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- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
- Schael, S., et al.
(author)
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Electroweak measurements in electron positron collisions at W-boson-pair energies at LEP
- 2013
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In: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 532:4, s. 119-244
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Research review (peer-reviewed)abstract
- Electroweak measurements performed with data taken at the electron positron collider LEP at CERN from 1995 to 2000 are reported. The combined data set considered in this report corresponds to a total luminosity of about 3 fb(-1) collected by the four LEP experiments ALEPH, DELPHI, 13 and OPAL, at centre-of-mass energies ranging from 130 GeV to 209 GeV. Combining the published results of the four LEP experiments, the measurements include total and differential cross-sections in photon-pair, fermion-pair and four-fermion production, the latter resulting from both double-resonant WW and ZZ production as well as singly resonant production. Total and differential cross-sections are measured precisely, providing a stringent test of the Standard Model at centre-of-mass energies never explored before in electron positron collisions. Final-state interaction effects in four-fermion production, such as those arising from colour reconnection and Bose Einstein correlations between the two W decay systems arising in WW production, are searched for and upper limits on the strength of possible effects are obtained. The data are used to determine fundamental properties of the W boson and the electroweak theory. Among others, the mass and width of the W boson, m(w) and Gamma(w), the branching fraction of W decays to hadrons, B(W -> had), and the trilinear gauge-boson self-couplings g(1)(Z), K-gamma and lambda(gamma), are determined to be: m(w) = 80.376 +/- 0.033 GeV Gamma(w) = 2.195 +/- 0.083 GeV B(W -> had) = 67.41 +/- 0.27% g(1)(Z) = 0.984(-0.020)(+0.018) K-gamma - 0.982 +/- 0.042 lambda(gamma) = 0.022 +/- 0.019. (C) 2013 Elsevier B.V. All rights reserved.
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| 29. |
- Asselbergs, Folkert W., et al.
(author)
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Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
- 2012
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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| 30. |
- Berglund, Erik, et al.
(author)
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Clinical Significance of Alloantibodies in Hand Transplantation : A Multicenter Study
- 2019
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In: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0041-1337 .- 1534-6080. ; 103:10, s. 2173-2182
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Journal article (peer-reviewed)abstract
- Background. Donor-specific antibodies (DSAs) have a strong negative correlation with long-term survival in solid organ transplantation. Although the clinical significance of DSA and antibody-mediated rejection (AMR) in upper extremity transplantation (UET) remains to be established, a growing number of single-center reports indicate their presence and potential clinical impact. Methods. We present a multicenter study assessing the occurrence and significance of alloantibodies in UET in reference to immunological parameters and functional outcome. Results. Our study revealed a high prevalence and early development of de novo DSA and non-DSA (43%, the majority detected within the first 3 postoperative y). HLA class II mismatch correlated with antibody development, which in turn significantly correlated with the incidence of acute cellular rejection. Cellular rejections preceded antibody development in almost all cases. A strong correlation between DSA and graft survival or function cannot be statistically established at this early stage but a correlation with a lesser outcome seems to emerge. Conclusions. While the phenotype and true clinical effect of AMR remain to be better defined, the high prevalence of DSA and the correlation with acute rejection highlight the need for optimizing immunosuppression, close monitoring, and the relevance of an HLA class II match in UET recipients.
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| 31. |
- Casalbuoni, Sara, et al.
(author)
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COLDDIAG: A Cold Vacuum Chamber for Diagnostics
- 2011
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In: IEEE Transactions on Applied Superconductivity. - 1051-8223. ; 21:3, s. 2300-2303
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Journal article (peer-reviewed)abstract
- One of the still open issues for the development of superconducting insertion devices is the understanding of the heat load induced by the beam passage. With the aim of measuring the beam heat load to a cold bore and in order to gain a deeper understanding in the beam heat load mechanisms, a cold vacuum chamber for diagnostics is under construction. We plan to have access with the same set-up to a number of different diagnostics, so we are implementing: i) retarding field analysers to measure the electron flux, ii) temperature sensors to measure the total heat load, iii) pressure gauges, iv) and mass spectrometers to measure the gas content. The inner vacuum chamber will be removable in order to test different geometries and materials. COLDDIAG is built to fit in a short straight section at ANKA, but we are proposing its installation in different synchrotron light sources with different energies and beam characteristics. A first installation in DIAMOND is planned in June 2011. Here we describe the technical design report of this device and the planned measurements with beam.
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| 32. |
- Clarke, Gerard, et al.
(author)
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Longitudinal Associations Between Persistent Post-Concussion Symptoms and Blood Biomarkers of Inflammation and CNS-Injury Following Mild Traumatic Brain Injury
- 2024
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In: Journal of neurotrauma. - 1557-9042. ; 41:7-8, s. 862-878
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Journal article (peer-reviewed)abstract
- The aim of our study was to investigate the biological underpinnings of persistent post-concussion symptoms (PPCS) at 3 months following mild traumatic brain injury (mTBI). Patients (n = 192, 16-60 years) with mTBI, defined as Glasgow Coma Scale (GCS) score between 13 and 15, loss of consciousness (LOC)<30 min and post-traumatic amnesia (PTA)<24 hours were included. Blood samples were collected at admission (within 72 hours), 2 weeks and 3 months. From the blood, concentrations of blood biomarkers associated with CNS damage (GFAP, NFL and tau) and inflammation (IFN, IL-8, eotaxin, MIP-1, MCP-1, IP-10, IL-17A, IL-9, TNF, FGF-basic PDGF and IL-1ra) were obtained. Demographic and injury-related factors investigated were age, sex, GCS score, LOC, PTA duration, traumatic intracranial finding on MRI (within 72 hours), and extracranial injuries. Delta values, i.e., timepoint differences in biomarker concentrations between 2 weeks minus admission and 3 months minus admission, were also calculated. PPCS was assessed with the British Columbia Post-Concussion Symptom Inventory (BC-PSI). In single variable analyses, longer PTA duration and a higher proportion of intracranial findings on MRI were found in the PPCS group, but no single biomarker differentiated those with PPCS from those without. In multivariable models, female sex, longer PTA duration, MRI findings and lower GCS scores were associated with increased risk of PPCS. Inflammation markers, but not GFAP, NFL or tau, were associated with PPCS. At admission, higher concentrations of IL-8 and IL-9 and lower concentrations of TNF, IL-17a, and MCP-1 were associated with greater likelihood of PPCS; at 2 weeks, higher IL-8 and lower IFN were associated with PPCS; at 3 months, higher PDGF was associated with PPCS. Higher delta values of PDGF, IL-17A and FGF-basic at 2 weeks compared to admission, MCP-1 at 3 months compared to admission and TNF at 2 weeks and 3 months compared to admission were associated with greater likelihood of PPCS. Higher IL-9 delta values at both timepoint comparisons were negatively associated with PPCS. Discriminability of individual CNS-injury and inflammation biomarkers for PPCS was around chance level, while the optimal combination of biomarkers yielded AUCs between 0.62 and 0.73. We demonstrate a role of biological factors on PPCS, including both positive and negative effects of inflammation biomarkers that differed based on sampling timepoint after mTBI. PPCS was associated more with acute inflammatory processes, rather than ongoing inflammation or CNS-injury biomarkers. However, the modest discriminative ability of the models suggests other factors are more important in the development of PPCS.
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| 33. |
- Conley, Daniel, et al.
(author)
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Past, present and future state of the biogeochemical Si cycle in the Baltic Sea
- 2008
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In: Journal of Marine Systems. - : Elsevier BV. - 0924-7963 .- 1879-1573. ; 73:3-4, s. 338-346
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Journal article (peer-reviewed)abstract
- The Baltic Sea is one of many aquatic ecosystems that show long-term declines in dissolved silicate (DSi) concentrations due to anthropogenic alteration of the biogeochemical Si cycle. Reductions in DSi in aquatic ecosystems have been coupled to hydrological regulation reducing inputs, but also with eutrophication, although the relative significance of both processes remains unknown for the observed reductions in DSi concentrations. Here we combine present and historical data on water column DSi concentrations, together with estimates of present river DSi loads to the Baltic, the load prior to damming together with estimates of the long-term accumulation of BSi in sediments. In addition, a model has been used to evaluate the past, present and future state of the biogeochemical Si cycle in the Baltic Sea. The present day DSi load to the Baltic Sea is 855 ktons y(-1). Hydrological regulation and eutrophication of inland waters can account for a reduction of 420 ktons y(-1) less riverine DSi entering the Baltic Sea today. Using published data on basin-wide accumulation rates we estimate that 1074 ktons y(-1) of biogenic silica (BSi) is accumulating in the sediments, which is 36% higher than earlier estimates from the literature (791 ktons y(-1)). The difference is largely due to the high reported sedimentation rates in the Bothnian Sea and the Bothnian Bay. Using river DSi loads and estimated BSi accumulation, our model was not able to estimate water column DSi concentrations as burial estimates exceeded DSi inputs. The model was then used to estimate the BSi burial from measured DSi concentrations and DSj load. The model estimate for the total burial of BSi in all three basins was 620 ktons y(-1), 74% less than estimated from sedimentation rates and sediment BSi concentrations. The model predicted 20% less BSi accumulation in the Baltic Proper and 10% less in the Bothnian Bay than estimated, but with significantly less BSi accumulation in the Bothnian Sea by a factor of 3. The model suggests there is an overestimation of basin-wide sedimentation rates in the Bothnian Bay and the Bothnian Sea. In the Baltic Proper, modelling shows that historical DSi concentrations were 2.6 times higher at the turn of the last century (ca. 1900) than at present. Although the DSi decrease has leveled out and at present there are only restricted areas of the Baltic Sea with limiting DSi concentrations, further declines in DSi concentrations will lead to widespread DSi limitation of diatoms with severe implications for the food web.
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| 36. |
- Gómez-Martínez, Daniela, et al.
(author)
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Phenotypic and transcriptomic acclimation of the green microalga Raphidocelis subcapitata to high environmental levels of the herbicide diflufenican
- 2023
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In: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 875
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Journal article (peer-reviewed)abstract
- Herbicide pollution poses a worldwide threat to plants and freshwater ecosystems. However, the understanding of how organisms develop tolerance to these chemicals and the associated trade-off expenses are largely unknown. This study aims to investigate the physiological and transcriptional mechanisms underlying the acclimation of the green microalgal model species Raphidocelis subcapitata (Selenastraceae) towards the herbicide diflufenican, and the fitness costs associated with tolerance development. Algae were exposed for 12 weeks (corresponding to 100 generations) to diflufenican at the two environmental concentrations 10 and 310 ng/L. The monitoring of growth, pigment composition, and photosynthetic performance throughout the experiment revealed an initial dose-dependent stress phase (week 1) with an EC50 of 397 ng/L, followed by a time-dependent recovery phase during weeks 2 to 4. After week 4, R. subcapitata was acclimated to diflufenican exposure with a similar growth rate, content of carotenoids, and photosynthetic performance as the unexposed control algae. This acclimation state of the algae was explored in terms of tolerance acquisition, changes in the fatty acids composition, diflufenican removal rate, cell size, and changes in mRNA gene expression profile, revealing potential fitness costs associated with acclimation, such as up-regulation of genes related to cell division, structure, morphology, and reduction of cell size. Overall, this study demonstrates that R. subcapitata can quickly acclimate to environmental but toxic levels of diflufenican; however, the acclimation is associated with trade-off expenses that result in smaller cell size.
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| 37. |
- Grüning, Björn, et al.
(author)
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Bioconda: A sustainable and comprehensive software distribution for the life sciences
- 2017
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Other publication (other academic/artistic)abstract
- We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi-platform and language-agnostic package manager Conda. Currently, Bioconda offers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bioconda improves analysis reproducibility by allowing users to define isolated environments with defined software versions, all of which are easily installed and managed without administrative privileges.
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| 38. |
- Holmes, Michael V., et al.
(author)
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Mendelian randomization of blood lipids for coronary heart disease
- 2015
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In: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 36:9, s. 539-539
-
Journal article (peer-reviewed)abstract
- Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a priormeta-analysis (threshold P < 2 x 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P <= 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestrictedallele score (48SNPs) was associated with CHD(OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
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| 40. |
- Kaptoge, S., et al.
(author)
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C-Reactive Protein, Fibrinogen, and Cardiovascular Disease Prediction
- 2012
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:14, s. 1310-1320
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Journal article (peer-reviewed)abstract
- Background There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. Methods We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. Results The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P < 0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (< 10%), " intermediate" (10% to < 20%), and "high" (>= 20%) (P < 0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of >= 20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. Conclusions In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.)
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| 41. |
- Lee, Byung-Boong, et al.
(author)
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Venous hemodynamic changes in lower limb venous disease : the UIP consensus according to scientific evidence
- 2016
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In: International Journal of Angiology. - : Springer. - 0392-9590 .- 1827-1839. ; 35:3, s. 236-352
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Journal article (peer-reviewed)abstract
- There are excellent guidelines for clinicians to manage venous diseases but few reviews to assess their hemodynamic background. Hemodynamic concepts that evolved in the past have largely remained unchallenged in recent decades, perhaps due to their often complicated nature and in part due to emergence of new diagnostic techniques. Duplex ultrasound scanning and other imaging techniques which evolved in the latter part of the 20th century have dominated investigation. They have greatly improved our understanding of the anatomical patterns of venous reflux and obstruction. However, they do not provide the physiological basis for understanding the hemodynamics of flow, pressure, compliance and resistance. Hemodynamic investigations appear to provide a better correlation with post-treatment clinical outcome and quality of life than ultrasound findings. There is a far better prospect for understanding the complete picture of the patient's disability and response to management by combining ultrasound with hemodynamic studies. Accordingly, at the instigation of Dr Angelo Scuderi, the Union Internationale de Phlebologie (UIP) executive board commissioned a large number of experts to assess all aspects of management for venous disease by evidence-based principles. These included experts from various member societies including the European Venous Forum (EVF), American Venous Forum (AVF), American College of Phlebology (ACP) and Cardiovascular Disease Educational and Research Trust (CDERT). Their aim was to confirm or dispel long-held hemodynamic principles and to provide a comprehensive review of venous hemodynamic concepts underlying the pathophysiology of lower limb venous disorders, their usefulness for investigating patients and the relevant hemodynamic changes associated with various forms of treatment. Chapter 1 is devoted to basic hemodynamic concepts and normal venous physiology. Chapter 2 presents the mechanism and magnitude of hemodynamic changes in acute deep vein thrombosis indicating their pathophysiological and clinical significance. Chapter 3 describes the hemodynamic changes that occur in different classes of chronic venous disease and their relation to the anatomic extent of disease in the macrocirculation and microcirculation. The next four chapters (Chapters 4-7) describe the hemodynamic changes resulting from treatment by compression using different materials, intermittent compression devices, pharmacological agents and finally surgical or endovenous ablation. Chapter 8 discusses the unique hemodynamic features associated with alternative treatment techniques used by the CHIVA and ASVAL. Chapter 9 describes the hemodynamic effects following treatment to relieve pelvic reflux and obstruction. Finally, Chapter 10 demonstrates that contrary to general belief there is a moderate to good correlation between certain hemodynamic measurements and clinical severity of chronic venous disease. The authors believe that this document will be a timely asset to both clinicians and researchers alike. It is directed towards surgeons and physicians who are anxious to incorporate the conclusions of research into their daily practice. It is also directed to postgraduate trainees, vascular technologists and bioengineers, particularly to help them understand the hemodynamic background to pathophysiology, investigations and treatment of patients with venous disorders. Hopefully it will be a platform for those who would like to embark on new research in the field of venous disease.
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| 42. |
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| 43. |
- Locke, Adam E, et al.
(author)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Journal article (peer-reviewed)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 44. |
- Loley, C, et al.
(author)
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No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis
- 2016
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 35278-
-
Journal article (peer-reviewed)abstract
- In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.
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| 45. |
- Mann, G. W., et al.
(author)
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Intercomparison and evaluation of global aerosol microphysical properties among AeroCom models of a range of complexity
- 2014
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In: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 14:9, s. 4679-4713
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Journal article (peer-reviewed)abstract
- Many of the next generation of global climate models will include aerosol schemes which explicitly simulate the microphysical processes that determine the particle size distribution. These models enable aerosol optical properties and cloud condensation nuclei (CCN) concentrations to be determined by fundamental aerosol processes, which should lead to a more physically based simulation of aerosol direct and indirect radiative forcings. This study examines the global variation in particle size distribution simulated by 12 global aerosol microphysics models to quantify model diversity and to identify any common biases against observations. Evaluation against size distribution measurements from a new European network of aerosol supersites shows that the mean model agrees quite well with the observations at many sites on the annual mean, but there are some seasonal biases common to many sites. In particular, at many of these European sites, the accumulation mode number concentration is biased low during winter and Aitken mode concentrations tend to be overestimated in winter and underestimated in summer. At high northern latitudes, the models strongly underpredict Aitken and accumulation particle concentrations compared to the measurements, consistent with previous studies that have highlighted the poor performance of global aerosol models in the Arctic. In the marine boundary layer, the models capture the observed meridional variation in the size distribution, which is dominated by the Aitken mode at high latitudes, with an increasing concentration of accumulation particles with decreasing latitude. Considering vertical profiles, the models reproduce the observed peak in total particle concentrations in the upper troposphere due to new particle formation, although modelled peak concentrations tend to be biased high over Europe. Overall, the multimodel-mean data set simulates the global variation of the particle size distribution with a good degree of skill, suggesting that most of the individual global aerosol microphysics models are performing well, although the large model diversity indicates that some models are in poor agreement with the observations. Further work is required to better constrain size-resolved primary and secondary particle number sources, and an improved understanding of nucleation and growth (e. g. the role of nitrate and secondary organics) will improve the fidelity of simulated particle size distributions.
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| 46. |
- Mavaddat, Nasim, et al.
(author)
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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 2015
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
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Journal article (peer-reviewed)abstract
- Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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| 47. |
- McCloy, John S., et al.
(author)
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Reproduction of melting behavior for vitrified hillforts based on amphibolite, granite, and basalt lithologies
- 2021
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11
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Journal article (peer-reviewed)abstract
- European Bronze and Iron Age vitrified hillforts have been known since the 1700s, but archaeological interpretations regarding their function and use are still debated. We carried out a series of experiments to constrain conditions that led to the vitrification of the inner wall rocks in the hillfort at Broborg, Sweden. Potential source rocks were collected locally and heat treated in the laboratory, varying maximum temperature, cooling rate, and starting particle size. Crystalline and amorphous phases were quantified using X-ray diffraction both in situ, during heating and cooling, and ex situ, after heating and quenching. Textures, phases, and glass compositions obtained were compared with those for rock samples from the vitrified part of the wall, as well as with equilibrium crystallization calculations. ‘Dark glass’ and its associated minerals formed from amphibolite or dolerite rocks melted at 1000–1200 °C under reducing atmosphere then slow cooled. ‘Clear glass’ formed from non-equilibrium partial melting of feldspar in granitoid rocks. This study aids archaeological forensic investigation of vitrified hillforts and interpretation of source rock material by mapping mineralogical changes and glass production under various heating conditions.
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| 48. |
- Nelson, C. P., et al.
(author)
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Genetically Determined Height and Coronary Artery Disease
- 2015
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 372:17, s. 1608-1618
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Journal article (peer-reviewed)abstract
- BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.RESULTS We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.CONCLUSIONS There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association.
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| 49. |
- Nevers, Yannis, et al.
(author)
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The Quest for Orthologs orthology benchmark service in 2022
- 2022
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In: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 50:W1, s. W623-W632
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Journal article (peer-reviewed)abstract
- The Orthology Benchmark Service (https://orthology.benchmarkservice.org) is the gold standard for orthology inference evaluation, supported and maintained by the Quest for Orthologs consortium. It is an essential resource to compare existing and new methods of orthology inference (the bedrock for many comparative genomics and phylogenetic analysis) over a standard dataset and through common procedures. The Quest for Orthologs Consortium is dedicated to maintaining the resource up to date, through regular updates of the Reference Proteomes and increasingly accessible data through the OpenEBench platform. For this update, we have added a new benchmark based on curated orthology assertion from the Vertebrate Gene Nomenclature Committee, and provided an example meta-analysis of the public predictions present on the platform.
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| 50. |
- Nikpay, Majid, et al.
(author)
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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
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Journal article (peer-reviewed)abstract
- Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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