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1.
  • Craddock, Nick, et al. (author)
  • Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
  • 2010
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
  • Journal article (peer-reviewed)abstract
    • Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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2.
  • van der Valk, Ralf J P, et al. (author)
  • A novel common variant in DCST2 is associated with length in early life and height in adulthood.
  • 2015
  • In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 24:4, s. 1155-68
  • Journal article (peer-reviewed)abstract
    • Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
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  • Horikoshi, Momoko, et al. (author)
  • New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
  • 2013
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:1
  • Journal article (peer-reviewed)abstract
    • Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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4.
  • Hudson, Lawrence N, et al. (author)
  • The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
  • 2017
  • In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
  • Journal article (peer-reviewed)abstract
    • The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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5.
  • Stephens, Lucas, et al. (author)
  • Archaeological assessment reveals Earth’s early transformation through land use
  • 2019
  • In: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 365:6456, s. 897-902
  • Journal article (peer-reviewed)abstract
    • Humans began to leave lasting impacts on Earth’s surface starting 10,000 to 8000 years ago. Through a synthetic collaboration with archaeologists around the globe, Stephens et al. compiled a comprehensive picture of the trajectory of human land use worldwide during the Holocene (see the Perspective by Roberts). Hunter-gatherers, farmers, and pastoralists transformed the face of Earth earlier and to a greater extent than has been widely appreciated, a transformation that was essentially global by 3000 years before the present.Science, this issue p. 897; see also p. 865Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth’s transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.
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  • Bray, Robert John, et al. (author)
  • Burning material behaviour in hypoxic environments : An experimental study examining a representative storage arrangement of acrylonitrile butadiene styrene, polyethylene bubble wrap, and cardboard layers as a composite system
  • 2022
  • In: Fire and Materials. - : Wiley. - 0308-0501 .- 1099-1018. ; 46:1, s. 313-328
  • Journal article (peer-reviewed)abstract
    • Cone calorimeter and controlled atmosphere cone calorimeter experiments were conducted on various samples. The intent of the tests was to examine the behavior of uniform and composite samples in a range of thicknesses, irradiances, and oxygen concentrations. Single, uniform layers of acrylonitrile butadiene styrene (ABS) were compared to a composite mix, comprising of ABS with a surface layer of cardboard and a secondary layer of polyethylene bubble wrap (intended to represent a potential storage arrangement). The horizontal samples have been tested at irradiances of 25 and 50 kW/m2 and oxygen concentrations of 20.95%, 17%, and 15% to examine a range of significant variables. Results for the uniform arrangement indicated various correlations, previously observed in the works of others, such as the relationships typically described between applied heat flux, ignitability, heat release rate and the effect of the introduction of hypoxic conditions. However, results were shown to change significantly when samples were arranged to feature composite layers. A hypothesized cause of the behavioral change, namely the soot and char residual introduced from the incomplete combustion of the cardboard layer, highlights further important variables that require consideration in material testing under hypoxic conditions. Such variables, namely specific material behaviors and sample orientation, must be sufficiently captured in the design methodologies of systems reliant upon the introduction of hypoxic conditions. It is concluded that sufficiently capturing a wider range of variables in burning materials under hypoxic conditions will introduce further design resilience and help optimize fire protection/prevention methods.
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9.
  • Cromer, M. Kyle, et al. (author)
  • Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas
  • 2015
  • In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:13, s. 4062-4067
  • Journal article (peer-reviewed)abstract
    • Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca2+ channel); both are expressed at very low levels in normal beta-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca2+ signaling pathways involved in insulin secretion.
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10.
  • Rando, Halie M, et al. (author)
  • Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through analysis of Viral Genomics and Structure
  • 2021
  • Other publication (other academic/artistic)abstract
    • The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world infecting tens of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host. Because the genomic content of coronaviruses, which specifies the virus's structure, is highly conserved, early genomic analysis provided a significant head start in predicting viral pathogenesis. The pathogenesis of the virus offers insights into symptomatology, transmission, and individual susceptibility. Additionally, prior research into interactions between the human immune system and coronaviruses has identified how these viruses can evade the immune system's protective mechanisms. We also explore systems-level research into the regulatory and proteomic effects of SARS-CoV-2 infection and the immune response. Understanding the structure and behavior of the virus serves to contextualize the many facets of the COVID-19 pandemic and can influence efforts to control the virus and treat the disease.
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11.
  • Rando, Halie M, et al. (author)
  • Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through Analysis of Viral Genomics and Structure
  • 2021
  • In: mSystems. - 2379-5077. ; 6:5
  • Research review (peer-reviewed)abstract
    • The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world and infected hundreds of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host. Because the genomic content of coronaviruses, which specifies the virus's structure, is highly conserved, early genomic analysis provided a significant head start in predicting viral pathogenesis and in understanding potential differences among variants. The pathogenesis of the virus offers insights into symptomatology, transmission, and individual susceptibility. Additionally, prior research into interactions between the human immune system and coronaviruses has identified how these viruses can evade the immune system's protective mechanisms. We also explore systems-level research into the regulatory and proteomic effects of SARS-CoV-2 infection and the immune response. Understanding the structure and behavior of the virus serves to contextualize the many facets of the COVID-19 pandemic and can influence efforts to control the virus and treat the disease. IMPORTANCE COVID-19 involves a number of organ systems and can present with a wide range of symptoms. From how the virus infects cells to how it spreads between people, the available research suggests that these patterns are very similar to those seen in the closely related viruses SARS-CoV-1 and possibly Middle East respiratory syndrome-related CoV (MERS-CoV). Understanding the pathogenesis of the SARS-CoV-2 virus also contextualizes how the different biological systems affected by COVID-19 connect. Exploring the structure, phylogeny, and pathogenesis of the virus therefore helps to guide interpretation of the broader impacts of the virus on the human body and on human populations. For this reason, an in-depth exploration of viral mechanisms is critical to a robust understanding of SARS-CoV-2 and, potentially, future emergent human CoVs (HCoVs).
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12.
  • Webb, Ryan, et al. (author)
  • Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus
  • 2009
  • In: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:4, s. 1076-1084
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. The aim of this study was to examine methyl-CpG-binding protein 2 gene (MECP2) polymorphisms in a large cohort of patients with lupus and control subjects, and to determine the functional consequences of the lupus-associated MECP2 haplotype. METHODS: We genotyped 18 single-nucleotide polymorphisms within MECP2, located on chromosome Xq28, in a large cohort of patients with lupus and control subjects of European descent. We studied the functional effects of the lupus-associated MECP2 haplotype by determining gene expression profiles in B cell lines in female lupus patients with and those without the lupus-associated MECP2 risk haplotype. RESULTS: We confirmed, replicated, and extended the genetic association between lupus and genetic markers within MECP2 in a large independent cohort of lupus patients and control subjects of European descent (odds ratio 1.35, P = 6.65 x 10(-11)). MECP2 is a dichotomous transcription regulator that either activates or represses gene expression. We identified 128 genes that are differentially expressed in lupus patients with the disease-associated MECP2 haplotype; most ( approximately 81%) were up-regulated. Genes that were up-regulated had significantly more CpG islands in their promoter regions compared with genes that were down-regulated. Gene ontology analysis using the differentially expressed genes revealed significant association with epigenetic regulatory mechanisms, suggesting that these genes are targets for MECP2 regulation in B cells. Furthermore, at least 13 of the 104 up-regulated genes are regulated by interferon. The disease-risk MECP2 haplotype was associated with increased expression of the MECP2 transcription coactivator CREB1 and decreased expression of the corepressor histone deacetylase 1. CONCLUSION: Polymorphism in the MECP2 locus is associated with lupus and, at least in part, contributes to the interferon signature observed in lupus patients.
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  • 2021
  • swepub:Mat__t
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  • Al Khalidi, Marwa, et al. (author)
  • The positive impact of negative role models
  • 2015
  • Reports (other academic/artistic)abstract
    • The attitude of teachers towards students can vary substantially in relation to different factors, such as educational background, pedagogical training, teaching methods, etc. In this paper, we explore the impact of negative role-models on future teaching. In particular, past experiences of teachers as students as well as the contextual influence of other teachers on their future teaching has been explored. The scope of this paper is to assess the possible impact that negative role-models may have on teaching performance, methods and quality. While the positive impact of positive role-models have been deeply investigated in the literature, the study of the impact of negative role-models is somewhat controversial. To investigate the positive impact of negative role-models, the key factors involved in the influence of role-models are presented and discussed through a set of case studies. Recommendations to address problematic cases are also presented.
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15.
  • Apel, Maria, et al. (author)
  • Variants in RUNX3 Contribute to Susceptibility to Psoriatic Arthritis, Exhibiting Further Common Ground With Ankylosing Spondylitis
  • 2013
  • In: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 65:5, s. 1224-1231
  • Journal article (peer-reviewed)abstract
    • Objective Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. Methods Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. Results Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 x 108 by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.151.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 x 102; OR 1.13 [95% CI 1.001.28]), indicating a role in the skin manifestations of psoriasis. Conclusion Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cellmediated diseases.
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  • Barton, John J., et al. (author)
  • Dialing for Displays: Session Initiation Protocol for Opportunistic Augmentation
  • 2006. - 1
  • Conference paper (peer-reviewed)abstract
    • Opportunistic augmentation denotes connecting a personal mobile device to another device to gain a transient advantage for the user. For example, a mobile phone user might borrow a large display and keyboard from a desktop personal computer. This uniquely ubiquitous computing activity requires effective device and service discovery as well as appropriate media usable across two or more devices. In this paper we show how Session Initiation Protocol (SIP), the call signaling protocol for Voice over IP, effectively separates discovery from media-rendering selection in opportunistic augmentation. This separation improves system flexibility while allowing users or system administrators to choose the most appropriate discovery technologies for the environment. We also describe two phone-centric discovery mechanisms and demonstrate the practicality of the system by implementation and use in a test environment.
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  • Barton, John, et al. (author)
  • The effect of oxygen concentration on selected industrial products in the open controlled atmosphere cone calorimeter
  • 2022
  • In: Fire and Materials. - : Wiley. - 0308-0501 .- 1099-1018. ; 46:4, s. 617-627
  • Journal article (peer-reviewed)abstract
    • Past research on the effect of oxygen concentration on the heat release rate and carbon monoxide yield has focused on materials in isolation and there is a lack of research that studies end-use products. This paper investigates the effect of oxygen concentration on the heat release rate per unit area (HRRPUA) and carbon monoxide yield for two different cables and a mineral oil used as an operating fluid for vacuum pumps. A standard cone calorimeter was used to conduct the tests at an ambient oxygen concentration of 21% and an open controlled atmosphere cone calorimeter (OCACC) was used for the tests conducted below 21%. The OCACC allows cone calorimeter tests to be run at different oxygen concentrations by attaching a chamber to the standard cone calorimeter. The effects of oxygen concentration on the HRRPUA and carbon monoxide yield for the cables were limited when there was flaming over the entire exposed surface area. For the mineral oil, there was a large decrease in the HRPPUA at a reduced oxygen concentration, but the carbon monoxide yield appeared to be unaffected.
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  • Beaumont, Robin N, et al. (author)
  • Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
  • 2018
  • In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 1460-2083 .- 0964-6906. ; 27:4, s. 742-756
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
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  • Bowes, John, et al. (author)
  • PTPN22 is associated with susceptibility to psoriatic arthritis but not psoriasis : evidence for a further PsA-specific risk locus
  • 2015
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 74:10, s. 1882-1885
  • Journal article (peer-reviewed)abstract
    • Objectives Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis; it has a higher estimated genetic component than psoriasis alone, however most genetic susceptibility loci identified for PsA to date are also shared with psoriasis. Here we attempt to validate novel single nucleotide polymorphisms selected from our recent PsA Immunochip study and determine specificity to PsA. Methods A total of 15 single nucleotide polymorphisms were selected (P-Immunochip <1x10(-4)) for validation genotyping in 1177 cases and 2155 controls using TaqMan. Meta-analysis of Immunochip and validation data sets consisted of 3139 PsA cases and 11 078 controls. Novel PsA susceptibility loci were compared with data from two large psoriasis studies (WTCCC2 and Immunochip) to determine PsA specificity. Results We found genome-wide significant association to rs2476601, mapping to PTPN22 (p=1.49x10(-9), OR=1.32), but no evidence for association in the psoriasis cohort (p=0.34) and the effect estimates were significantly different between PsA and psoriasis (p=3.2x10(-4)). Additionally, we found genome-wide significant association to the previously reported psoriasis risk loci; NOS2 (rs4795067, p=5.27x10(-9)). Conclusions For the first time, we report genome-wide significant association of PTPN22 (rs2476601) to PsA susceptibility, but no evidence for association to psoriasis.
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  • Brovkin, Victor, et al. (author)
  • Past abrupt changes, tipping points and cascading impacts in the Earth system
  • 2021
  • In: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 14:8, s. 550-558
  • Research review (peer-reviewed)abstract
    • A synthesis of intervals of rapid climatic change evident in the geological record reveals some of the Earth system processes and tipping points that could lead to similar events in the future. The geological record shows that abrupt changes in the Earth system can occur on timescales short enough to challenge the capacity of human societies to adapt to environmental pressures. In many cases, abrupt changes arise from slow changes in one component of the Earth system that eventually pass a critical threshold, or tipping point, after which impacts cascade through coupled climate-ecological-social systems. The chance of detecting abrupt changes and tipping points increases with the length of observations. The geological record provides the only long-term information we have on the conditions and processes that can drive physical, ecological and social systems into new states or organizational structures that may be irreversible within human time frames. Here, we use well-documented abrupt changes of the past 30 kyr to illustrate how their impacts cascade through the Earth system. We review useful indicators of upcoming abrupt changes, or early warning signals, and provide a perspective on the contributions of palaeoclimate science to the understanding of abrupt changes in the Earth system.
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  • Castellani, Carlo, et al. (author)
  • Benchmarks for Cystic Fibrosis carrier screening: A European consensus document
  • 2010
  • In: Journal of Cystic Fibrosis. - : Elsevier BV. - 1873-5010 .- 1569-1993. ; 9:3, s. 165-178
  • Research review (peer-reviewed)abstract
    • This paper presents an overview of the conclusions from an international conference convened to address current issues related to the provision of Cystic Fibrosis carrier screening within Europe. Consensus was not aimed at stating whether such a programme should be implemented. Instead the focus was to provide a framework for countries and agencies who are considering or planning its establishment. The general principles and target population of Cystic Fibrosis carrier screening, advantages and disadvantages, health economics, monitoring and future evaluative and research directions were covered. A range of screening strategies have been assessed and compared: pre-conceptional and prenatal screening; individual and couple screening; sequential and simultaneous sampling or testing. Furthermore, technical issues were examined with respect to the choice of the panel of mutations, its detection rate, sensitivity, management of intermediate 'at-risk' couples, screening approach to different populations and ethnic minorities, and assurance of laboratory quality control. The consensus statement also aims to establish the benchmarks for communicating with health care providers, the general public and potential and actual participants before and after the genetic test. (C) 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
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  • Cloarec, Olivier, et al. (author)
  • Evaluation of the Orthogonal Projection on Latent Structure Model Limitations Caused by Chemical Shift Variability and Improved Visualization of Biomarker Changes in 1H NMR Spectroscopic Metabonomic Studies
  • 2005
  • In: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 77:2, s. 517-26
  • Journal article (peer-reviewed)abstract
    • In general, applications of metabonomics using biofluid NMR spectroscopic analysis for probing abnormal biochemical profiles in disease or due to toxicity have all relied on the use of chemometric techniques for sample classification. However, the well-known variability of some chemical shifts in 1H NMR spectra of biofluids due to environmental differences such as pH variation, when coupled with the large number of variables in such spectra, has led to the situation where it is necessary to reduce the size of the spectra or to attempt to align the shifting peaks, to get more robust and interpretable chemometric models. Here, a new approach that avoids this problem is demonstrated and shows that, moreover, inclusion of variable peak position data can be beneficial and can lead to useful biochemical information. The interpretation of chemometric models using combined back-scaled loading plots and variable weights demonstrates that this peak position variation can be handled successfully and also often provides additional information on the physicochemical variations in metabonomic data sets.
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  • Cloarec, Olivier, et al. (author)
  • Statistical Total Correlation Spectroscopy: An Exploratory Approach for Latent Biomarker Identification from Metabolic 1H NMR Data Sets
  • 2005
  • In: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 77:5, s. 1282-89
  • Journal article (peer-reviewed)abstract
    • We describe here the implementation of the statistical total correlation spectroscopy (STOCSY) analysis method for aiding the identification of potential biomarker molecules in metabonomic studies based on NMR spectroscopic data. STOCSY takes advantage of the multicollinearity of the intensity variables in a set of spectra (in this case 1H NMR spectra) to generate a pseudo-two-dimensional NMR spectrum that displays the correlation among the intensities of the various peaks across the whole sample. This method is not limited to the usual connectivities that are deducible from more standard two-dimensional NMR spectroscopic methods, such as TOCSY. Moreover, two or more molecules involved in the same pathway can also present high intermolecular correlations because of biological covariance or can even be anticorrelated. This combination of STOCSY with supervised pattern recognition and particularly orthogonal projection on latent structure-discriminant analysis (O-PLS-DA) offers a new powerful framework for analysis of metabonomic data. In a first step O-PLS-DA extracts the part of NMR spectra related to discrimination. This information is then cross-combined with the STOCSY results to help identify the molecules responsible for the metabolic variation. To illustrate the applicability of the method, it has been applied to 1H NMR spectra of urine from a metabonomic study of a model of insulin resistance based on the administration of a carbohydrate diet to three different mice strains (C57BL/6Oxjr, BALB/cOxjr, and 129S6/SvEvOxjr) in which a series of metabolites of biological importance can be conclusively assigned and identified by use of the STOCSY approach.
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  • Dalen, Love, et al. (author)
  • Identifying Bird Remains Using Ancient DNA Barcoding
  • 2017
  • In: Genes. - : MDPI AG. - 2073-4425. ; 8:6
  • Journal article (peer-reviewed)abstract
    • Bird remains that are difficult to identify taxonomically using morphological methods, are common in the palaeontological record. Other types of challenging avian material include artefacts and food items from endangered taxa, as well as remains from aircraft strikes. We here present a DNA-based method that enables taxonomic identification of bird remains, even from material where the DNA is heavily degraded. The method is based on the amplification and sequencing of two short variable parts of the 16S region in the mitochondrial genome. To demonstrate the applicability of this approach, we evaluated the method on a set of Holocene and Late Pleistocene postcranial bird bones from several palaeontological and archaeological sites in Europe with good success.
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  • Esquivel, Karla Muñoz, et al. (author)
  • Factors influencing continued wearable device use in older adult populations : quantitative study
  • 2023
  • In: JMIR Aging. - : JMIR Publications Inc.. - 2561-7605. ; 6
  • Journal article (peer-reviewed)abstract
    • Background: The increased use of wearable sensor technology has highlighted the potential for remote telehealth services such as rehabilitation. Telehealth services incorporating wearable sensors are most likely to appeal to the older adult population in remote and rural areas, who may struggle with long commutes to clinics. However, the usability of such systems often discourages patients from adopting these services.Objective: This study aimed to understand the usability factors that most influence whether an older adult will decide to continue using a wearable device.Methods: Older adults across 4 different regions (Northern Ireland, Ireland, Sweden, and Finland) wore an activity tracker for 7 days under a free-living environment protocol. In total, 4 surveys were administered, and biometrics were measured by the researchers before the trial began. At the end of the trial period, the researchers administered 2 further surveys to gain insights into the perceived usability of the wearable device. These were the standardized System Usability Scale (SUS) and a custom usability questionnaire designed by the research team. Statistical analyses were performed to identify the key factors that affect participants’ intention to continue using the wearable device in the future. Machine learning classifiers were used to provide an early prediction of the intention to continue using the wearable device.Results: The study was conducted with older adult volunteers (N=65; mean age 70.52, SD 5.65 years) wearing a Xiaomi Mi Band 3 activity tracker for 7 days in a free-living environment. The results from the SUS survey showed no notable difference in perceived system usability regardless of region, sex, or age, eliminating the notion that usability perception differs based on geographical location, sex, or deviation in participants’ age. There was also no statistically significant difference in SUS score between participants who had previously owned a wearable device and those who wore 1 or 2 devices during the trial. The bespoke usability questionnaire determined that the 2 most important factors that influenced an intention to continue device use in an older adult cohort were device comfort (τ=0.34) and whether the device was fit for purpose (τ=0.34). A computational model providing an early identifier of intention to continue device use was developed using these 2 features. Random forest classifiers were shown to provide the highest predictive performance (80% accuracy). After including the top 8 ranked questions from the bespoke questionnaire as features of our model, the accuracy increased to 88%.Conclusions: This study concludes that comfort and accuracy are the 2 main influencing factors in sustaining wearable device use. This study suggests that the reported factors influencing usability are transferable to other wearable sensor systems. Future work will aim to test this hypothesis using the same methodology on a cohort using other wearable technologies.
  •  
29.
  •  
30.
  • Flanagan, Sarah E, et al. (author)
  • Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
  • 2014
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:8, s. 812-814
  • Journal article (peer-reviewed)abstract
    • Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.
  •  
31.
  • Gilbert, Benjamin, et al. (author)
  • A bioenergetic framework for the temperature dependence of trophic interactions
  • 2014
  • In: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 17:8, s. 902-914
  • Journal article (peer-reviewed)abstract
    • Changing temperature can substantially shift ecological communities by altering the strength and stability of trophic interactions. Because many ecological rates are constrained by temperature, new approaches are required to understand how simultaneous changes in multiple rates alter the relative performance of species and their trophic interactions. We develop an energetic approach to identify the relationship between biomass fluxes and standing biomass across trophic levels. Our approach links ecological rates and trophic dynamics to measure temperature-dependent changes to the strength of trophic interactions and determine how these changes alter food web stability. It accomplishes this by using biomass as a common energetic currency and isolating three temperature-dependent processes that are common to all consumer-resource interactions: biomass accumulation of the resource, resource consumption and consumer mortality. Using this framework, we clarify when and how temperature alters consumer to resource biomass ratios, equilibrium resilience, consumer variability, extinction risk and transient vs. equilibrium dynamics. Finally, we characterise key asymmetries in species responses to temperature that produce these distinct dynamic behaviours and identify when they are likely to emerge. Overall, our framework provides a mechanistic and more unified understanding of the temperature dependence of trophic dynamics in terms of ecological rates, biomass ratios and stability.
  •  
32.
  • Gurke, Robert, et al. (author)
  • Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis
  • 2022
  • In: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:10
  • Research review (peer-reviewed)abstract
    • The definitive diagnosis and early treatment of many immune-mediated inflammatory diseases (IMIDs) is hindered by variable and overlapping clinical manifestations. Psoriatic arthritis (PsA), which develops in similar to 30% of people with psoriasis, is a key example. This mixed-pattern IMID is apparent in entheseal and synovial musculoskeletal structures, but a definitive diagnosis often can only be made by clinical experts or when an extensive progressive disease state is apparent. As with other IMIDs, the detection of multimodal molecular biomarkers offers some hope for the early diagnosis of PsA and the initiation of effective management and treatment strategies. However, specific biomarkers are not yet available for PsA. The assessment of new markers by genomic and epigenomic profiling, or the analysis of blood and synovial fluid/tissue samples using proteomics, metabolomics and lipidomics, provides hope that complex molecular biomarker profiles could be developed to diagnose PsA. Importantly, the integration of these markers with high-throughput histology, imaging and standardized clinical assessment data provides an important opportunity to develop molecular profiles that could improve the diagnosis of PsA, predict its occurrence in cohorts of individuals with psoriasis, differentiate PsA from other IMIDs, and improve therapeutic responses. In this review, we consider the technologies that are currently deployed in the EU IMI2 project HIPPOCRATES to define biomarker profiles specific for PsA and discuss the advantages of combining multi-omics data to improve the outcome of PsA patients.
  •  
33.
  • Hüffmeier, Ulrike, et al. (author)
  • Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis
  • 2010
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 996-999
  • Journal article (peer-reviewed)abstract
    • Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.
  •  
34.
  • Ishigaki, Kazuyoshi, et al. (author)
  • Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
  • 2022
  • In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
  • Journal article (peer-reviewed)abstract
    • Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
  •  
35.
  • Javal, Marion, et al. (author)
  • The Effect of Oxygen Limitation on a Xylophagous Insect's Heat Tolerance Is Influenced by Life-Stage Through Variation in Aerobic Scope and Respiratory Anatomy
  • 2019
  • In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
  • Journal article (peer-reviewed)abstract
    • Temperature has a profound impact on insect fitness and performance via metabolic, enzymatic or chemical reaction rate effects. However, oxygen availability can interact with these thermal responses in complex and often poorly understood ways, especially in hypoxia-adapted species. Here we test the hypothesis that thermal limits are reduced under low oxygen availability - such as might happen when key life-stages reside within plants - but also extend this test to attempt to explain that the magnitude of the effect of hypoxia depends on variation in key respiration-related parameters such as aerobic scope and respiratory morphology. Using two life-stages of a xylophagous cerambycid beetle, Cacosceles (Zelogenes) newmannii we assessed oxygen-limitation effects on metabolic performance and thermal limits. We complement these physiological assessments with high-resolution 3D (micro-computed tomography scan) morphometry in both life-stages. Results showed that although larvae and adults have similar critical thermal maxima (CTmax) under normoxia, hypoxia reduces metabolic rate in adults to a greater extent than it does in larvae, thus reducing aerobic scope in the former far more markedly. In separate experiments, we also show that adults defend a tracheal oxygen (critical) setpoint more consistently than do larvae, indicated by switching between discontinuous gas exchange cycles (DGC) and continuous respiratory patterns under experimentally manipulated oxygen levels. These effects can be explained by the fact that the volume of respiratory anatomy is positively correlated with body mass in adults but is apparently size-invariant in larvae. Thus, the two life-stages of C. newmannii display key differences in respiratory structure and function that can explain the magnitude of the effect of hypoxia on upper thermal limits.
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36.
  • Jiang, Mingkai, et al. (author)
  • The fate of carbon in a mature forest under carbon dioxide enrichment
  • 2020
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 580:7802, s. 227-231
  • Journal article (peer-reviewed)abstract
    • Atmospheric carbon dioxide enrichment (eCO2) can enhance plant carbon uptake and growth1–5, thereby providing an important negative feedback to climate change by slowing the rate of increase of the atmospheric CO2 concentration6. Although evidence gathered from young aggrading forests has generally indicated a strong CO2 fertilization effect on biomass growth3–5, it is unclear whether mature forests respond to eCO2 in a similar way. In mature trees and forest stands7–10, photosynthetic uptake has been found to increase under eCO2 without any apparent accompanying growth response, leaving the fate of additional carbon fixed under eCO2 unclear4,5,7–11. Here using data from the first ecosystem-scale Free-Air CO2 Enrichment (FACE) experiment in a mature forest, we constructed a comprehensive ecosystem carbon budget to track the fate of carbon as the forest responded to four years of eCO2 exposure. We show that, although the eCO2 treatment of +150 parts per million (+38 per cent) above ambient levels induced a 12 per cent (+247 grams of carbon per square metre per year) increase in carbon uptake through gross primary production, this additional carbon uptake did not lead to increased carbon sequestration at the ecosystem level. Instead, the majority of the extra carbon was emitted back into the atmosphere via several respiratory fluxes, with increased soil respiration alone accounting for half of the total uptake surplus. Our results call into question the predominant thinking that the capacity of forests to act as carbon sinks will be generally enhanced under eCO2, and challenge the efficacy of climate mitigation strategies that rely on ubiquitous CO2 fertilization as a driver of increased carbon sinks in global forests.
  •  
37.
  • Kelly, Daniel, et al. (author)
  • Feasibility of sensor technology for balance assessment in home rehabilitation settings
  • 2021
  • In: Sensors. - : MDPI. - 1424-8220. ; 21:13
  • Journal article (peer-reviewed)abstract
    • The increased use of sensor technology has been crucial in releasing the potential for remote rehabilitation. However, it is vital that human factors, that have potential to affect real-world use, are fully considered before sensors are adopted into remote rehabilitation practice. The smart sensor devices for rehabilitation and connected health (SENDoc) project assesses the human factors associated with sensors for remote rehabilitation of elders in the Northern Periphery of Europe. This article conducts a literature review of human factors and puts forward an objective scoring system to evaluate the feasibility of balance assessment technology for adaption into remote rehabilitation settings. The main factors that must be considered are: Deployment constraints, usability, comfort and accuracy. This article shows that improving accuracy, reliability and validity is the main goal of research focusing on developing novel balance assessment technology. However, other aspects of usability related to human factors such as practicality, comfort and ease of use need further consideration by researchers to help advance the technology to a state where it can be applied in remote rehabilitation settings.
  •  
38.
  • Kenny, Lorna, et al. (author)
  • The Views and Needs of People With Parkinson Disease Regarding Wearable Devices for Disease Monitoring : Mixed Methods Exploration
  • 2022
  • In: JMIR Formative Research. - : JMIR Publications Inc.. - 2561-326X. ; 6:1
  • Journal article (peer-reviewed)abstract
    • Background: Wearable devices can diagnose, monitor, and manage neurological disorders such as Parkinson disease. With a growing number of wearable devices, it is no longer a case of whether a wearable device can measure Parkinson disease motor symptoms, but rather which features suit the user. Concurrent with continued device development, it is important to generate insights on the nuanced needs of the user in the modern era of wearable device capabilities.Objective: This study aims to understand the views and needs of people with Parkinson disease regarding wearable devices for disease monitoring and management.Methods: This study used a mixed method parallel design, wherein survey and focus groups were concurrently conducted with people living with Parkinson disease in Munster, Ireland. Surveys and focus group schedules were developed with input from people with Parkinson disease. The survey included questions about technology use, wearable device knowledge, and Likert items about potential device features and capabilities. The focus group participants were purposively sampled for variation in age (all were aged >50 years) and sex. The discussions concerned user priorities, perceived benefits of wearable devices, and preferred features. Simple descriptive statistics represented the survey data. The focus groups analyzed common themes using a qualitative thematic approach. The survey and focus group analyses occurred separately, and results were evaluated using a narrative approach.Results: Overall, 32 surveys were completed by individuals with Parkinson disease. Four semistructured focus groups were held with 24 people with Parkinson disease. Overall, the participants were positive about wearable devices and their perceived benefits in the management of symptoms, especially those of motor dexterity. Wearable devices should demonstrate clinical usefulness and be user-friendly and comfortable. Participants tended to see wearable devices mainly in providing data for health care professionals rather than providing feedback for themselves, although this was also important. Barriers to use included poor hand function, average technology confidence, and potential costs. It was felt that wearable device design that considered the user would ensure better compliance and adoption.Conclusions: Wearable devices that allow remote monitoring and assessment could improve health care access for patients living remotely or are unable to travel. COVID-19 has increased the use of remotely delivered health care; therefore, future integration of technology with health care will be crucial. Wearable device designers should be aware of the variability in Parkinson disease symptoms and the unique needs of users. Special consideration should be given to Parkinson disease-related health barriers and the users' confidence with technology. In this context, a user-centered design approach that includes people with Parkinson disease in the design of technology will likely be rewarded with improved user engagement and the adoption of and compliance with wearable devices, potentially leading to more accurate disease management, including self-management.
  •  
39.
  • Lagerholm, Vendela K., et al. (author)
  • Range shifts or extinction? Ancient DNA and distribution modelling reveal past and future responses to climate warming in cold-adapted birds
  • 2017
  • In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 23:4, s. 1425-1435
  • Journal article (peer-reviewed)abstract
    • Global warming is predicted to cause substantial habitat rearrangements, with the most severe effects expected to occur in high-latitude biomes. However, one major uncertainty is whether species will be able to shift their ranges to keep pace with climate-driven environmental changes. Many recent studies on mammals have shown that past range contractions have been associated with local extinctions rather than survival by habitat tracking. Here, we have used an interdisciplinary approach that combines ancient DNA techniques, coalescent simulations and species distribution modelling, to investigate how two common cold-adapted bird species, willow and rock ptarmigan (Lagopus lagopus and Lagopus muta), respond to long-term climate warming. Contrary to previous findings in mammals, we demonstrate a genetic continuity in Europe over the last 20 millennia. Results from back-casted species distribution models suggest that this continuity may have been facilitated by uninterrupted habitat availability and potentially also the greater dispersal ability of birds. However, our predictions show that in the near future, some isolated regions will have little suitable habitat left, implying a future decrease in local populations at a scale unprecedented since the last glacial maximum.
  •  
40.
  • Lehmann, Philipp, et al. (author)
  • Complex responses of global insect pests to climate warming
  • 2020
  • In: Frontiers in Ecology and the Environment. - : Wiley. - 1540-9295 .- 1540-9309. ; 18:3, s. 141-150
  • Research review (peer-reviewed)abstract
    • Although it is well known that insects are sensitive to temperature, how they will be affected by ongoing global warming remains uncertain because these responses are multifaceted and ecologically complex. We reviewed the effects of climate warming on 31 globally important phytophagous (plant-eating) insect pests to determine whether general trends in their responses to warming were detectable. We included four response categories (range expansion, life history, population dynamics, and trophic interactions) in this assessment. For the majority of these species, we identified at least one response to warming that affects the severity of the threat they pose as pests. Among these insect species, 41% showed responses expected to lead to increased pest damage, whereas only 4% exhibited responses consistent with reduced effects; notably, most of these species (55%) demonstrated mixed responses. This means that the severity of a given insect pest may both increase and decrease with ongoing climate warming. Overall, our analysis indicated that anticipating the effects of climate warming on phytophagous insect pests is far from straightforward. Rather, efforts to mitigate the undesirable effects of warming on insect pests must include a better understanding of how individual species will respond, and the complex ecological mechanisms underlying their responses.
  •  
41.
  • Lin, Yan-Shih, et al. (author)
  • Optimal stomatal behaviour around the world
  • 2015
  • In: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 5, s. 459-464
  • Journal article (peer-reviewed)abstract
    • Stomatal conductance (gs) is a key land-surface attribute as it links transpiration, the dominant component of global land evapotranspiration, and photosynthesis, the driving force of the global carbon cycle. Despite the pivotal role of gs in predictions of global water and carbon cycle changes, a globalscale database and an associated globally applicable model of gs that allow predictions of stomatal behaviour are lacking. Here,we present a database of globally distributed gs obtained in the field for a wide range of plant functional types (PFTs) and biomes. We find that stomatal behaviour differs among PFTs according to their marginal carbon cost of water use, as predicted by the theory underpinning the optimal stomatal model1 and the leaf and wood economics spectrum2,3.We also demonstrate a global relationship with climate. These findings provide a robust theoretical framework for understanding and predicting the behaviour of gs across biomes and across PFTs that can be applied to regional, continental and global-scale modelling of ecosystem productivity, energy balance and ecohydrological processes in a future changing climate.
  •  
42.
  • Lin, Yan-Shih, et al. (author)
  • Optimal stomatal behaviour around the world
  • 2015
  • In: Nature Climate Change. - 1758-6798 .- 1758-678X. ; 5:5, s. 459-464
  • Journal article (peer-reviewed)abstract
    • Stomatal conductance (g(s)) is a key land-surface attribute as it links transpiration, the dominant component of global land evapotranspiration, and photosynthesis, the driving force of the global carbon cycle. Despite the pivotal role of g(s) in predictions of global water and carbon cycle changes, a global-scale database and an associated globally applicable model of g(s) that allow predictions of stomatal behaviour are lacking. Here, we present a database of globally distributed g(s) obtained in the field for a wide range of plant functional types (PFTs) and biomes. We find that stomatal behaviour differs among PFTs according to their marginal carbon cost of water use, as predicted by the theory underpinning the optimal stomatal model(1) and the leaf and wood economics spectrum(2,3). We also demonstrate a global relationship with climate. These findin g(s) provide a robust theoretical framework for understanding and predicting the behaviour of g(s) across biomes and across PFTs that can be applied to regional, continental and global-scale modelling of ecosystem productivity, energy balance and ecohydrological processes in a future changing climate.
  •  
43.
  • Ling, Stephanie F., et al. (author)
  • Population Pharmacokinetic Analysis and Simulation of Alternative Dosing Regimens for Biosimilars to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis
  • 2024
  • In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 16:6, s. 702-702
  • Journal article (peer-reviewed)abstract
    • Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient’s circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy.
  •  
44.
  • Madsen, Dan, et al. (author)
  • Fire-Induced Radiological Integrated Assessment : Fire properties of selected materials and products
  • 2019
  • Reports (other academic/artistic)abstract
    • Characterization of emissions from fires in a laboratory-controlled environment are presented in this report. The project is initiated by the CERN HSE Unit and is called FIRIA, Fire-Induced Radiological Integrated Assessment. The objective of FIRIA is to enhance the knowledge of aerosols emitted from fires in order to develop dispersion models of radiologically-activated material in case of fire. In this report, several normally occurring combustible products and materials are tested in a standardized setup for fire tests, the cone calorimeter. In the cone calorimeter, standardized fire tests according to ISO 5660-1:2015 have been performed as well as fire tests at reduced oxygen concentrations in a vitiated air chamber. As an additional setup, aerosol measurement equipment was coupled to the cone calorimeter ventilation duct to characterize the emitted aerosols as in the particle size distribution, mass yield and elemental analysis.The results show peak heat release rates for oil at 1100 kW/m2 at an incident heat flux of 50 kW/m2. Similar results for the plastic materials were 800 kW/m2. For cables and insulating plastic materials peak heat release rates at an incident heat flux of 50 kW/m2 were around 350 kW/m2. Significant for most of the cables was a heat release rate curve with two distinct peaks. This is proposed to be due to the outer combustible sheath burning first followed by the interior plastic insulating material of the cables burning. There could also be heat transfer effects and cracking of the material surface contributing to the two peaks. Nevertheless, for some cables a low incident heat flux led to only one peak indicating that only the sheath ignited. Time to ignition varied between the materials but was increased as the incident heat flux decreased. Reduced oxygen concentration in the vitiated air chamber also prolonged the ignition time as well as the heat release rates. The critical heat flux to ignite the cables was calculated to be just below 10 kW/m2. The oil and two cable types were tested in the vitiated air chamber to perform tests at reduced oxygen concentrations. These tests were performed to retrieve specific fire properties as well as specific emissions from such conditions. The tests were performed with a progressively lower oxygen concentrations until no ignition of the sample occurred. Results showed an ignition limit around 11-13 % oxygen at incident heat fluxes of 20-30 kW/m2. The tests in the vitiated air chamber is described in subreport FIRIA- Fire properties of selected materials and products in reduced oxygen conditions.
  •  
45.
  • Madsen, Dan, et al. (author)
  • Fire-Induced Radiological Integrated Assessment : Fire properties of selected materials and products in reduce oxygen conditions
  • 2019
  • Reports (other academic/artistic)abstract
    • Characterization of emissions from fires in a laboratory-controlled environment are presented in this report. The project is initiated by the CERN HSE Unit and is called FIRIA, Fire-Induced Radiological Integrated Assessment. The objective of FIRIA is to enhance the knowledge of aerosols emitted from fires in order to develop dispersion models of radiologically-activated material in case of fire. Standard cone calorimeter test were done on a variety of combustible products and materials and the results are presented in the report FD03 Fire-Induced Radiological Integrated Assessment - Fire properties of selected materials and products.In this report, a vitiated air chamber was used to test an oil and two cables at reduced oxygen concentrations that were also tested in the FD03 report. The vitiated air chamber was attached to the standard cone calorimeter and a reduction in oxygen concentration was achieved by mixing nitrogen with compressed air. This general setup has been referred to as the open controlled atmosphere cone calorimeter (CACC).This report contains fire properties of the oil and cables at different irradiances and oxygen concentrations. The properties included are the ignition time, mass loss rate, heat release rate per unit area (HRRPUA), carbon dioxide yield, carbon monoxide yield, heat of combustion, and extinction coefficient.The results from the reduced oxygen concentration tests were compared with the results from the FD03 report. Some observations from the comparison are: An increase in the ignition time when compared to tests done in the standard cone calorimeter occurred for the oil and both cables at the lowest oxygen concentration tested for each irradiance level. The average carbon monoxide yields remained relatively constant or increased with decreases in the oxygen concentration. A reduction in the oxygen concentration generally resulted in a decrease in the mass loss rate and heat release rate per unit area (HRRPUA). However, one of the cables, referred to as cable 4 (C04), did not have a reduction in the mass loss rate and HRRPUA when exposed to an irradiance of 50 kW/m2. Cable 8 (C08) also had a higher peak mass loss rate and peak HRRPUA when tested at an oxygen concentration of 17% though the mass loss rate and HRRPUA was lower than the standard cone calorimeter result for most of the test.The limiting oxygen concentration using nitrogen to dilute air was also estimated at an irradiance of 20 kW/m2 for the oil and 30 kW/m2 for the cables. The estimated limiting oxygen concentrations were: Oil: between 11% (no ignition) and 13% (ignition) at an irradiance of 20 kW/m2 Cable 4: between 12% (no ignition) and 14% (ignition) at an irradiance of 30 kW/m2 Cable 8: between 13% (no ignition) and 15% (ignition) at an irradiance of 30 kW/m2
  •  
46.
  • Madsen, Dan, et al. (author)
  • Fire testing of aerosols and propane bottles
  • 2017
  • In: 15th International Conference and Exhibition on Fire and Materials 2017. - 9781510846746 ; 2, s. 924-936
  • Conference paper (peer-reviewed)abstract
    • Aerosol-And propane bottles for consumers, including hairspray, lubricants, etc. were tested for exposure from fire. The tested bottles had a volume between 15- 400 ml of product mixed with propane and bottles with propane only containing 0.35, 0.45, 5 and 6 kg of propane. The aerosol-And propane bottles were exposed to a heptane pool fire, corresponding to properties of common available flammable liquids for sale in stores. The experiments showed that the aerosol bottles exposed to fire exploded within a few minutes only and that this resulted in clouds of burning vapor as well as shrapnel affecting the vicinity. An experiment with several such aerosol bottles exposed to fire on a shelf in an enclosure, showed that unexploded aerosol bottles acted as projectiles when adjacent bottles exploded. Also, the explosion resulted in a high pressure, affecting building components. Experiments with propane bottles exposed to fire showed that such bottles release pressure in different ways, depending on their type and construction. During the experiments, the bottles released their pressure through a pressure valve or melting fuse within a few minutes only. During comparative experiments with propane bottles without safety devices, the bottles exploded within a few minutes only, resulting in large burning vapor clouds and shrapnel being thrown as far as approximately 80 m. Recommendations based on the experiments included suggestions on the maximum amount of combustible liquids which should be stored together with aerosol bottles. Recommendations were also given regarding the relevance of safety devices and securing propane bottles so that they can't move if safety devices activates when bottles are exposed to fire.
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47.
  • Malmborg, Vilhelm, et al. (author)
  • Fire-induced radiological integrated assessment : aerosol characterization
  • 2019
  • Reports (other academic/artistic)abstract
    • This report on detailed aerosol characterization of fire smoke emissions is part of the Fire-Induced Radiological Integrated Assessment (FIRIA; CERN, Switzerland). In this study, carried out at Lund University, a number of materials were combusted in a cone calorimeter at varied heat fluxes. In a few experiments, the effect of reduced O2 content of supply air was investigated (vitiated conditions). The materials included electrical components, magnets, plastic components, oil and cables and were selected due to their high probability of experiencing ionizing radiation in the research facilities at CERN. The aerosol particle yield in the combustion emissions was determined in terms of number and mass emissions. In addition, the particle physical properties in terms of size distributions, the mass - mobility relationship, and the black carbon fraction of emitted particles was determined. Finally, the particle morphology was determined with transmission electron microscopy (TEM) and elemental composition of trace elements by ICP-MS. The total range of aerosol mass yields spanned from approximately 0.005 (g/g fuel) to 0.23 (g/g fuel). Electrical components and magnets were identified as the combustibles with highest mass yields. Mass yields for cables spanned from 0.005-0.09 g/g fuel. The emissions were highly dynamic, with rapid shifts in concentrations and the particle number size distribution as measured with a fast mobility spectrometer (DMS500). The number yields ranged from approximately 0.05*10^14 to 2*10^14 emitted particles per gram of fuel and was measured within the size range 5-1000 nm. The emissions could be parameterized for future modelling applications into nucleation mode particles (with geometric mean diameter that varied between 20-50 nm) and accumulation mode particles (with geometric mean diameter 100-230 nm). The aerosol mass yields were governed primarily by the concentration and size distribution of accumulation mode particles. Mass yields were determined from 1) Impactor measurements (Dekati Gravimetric Impactor) and 2) Simultaneous measurements of the electrical mobility size distribution (DMS500) and effective density distribution (DMA-APM). The general agreement between the two techniques was good (R2=0.93). Black carbon is indicative of refractory carbonaceous particles which form in fuel rich conditions of the hot flame environment and associated with the black color of soot (smoke). Black carbon yields were for most experiments similar to the derived mass yields. TEM images showed typical refractory black carbon aggregates at high BC fractions. The primary particle size was larger than for diesel exhaust. However, at reduced heat flux and during vitiated combustion (reduced O2 concentration), black carbon yields were sometimes much lower than the derived particle mass yields. TEM analysis for a sample with low BC fraction showed only very few particles and those that were found had distinctly different properties to the high BC fraction sample. We hypothesize that particles emitted under these conditions were dominated by low volatility organic matter formed in the pyrolysis of the materials. Such components were likely co-emitted with black carbon also in conventional experiments, although in minor mass fractions. Based on previous studies it can be hypothesized that H:C ratios are low for the cases with high BC fraction.
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48.
  • Moore, Kevin, et al. (author)
  • Older adults’ experiences with using wearable devices : Qualitative systematic review and meta-synthesis
  • 2021
  • In: JMIR mhealth and uhealth. - : JMIR Publications. - 2291-5222. ; 9:6
  • Research review (peer-reviewed)abstract
    • Background: Older adults may use wearable devices for various reasons, ranging from monitoring clinically relevant health metrics or detecting falls to monitoring physical activity. Little is known about how this population engages with wearable devices, and no qualitative synthesis exists to describe their shared experiences with long-term use.Objective: This study aims to synthesize qualitative studies of user experience after a multi-day trial with a wearable device to understand user experience and the factors that contribute to the acceptance and use of wearable devices.Methods: We conducted a systematic search in CINAHL, APA PsycINFO, PubMed, and Embase (2015-2020; English) with fixed search terms relating to older adults and wearable devices. A meta-synthesis methodology was used. We extracted themes from primary studies, identified key concepts, and applied reciprocal and refutational translation techniques; findings were synthesized into third-order interpretations, and finally, a “line-of-argument” was developed. Our overall goal was theory development, higher-level abstraction, and generalizability for making this group of qualitative findings more accessible.Results: In total, we reviewed 20 papers; 2 evaluated fall detection devices, 1 tested an ankle-worn step counter, and the remaining 17 tested activity trackers. The duration of wearing ranged from 3 days to 24 months. The views of 349 participants (age: range 51-94 years) were synthesized. Four key concepts were identified and outlined: motivation for device use, user characteristics (openness to engage and functional ability), integration into daily life, and device features. Motivation for device use is intrinsic and extrinsic, encompassing many aspects of the user experience, and appears to be as, if not more, important than the actual device features. To overcome usability barriers, an older adult must be motivated by the useful purpose of the device. A device that serves its intended purpose adds value to the user’s life. The user’s needs and the support structure around the device—aspects that are often overlooked—seem to play a crucial role in long-term adoption. Our “line-of-argument” model describes how motivation, ease of use, and device purpose determine whether a device is perceived to add value to the user’s life, which subsequently predicts whether the device will be integrated into the user’s life.Conclusions: The added value of a wearable device is the resulting balance of motivators (or lack thereof), device features (and their accuracy), ease of use, device purpose, and user experience. The added value contributes to the successful integration of the device into the daily life of the user. Useful device features alone do not lead to continued use. A support structure should be placed around the user to foster motivation, encourage peer engagement, and adapt to the user’s preferences.
  •  
49.
  • Nieddu, Valentina, et al. (author)
  • Engineered human mesenchymal stem cells for neuroblastoma therapeutics
  • 2019
  • In: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 42:1, s. 35-42
  • Journal article (peer-reviewed)abstract
    • Drug-resistant neuroblastoma remains a major challenge in paediatric oncology and novel and less toxic therapeutic approaches are urgently needed to improve survival and reduce the side effects of traditional therapeutic interventions. Mesenchymal stem cells (MSCs) are an attractive candidate for cell and gene therapy since they are recruited by and able to infiltrate tumours. This feature has been exploited by creating genetically modified MSCs that are able to combat cancer by delivering therapeutic molecules. Whether neuroblastomas attract systemically delivered MSCs is still controversial. We investigated whether MSCs engineered to express tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) could: i) cause death of classic and primary neuroblastoma cell lines in vitro; ii) migrate to tumour sites in vivo; and iii) reduce neuroblastoma growth in xenotrans-plantation experiments. We observed that classic and primary neuroblastoma cell lines expressing death receptors could be killed by TRAIL-loaded MSCs in vitro. When injected in the peritoneum of neuroblastoma-bearing mice, TRAIL-MSCs migrated to tumour sites, but were unable to change the course of cancer development. These results indicated that MSCs have the potential to be used to deliver drugs in neuroblastoma patients, but more effective biopharmaceuticals should be used instead of TRAIL.
  •  
50.
  • Okada, Yukinori, et al. (author)
  • Genetics of rheumatoid arthritis contributes to biology and drug discovery
  • 2014
  • In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
  • Journal article (peer-reviewed)abstract
    • A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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