Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smokers : implications for autoimmunity in rheumatoid arthritis

Introduction: Smoking is a well-established risk factor for rheumatoid arthritis (RA), and it has been proposed that smoking-induced citrullination renders autoantigens immunogenic. To investigate this mechanism, we examined human lung tissue from 40 subjects with defined smoking status, with or without chronic obstructive pulmonary disease (COPD), and control tissues from other organs for citrullinated proteins and the deiminating enzymes peptidylarginine deiminase type-2 (PAD2) and -4 (PAD4). Methods: Lung tissue samples, dissected from lobectomy specimens from 10 never smokers, 10 smokers without airflow limitation, 13 COPD smokers and eight COPD ex-smokers, and control tissue samples (spleen, skeletal muscle, liver, ovary, lymph node, kidney and heart), were analysed for citrullinated proteins, PAD2 and PAD4 by immunoblotting. Citrulline and homocitrulline residues in enolase and vimentin were analysed by partial purification by gel electrophoresis followed by mass spectrometry in 12 of the lung samples and one from each control tissues. Band intensities were scored semi-quantitatively and analysed by two-tailed Mann-Whitney T-test. Results: Within the lung tissue samples, citrullinated proteins, PAD2 and PAD4 were found in all samples, with an increase in citrullination in COPD (P = 0.039), but minimal difference between smokers and non-smokers (P = 0.77). Citrullination was also detected at lower levels in the tissues from other organs, principally in lymph node, kidney and skeletal muscle. Mass spectrometry of the lung samples showed that vimentin was citrullinated at positions 71, 304, 346, 410 and 450 in non-smokers and smokers both with and without COPD. A homocitrulline at position 104 was found in four out of six COPD samples and one out of six non-COPD. Citrulline-450 was also found in three of the control tissues. There were no citrulline or homocitrulline residues demonstrated in a-enolase. Conclusions: We have shown evidence of citrullination of vimentin, a major autoantigen in RA, in both non-smokers and smokers. The increase in citrullinated proteins in COPD suggests that citrullination in the lungs of smokers is mainly due to inflammation. The ubiquity of citrullination of vimentin in the lungs and other tissues suggests that the relationship between smoking and autoimmunity in RA may be more complex than previously thought

Cost-effectiveness of the Australian Medical Sheepskin for the prevention of pressure ulcers in somatic nursing home patients: study protocol for a prospective multi-centre randomised controlled trial (ISRCTN17553857)

<p>Abstract</p> <p>Background</p> <p>Pressure ulcers are a major problem, especially in nursing home patients, although they are regarded as preventable and there are many pressure relieving methods and materials. One such pressure relieving material is the recently developed Australian Medical Sheepskin, which has been shown in two randomized controlled trials <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr></abbrgrp> to be an effective intervention in the prevention of sacral pressure ulcers in hospital patients. However, the use of sheepskins has been debated and in general discouraged by most pressure ulcer working groups and pressure ulcer guidelines, but these debates were based on old forms of sheepskins. Furthermore, nothing is yet known about the (cost-)effectiveness of the Australian Medical sheepskin in nursing home patients.</p> <p>The objective of this study is to assess the effects and costs of the use of the Australian Medical Sheepskin combined with usual care with regard to the prevention of sacral pressure ulcers in somatic nursing home patients, versus usual care only.</p> <p>Methods/Design</p> <p>In a multi-centre randomised controlled trial 750 patients admitted for a primarily somatic reason to one of the five participating nursing homes, and not having pressure ulcers on the sacrum at admission, will be randomized to either usual care only or usual care plus the use of the Australian Medical Sheepskin as an overlay on the mattress.</p> <p>Outcome measures are: incidence of sacral pressure ulcers in the first month after admission; sacrum pressure ulcer free days; costs; patient comfort; and ease of use. The skin of all the patients will be observed once a day from admission on for 30 days. Patient characteristics and pressure risk scores are assessed at admission and at day 30 after it.</p> <p>Additional to the empirical phase, systematic reviews will be performed in order to obtain data for economic weighting and modelling.</p> <p>The protocol is registered in the Controlled Trial Register as ISRCTN17553857.</p

Upper Kellwasser carbon isotope excursion pre-dates the F–F boundary in the Upper Devonian Lennard shelf carbonate system, Canning Basin, Western Australia

Here we report four high-resolution carbon isotope records in addition to trace element data for the Frasnian–Famennian (F–F) boundary interval in the Lennard Shelf carbonate system of the Canning Basin, Western Australia. This region lacks the characteristic black shale horizons associated with the global Late Devonian Kellwasser extinction events, yet still exhibits a trend in carbon isotope character similar to what has been reported from elsewhere in the world (two positive δ13C excursions with ~3–4‰ amplitudes). Enrichments in select trace element ratios suggest that both excursions are related to periods of oxygen deprivation and perhaps increased biological productivity. Given the continuous and stratigraphically expanded nature of Lennard Shelf sections, together with high-density sampling constrained by both conodont biostratigraphy and magnetostratigraphy, we observe that the Upper Kellwasser isotope excursion (maximum δ13C values) and associated trace element enrichments occur distinctly lower than the F–F boundary level. These results have implications for the paleoenvironmental conditions leading up to the Late Devonian Mass Extinction in terms of ocean chemistry and circulation patterns. This data set allows for a rare, detailed look at the temporal relationship between the Kellwasser events and the F–F boundary and constrains the pattern of carbon isotope perturbations at the intra-zonal scale

Digital Storytelling for Historical Understanding: Treaty Education for Reconciliation

This paper presents the findings of a research project that sought to interrogate the possibilities of digital storytelling as a pathway towards a more complete understanding of treaties and the treaty relationship in western Canada. This research is situated in the province of Saskatchewan, where treaty education (that is, education about the history of the numbered treaties signed between First Nations people and the British Crown, as well as the subsequent history of the treaty relationship) has been mandatory for almost a decade. The paper details a two-year journey alongside elementary educators as they used digital storytelling to take up treaty education in their classrooms. We present an overview of the research project as well as the narratives of a teacher, a researcher, and a Cree knowledge keeper, all of whom were involved in and reflected on the research journey. We consider the research findings alongside these narratives in order to explore the possibilities that digital storytelling might offer as we, as a Canadian nation, move towards reconciliation with Aboriginal people within a Canadian context of ongoing colonialism. Questo articolo presenta i risultati di un progetto di ricerca che ha cercato di indagare sulle possibilità della narrazione digitale di storie (storytelling) come percorso verso una comprensione più completa dei trattati e del rapporto fra i trattati nel Canada occidentale. Questa indagine è situata nella provincia di Saskatchewan, dove l'istruzione sui trattati (cioè, l'educazione sulla storia dei trattati numerati firmati tra la Prima Nazione e la Corona Britannica, così come la storia successiva del rapporto fra i trattati) è stato obbligatorio per quasi un decennio. Il saggio riporta un percorso di due anni con insegnanti di scuola elementare che hanno usato lo storytelling digitale per fare l'educazione ai trattati nelle loro classi. Presentiamo una panoramica del progetto di ricerca ed i racconti di un insegnante, di un ricercatore, e un guardiano Cree della conoscenza, i quali sono stati coinvolti nella ricerca e riflettono sul percorso svolto. Consideriamo i risultati dell’indagine insieme a questi racconti, al fine di esplorare le possibilità che la narrazione digitale potrebbe offrire dato che noi, come nazione canadese, procediamo verso la riconciliazione con gli aborigeni in un contesto canadese di colonialismo in corso

Ultra-fast Au(III)-mediated Arylation of Cysteine

Through mechanistic work and rational design, we have developed the fastest organometallic abiotic Cys bioconjugation. As a result, the developed organometallic Au(III) bioconjugation reagents enable selective labeling of Cys moieties down to pM concentrations and allow for the rapid construction of complex heterostructures from peptides, proteins, and oligonucleo-tides. This work showcases how organometallic chemistry can be interfaced with biomolecules and lead to the range of reac-tivities that are largely unmatched by classical organic chemistry tools

Integrated stratigraphic correlation of Upper Devonian platform-to-basin carbonate sequences, Lennard Shelf, Canning Basin, Western Australia: advances in carbonate margin-to-slope sequence stratigraphy and stacking patterns

High-resolution, time-significant correlations are integral to meaningful stratigraphic frameworks in depositional systems, but may be difficult to achieve using traditional sequence stratigraphic or biostratigraphic approaches alone, particularly in geologically complex settings. In steep, reefal carbonate margin-to-slope systems, such correlations are essential to unravel shelf-to-basin transitions, characterize strike variability, and develop predictive sequence stratigraphic models – concepts which are currently poorly understood in these heterogeneous settings. The Canning Basin Chronostratigraphy Project (CBCP) integrates multiple independent datasets (including biostratigraphy, magnetostratigraphy, stable isotope chemostratigraphy, and sequence stratigraphy) extracted from Upper Devonian (Frasnian and Famennian) reefal platform exposures along the Lennard Shelf, Canning Basin, Western Australia. These were used to generate a well-constrained stratigraphic framework and shelf-to-basin composite reconstruction of the carbonate system. The resultant integrated framework allows for unprecedented analysis of carbonate margin-to-slope heterogeneity, depositional architecture, and sequence stratigraphy along the Lennard Shelf. Systems tract architecture, facies partitioning, and stacking patterns of margin to lower-slope environments were assessed for six composite-scale sequences that form part of a transgressive-to-regressive supersequence and span the Frasnian-Famennian (F-F) biotic crisis. Variations are apparent in margin styles, foreslope facies proportions, dominant resedimentation processes, downslope contributing sediment factories, and vertical rock successions, related to hierarchical accommodation signals and ecological changes associated with F-F boundary. We present these results in the form of carbonate margin-to-basin sequence stratigraphic models and associations that link seismic-scale architecture to fine-scale facies heterogeneity. These models provide a predictive foundation for characterization of steep-sided flanks of reefal carbonate platform systems that is useful for both industry and academia. This study emphasizes the utility of an integrated stratigraphic approach and the insights gained from better-constrained facies and stratal architecture analysis; insights that were not achievable with traditional sequence stratigraphic or biostratigraphic techniques alone

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition