Cosmology and Astrophysics from Relaxed Galaxy Clusters II: Cosmological Constraints

We present cosmological constraints from measurements of the gas mass fraction, $f_{gas}$, for massive, dynamically relaxed galaxy clusters. Our data set consists of Chandra observations of 40 such clusters, identified in a comprehensive search of the Chandra archive, as well as high-quality weak gravitational lensing data for a subset of these clusters. Incorporating a robust gravitational lensing calibration of the X-ray mass estimates, and restricting our measurements to the most self-similar and accurately measured regions of clusters, significantly reduces systematic uncertainties compared to previous work. Our data for the first time constrain the intrinsic scatter in $f_{gas}$, $(7.4\pm2.3)$% in a spherical shell at radii 0.8-1.2 $r_{2500}$, consistent with the expected variation in gas depletion and non-thermal pressure for relaxed clusters. From the lowest-redshift data in our sample we obtain a constraint on a combination of the Hubble parameter and cosmic baryon fraction, $h^{3/2}\Omega_b/\Omega_m=0.089\pm0.012$, that is insensitive to the nature of dark energy. Combined with standard priors on $h$ and $\Omega_b h^2$, this provides a tight constraint on the cosmic matter density, $\Omega_m=0.27\pm0.04$, which is similarly insensitive to dark energy. Using the entire cluster sample, extending to $z>1$, we obtain consistent results for $\Omega_m$ and interesting constraints on dark energy: $\Omega_\Lambda=0.65^{+0.17}_{-0.22}$ for non-flat $\Lambda$CDM models, and $w=-0.98\pm0.26$ for flat constant-$w$ models. Our results are both competitive and consistent with those from recent CMB, SNIa and BAO data. We present constraints on models of evolving dark energy from the combination of $f_{gas}$ data with these external data sets, and comment on the possibilities for improved $f_{gas}$ constraints using current and next-generation X-ray observatories and lensing data. (Abridged)Comment: 25 pages, 14 figures, 8 tables. Accepted by MNRAS. Code and data can be downloaded from http://www.slac.stanford.edu/~amantz/work/fgas14/ . v2: minor fix to table 1, updated bibliograph

Robust Weak-lensing Mass Calibration of Planck Galaxy Clusters

In light of the tension in cosmological constraints reported by the Planck team between their SZ-selected cluster counts and Cosmic Microwave Background (CMB) temperature anisotropies, we compare the Planck cluster mass estimates with robust, weak-lensing mass measurements from the Weighing the Giants (WtG) project. For the 22 clusters in common between the Planck cosmology sample and WtG, we find an overall mass ratio of \left = 0.688 \pm 0.072. Extending the sample to clusters not used in the Planck cosmology analysis yields a consistent value of $\left< M_{Planck}/M_{\rm WtG} \right> = 0.698 \pm 0.062$ from 38 clusters in common. Identifying the weak-lensing masses as proxies for the true cluster mass (on average), these ratios are $\sim 1.6\sigma$ lower than the default mass bias of 0.8 assumed in the Planck cluster analysis. Adopting the WtG weak-lensing-based mass calibration would substantially reduce the tension found between the Planck cluster count cosmology results and those from CMB temperature anisotropies, thereby dispensing of the need for "new physics" such as uncomfortably large neutrino masses (in the context of the measured Planck temperature anisotropies and other data). We also find modest evidence (at 95 per cent confidence) for a mass dependence of the calibration ratio and discuss its potential origin in light of systematic uncertainties in the temperature calibration of the X-ray measurements used to calibrate the Planck cluster masses. Our results exemplify the critical role that robust absolute mass calibration plays in cluster cosmology, and the invaluable role of accurate weak-lensing mass measurements in this regard.Comment: 5 pages, 2 figure

Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD

SummaryBackgroundCombining maintenance medications with different mechanisms of action may improve outcomes in COPD. In this study we evaluated the efficacy and safety of fluticasone/salmeterol (FSC) (250/50 mcg twice daily) when added to tiotropium (18 mcg once daily) (TIO) in subjects with symptomatic moderate to severe COPD.MethodsThis was a 24-week, randomized, double-blind, parallel group, multi-center study. Subjects 40 years or older with cigarette smoking history ≥10 pack-years and with the diagnosis of COPD and post-bronchodilator FEV1 ≥40 to ≤ 80% of predicted normal and FEV1/FVC of ≤0.70 were enrolled. Following a 4-week treatment with open-label TIO 18 mcg once daily, subjects were randomized in a double-blind fashion to either the addition of FSC 250/50 DISKUS twice daily or matching placebo. The primary efficacy endpoint was AM pre-dose FEV1 and secondary endpoints included other measures of lung function, rescue albuterol use, health status and exacerbations.ResultsThe addition of FSC to TIO significantly improved lung function indices including AM pre-dose FEV1, 2 h post-dose FEV1, AM pre-dose FVC, 2 h post-dose FVC and AM pre-dose IC compared with TIO alone. Furthermore, this combination was superior to TIO alone in reducing rescue albuterol use. However, there were no significant differences between the treatment groups in health status or COPD exacerbations. The incidence of adverse events was similar in both groups.ConclusionsThe addition of FSC to subjects with COPD treated with TIO significantly improves lung function without increasing the risk of adverse events. NCT00784550

Absence of gemin5 from SMN complexes in nuclear Cajal bodies

<p>Abstract</p> <p>Background</p> <p>Spinal muscular atrophy is caused by reduced levels of the survival of motor neurons (SMN) protein. SMN is found in large complexes with Sm proteins and at least eight other proteins, including seven "gemins". These complexes are involved in the assembly of snRNPs in the cytoplasm and their transport into the nucleus, but the precise roles of the individual protein components are largely unknown.</p> <p>Results</p> <p>We have investigated the subcellular distribution of gemins using novel antibodies against gemins 3–7, and existing mAbs against SMN, gemin2, unrip, fibrillarin and profilin II. Most gemins were equally distributed between nuclear and cytoplasmic fractions of HeLa cells, but gemin5 and unrip were more abundant in the cytoplasm. In a cytoplasmic extract obtained by mild disruption of HeLa cells, nearly all the SMN and gemins 2–4 were in large complexes, but most of the gemin5 sedimented separately with a lower S value. Most of the unrip sedimented with gemins 6 and 7 near the top of the sucrose density gradients, separate from both SMN and gemin5. Anti-SMN mAbs pulled down gemin5 from cytoplasmic extracts, but not from nuclear extracts, and gemin5 did not co-sediment with large SMN complexes in nuclear extracts. These data suggest that gemin5 is easily detached from SMN-gemin complexes in the nucleus. By immuno-histochemistry, gemin5 was rarely detectable in nuclear gems/Cajal bodies, although it was accessible to antibody and easily detectable when present. This suggests that gemin5 is normally absent from SMN complexes in these nuclear storage sites.</p> <p>Conclusion</p> <p>We conclude that SMN complexes usually exist without gemin5 in nuclear gems/Cajal bodies. Gemin5 is believed to be involved in capturing snRNA into SMN complexes in the cytoplasm for transport into the nucleus. We hypothesize that gemin5, though present in the nucleus, is no longer needed for SMN complex function during the time these complexes are stored in gems/Cajal bodies.</p

A Board Level Intervention to Develop Organisation-Wide Quality Improvement Strategies: Cost-Consequences Analysis in 15 Healthcare Organisations.

BACKGROUND: Hospital boards have statutory responsibility for upholding the quality of care in their organisations. International research on quality in hospitals resulted in a research-based guide to help senior hospital leaders develop and implement quality improvement (QI) strategies, the QUASER Guide. Previous research has established a link between board practices and quality of care; however, to our knowledge, no board-level intervention has been evaluated in relation to its costs and consequences. The aim of this research was to evaluate these impacts when the QUASER Guide was implemented in an organisational development intervention (iQUASER). METHODS: We conducted a 'before and after' cost-consequences analysis (CCA), as part of a mixed methods evaluation. The analysis combined qualitative data collected from 66 interviews, 60 hours of board meeting observations and documents from 15 healthcare organisations, of which 6 took part on iQUASER, and included direct and opportunity costs associated with the intervention. The consequences focused on the development of an organisation-wide QI strategy, progress on addressing 8 dimensions of QI (the QUASER challenges), how organisations compared to benchmarks, engagement with the intervention and progress in the implementation of a QI project. RESULTS: We found that participating organisations made greater progress in developing an organisation-wide QI strategy and became more similar to the high-performing benchmark than the comparators. However, progress in addressing all 8 QUASER challenges was only observed in one organisation. Stronger engagement with the intervention was associated with the implementation of a QI project. On average, iQUASER costed £23 496 per participating organisation, of which approximately 44% were staff time costs. Organisations that engaged less with the intervention had lower than average costs (£21 267 per organisation), but also failed to implement an organisation-wide QI project. CONCLUSION: We found a positive association between level of engagement with the intervention, development of an organisation-wide QI strategy and the implementation of an organisation-wide QI project. Support from the board, particularly the chair and chief executive, for participation in the intervention, is important for organisations to accrue most benefit. A board-level intervention for QI, such as iQUASER, is relatively inexpensive as a proportion of an organisation's budget

Two alternatively-spliced human nebulin isoforms with either exon 143 or exon 144 and their developmental regulation

Nebulin is a very large protein required for assembly of the contractile machinery in muscle. Mutations in the nebulin gene NEB are a common cause of nemaline myopathy. Nebulin mRNA is alternatively-spliced so that each mRNA contains either exon 143 or exon 144. We have produced monoclonal antibodies specific for the regions of nebulin encoded by these two exons, enabling analysis of expression of isoforms at the protein level for the first time. All antibodies recognized a protein of the expected size (600-900 kD) and stained cross-striations of sarcomeres in muscle sections. Expression of exon 143 is developmentally-regulated since newly-formed myotubes in cell culture expressed nebulin with exon 144 only; this was confirmed at the mRNA level by qPCR. In fetal muscle, nebulin with exon 143 was expressed in some myotubes by 12-weeks of gestation and strongly-expressed in most myotubes by 17-weeks. In mature human muscle, the exon 144 antibody stained all fibres, but the exon 143 antibody staining varied from very strong in some fibres to almost-undetectable in other fibres. The results show that nebulin containing exon 144 is the default isoform early in myogenesis, while regulated expression of nebulin containing exon 143 occurs at later stages of muscle development.Peer reviewe

Primary laminopathy fibroblasts display altered genome organization and apoptosis

A number of diseases associated with specific tissue degeneration and premature aging have mutations in the nuclear envelope proteins A-type lamins or emerin. Those diseases with A-type lamin mutation are inclusively termed laminopathies. Due to various hypothetical roles of nuclear envelope proteins in genome function we investigated whether alterations to normal genomic behaviour are apparent in cells with mutations in A-type lamins and emerin. Even though the distributions of these proteins in proliferating laminopathy fibroblasts appear normal, there is abnormal nuclear positioning of both chromosome 18 and 13 territories, from the nuclear periphery to the interior. This genomic organization mimics that found in normal nonproliferating quiescent or senescent cells. This finding is supported by distributions of modified pRb in the laminopathy cells. All laminopathy cell lines tested and an X-linked Emery-Dreifuss muscular dystrophy cell line also demonstrate increased incidences of apoptosis. The most extreme cases of apoptosis occur in cells derived from diseases with mutations in the tail region of the LMNA gene, such as Dunningan-type familial partial lipodystrophy and mandibuloacral dysplasia, and this correlates with a significant level of micronucleation in these cells