| 1. |
- Artigas Soler, María, et al.
(författare)
-
Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
-
Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
|
|
| 2. |
- Loth, Daan W, et al.
(författare)
-
Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
-
Tidskriftsartikel (refereegranskat)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
|
|
| 3. |
- Aschard, Hugues, et al.
(författare)
-
Evidence for large-scale gene-by-smoking interaction effects on pulmonary function
- 2017
-
Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 46:3, s. 894-904
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.METHODS: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.RESULTS: We identified an interaction (βint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV 1: /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.CONCLUSIONS: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.
|
|
| 4. |
- Jackson, Victoria E, et al.
(författare)
-
Meta-analysis of exome array data identifies six novel genetic loci for lung function.
- 2018
-
Ingår i: Wellcome open research. - : F1000 Research Ltd. - 2398-502X. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
|
|
| 5. |
- Joshi, Peter K, et al.
(författare)
-
Directional dominance on stature and cognition in diverse human populations
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
-
Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
|
|
| 6. |
- Nelson, Laura, et al.
(författare)
-
FKBPL: a marker of good prognosis in breast cancer.
- 2015
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12209-12223
-
Tidskriftsartikel (refereegranskat)abstract
- FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL's prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14-1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07-1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13-1.58, p < 0.001, and HR = 1.25, 95% CI 1.04-1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05-1.65, p = 0.02 and HR = 1.23 95% CI 0.99-1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic.
|
|
| 7. |
- Sakornsakolpat, Phuwanat, et al.
(författare)
-
Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
- 2019
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:3, s. 494-505
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
|
|
| 8. |
- Tang, Wenbo, et al.
(författare)
-
Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:7, s. e100776-
-
Tidskriftsartikel (refereegranskat)abstract
- 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 x 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 x 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.
|
|
| 9. |
- Achtert, Peggy, et al.
(författare)
-
Properties of Arctic liquid and mixed-phase clouds from shipborne Cloudnet observations during ACSE 2014
- 2020
-
Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 20:23, s. 14983-15002
-
Tidskriftsartikel (refereegranskat)abstract
- This study presents Cloudnet retrievals of Arctic clouds from measurements conducted during a 3-month research expedition along the Siberian shelf during summer and autumn 2014. During autumn, we find a strong reduction in the occurrence of liquid clouds and an increase for both mixed-phase and ice clouds at low levels compared to summer. About 80 % of all liquid clouds observed during the research cruise show a liquid water path below the infrared black body limit of approximately 50 g m(-2). The majority of mixed-phase and ice clouds had an ice water path below 20 g m(-2). Cloud properties are analysed with respect to cloud-top temperature and boundary layer structure. Changes in these parameters have little effect on the geometric thickness of liquid clouds while mixed-phase clouds during warm-air advection events are generally thinner than when such events were absent. Cloud-top temperatures are very similar for all mixed-phase clouds. However, more cases of lower cloudtop temperature were observed in the absence of warm-air advection. Profiles of liquid and ice water content are normalized with respect to cloud base and height. For liquid water clouds, the liquid water content profile reveals a strong increase with height with a maximum within the upper quarter of the clouds followed by a sharp decrease towards cloud top. Liquid water content is lowest for clouds observed below an inversion during warm-air advection events. Most mixedphase clouds show a liquid water content profile with a very similar shape to that of liquid clouds but with lower maximum values during events with warm air above the planetary boundary layer. The normalized ice water content profiles in mixed-phase clouds look different from those of liquid water content. They show a wider range in maximum values with the lowest ice water content for clouds below an inversion and the highest values for clouds above or extending through an inversion. The ice water content profile generally peaks at a height below the peak in the liquid water content profile - usually in the centre of the cloud, sometimes closer to cloud base, likely due to particle sublimation as the crystals fall through the cloud.
|
|
| 10. |
- Bank, Sakarias Einar Sefik
(författare)
-
Promoting Air Quality Policy Adoption and Change
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Air pollution is a localised issue but negatively influences health and finance globally. Conurbations and regional governments struggle to find the best policy solutions to meet air quality limit levels while competing over resources and attempting to secure growth. As such, methods to increase the adoption of effective pollution-focused policies are warranted. This thesis has set out to create a framework for understanding the relationship between behaviour change of policy makers and the adoption of new air quality policies at regional levels of government. Chapter four of this thesis looked into the quality and results of previous literature through a systematic review (study 1), investigating how previous interventions have attempted to promote policy adoption. Within chapter five, a vignette study with policy practitioners (study 2; n = 15) was conducted to evaluate the use of intervention functions. Alongside the vignette study, an online questionnaire looked at perceived barriers to policy adoption. Data from both were amalgamated using thematic analysis. Finally, in chapter six, the use of interventions to promote air quality policy and the state of current UK air quality policy was reviewed (study 3). Collectively these studies have contributed to the understanding of how intervention functions influence policy intention formation and policy adoption. The combined outcomes of these studies suggest a) a need for increased education of policymakers and b) for councils to share learning and take inspiration from each other. Throughout the studies, key barriers to policy intentions and policy adoption were investigated, the most prominent being economic and administrative barriers. Within chapter seven, results are summarised and directions for future research and practice are suggested.
|
|
| 11. |
- Bolhuis, Koen, et al.
(författare)
-
Risk of Psychosis Among Individuals Who Have Presented to Hospital With Self-harm : A Prospective Nationwide Register Study in Sweden
- 2024
-
Ingår i: Schizophrenia Bulletin. - : Oxford University Press. - 0586-7614 .- 1745-1701.
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND HYPOTHESIS: Recent research showed that young people who presented to hospital with self-harm in Finland had a significantly elevated risk of later psychosis. We investigated the prospective relationship between hospital presentation for self-harm and risk of psychosis in an unprecedentedly large national Swedish cohort.STUDY DESIGN: We used inpatient and outpatient healthcare registers to identify all individuals born between 1981 and 1993 who were alive and living in Sweden on their 12th birthday and who presented to hospital one or more times with self-harm. We compared them with a matched cohort, followed up for up to 20 years, and compared the cumulative incidence of psychotic disorders. Furthermore, we examined whether the strength of the relationship between hospital presentation for self-harm and later psychosis changed over time by examining for cohort effects.STUDY RESULTS: In total, 28 908 (2.0%) individuals presented to hospital with self-harm without prior psychosis diagnosis during the follow-up. For individuals who presented to hospital with self-harm, the cumulative incidence of diagnosed psychosis was 20.7% at 20 years follow-up (hazard radio = 13.9, 95% CI 13.3-14.6, P-value <5 × 10-308). There was no evidence of a dilution of the effect over time: while the incidence of hospital self-harm presentation increased, this did not result in an attenuation over time of the strength of the relationship between hospital self-harm presentation and subsequent psychosis.CONCLUSIONS: Individuals who present to hospital with self-harm in their teens and 20s represent an important risk group for psychosis prediction and prevention.
|
|
| 12. |
- Ehlén, Åsa, et al.
(författare)
-
Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer
- 2010
-
Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 8, s. 78-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: We recently demonstrated that increased expression of the RNA-binding protein RBM3 is associated with a favourable prognosis in breast cancer. The aim of this study was to examine the prognostic value of RBM3 mRNA and protein expression in epithelial ovarian cancer (EOC) and the cisplatin response upon RBM3 depletion in a cisplatin-sensitive ovarian cancer cell line. Methods: RBM3 mRNA expression was analysed in tumors from a cohort of 267 EOC cases (Cohort I) and RBM3 protein expression was analysed using immunohistochemistry (IHC) in an independent cohort of 154 prospectively collected EOC cases (Cohort II). Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between RBM3 and recurrence free survival (RFS) and overall survival (OS). Immunoblotting and IHC were used to examine the expression of RBM3 in a cisplatin-resistant ovarian cancer cell line A2780-Cp70 and its cisplatin-responsive parental cell line A2780. The impact of RBM3 on cisplatin response in EOC was assessed using siRNA-mediated silencing of RBM3 in A2780 cells followed by cell viability assay and cell cycle analysis. Results: Increased RBM3 mRNA expression was associated with a prolonged RFS (HR = 0.64, 95% CI = 0.47-0.86, p = 0.003) and OS (HR = 0.64, 95% CI = 0.44-0.95, p = 0.024) in Cohort I. Multivariate analysis confirmed that RBM3 mRNA expression was an independent predictor of a prolonged RFS, (HR = 0.61, 95% CI = 0.44-0.84, p = 0.003) and OS (HR = 0.62, 95% CI = 0.41-0.95; p = 0.028) in Cohort I. In Cohort II, RBM3 protein expression was associated with a prolonged OS (HR = 0.53, 95% CI = 0.35-0.79, p = 0.002) confirmed by multivariate analysis (HR = 0.61, 95% CI = 0.40-0.92, p = 0.017). RBM3 mRNA and protein expression levels were significantly higher in the cisplatin sensitive A2780 cell line compared to the cisplatin resistant A2780-Cp70 derivative. siRNA-mediated silencing of RBM3 expression in the A2780 cells resulted in a decreased sensitivity to cisplatin as demonstrated by increased cell viability and reduced proportion of cells arrested in the G2/M-phase. Conclusions: These data demonstrate that RBM3 expression is associated with cisplatin sensitivity in vitro and with a good prognosis in EOC. Taken together these findings suggest that RBM3 may be a useful prognostic and treatment predictive marker in EOC.
|
|
| 13. |
- Gallagher, William M., et al.
(författare)
-
Molecular basis of cell-biomaterial interaction: Insights gained from transcriptomic and proteomic studies
- 2006
-
Ingår i: Biomaterials. - : Elsevier BV. - 1878-5905 .- 0142-9612. ; 27:35, s. 5871-5882
-
Forskningsöversikt (refereegranskat)abstract
- With the growing interest in clinical interventions that involve medical devices, the role for new biomaterials in modern medicine is currently expanding at a phenomenal rate. Failure of most implant materials stems from an inability to predict and control biological phenomena, such as protein adsorption and cell interaction, resulting in an inappropriate host response to the materials. Contemporary advances in biological investigation are starting to shift focus in the biomaterials field, in particular with the advent of high-throughput methodologies for gene and protein expression profiling. Here, we examine the role that emerging transcriptomic and proteomic technologies could play in relation to biomaterial development and usage. Moreover, a number of studies are highlighted which have utilized such approaches in order to try to create a deeper understanding of cell-biomaterial interactions and, hence, improve our ability to predict and control the biocompatibility of new materials. (c) 2006 Elsevier Ltd. All rights reserved.
|
|
| 14. |
- Hancock, Dana B, et al.
(författare)
-
Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
- 2012
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:12, s. e1003098-
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
|
|
| 15. |
- Holmes, Emily A., et al.
(författare)
-
Multidisciplinary research priorities for the COVID-19 pandemic : a call for action for mental health science
- 2020
-
Ingår i: Lancet psychiatry. - 2215-0374 .- 2215-0366. ; 7:6, s. 547-560
-
Tidskriftsartikel (refereegranskat)abstract
- The coronavirus disease 2019 (COVID-19) pandemic is having a profound effect on all aspects of society, including mental health and physical health. We explore the psychological, social, and neuroscientific effects of COVID-19 and set out the immediate priorities and longer-term strategies for mental health science research. These priorities were informed by surveys of the public and an expert panel convened by the UK Academy of Medical Sciences and the mental health research charity, MQ: Transforming Mental Health, in the first weeks of the pandemic in the UK in March, 2020. We urge UK research funding agencies to work with researchers, people with lived experience, and others to establish a high level coordination group to ensure that these research priorities are addressed, and to allow new ones to be identified over time. The need to maintain high-quality research standards is imperative. International collaboration and a global perspective will be beneficial. An immediate priority is collecting high-quality data on the mental health effects of the COVID-19 pandemic across the whole population and vulnerable groups, and on brain function, cognition, and mental health of patients with COVID-19. There is an urgent need for research to address how mental health consequences for vulnerable groups can be mitigated under pandemic conditions, and on the impact of repeated media consumption and health messaging around COVID-19. Discovery, evaluation, and refinement of mechanistically driven interventions to address the psychological, social, and neuroscientific aspects of the pandemic are required. Rising to this challenge will require integration across disciplines and sectors, and should be done together with people with lived experience. New funding will be required to meet these priorities, and it can be efficiently leveraged by the UK's world-leading infrastructure. This Position Paper provides a strategy that may be both adapted for, and integrated with, research efforts in other countries.
|
|
| 16. |
- Kanhai, La Daana K., et al.
(författare)
-
Deep sea sediments of the Arctic Central Basin: A potential sink for microplastics
- 2019
-
Ingår i: Deep-Sea Research Part I: Oceanographic Research Papers. - : Elsevier BV. - 0967-0637 .- 1879-0119. ; 145, s. 137-142
-
Tidskriftsartikel (refereegranskat)abstract
- Deep sea sediments have emerged as a potential sink for microplastics in the marine environment. The discovery of microplastics in various environmental compartments of the Arctic Central Basin (ACB) suggested that these contaminants were potentially being transported to the deep-sea realm of this oceanic basin. For the first time, the present study conducted a preliminary assessment to determine whether microplastics were present in surficial sediments from the ACB. Gravity and piston corers were used to retrieve sediments from depths of 855-4353 m at 11 sites in the ACB during the Arctic Ocean 2016 (AO16) expedition. Surficial sediments from the various cores were subjected to density flotation with sodium tungstate dihydrate solution (Na2WO4 center dot 2H(2)O, density 1.4 g cm(-3)). Potential microplastics were isolated and analysed by Fourier Transform Infrared (FT-IR) spectroscopy. Of the surficial samples, 7 of the 11 samples contained synthetic polymers which included polyester (n = 3), polystyrene (n = 2), polyacrylonitrile (n = 1), polypropylene (n = 1), polyvinyl chloride (n = 1) and polyamide (n = 1). Fibres (n = 5) and fragments (n = 4) were recorded in the samples. In order to avoid mis-interpretation, these findings musi be taken in the context that (i) sampling equipment did not guarantee retrieval of undisturbed surficial sediments, (ii) low sample volumes were analysed (similar to 10 g per site), (iii) replicate sediment samples per site was not possible, (iv) no air contamination checks were included during sampling and, (v) particles < 100 mu m were automatically excluded from analysis. While the present study provides preliminary indication that microplastics may be accumulating in the deep-sea realm of the ACB, further work is necessary to assess microplastic abundance, distribution and composition in surficial sediments of the ACB.
|
|
| 17. |
- Kanhai, La Daana K., et al.
(författare)
-
Microplastics in sea ice and seawater beneath ice floes from the Arctic Ocean
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Within the past decade, an alarm was raised about microplastics in the remote and seemingly pristine Arctic Ocean. To gain further insight about the issue, microplastic abundance, distribution and composition in sea ice cores (n = 25) and waters underlying ice floes (n = 22) were assessed in the Arctic Central Basin (ACB). Potential microplastics were visually isolated and subsequently analysed using Fourier Transform Infrared (FT-IR) Spectroscopy. Microplastic abundance in surface waters underlying ice floes (0-18 particles m-3) were orders of magnitude lower than microplastic concentrations in sea ice cores (2-17 particles L-1). No consistent pattern was apparent in the vertical distribution of microplastics within sea ice cores. Backward drift trajectories estimated that cores possibly originated from the Siberian shelves, western Arctic and central Arctic. Knowledge about microplastics in environmental compartments of the Arctic Ocean is important in assessing the potential threats posed by microplastics to polar organisms.
|
|
| 18. |
- McCusker, Gillian Young, et al.
(författare)
-
Evaluating Arctic clouds modelled with the Unified Model and Integrated Forecasting System
- 2023
-
Ingår i: Atmospheric Chemistry And Physics. - 1680-7316 .- 1680-7324. ; 23:8, s. 4819-4847
-
Tidskriftsartikel (refereegranskat)abstract
- By synthesising remote-sensing measurements made in the central Arctic into a model-gridded Cloudnet cloud product, we evaluate how well the Met Office Unified Model (UM) and the European Centre for Medium-Range Weather Forecasting (ECMWF) Integrated Forecasting System (IFS) capture Arctic clouds and their associated interactions with the surface energy balance and the thermodynamic structure of the lower troposphere. This evaluation was conducted using a 4-week observation period from the Arctic Ocean 2018 expedition, where the transition from sea ice melting to freezing conditions was measured. Three different cloud schemes were tested within a nested limited-area model (LAM) configuration of the UM – two regionally operational single-moment schemes (UM_RA2M and UM_RA2T) and one novel double-moment scheme (UM_CASIM-100) – while one global simulation was conducted with the IFS, utilising its default cloud scheme (ECMWF_IFS).Consistent weaknesses were identified across both models, with both the UM and IFS overestimating cloud occurrence below 3 km. This overestimation was also consistent across the three cloud configurations used within the UM framework, with >90 % mean cloud occurrence simulated between 0.15 and 1 km in all the model simulations. However, the cloud microphysical structure, on average, was modelled reasonably well in each simulation, with the cloud liquid water content (LWC) and ice water content (IWC) comparing well with observations over much of the vertical profile. The key microphysical discrepancy between the models and observations was in the LWC between 1 and 3 km, where most simulations (all except UM_RA2T) overestimated the observed LWC.Despite this reasonable performance in cloud physical structure, both models failed to adequately capture cloud-free episodes: this consistency in cloud cover likely contributes to the ever-present near-surface temperature bias in every simulation. Both models also consistently exhibited temperature and moisture biases below 3 km, with particularly strong cold biases coinciding with the overabundant modelled cloud layers. These biases are likely due to too much cloud-top radiative cooling from these persistent modelled cloud layers and were consistent across the three UM configurations tested, despite differences in their parameterisations of cloud on a sub-grid scale. Alarmingly, our findings suggest that these biases in the regional model were inherited from the global model, driving a cause–effect relationship between the excessive low-altitude cloudiness and the coincident cold bias. Using representative cloud condensation nuclei concentrations in our double-moment UM configuration while improving cloud microphysical structure does little to alleviate these biases; therefore, no matter how comprehensive we make the cloud physics in the nested LAM configuration used here, its cloud and thermodynamic structure will continue to be overwhelmingly biased by the meteorological conditions of its driving model.
|
|
| 19. |
- Michaut, Magali, et al.
(författare)
-
Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.
|
|
| 20. |
- O’Connor, Antoinette, et al.
(författare)
-
Tau accumulation in autosomal dominant Alzheimer’s disease: a longitudinal [18F]flortaucipir study
- 2023
-
Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Cortical tau accumulation is a key pathological event that partly defines Alzheimer’s disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation. All had baseline flortaucipir (FTP) PET, MRI and clinical assessments; 26 individuals had more than one FTP PET scan. Standardised uptake value ratios (SUVRs) in prespecified regions of interest (ROIs) were obtained using inferior cerebellar grey matter as the reference region. We compared the changes in FTP SUVRs between presymptomatic carriers, symptomatic carriers and non-carriers, adjusting for age, sex and study site. We also investigated the relationship between regional FTP SUVRs and estimated years to/from symptom onset (EYO). Compared to both non-carriers and presymptomatic carriers, FTP SUVRs were significantly higher in symptomatic carriers in all ROIs tested (p < 0.001). There were no significant regional differences between presymptomatic carriers and non-carriers in FTP SUVRs, or their rates of change (p > 0.05), although increased FTP signal uptake was seen posteriorly in some individuals around the time of expected symptom onset. When we examined the relationship of FTP SUVR with respect to EYO, the earliest significant regional difference between mutation carriers and non-carriers was detected within the precuneus prior to estimated symptom onset in some cases. This study supports preliminary studies suggesting that presymptomatic tau tracer uptake is rare in ADAD. In cases where early uptake was seen, there was often a predilection for posterior regions (the precuneus and post-cingulate) as opposed to the medial temporal lobe, highlighting the importance of examining in vivo tau uptake beyond the confines of traditional Braak staging.
|
|
| 21. |
|
|
| 22. |
- Strickson, Sam, et al.
(författare)
-
Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex
- 2023
-
Ingår i: European Respiratory Journal. - 0903-1936. ; 62:3
-
Tidskriftsartikel (refereegranskat)abstract
- Background Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33ox) is thought to limit its activity. We investigated whether IL-33ox has functional activities that are independent of ST2 in the airway epithelium. Methods In vitro epithelial damage assays and three-dimensional, air–liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33ox. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. Results We demonstrate that IL-33ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro. IL-33ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33ox were enriched in airway epithelia from patients with severe COPD. Conclusions Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and mucoobstructive features in COPD.
|
|
