Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

A Mutation in Myo15 Leads to Usher-Like Symptoms in LEW/Ztm-ci2 Rats

The LEW/Ztm-ci2 rat is an animal model for syndromal deafness that arose from a spontaneous mutation. Homozygous animals show locomotor abnormalities like lateralized circling behavior. Additionally, an impaired vision can be observed in some animals through behavioral studies. Syndromal deafness as well as retinal degeneration are features of the Usher syndrome in humans. In the present study, the mutation was identified as a base substitution (T->C) in exon 56 of Myo15, leading to an amino acid exchange from leucine (Leu) to proline (Pro) within the carboxy-terminal MyTH4 domain in the proteins' tail region. Myo15 mRNA was expressed in the retina as demonstrated for the first time with the help of in-situ hybridization and PCR. To characterize the visual phenotype, rats were examined by scotopic and photopic electroretinography and, additionally, histological analyses of the retinas were conducted. The complete loss of sight was detected along with a severe degeneration of photoreceptor cells. Interestingly, the manifestation of the disease does not solely depend on the mutation, but also on environmental factors. Since the LEW/Ztm-ci2 rat features the entire range of symptoms of the human Usher syndrome we think that this strain is an appropriate model for this disease. Our findings display that mutations in binding domains of myosin XV do not only cause non-syndromic hearing loss but can also lead to syndromic disorders including retinal dysfunction

Evidence of positive selection associated with placental loss in tiger sharks

Background: All vertebrates initially feed their offspring using yolk reserves. In some live-bearing species these yolk reserves may be supplemented with extra nutrition via a placenta. Sharks belonging to the Carcharhinidae family are all live-bearing, and with the exception of the tiger shark (Galeocerdo cuvier), develop placental connections after exhausting yolk reserves. Phylogenetic relationships suggest the lack of placenta in tiger sharks is due to secondary loss. This represents a dramatic shift in reproductive strategy, and is likely to have left a molecular footprint of positive selection within the genome. Results: We sequenced the transcriptome of the tiger shark and eight other live-bearing shark species. From this data we constructed a time-calibrated phylogenetic tree estimating the tiger shark lineage diverged from the placental carcharhinids approximately 94 million years ago. Along the tiger shark lineage, we identified five genes exhibiting a signature of positive selection. Four of these genes have functions likely associated with brain development (YWHAE and ARL6IP5) and sexual reproduction (VAMP4 and TCTEX1D2). Conclusions: Our results indicate the loss of placenta in tiger sharks may be associated with subsequent adaptive changes in brain development and sperm production

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10‾⁴⁹), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.This work was funded by a Medical Research Council (MRC) strategic award to M.D.T., I.P.H., D.S. and L.V.W. (MC_PC_12010). This research has been conducted using the UK Biobank Resource under application 648. This article presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health. This research used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details can be found in the Supplementary Note

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

THE SOCIAL BIBLE: SCRIPTURAL EXCHANGE AND INTERRACIAL FELLOWSHIP IN NINETEENTH-CENTURY AMERICAN LITERATURE

This dissertation examines how nineteenth-century American authors represented the Bible as a shared public text that people read together while they were on trains, in hospitals, on the battlefield, and abroad. By engaging with recent scholarship on postsecularism, deliberative democracy, and the jeremiad, this study seeks to show how authors brought the Bible into the public sphere and figured shared reading as a site of democratic collaboration across cultural and racial divides. These writers also used biblical allusion to rebuke the nation for failing to meet its democratic ideals and to urge social reform. The Bible’s significance as a cultural touchstone offered writers a canvas to both critique the nation’s prejudice and invite readers into a fellowship of equals. Chapter 1 examines how Herman Melville’s Omoo (1847) uses nineteenth-century perceptions of the Apostles Peter and Paul to decry abusive missionary contact in Polynesia and to advocate for a more tolerant approach to intercultural contact. In these scenes of multicultural encounter, racial equality depends on white Christian readers surrendering their claims to interpretive dominance and social supremacy and showing a willingness to learn new spiritual insights from Indigenous Polynesian readers. Chapter 2 explores how Harriet Beecher Stowe and Hannah Crafts envision African American bible readers as knowledgeable and empowered interpreters and use these interpreters to defy white oppression and form a multicultural democratic space. Chapter 3 examines how Native American authors S. Alice Callahan, Zitkala-Ša, and Leslie Marmon Silko integrated the Bible into Indigenous spirituality and used biblical prophecy to rebuke white colonialism. Chapter 4 analyzes how Pauline Hopkins’s Of One Blood (1902–1903) uses biblical references to challenge Jim Crow segregation and encourage interracial community. Each of these authors urges greater respect for marginalized communities while also rebuking those in power and warning of future desolation if they continue their oppression. Bible-reading scenes envision collaborations that transform one or both readers, with the democratic ideal being found in the equal meeting of minds

"Once Gone Through, We Trace Round Again": The Cyclical Journey of Belief and Unbelief in Herman Melville's Later Works

This thesis explores Herman Melville's struggling relationship between belief and unbelief in Moby-Dick, “Benito Cereno” and Clarel. Melville’s travel to the Marquesas gave him a sense of cultural relativity which prompted questions about his faith that continually remerged even as he found answers. In spite of overwhelming skepticism, Melville was unwilling to fully relinquish his faith because belief also offered comfort. Being trapped in a space where he could not fully believe but was equally unable to detach himself from faith, Melville discovered Ralph Waldo Emerson’s concept of double consciousness which served as a theoretical framework for his feelings of internal liminality. Melville drew on Emerson’s ideas to propose a wrestling form of belief. The Melvillean believer discovers questions which produce doubt and then seeks answers. These answered questions produce a brief sense of peace before further questions assert themselves and the struggling believer must begin his journey once again

Self‐supporting wound care mobile applications for nurses ::a scoping review

Aim : This study provides an overview of the literature to identify and map the types of available evidence on self-supporting mobile applications used by nurses in wound care regarding their development, evaluation and outcomes for patients, nurses and the healthcare system. Design : Scoping review. Review Method : Joanna Briggs Institute scoping review methodology was used. Data Sources : A search was performed using MEDLINE, Embase, CINAHL (via EBSCO), Web of Science, LiSSa (Littérature Scientifique en Santé), Cochrane Wounds, Érudit and grey literature, between April and October 2022, updated in April 2023, to identify literature published in English and French. Results : Eleven studies from 14 publications met the inclusion criteria. Mostly descriptive, the included studies presented mobile applications that nurses used, among other things, to assess wounds and support clinical decision-making. The results described how nurses were iteratively involved in the process of developing and evaluating mobile applications using various methods such as pilot tests. The three outcomes most frequently reported by nurses were as follows: facilitating care, documentation on file and access to evidence-based data. Conclusion : The potential of mobile applications in wound care is within reach. Nurses are an indispensable player in the successful development of these tools

Bone mineral density in independent elderly women with different physical and functional profiles and vitamin D receptor gene polymorphisms

The aim of the study was to compare BMD among physically independent elderly women with different physical-functional profiles and vitamin D receptor gene (VDR) polymorphisms, as well as to analyze the effect of the interaction between these last two aspects on BMD. Overall, 165 elderly women had BMD assessed by bone densitometry. Handgrip and lower limb strength and functional exercise capacity (6MWT) were also assessed. VDR polymorphisms (TaqI, BsmI, ApaI and FokI) were analyzed by polymerase chain reaction. For analyses, elderly women were categorized according to their performance on physical-functional tests into low performance (LP; 75th percentile). Regarding functional exercise capacity, LP group showed lower BMD compared to HP and NP groups (p=0,003). With respect to handgrip strength, there was a trend for LP group to have lower bone mineral density compared to NP group (p=0.08). No differences were observed in femur and lumbar BMD in comparisons among the different VDR genotypes (0.07≤p≤0.94); among different groups regarding lower limb strength (p=0.49) and in the interaction analysis among variables (0.17≤p≤0.77). It was concluded that physically independent elderly women with low functional exercise capacity have lower bone mineral density than those classified as normal and high performance. However, apparently, there is no effect of the interaction between VDR gene polymorphisms and physical and functional factors on BMD