| 1. |
- Kattge, Jens, et al.
(author)
-
TRY plant trait database - enhanced coverage and open access
- 2020
-
In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
-
Journal article (peer-reviewed)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
|
|
| 2. |
- Alimena, Juliette, et al.
(author)
-
Searching for long-lived particles beyond the Standard Model at the Large Hadron Collider
- 2020
-
In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 47:9
-
Journal article (peer-reviewed)abstract
- Particles beyond the Standard Model (SM) can generically have lifetimes that are long compared to SM particles at the weak scale. When produced at experiments such as the Large Hadron Collider (LHC) at CERN, these long-lived particles (LLPs) can decay far from the interaction vertex of the primary proton-proton collision. Such LLP signatures are distinct from those of promptly decaying particles that are targeted by the majority of searches for new physics at the LHC, often requiring customized techniques to identify, for example, significantly displaced decay vertices, tracks with atypical properties, and short track segments. Given their non-standard nature, a comprehensive overview of LLP signatures at the LHC is beneficial to ensure that possible avenues of the discovery of new physics are not overlooked. Here we report on the joint work of a community of theorists and experimentalists with the ATLAS, CMS, and LHCb experiments-as well as those working on dedicated experiments such as MoEDAL, milliQan, MATHUSLA, CODEX-b, and FASER-to survey the current state of LLP searches at the LHC, and to chart a path for the development of LLP searches into the future, both in the upcoming Run 3 and at the high-luminosity LHC. The work is organized around the current and future potential capabilities of LHC experiments to generally discover new LLPs, and takes a signature-based approach to surveying classes of models that give rise to LLPs rather than emphasizing any particular theory motivation. We develop a set of simplified models; assess the coverage of current searches; document known, often unexpected backgrounds; explore the capabilities of proposed detector upgrades; provide recommendations for the presentation of search results; and look towards the newest frontiers, namely high-multiplicity 'dark showers', highlighting opportunities for expanding the LHC reach for these signals.
|
|
| 3. |
- Patterson, Nick, et al.
(author)
-
Large-scale migration into Britain during the Middle to Late Bronze Age
- 2022
-
In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; , s. 588-594
-
Journal article (peer-reviewed)abstract
- Present-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data from 793 individuals, increasing data from the Middle to Late Bronze and Iron Age in Britain by 12-fold, and Western and Central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of Iron Age people of England and Wales, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and Britain's independent genetic trajectory is also reflected in the rise of the allele conferring lactase persistence to ~50% by this time compared to ~7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period.
|
|
| 4. |
- Beecham, Ashley H, et al.
(author)
-
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
-
Journal article (peer-reviewed)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
|
|
| 5. |
- Cope, Henry, et al.
(author)
-
Routine omics collection is a golden opportunity for European human research in space and analog environments
- 2022
-
In: PATTERNS. - : Elsevier BV. - 2666-3899. ; 3:10, s. 100550-
-
Journal article (peer-reviewed)abstract
- Widespread generation and analysis of omics data have revolutionized molecular medicine on Earth, yet its power to yield new mechanistic insights and improve occupational health during spaceflight is still to be fully realized in humans. Nevertheless, rapid technological advancements and ever-regular spaceflight programs mean that longitudinal, standardized, and cost-effective collection of human space omics data are firmly within reach. Here, we consider the practicality and scientific return of different sampling methods and omic types in the context of human spaceflight, We also appraise ethical and legal considerations pertinent to omics data derived from European astronauts and spaceflight participants (SFPs). Ultimately, we propose that a routine omics collection program in spaceflight and analog environments presents a golden opportunity. Unlocking this bright future of artificial intelligence (AI)-driven analyses and personalized medicine approaches will require further investigation into best practices, including policy design and standardization of omics data, metadata, and sampling methods.
|
|
| 6. |
- Ekholm, Victor, et al.
(author)
-
Anomalous surface behavior of hydrated guanidinium ions due to ion pairing
- 2018
-
In: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 148:14
-
Journal article (peer-reviewed)abstract
- Surface affinity of aqueous guanidinium chloride (GdmCl) is compared to that of aqueous tetrapropylammonium chloride (TPACl) upon addition of sodium chloride (NaCl) or disodium sulfate (Na2SO4). The experimental results have been acquired using the surface sensitive technique X-ray photoelectron spectroscopy on a liquid jet. Molecular dynamics simulations have been used to produce radial distribution functions and surface density plots. The surface affinities of both TPA(+) and Gdm(+) increase upon adding NaCl to the solution. With the addition of Na2SO4, the surface affinity of TPA(+) increases, while that of Gdm(+) decreases. From the results of MD simulations it is seen that Gdm(+) and SO42- ions form pairs. This finding can be used to explain the decreased surface affinity of Gdm(+) when co-dissolved with SO42- ions. Since SO42- ions avoid the surface due to the double charge and strong water interaction, the Gdm(+)-SO42- ion pair resides deeper in the solutions' bulk than the Gdm(+) ions. Since TPA(+) does not form ion pairs with SO42-, the TPA(+) ions are instead enriched at the surface.
|
|
| 7. |
- Forbes, Ruaridh, et al.
(author)
-
Time-resolved site-selective imaging of predissociation and charge transfer dynamics : The CH3I B-band
- 2020
-
In: Journal of Physics B: Atomic, Molecular and Optical Physics. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 53:22
-
Journal article (peer-reviewed)abstract
- The predissociation dynamics of the 6s (B2E) Rydberg state of gas-phase CH3I were investigated by time-resolved Coulomb-explosion imaging using extreme ultraviolet (XUV) free-electron laser pulses. Inner-shell ionization at the iodine 4d edge was utilized to provide a site-specific probe of the ensuing dynamics. The combination of a velocity-map imaging (VMI) spectrometer coupled with the pixel imaging mass spectrometry (PImMS) camera permitted three-dimensional ionic fragment momenta to be recorded simultaneously for a wide range of iodine charge states. In accord with previous studies, initial excitation at 201.2 nm results in internal conversion and subsequent dissociation on the lower-lying A-state surface on a picosecond time scale. Examination of the time-dependent yield of low kinetic energy iodine fragments yields mechanistic insights into the predissociation and subsequent charge transfer following multiple ionization of the iodine products. The effect of charge transfer was observed through differing delay-dependencies of the various iodine charge states, from which critical internuclear distances for charge transfer could be inferred and compared to a classical over-the-barrier model. Time-dependent photofragment angular anisotropy parameters were extracted from the central slice of the Newton sphere, without Abel inversion, and highlight the effect of rotation of the parent molecule before dissociation, as observed in previous
|
|
| 8. |
- Forslund, Tommie, et al.
(author)
-
El Apego Va a Juicio: Problemas de Custodia y Protección Infantil : [Attachment goes to court: Child protection and custody issues]
- 2021
-
In: Anuario de psicología jurídica. - : Colegio Oficial de la Psicologia de Madrid. - 1133-0740 .- 2174-0542. ; 32:1, s. 115-139
-
Journal article (peer-reviewed)abstract
- Attachment theory and research are drawn upon in many applied settings, including family courts, but misunderstandings are widespread and sometimes result in misapplications. The aim of this consensus statement is, therefore, to enhance understanding, counter misinformation, and steer family-court utilisation of attachment theory in a supportive, evidence-based direction, especially with regard to child protection and child custody decision-making. This article is divided into two parts. In the first part, we address problems related to the use of attachment theory and research in family courts, and discuss reasons for these problems. To this end, we examine family court applications of attachment theory in the current context of the best-interest-of-the-child standard, discuss misunderstandings regarding attachment theory, and identify factors that have hindered accurate implementation. In the second part, we provide recommendations for the application of attachment theory and research. To this end, we set out three attachment principles: the child's need for familiar, non-abusive caregivers; the value of continuity of good-enough care; and the benefits of networks of attachment relationships. We also discuss the suitability of assessments of attachment quality and caregiving behaviour to inform family court decision-making. We conclude that assessments of caregiver behaviour should take center stage. Although there is dissensus among us regarding the use of assessments of attachment quality to inform child custody and child-protection decisions, such assessments are currently most suitable for targeting and directing supportive interventions. Finally, we provide directions to guide future interdisciplinary research collaboration.
|
|
| 9. |
|
|
| 10. |
- Gaziano, Liam, et al.
(author)
-
Mild-to-moderate kidney dysfunction and cardiovascular disease : Observational and mendelian randomization analyses
- 2022
-
In: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 146:20, s. 1507-1517
-
Journal article (peer-reviewed)abstract
- BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
|
|
| 11. |
- Kassebaum, Nicholas J., et al.
(author)
-
Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015
- 2016
-
In: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1603-1658
-
Journal article (peer-reviewed)abstract
- Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs off set by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2.9 years (95% uncertainty interval 2.9-3.0) for men and 3.5 years (3.4-3.7) for women, while HALE at age 65 years improved by 0.85 years (0.78-0.92) and 1.2 years (1.1-1.3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum.
|
|
| 12. |
- Marra, Giancarlo, et al.
(author)
-
Impact of Epithelial Histological Types, Subtypes, and Growth Patterns on Oncological Outcomes for Patients with Nonmetastatic Prostate Cancer Treated with Curative Intent: A Systematic Review.
- 2023
-
In: European urology. - 0302-2838 .- 1873-7560. ; 84:1, s. 65-85
-
Journal article (peer-reviewed)abstract
- The optimal management for men with prostate cancer (PCa) with unconventional histology (UH) is unknown. The outcome for these cancers might be worse than for conventional PCa and so different approaches may be needed.To compare oncological outcomes for conventional and UH PCa in men with localized disease treated with curative intent.A systematic review adhering to the Referred Reporting Items for Systematic Reviews and Meta-Analyses was prospectively registered on PROSPERO (CRD42022296013) was performed in July 2021.We screened 3651 manuscripts and identified 46 eligible studies (reporting on 1871814 men with conventional PCa and 6929 men with 10 different PCa UHs). Extraprostatic extension and lymph node metastases, but not positive margin rates, were more common with UH PCa than with conventional tumors. PCa cases with cribriform pattern, intraductal carcinoma, or ductal adenocarcinoma had higher rates of biochemical recurrence and metastases after radical prostatectomy than for conventional PCa cases. Lower cancer-specific survival rates were observed for mixed cribriform/intraductal and cribriform PCa. By contrast, pathological findings and oncological outcomes for mucinous and prostatic intraepithelial neoplasia (PIN)-like PCa were similar to those for conventional PCa. Limitations of this review include low-quality studies, a risk of reporting bias, and a scarcity of studies that included radiotherapy.Intraductal, cribriform, and ductal UHs may have worse oncological outcomes than for conventional and mucinous or PIN-like PCa. Alternative treatment approaches need to be evaluated in men with these cancers.We reviewed the literature to explore whether prostate cancers with unconventional growth patterns behave differently to conventional prostate cancers. We found that some unconventional growth patterns have worse outcomes, so we need to investigate if they need different treatments. Urologists should be aware of these growth patterns and their clinical impact.
|
|
| 13. |
- Mason, Lucy R., et al.
(author)
-
Population responses of bird populations to climate change on two continents vary with species’ ecological traits but not with direction of change in climate suitability
- 2019
-
In: Climatic Change. - : Springer Science and Business Media LLC. - 0165-0009 .- 1573-1480. ; 157:3-4, s. 337-354
-
Journal article (peer-reviewed)abstract
- Climate change is a major global threat to biodiversity with widespread impacts on ecological communities. Evidence for beneficial impacts on populations is perceived to be stronger and more plentiful than that for negative impacts, but few studies have investigated this apparent disparity, or how ecological factors affect population responses to climatic change. We examined the strength of the relationship between species-specific regional population changes and climate suitability trends (CST), using 30-year datasets of population change for 525 breeding bird species in Europe and the USA. These data indicate a consistent positive relationship between population trend and CST across the two continents. Importantly, we found no evidence that this positive relationship differs between species expected to be negatively and positively impacted across the entire taxonomic group, suggesting that climate change is causing equally strong, quantifiable population increases and declines. Species’ responses to changing climatic suitability varied with ecological traits, however, particularly breeding habitat preference and body mass. Species associated with inland wetlands responded most strongly and consistently to recent climatic change. In Europe, smaller species also appeared to respond more strongly, whilst the relationship with body mass was less clear-cut for North American birds. Overall, our results identify the role of certain traits in modulating responses to climate change and emphasise the importance of long-term data on abundance for detecting large-scale species’ responses to environmental changes.
|
|
| 14. |
- O’Neill, Hagen M., et al.
(author)
-
The importance of direct and indirect trophic interactions in determining the presence of a locally rare day-flying moth
- 2022
-
In: Oecologia. - : Springer. - 0029-8549 .- 1432-1939. ; 198, s. 531-542
-
Journal article (peer-reviewed)abstract
- Ecosystem engineers affect other organisms by creating, maintaining or modifying habitats, potentially supporting species of conservation concern. However, it is important to consider these interactions alongside non-engineering trophic pathways. We investigated the relative importance of trophic and non-trophic effects of an ecosystem engineer, red deer, on a locally rare moth, the transparent burnet (Zygaena purpuralis). This species requires specific microhabitat conditions, including the foodplant, thyme, and bare soil for egg-laying. The relative importance of grazing (i.e., trophic effect of modifying microhabitat) and trampling (i.e., non-trophic effect of exposing bare soil) by red deer on transparent burnet abundance is unknown. We tested for these effects using a novel method of placing pheromone-baited funnel traps in the field. Imago abundance throughout the flight season was related to plant composition, diversity and structure at various scales around each trap. Indirect effects of red deer activity were accounted for by testing red deer pellet and trail presence against imago abundance. Imago abundance was positively associated with thyme and plant diversity, whilst negatively associated with velvet grass and heather species cover. The presence of red deer pellets and trails were positively associated with imago abundance. The use of these sites by red deer aids the transparent burnet population via appropriate levels of grazing and the provision of a key habitat condition, bare soil, in the form of deer trails. This study shows that understanding how both trophic and non-trophic interactions affect the abundance of a species provides valuable insights regarding conservation objectives.
|
|
| 15. |
- Ortiz-Fernandez, Lourdes, et al.
(author)
-
Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study
- 2021
-
In: American Journal of Human Genetics. - CAMBRIDGE, MA USA : Cell Press. - 0002-9297 .- 1537-6605. ; 108:1, s. 84-99
-
Journal article (peer-reviewed)abstract
- Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 x 10(-s)) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.
|
|
| 16. |
- Sawcer, Stephen, et al.
(author)
-
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
-
Journal article (peer-reviewed)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
|
|
| 17. |
- Schmidt, Amand F., et al.
(author)
-
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
-
In: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
-
Journal article (peer-reviewed)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
|
|
| 18. |
- Stephens, Philip A., et al.
(author)
-
Consistent response of bird populations to climate change on two continents
- 2016
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 352:6281, s. 84-87
-
Journal article (peer-reviewed)abstract
- Global climate change is a major threat to biodiversity. Large-scale analyses have generally focused on the impacts of climate change on the geographic ranges of species and on phenology, the timing of ecological phenomena. We used long-term monitoring of the abundance of breeding birds across Europe and the United States to produce, for both regions, composite population indices for two groups of species: those for which climate suitability has been either improving or declining since 1980. The ratio of these composite indices, the climate impact indicator (CII), reflects the divergent fates of species favored or disadvantaged by climate change. The trend in CII is positive and similar in the two regions. On both continents, interspecific and spatial variation in population abundance trends are well predicted by climate suitability trends.
|
|
| 19. |
|
|
| 20. |
- Vazdar, Mario, et al.
(author)
-
Arginine "magic" : Guanidinium Like-Charge Ion Pairing from Aqueous Salts to Cell Penetrating Peptides
- 2018
-
In: Accounts of Chemical Research. - : American Chemical Society (ACS). - 0001-4842 .- 1520-4898. ; 51:6, s. 1455-1464
-
Journal article (peer-reviewed)abstract
- It is a textbook knowledge that charges of the same polarity repel each other. For two monovalent ions in the gas phase at a close contact this repulsive interaction amounts to hundreds of kilojoules per mole. In aqueous solutions, however, this Coulomb repulsion is strongly attenuated by a factor equal to the dielectric constant of the medium. The residual repulsion, which now amounts only to units of kilojoules per mole, may be in principle offset by attractive interactions. Probably the smallest cationic pair, where a combination of dispersion and cavitation forces overwhelms the Coulomb repulsion, consists of two guanidinium ions in water. Indeed, by a combination of molecular dynamics with electronic structure calculations and electrophoretic, as well as spectroscopic, experiments, we have demonstrated that aqueous guanidinium cations form (weakly) thermodynamically stable like-charge ion pairs.The importance of pairing of guanidinium cations in aqueous solutions goes beyond a mere physical curiosity, since it has significant biochemical implications. Guanidinium chloride is known to be an efficient and flexible protein denaturant. This is due to the ability of the orientationally amphiphilic guanidinium cations to disrupt various secondary structural motifs of proteins by pairing promiscuously with both hydrophobic and hydrophilic groups, including guanidinium-containing side chains of arginines.The fact that the cationic guanidinium moiety forms the dominant part of the arginine side chain implies that the like-charge ion pairing may also play a role for interactions between peptides and proteins. Indeed, arginine-arginine pairing has been frequently found in structural protein databases. In particular, when strengthened by a presence of negatively charged glutamate, aspartate, or C-terminal carboxylic groups, this binding motif helps to stabilize peptide or protein dimers and is also found in or near active sites of several enzymes.The like-charge pairing of the guanidinium side-chain groups may also hold the key to the understanding of the arginine "magic", that is, the extraordinary ability of arginine-rich polypeptides to passively penetrate across cellular membranes. Unlike polylysines, which are also highly cationic but lack the ease in crossing membranes, polyarginines do not exhibit mutual repulsion. Instead, they accumulate at the membrane, weaken it, and might eventually cross in a concerted, "train-like" manner. This behavior of arginine-rich cell penetrating peptides can be exploited when devising smart strategies how to deliver in a targeted way molecular cargos into the cell.
|
|
| 21. |
- Vos, Theo, et al.
(author)
-
Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013
- 2015
-
In: The Lancet. - 1474-547X .- 0140-6736. ; 386:9995, s. 743-800
-
Journal article (peer-reviewed)abstract
- Background Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013. Methods Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries. Findings Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2.4 billion and 1.6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537.6 million in 1990 to 764.8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114.87 per 1000 people to 110.31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21.1% in 1990 to 31.2% in 2013. Interpretation Ageing of the world's population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to non-fatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.
|
|
| 22. |
- Whittaker, Jackie L., et al.
(author)
-
Toward designing human intervention studies to prevent osteoarthritis after knee injury : A report from an interdisciplinary OARSI 2023 workshop
- 2024
-
In: Osteoarthritis and Cartilage Open. - 2665-9131. ; 6:2
-
Journal article (peer-reviewed)abstract
- Objective: The global impact of osteoarthritis is growing. Currently no disease modifying osteoarthritis drugs/therapies exist, increasing the need for preventative strategies. Knee injuries have a high prevalence, distinct onset, and strong independent association with post-traumatic osteoarthritis (PTOA). Numerous groups are embarking upon research that will culminate in clinical trials to assess the effect of interventions to prevent knee PTOA despite challenges and lack of consensus about trial design in this population. Our objectives were to improve awareness of knee PTOA prevention trial design and discuss state-of-the art methods to address the unique opportunities and challenges of these studies. Design: An international interdisciplinary group developed a workshop, hosted at the 2023 Osteoarthritis Research Society International Congress. Here we summarize the workshop content and outputs, with the goal of moving the field of PTOA prevention trial design forward. Results: Workshop highlights included discussions about target population (considering risk, homogeneity, and possibility of modifying osteoarthritis outcome); target treatment (considering delivery, timing, feasibility and effectiveness); comparators (usual care, placebo), and primary symptomatic outcomes considering surrogates and the importance of knee function and symptoms other than pain to this population. Conclusions: Opportunities to test multimodal PTOA prevention interventions across preclinical models and clinical trials exist. As improving symptomatic outcomes aligns with patient and regulator priorities, co-primary symptomatic (single or aggregate/multidimensional outcome considering function and symptoms beyond pain) and structural/physiological outcomes may be appropriate for these trials. To ensure PTOA prevention trials are relevant and acceptable to all stakeholders, future research should address critical knowledge gaps and challenges.
|
|
| 23. |
-
- 2019
-
Journal article (peer-reviewed)
|
|
