity curves of ZZ Mic and BE Lyn. The radial velocity curve and the O-C diagram of CY Aqr are consistent with the long-period binary hypothesis. We took new time series photometry on XX Cyg, DY Her and DY Peg, with which we updated their O-C diagrams.Comment: 15 pages, 16 pages, accepted for publication in MNRA

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “S-XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A’s in vivo half-life; and that S-XL6 crosses the blood–brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS

Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E

Background: Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood. Methods: Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding. Results: We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE. Conclusion: The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.Applied Science, Faculty ofMedicine, Faculty ofScience, Faculty ofOther UBCNon UBCBiomedical Engineering, School ofMedicine, Department ofNeurology, Division ofPathology and Laboratory Medicine, Department ofPhysics and Astronomy, Department ofReviewedFacult

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β-amyloid and α-synuclein trigger microglial NLRP3 activation, leading to caspase-1 activation and IL-1β secretion. Both caspase-1 and IL-1β contribute to disease progression in the mouse SOD1 model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1 mice microglia do not express NLRP3, and SOD1 protein generated IL-1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3-GFP gene knock-in mice that microglia express NLRP3 in SOD1 mice. We show that both aggregated and soluble SOD1 activates inflammasome in primary mouse microglia leading caspase-1 and IL-1β cleavage, ASC speck formation, and the secretion of IL-1β in a dose- and time-dependent manner. Importantly, SOD1 was unable to induce IL-1β secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1-induced microglial IL-1β secretion. Microglial NLRP3 upregulation was also observed in the TDP-43 ALS mouse model, and TDP-43 wild-type and mutant proteins could also activate microglial inflammasomes in a NLRP3-dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1 -mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression