| 1. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 2. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 3. |
- Feitosa, Mary F., et al.
(författare)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 4. |
- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 5. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 6. |
- Müser, M. H., et al.
(författare)
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Meeting the Contact-Mechanics Challenge
- 2017
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Ingår i: Tribology letters. - : Springer New York LLC. - 1023-8883 .- 1573-2711. ; 65:4
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Tidskriftsartikel (refereegranskat)abstract
- This paper summarizes the submissions to a recently announced contact-mechanics modeling challenge. The task was to solve a typical, albeit mathematically fully defined problem on the adhesion between nominally flat surfaces. The surface topography of the rough, rigid substrate, the elastic properties of the indenter, as well as the short-range adhesion between indenter and substrate, were specified so that diverse quantities of interest, e.g., the distribution of interfacial stresses at a given load or the mean gap as a function of load, could be computed and compared to a reference solution. Many different solution strategies were pursued, ranging from traditional asperity-based models via Persson theory and brute-force computational approaches, to real-laboratory experiments and all-atom molecular dynamics simulations of a model, in which the original assignment was scaled down to the atomistic scale. While each submission contained satisfying answers for at least a subset of the posed questions, efficiency, versatility, and accuracy differed between methods, the more precise methods being, in general, computationally more complex. The aim of this paper is to provide both theorists and experimentalists with benchmarks to decide which method is the most appropriate for a particular application and to gauge the errors associated with each one..
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| 7. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 8. |
- Stolk, Lisette, et al.
(författare)
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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 260-268
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Tidskriftsartikel (refereegranskat)abstract
- To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
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| 9. |
- Elks, Cathy E, et al.
(författare)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Tidskriftsartikel (refereegranskat)abstract
- To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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| 10. |
- Becker, Joel, et al.
(författare)
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Resource profile and user guide of the Polygenic Index Repository
- 2021
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Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 51:6, s. 694-695
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies—some not previously published—from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the ‘additive SNP factor’. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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| 11. |
- Bennett, A. I., et al.
(författare)
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Contact Measurements of Randomly Rough Surfaces
- 2017
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Ingår i: Tribology letters. - : Springer Science and Business Media, LLC. - 1023-8883 .- 1573-2711. ; 65:4
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Tidskriftsartikel (refereegranskat)abstract
- This manuscript presents an experimental effort to directly measure contact areas and the details behind these scaled experiments on a randomly rough model surface used in the “Contact Mechanics Challenge” (2017). For these experiments, the randomly rough surface model was scaled up by a factor of 1000× to give a 100 mm square sample that was 3D printed from opaque polymethylmethacrylate (PMMA). This sample was loaded against various optically smooth and transparent samples of PDMS that were approximately 15 mm thick and had a range in elastic modulus from 14 kPa to 2.1 MPa. During loading, a digital camera recorded contact locations by imaging the scattering of light that occurs off of the PMMA rough surface when it was in contact with the PDMS substrate. This method of illuminating contact areas is called frustrated total internal reflection and is performed by creating a condition of total internal reflection within the unperturbed PDMS samples. Contact or deformation of the surface results in light being diffusely transmitted from the PDMS and detected by the camera. For these experiments, a range of reduced pressure (nominal pressure/elastic modulus) from below 0.001 to over 1.0 was examined, and the resulting relative contact area (real area of contact/apparent area of contact) was found to increase from below 0.1% to over 60% at the highest pressures. The experimental uncertainties associated with experiments are discussed, and the results are compared to the numerical results from the simulation solution to the “Contact Mechanics Challenge.” The simulation results and experimental results of the relative contact areas as a function of reduced pressure are in agreement (within experimental uncertainties).
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| 12. |
- Harris, Kathryn L, et al.
(författare)
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Wear Debris Mobility, Aligned Surface Roughness, and the Low Wear Behavior of Filled Polytetrafluoroethylene
- 2015
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Ingår i: Tribology letters. - : Springer New York LLC. - 1023-8883 .- 1573-2711. ; 60:1
-
Tidskriftsartikel (refereegranskat)abstract
- PTFE/α-alumina composites are well known to exhibit very low wear rates compared to unfilled PTFE and various other PTFE-matrix composites. The improved wear life of these composites is attributed in part to the formation of a uniform protective transfer film on the metal countersurface. It is postulated that the retention of transferred material and the recirculation of third bodies between the transfer film and running surface of the polymer composite are necessary for the maintenance of low wear within this tribological system. The accumulation of these third bodies was observed in reciprocating sliding tests on countersamples prescribed with aligned roughness. Wear performance of the polymer composite was tested as a function of the between the sliding direction and the aligned roughness of the countersample, ranging from parallel to perpendicular to the sliding direction. The wear rate of roughness oriented with the sliding direction was 300 times higher than roughness perpendicular to the sliding direction, revealing the importance of surface morphology and third body retention.
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| 13. |
- McGhee, A. J., et al.
(författare)
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Contact and Deformation of Randomly Rough Surfaces with Varying Root-Mean-Square Gradient
- 2017
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Ingår i: Tribology letters. - : Springer New York LLC. - 1023-8883 .- 1573-2711. ; 65:4
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Tidskriftsartikel (refereegranskat)abstract
- The “Contact Mechanics Challenge” posed to the tribology community by Müser and Dapp in 2015 detailed a 100 µm × 100 µm randomly rough surface with a root-mean-square gradient of unity, g ¯ = 1. Many surfaces, both natural and synthetic, can be described as randomly rough, but rarely with a root-mean-square gradient as steep as g ¯ = 1. The selection of such a challenging surface parameter was intentional, but potentially limiting for broad comparisons across existing models and theories which may be limited by small-slope approximations. In this manuscript, the root-mean-square gradients (g ¯) of the “Contact Mechanics Challenge” surface were produced on 1000 × scaled models such that there were three different surfaces for study with g¯=0.2,0.5, and 1. In situ measurements of the real area of contact and contact area distributions were performed using frustrated total internal reflectance along with surface deformation measurements performed using digital image correlation. These optical in situ experiments used the scaled 3D-printed rough surfaces that were loaded into contact with smooth, flat, and elastic samples that were made from unfilled PDMS: (10:1) E* = 2.1 MPa Δγ = 4 mJ/m2; (20:1) E* = 0.75 MPa Δγ = 3 mJ/m2; (30:1) E* = 0.24 MPa Δγ = 2 mJ/m2. All of the loading was performed using a uniaxial load frame under force control. A Green’s function molecular dynamics simulation assuming the small-slope approximation was compared to all experimental data. These measurements reveal that decreasing root-mean-square gradient noticeably increases real area of contact area under conditions of “equal” applied load, but variations in the root-mean-square gradient did not significantly alter the contact patch geometry under conditions of nearly equal real area of contact. Including g ¯ in the reduced pressure (p= P/ (E∗ g ¯)) reduced the root-mean-square error between the simulation (g ¯ = 1) and all experimental data for the relative area of contact as a function of reduced pressure over the entire range of surfaces, materials, and loads tested.
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| 14. |
- Rowe, K. G., et al.
(författare)
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Lessons from the lollipop : Biotribology, tribocorrosion, and irregular surfaces
- 2014
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Ingår i: Tribology letters. - : Springer New York LLC. - 1023-8883 .- 1573-2711. ; 56:2, s. 273-280
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Tidskriftsartikel (refereegranskat)abstract
- Biotribology and tribocorrosion are often not included in numerical or computational modeling efforts to predict wear because of the apparent complexity in the geometry, the variability in removal rates, and the challenge associated with mixing time-dependent removal processes such as corrosion with cyclic material removal from wear. The lollipop is an accessible bio-tribocorrosion problem that is well known but underexplored scientifically as a tribocorrosion process. Stress-assisted dissolution was found to be the dominant tribocorrosion process driving material removal in this system. A model of material removal was described and approached by lumping the intrinsically time-dependent process with a mechanically driven process into a single cyclic volumetric material removal rate. This required the collection of self-reported wear data from 58 participants that were used in conjunction with statistical analysis of actual lollipop cross-sectional information. Thousands of repeated numerical simulations of material removal and shape evolution were conducted using a simple Monte Carlo process that varied the input parameters and geometries to match the measured variability. The resulting computations were analyzed to calculate both the average number of licks required to reach the Tootsie Roll® center of a Tootsie Roll® pop, as well as the expected variation thereof.
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| 15. |
- Sidebottom, M. A., et al.
(författare)
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Ultralow wear Perfluoroalkoxy (PFA) and alumina composites
- 2016
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Ingår i: Wear. - : Elsevier Ltd. - 0043-1648 .- 1873-2577. ; 362-363, s. 179-185
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Tidskriftsartikel (refereegranskat)abstract
- Fluoropolymers have unique mechanical, chemical, and tribological properties (low friction coefficients) but their use as solid lubricants is inhibited by high wear rates (1-5×10-4 mm3/Nm). The addition of certain types of α-alumina has been shown to reduce the wear rate of PTFE by over three orders of magnitude, but due to its extremely high molecular weight PTFE cannot be screw injection molded. However, PFA, a perfluorinated copolymer of tetrafluoroethylene (TFE) and a perfluorinated alkylvinyl ether (PAVE), can be. Teflon® PFA 340 samples with various weight fractions of α-alumina (0%, 5%, 7.5%, 10%) were injection molded, and samples from each mold were wear tested against stainless steel (P=6.3 MPa, v=50.8 mm/s). Experiments showed that the friction behavior of the PFA 340-α alumina composite was very close to that of both unfilled PFA 340 and PTFE-α alumina composites. The wear rate of unfilled PFA 340 was 1.4×10-4 mm3/Nm, and dropped to 4.0×10-8 mm3/Nm for the PFA-α alumina composites. Just as in the case of PTFE-α alumina composites, these PFA composites generated brown-colored tribofilms on both the polymer and metal surfaces, which were indicative of tribochemical changes. ATR-IR and FTIR spectra of each surface showed evidence for the generation of perfluorinated carboxylate salts and waters of hydration. This spectral similarity between PTFE and PFA 340 samples shows that the same tribological mechanism found in PTFE-α alumina composites is responsible for ultralow wear in PFA-α alumina composites as well.
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| 16. |
- Belay, Mulugeta, et al.
(författare)
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Detection of Mycobacterium tuberculosis complex DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic tuberculosis contacts : an observational study
- 2021
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Ingår i: The Lancet Microbe. - 2666-5247. ; 2:6, s. 267-275
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Tidskriftsartikel (refereegranskat)abstract
- Background: Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for Mycobacterium tuberculosis complex bacilli during latent tuberculosis infection. Our aim was to determine whether M tuberculosis complex DNA is detectable in CD34-positive peripheral blood mononuclear cells (PBMCs) isolated from asymptomatic adults living in a setting with a high tuberculosis burden. Methods: We did a cross-sectional study in Ethiopia between Nov 22, 2017, and Jan 10, 2019. Digital PCR (dPCR) was used to determine whether M tuberculosis complex DNA was detectable in PBMCs isolated from 100 mL blood taken from asymptomatic adults with HIV infection or a history of recent household or occupational exposure to an index case of human or bovine tuberculosis. Participants were recruited from HIV clinics, tuberculosis clinics, and cattle farms in and around Addis Ababa. A nested prospective study was done in a subset of HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy was effective in clearing M tuberculosis complex DNA from PBMCs. Follow-up was done between July 20, 2018, and Feb 13, 2019. QuantiFERON-TB Gold assays were also done on all baseline and follow-up samples. Findings: Valid dPCR data (ie, droplet counts >10 000 per well) were available for paired CD34-positive and CD34-negative PBMC fractions from 197 (70%) of 284 participants who contributed data to cross-sectional analyses. M tuberculosis complex DNA was detected in PBMCs of 156 of 197 participants with valid dPCR data (79%, 95% CI 74–85). It was more commonly present in CD34-positive than in CD34-negative fractions (154 [73%] of 197 vs 46 [23%] of 197; p<0·0001). Prevalence of dPCR-detected M tuberculosis complex DNA did not differ between QuantiFERON-negative and QuantiFERON-positive participants (77 [78%] of 99 vs 79 [81%] of 98; p=0·73), but it was higher in HIV-infected than in HIV-uninfected participants (67 [89%] of 75 vs 89 [73%] of 122, p=0·0065). By contrast, the proportion of QuantiFERON-positive participants was lower in HIV-infected than in HIV-uninfected participants (25 [33%] of 75 vs 73 [60%] of 122; p<0·0001). Administration of isoniazid preventive therapy reduced the prevalence of dPCR-detected M tuberculosis complex DNA from 41 (95%) of 43 HIV-infected individuals at baseline to 23 (53%) of 43 after treatment (p<0·0001), but it did not affect the prevalence of QuantiFERON positivity (17 [40%] of 43 at baseline vs 13 [30%] of 43 after treatment; p=0·13). Interpretation: We report a novel molecular microbiological biomarker of latent tuberculosis infection with properties that are distinct from those of a commercial interferon-γ release assay. Our findings implicate the bone marrow as a niche for M tuberculosis in latently infected individuals. Detection of M tuberculosis complex DNA in PBMCs has potential applications in the diagnosis of latent tuberculosis infection, in monitoring response to preventive therapy, and as an outcome measure in clinical trials of interventions to prevent or treat latent tuberculosis infection. Funding: UK Medical Research Council.
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| 17. |
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| 18. |
- Ben-Avraham, Dan, et al.
(författare)
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The complex genetics of gait speed : Genome-wide meta-analysis approach
- 2017
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 9:1, s. 209-246
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
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| 19. |
- Bennett, A. I., et al.
(författare)
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Deformation Measurements of Randomly Rough Surfaces
- 2017
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Ingår i: Tribology letters. - : Springer Science and Business Media, LLC. - 1023-8883 .- 1573-2711. ; 65:4
-
Tidskriftsartikel (refereegranskat)abstract
- Measurements of surface deformations as part of the “Contact Mechanics Challenge” were collected using digital image correlation (DIC). For these experiments, a scaled version (1000×) of the periodic and random roughness surface provided for the “Contact Mechanics Challenge” was used. A 100 mm × 100 mm scale replica of the surface, approximately 10 mm thick, was 3D-printed using an opaque polymethylmethacrylate and pressed into contact against flat, transparent polydimethylsiloxane (PDMS) sheets with dead weight loads. Four different formulations of PDMS were used, and the resulting elastic moduli ranged from 64 kPa to 2.1 MPa. The DIC technique was used in situ to measure the deformation of the PDMS surface at each load increment from 22.5 to 450 N. Surface deformations in and out of contact were measured across the entire apparent area of contact and overlaid with the measurements of contact area to provide a complete description of the surface profile during loading. A direct comparison between these experiments and the simulations regarding the gap within the contact at a reduced pressure of 0.164 agrees to within ±10% when normalized to the maximum gap.
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| 20. |
- Harris, Kathryn L, et al.
(författare)
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PTFE Tribology and the Role of Mechanochemistry in the Development of Protective Surface Films
- 2015
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Ingår i: Macromolecules. - : American Chemical Society. - 0024-9297 .- 1520-5835. ; 48:11, s. 3739-3745
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Tidskriftsartikel (refereegranskat)abstract
- The wear and friction behavior of ultralow wear polytetrafluoroethylene (PTFE)/α-alumina composites first described by Burris and Sawyer in 2006 has been heavily studied, but the mechanisms responsible for the 4 orders of magnitude improvement in wear over unfilled PTFE are still not fully understood. It has been shown that the formation of a polymeric transfer film is crucial to achieving ultralow wear on a metal countersurface. However, the detailed chemical mechanism of transfer film formation and its role in the exceptional wear performance has yet to be described. There has been much debate about the role of chemical interactions between the PTFE, the filler, and the metal countersurface, and some researchers have even concluded that chemical changes are not an important part of the ultralow wear mechanism in these materials. Here, a "stripe" test allowed detailed spectroscopic studies of PTFE/α-alumina transfer films in various stages of development, which led to a proposed mechanism which accounts for the creation of chemically distinct films formed on both surfaces of the wear couple. PTFE chains are broken during sliding and undergo a series of reactions to produce carboxylate chain ends, which have been shown to chelate to both the metal surface and to the surface of the alumina filler particles. These tribochemical reactions form a robust polymer-on-polymer system that protects the steel countersurface and is able to withstand hundreds of thousands of cycles of sliding with almost no wear of the polymer composite after the initial run-in period. The mechanical scission of carbon-carbon bonds in the backbone of PTFE under conditions of sliding contact is supported mathematically using the Hamaker model for van der Waals interactions between polymer fibrils and the countersurface. The necessity for ambient moisture and oxygen is explained, and model experiments using small molecules confirm the reactions in the proposed mechanism. .
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| 21. |
- Krick, B. A., et al.
(författare)
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Ultralow wear fluoropolymer composites : Nanoscale functionality from microscale fillers
- 2016
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Ingår i: Tribology International. - : Elsevier Ltd. - 0301-679X .- 1879-2464. ; 95, s. 245-255
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Tidskriftsartikel (refereegranskat)abstract
- Polytetrafluoroethylene (PTFE) filled with certain alumina additives has wear rates over four orders of magnitude lower than unfilled PTFE. The mechanisms for this wear reduction have remained a mystery. In this work, we use a combination of techniques to show that porous, nanostructured alumina microfillers (not nanofillers) are critical for this wear reduction. The microscale alumina particles break during sliding into nanoscale fragments. X-ray microtomography, transmission electron microscopy and infrared spectroscopy reveal nanoscale alumina fragments accumulated in the tribofilms. Tribochemically generated carboxylate endgroups bond to metal species in the transfer film and to alumina fragments in the surface of the polymer composite. These mechanically reinforced tribofilms create robust sliding surfaces and lead to a dramatic reduction in wear. © 2015 The Authors.
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| 22. |
- Pitenis, A. A., et al.
(författare)
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In vacuo tribological behavior of polytetrafluoroethylene (ptfe) and alumina nanocomposites : The importance of water for ultralow wear
- 2014
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Ingår i: Tribology letters. - : Springer Science and Business Media LLC. - 1023-8883 .- 1573-2711. ; 53:1, s. 189-197
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Tidskriftsartikel (refereegranskat)abstract
- Polytetrafluoroethylene (PTFE) is widely regarded as an excellent candidate for solid lubrication in vacuum. However, it is often precluded from many practical applications due to its intrinsically high wear rate. Over the past decade, it has been discovered that small loading fractions of alumina nanofillers can increase the wear resistance of PTFE by three to four orders of magnitude. This dramatic increase in wear resistance has in turn prompted numerous tribological studies to examine the robustness of this performance. In this study, the wear and friction behavior of unfilled PTFE and PTFE and alumina nanocomposites were evaluated under a broad range of vacuum environments from 760 to 4 9 10-6 Torr. The nanocomposites of PTFE/alumina showed a dramatic increase in wear of over two orders of magnitude at the highest vacuum conditions. There appears to be an optimal vacuum environment around 1-10 Torr, in which these samples achieved the lowest wear rates of approximately 2.5 9 10-7 mm3/(Nm)
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| 23. |
- Pitenis, A. A., et al.
(författare)
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Ultralow wear PTFE and alumina composites : It is all about tribochemistry
- 2015
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Ingår i: Tribology letters. - : Springer New York LLC. - 1023-8883 .- 1573-2711. ; 57:2
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Tidskriftsartikel (refereegranskat)abstract
- Over the last decade, researchers have explored an intriguing polymer composite composed of granular polytetrafluoroethylene (PTFE) 7C and alumina particles. This material is extraordinary because a very small amount of alumina additive (<5 wt%) decreased the wear rate of the PTFE composite by over four orders of magnitude. Previous studies have shown that this wear resistance was initiated and maintained by the formation of a stable, robust, and uniform polymeric transfer film on the surface of the countersample. Although its importance to this tribological system is clear, the transfer film itself has not been well understood. Careful spectroscopic analysis throughout the stages of transfer film development revealed that tribochemistry plays a major role in the significant wear rate reductions achieved in PTFE and alumina composites. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy reveal that PTFE chains break due to the mechanical stresses at the wear surface and, in the presence of oxygen and water in the ambient environment, produce carboxylic acid end groups. These carboxylic acid end groups can chelate to the exposed metal on the steel surface and nucleate the formation of the transfer film. The resulting thin and robust fluoropolymer transfer film protects the surface of the steel and changes the sliding interface from polymer on steel to polymer on polymer transfer film. These effects keep friction coefficients and wear rates low and stable. Ultimately, the real mechanisms responsible for the exceptional wear performance of these materials are all about the tribochemistry.
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| 24. |
- Lee, James J, et al.
(författare)
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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
- 2018
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 50:8, s. 1112-1121
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Tidskriftsartikel (refereegranskat)abstract
- Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1million individuals and identify 1,271independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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| 25. |
- Urueã, J. M., et al.
(författare)
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Evolution and wear of fluoropolymer transfer films
- 2015
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Ingår i: Tribology letters. - : Springer New York LLC. - 1023-8883 .- 1573-2711. ; 57:2
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Tidskriftsartikel (refereegranskat)abstract
- Polytetrafluoroethylene (PTFE) is a solid lubricant known for its low friction coefficient and high wear rate. When filled with a low volume percent of alumina particles (5 wt%), its wear rate is decreased over four orders of magnitude. The development of a thin, uniform and well adhered transfer film during sliding is partially responsible for this decrease in wear rate by creating a low shear interface and forming a protective layer between the PTFE/alumina sample and metal countersample. In this work, a ''striped'' transfer film was generated by sliding up to one million reversals over a gradually decreasing stroke length. Wear and friction experiments were performed on a microtribometer to determine the robustness of the transfer film. Interferometry and profilometry were used to measure the height and wear of the film. Microscopy was used to investigate the morphology of the transfer film over sliding distance.
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