| 1. |
- Blom, Kristin, et al.
(författare)
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Eosinophil associated genes in the inflammatory bowel disease 4 region : Correlation to inflammatory bowel disease revealed
- 2012
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327 .- 2219-2840. ; 18:44, s. 6409-6419
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To study the association between inflammatory bowel disease (IBD) and genetic variations in eosinophil protein X (EPX) and eosinophil cationic protein (ECP). METHODS: DNA was extracted from ethylene diamine tetraacetic acid blood of 587 patients with Crohn's disease (CD), 592 with ulcerative colitis (UC) and 300 healthy subjects. The EPX405 (G > C, rs2013109), ECP434 (G > C, rs2073342) and ECP562 (G > C, rs2233860) gene polymorphisms were analysed, by the 5'-nuclease allelic discrimination assay. For determination of intracellular content of EPX and ECP in granulocytes, 39 blood samples was collected and extracted with a buffer containing cetyltrimethylammonium bromide. The intracellular content of EPX was analysed using an enzyme-linked immunosorbent assay. The intracellular content of ECP was analysed with the UniCAP (R) system as described by the manufacturer. Statistical tests for calculations of results were chi(2) test, Fisher's exact test, ANOVA, Student-Newman-Keuls test, and Kaplan-Meier survival curve with Log-rank test for trend, the probability values of P < 0.05 were considered statistically significant. RESULTS: The genotype frequency for males with UC and with an age of disease onset of >= 45 years (n = 57) was for ECP434 and ECP562, GG = 37%, GC = 60%, CC = 4% and GG = 51%, GC = 49%, CC = 0% respectively. This was significantly different from the healthy subject's genotype frequencies of ECP434 (GG = 57%, GC = 38%, CC = 5%; P = 0.010) and ECP562 (GG = 68%, GC = 29 /0,CC = 3%; P = 0.009). The genotype frequencies for females, with an age of disease onset of >= 45 years with CD (n = 62), was for the ECP434 and ECP562 genotypes GG = 37%, GC = 52%, CC = 11% and GG = 48%, GC = 47% and CC = 5% respectively. This was also statistically different from healthy controls for both ECP434 (P = 0.010) and ECP562 (P = 0.013). The intracellular protein concentration of EPX and ECP was calculated in mu g/10(6) eosinophils and then correlated to the EPX 405 genotypes. The protein content of EPX was highest in the patients with the CC genotype of EPX405 (GG = 4.65, GC = 5.93, and CC = 6.57) and for ECP in the patients with the GG genotype of EPX405 (GG = 2.70, GC = 2.47 and CC = 1.90). ANOVA test demonstrated a difference in intracellular protein content for EPX (P = 0.009) and ECP (P = 0.022). The age of disease onset was linked to haplotypes of the EPX405, ECP434 and ECP562 genotypes. Kaplan Maier curve showed a difference between haplotype distributions for the females with CD (P = 0.003). The highest age of disease onset was seen in females with the EPX405CC, ECP434GC, ECP562CC haplotype (34 years) and the lowest in females with the EPX405GC, ECP434GC, ECP562GG haplotype (21 years). For males with UC there was also a difference between the highest and lowest age of the disease onset (EPX405CC, ECP434CC, ECP562CC, mean 24 years vs EPX405GC, ECP434GC, ECP562GG, mean 34 years, P = 0.0009). The relative risk for UC patients with ECP434 or ECP562-GC/CC genotypes to develop dysplasia/cancer was 2.5 (95%CI: 1.2-5.4, P = 0.01) and 2.5 (95%CI: 1.1-5.4, P = 0.02) respectively, compared to patients carrying the GG-genotypes. CONCLUSION: Polymorphisms of EPX and ECP are associated to IBD in an age and gender dependent manner, suggesting an essential role of eosinophils in the pathophysiology of IBD.
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| 2. |
- Cai, Linjun, et al.
(författare)
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The Origin of Multiple Molecular Forms in Urine of HNL/NGAL
- 2010
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Ingår i: Clinical Journal of the American Society of Nephrology. - 1555-9041. ; 5:12, s. 2229-2235
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives: Several molecular forms of human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin (HNL/NGAL), a novel biomarker for acute kidney injury (AKI), have been found in urine. The origin of these different forms and the effect of antibody configuration on assay performances were investigated in this report. Design, setting, participants, & measurements: The molecular forms of HNL/NGAL from human neutrophils and present in urine obtained from cardiac surgery patients and patients with urinary tract infection (UTI), as well as secreted from HK-2 cells, were studied by Western blotting. The levels of HNL/NGAL in urine were measured by ELISAs. Kidney injury was simulated by incubation of HK-2 cells under stressful conditions. Results: The major molecular form of HNL/NGAL secreted by neutrophils is dimeric, whereas the major form secreted by HK-2 cells is monomeric. This was reflected by a predominance of the monomeric form in urine from patients with AKI and the dimeric form in patients with UTIs. The epitope specificities of the antibody used in the ELISAs had a profound effect on assay performance and paralleled differences of the antibodies to identify the different forms of urine HNL/NGAL. Conclusions: The monomeric form is the predominant form secreted by tubular epithelial cells, and the dimeric form is the predominant form secreted by neutrophils. The development of molecular form-specific assays for HNL/NGAL may be a means to identify the origin of HNL/NGAL in urine and construct more specific tools for the diagnosis of AKI.
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| 3. |
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| 4. |
- Eriksson, Johanna, et al.
(författare)
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Pulmonary absorption - estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis
- 2018
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER SCIENCE BV. - 0939-6411 .- 1873-3441. ; 124, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Permeation of inhaled drugs across the pulmonary epithelium can regulate the rate and extent of local drug absorption and hence the pulmonary tissue concentration. Therefore, understanding pulmonary epithelial transport could be important for successful design of novel inhaled medicines. To enhance understanding of pulmonary epithelial transport, drug transport data were generated for a set of inhaled compounds (n = 10) in the single-pass, isolated perfused rat lung model. A compartmental in silica model was used to estimate pulmonary permeability and tissue retention. The theoretical model was also used to re-analyze previously obtained historical drug transport data from the isolated perfused lung (n = 10) with re-circulating buffer. This was performed to evaluate the re-circulating model for assessing tissue retention measurements and to increase the number of data points. The tissue retention was an important parameter to estimate to be able to describe the drug transport profiles accurately of most of the investigated compounds. A relationship between the pulmonary permeability and the intrinsic (carrier-mediated transport inhibited) permeability of Caco-2 cell monolayers (n = 1-6) was also established. This correlation (R-2 = 0.76, p < .0001) suggests that intrinsic Caco-2 permeability measurements could offer early predictions of the passive transcellular permeability of lung epithelium to candidate drugs. Although, for some compounds a deviation from the correlation suggests that other transport mechanisms may coexist. The compartmental in silica model was successful in describing the pulmonary drug transport profiles of the investigated compounds and has potential for further development to investigate the effects of formulations with different features on the pulmonary overall absorption rate.
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| 5. |
- Fayolle, E. C., et al.
(författare)
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Protostellar and cometary detections of organohalogens
- 2017
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Ingår i: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 1:10, s. 703-708
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Tidskriftsartikel (refereegranskat)abstract
- Organohalogens, a class of molecules that contain at least one halogen atom bonded to carbon, are abundant on the Earth where they are mainly produced through industrial and biological processes(1). Consequently, they have been proposed as biomarkers in the search for life on exoplanets(2). Simple halogen hydrides have been detected in interstellar sources and in comets, but the presence and possible incorporation of more complex halogen-containing molecules such as organohalogens into planet-forming regions is uncertain(3,4). Here we report the interstellar detection of two isotopologues of the organohalogen CH3Cl and put some constraints on CH3F in the gas surrounding the low-mass protostar IRAS 16293-2422, using the Atacama Large Millimeter/submillimeter Array (ALMA). We also find CH3Cl in the coma of comet 67P/Churyumov-Gerasimenko (67P/C-G) by using the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis (ROSINA) instrument. The detections reveal an efficient pre-planetary formation pathway of organohalogens. Cometary impacts may deliver these species to young planets and should thus be included as a potential abiotical production source when interpreting future organohalogen detections in atmospheres of rocky planets.
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| 6. |
- Glimelius, Ingrid, 1975-, et al.
(författare)
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Predictors of histology, tissue eosinophilia and mast cell infiltration in Hodgkin's Lymphoma : a population-based study
- 2011
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 87:3, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Classical Hodgkin’s lymphoma (HL) lesions comprise few tumour cells, surrounded by numerous inflammatory cells. Like in other malignancies, the microenvironment is presumed to be clinically important in HL; however, microenvironment predictors remain poorly characterised. The aim of this study was to investigate how selected patient characteristics and genetic factors affect HL phenotype, in particular tissue eosinophilia, mast cell counts and HL histological subtype.Methods: In a population-based study, patients with HL were interviewed about potential HL risk factors. Available tumours, n = 448, were classified histologically; the number of eosinophils and mast cells were estimated, and eosinophil cationic protein (ECP) and eosinophil protein-x (EPX) gene polymorphisms were determined. Associations were assessed in regression models.Results: Self-reported history of asthma was predictive of having tumour eosinophilia [≥200 eosinophils/10 high power fields, univariate odds ratio (OR) = 2.22, 95% CI 1.06–4.64, P = 0.03]. High numbers of eosinophils were predominantly seen in patients carrying the genotype ECP434GG [multivariate relative levels (RLs) = 1.84, 95% CI 1.02–3.30, P = 0.04]. Lower number of eosinophils was seen in Epstein–Barr virus (EBV)-positive tumours (univariate RL = 0.52, 95% CI 0.3–0.9, P = 0.02) and in older patients (univariate RL = 0.85, 95% CI 0.73–0.99, P = 0.03). Well-known factors such as young age, female sex and EBV-negative status predicted nodular sclerosis histology.Conclusion: The number of eosinophils in HL tumours is influenced by patient traits such as asthma, ECP genotype and EBV status. EBV status was predictive of histology.
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| 7. |
- Glimelius, Ingrid, et al.
(författare)
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The effect of Eosinophil cationic protein (ECP) on Hodgkin lymphoma cell lines
- 2011
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Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X .- 1873-2399. ; 39:8, s. 850-858
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Tidskriftsartikel (refereegranskat)abstract
- Background In classical Hodgkin lymphoma (HL), many eosinophils in tumour tissue indicate poor prognosis, probably caused by stimulation of the tumour cells, the Hodgkin Reed Sternberg (HRS) cells. However, eosinophils are primarily known for their role in innate immunity, where one function is to secrete the toxic substances eosinophil cationic protein (ECP), and eosinophil protein X (EPX). The aim of this study was to investigate the effects of ECP on HRS cells in vitro.Method The fluorometric microculture cytotoxicity-assay (FMCA) measured survival index (SI) of cells from the HL cell lines HDLM-2, KMH2, and L428 after incubation with ECP or EPX. The gene products of a coding ECP polymorphism, ECP97arg and ECP97thr, and ECPs, with different levels of glycosylation were investigated. Flow cytometry was used to monitor the effects of ECP on markers of cell death.Results A concentration dependent reduction of SI was seen after ECP treatment. For the B-cell derived cell lines, KMH2 and L428, ECP was cytotoxic with a dose response relationship similar to a previously investigated small-cell lung cancer cell-line. In contrast, for HDLM-2, which is a cell line of T-cell origin, the cytotoxicity was even more pronounced at the lowest concentrations tested, and then reached a plateau at about 0.018µM. At a concentration of 0.14µM of ECP, an SI of 71%±1.9 was recorded for HDLM-2, which did not accentuate despite higher concentrations of ECP. ECP97arg and ECP97thr displayed similar cytotoxicity, and the level of glycosylation did not affect cytotoxicity for HDLM-2, in contrast to the small-cell lung cancer cell-line. For EPX, no or very limited reduction in SI was seen, compared to ECP (p<0.001). The majority of cells that died from ECP (the HDLM-2 cell line) were PI positive, and only a few were annexin V positive.Conclusions ECP is cytotoxic for HRS cells, but heterogeneity between cell lines was seen. The two cell lines of B-cell origin, KMH2 and L428, were sensitive to high ECP concentrations, but for HDLM-2, of T-cell origin, the cytotoxicity reached a plateau at higher concentrations. Thus, even at presumably high concentrations, ECP can be present around HRS cells without eradicating all cells.
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| 8. |
- Huyan, Fei, et al.
(författare)
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Effect of Solute Silicon on the Lattice Parameter of Ferrite in Ductile Irons
- 2014
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Ingår i: ISIJ International. - : Iron and Steel Institute of Japan. - 0915-1559 .- 1347-5460. ; 54:1, s. 248-250
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Tidskriftsartikel (refereegranskat)abstract
- The effect of solute silicon on the ferrite lattice parameter has been investigated using X-ray diffraction in cast ductile irons (DI) with nominal Si contents between 2.50 and 4.56 wt%. It was found that silicon changes the ferrite lattice parameter by –0.00185 Å per wt% Si. This contraction coefficient is three times larger than the most commonly used Si coefficient in the literature. Since substitutional solution by silicon contracts the ferrite lattice while the interstitial solution by carbon expands the lattice, the Si contraction coefficient found will have a significant effect on subsequent evaluation of the carbon content in austempered Si-alloyed ductile irons and steels.
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| 9. |
- Johansson, Per, et al.
(författare)
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On optimal re-randomization designs
- 2019
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Blocking is commonly used in randomized experiments to increase efficiency of estimation. A generalization of blocking is to remove allocations with imbalance in covariates between treated and control units, and thenrandomize within the set of allocations with balance in these covariates. This idea of rerandomization was formalized by [5], who suggested using the affinely invariant Mahalanobis distance between treated and control covariate means as the criterion for removing unbalanced allocations. [3] proposed reducing the set of balanced allocations to the minimum. Here we discuss the implication of such an ‘optimal’ rerandomization design for inferences to the units inthe sample and to the population from which the units in the sample were randomly drawn. We argue that, in general, it is a bad idea to seak the optimal design for an inference to the population because that inference typically only reflects uncertainty from the usually hypothetical random sampling, and not the randomization of treatment versus control.
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| 10. |
- Johansson, Per, et al.
(författare)
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On optimal rerandomization designs
- 2021
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Ingår i: Journal of The Royal Statistical Society Series B-statistical Methodology. - : John Wiley & Sons. - 1369-7412 .- 1467-9868. ; 83:2, s. 395-403
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Tidskriftsartikel (refereegranskat)abstract
- Blocking is commonly used in randomized experiments to increase efficiency of estimation. A generalization of blocking removes allocations with imbalance in covariate distributions between treated and control units, and then randomizes within the remaining set of allocations with balance. This idea of rerandomization was formalized by Morgan and Rubin (Annals of Statistics, 2012, 40, 1263-1282), who suggested using Mahalanobis distance between treated and control covariate means as the criterion for removing unbalanced allocations. Kallus (Journal of the Royal Statistical Society, Series B: Statistical Methodology, 2018, 80, 85-112) proposed reducing the set of balanced allocations to the minimum. Here we discuss the implication of such an 'optimal' rerandomization design for inferences to the units in the sample and to the population from which the units in the sample were randomly drawn. We argue that, in general, it is a bad idea to seek the optimal design for an inference because that inference typically only reflects uncertainty from the random sampling of units, which is usually hypothetical, and not the randomization of units to treatment versus control.
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| 11. |
- Johnsson, Martin, et al.
(författare)
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A sexual ornament in chickens is affected by pleiotropic alleles at HAO1 and BMP2, selected during domestication.
- 2012
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Domestication is one of the strongest forms of short-term, directional selection. Although selection is typically only exerted on one or a few target traits, domestication can lead to numerous changes in many seemingly unrelated phenotypes. It is unknown whether such correlated responses are due to pleiotropy or linkage between separate genetic architectures. Using three separate intercrosses between wild and domestic chickens, a locus affecting comb mass (a sexual ornament in the chicken) and several fitness traits (primarily medullary bone allocation and fecundity) was identified. This locus contains two tightly-linked genes, BMP2 and HAO1, which together produce the range of pleiotropic effects seen. This study demonstrates the importance of pleiotropy (or extremely close linkage) in domestication. The nature of this pleiotropy also provides insights into how this sexual ornament could be maintained in wild populations.
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| 12. |
- Johnsson, Martin, et al.
(författare)
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The role of pleiotropy and linkage in genes affecting a sexual ornament and bone allocation in the chicken.
- 2014
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Ingår i: Molecular ecology. - : Wiley. - 1365-294X .- 0962-1083. ; 23:9, s. 2275-86
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Tidskriftsartikel (refereegranskat)abstract
- Sexual selection and the ornaments that inform such choices have been extensively studied, particularly from a phenotypic perspective. Although more is being revealed about the genetic architecture of sexual ornaments, much still remains to be discovered. The comb of the chicken is one of the most widely recognized sexual ornaments, which has been shown to be correlated with both fecundity and bone allocation. In this study, we use a combination of multiple intercrosses between White Leghorn populations and wild-derived Red Junglefowl to, first, map quantitative trait loci (QTL) for bone allocation and, second, to identify expression QTL that correlate and colocalize with comb mass. These candidate quantitative genes were then assessed for potential pleiotropic effects on bone tissue and fecundity traits. We identify genes that correlate with both relative comb mass and bone traits suggesting a combination of both pleiotropy and linkage mediates gene regulatory variation in these traits.
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| 13. |
- Karlsson, Jan, et al.
(författare)
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Observation of the mechanisms causing two kinds of undercut during laser hybrid arc welding
- 2011
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Ingår i: Applied Surface Science. - : Elsevier BV. - 0169-4332 .- 1873-5584. ; 257:17, s. 7501-7506
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Tidskriftsartikel (refereegranskat)abstract
- Two different kinds of undercut were identified when laser hybrid welding hot rolled HSLA-steel in either the as-rolled condition or with the top surface mill scale removed. The presence of mill scale on the steel surface was found to give a sharp angled undercut combined with a sharp oxide inclusion at the edge of the weld which would have the same mechanical effect as a crack in this position. Removal of the surface oxides before welding resulted in the elimination of the oxide inclusions and a more rounded undercut geometry indicative of superior mechanical properties, particularly fatigue life. The mechanisms of the formation of both types of undercut have been analysed by high speed photography and SEM.
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| 14. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)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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| 15. |
- Kroon, Martin, Professor, 1974-, et al.
(författare)
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An Eulerian thermomechanical elastic-viscoplastic model with isotropic and directional hardening applied to computational welding mechanics
- 2021
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Ingår i: Acta Mechanica. - : Springer. - 0001-5970 .- 1619-6937. ; 232, s. 189-218
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Tidskriftsartikel (refereegranskat)abstract
- An Eulerian thermomechanical elastic-viscoplastic model with isotropic and directional hardening is used to analyse the residual mechanical state resulting from the arc welding of a multi-pass weld. Details of the weld test plate, weld filler material, and numerical implementation of the model are provided, including integration algorithms and consistent tangent modulus. For the computational welding mechanics analyses, the austenitic ASME stainless steel grade 316L was considered so that no phase transformations of solid states needed to be considered. The maximum residual stresses were found to be about 500-600 MPa, which is of the order of the yield stress of the base material. Variations in the heat input and the resulting weld cooling time had a significant influence both on the residual stress state and on the resulting geometry of the weld. The predicted stress levels were compared to the experimental results. Overall, the proposed Eulerian framework seems to be a promising tool for analysing melting/solidification processes and residual mechanical states.
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| 16. |
- Kroon, Martin, Professor, 1974-, et al.
(författare)
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Prediction of welding residual stresses using an Eulerian plasticity model
- 2022
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Ingår i: Proceedings M2D2022 - 9th International Conference on Mechanics and Materials in Design, Funchal/Portugal 26-30 June 2022. - 9789895475636 ; , s. 167-168
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Konferensbidrag (refereegranskat)abstract
- Solidification processes play an important role in several industrial processes, such as weldingand additive manufacturing, and the resulting residual stress state is often critical for thestructural integrity of the material. A thermomechanical model was developed for the analysisand prediction of such solidification processes. The approach is based on a model proposed byRubin (Int. J. Eng. Sci. 25, 1175-1191, 1987). This plasticity model was formulated for finitestrains using an Eulerian evolution equation for a unimodular elastic distortional deformationtensor. This evolution equation automatically ensures thermodynamic consistency andpreservation of isochoric inelastic deformations. A 2D problem in the form of a butt weld jointwas analyzed. The main outcome from the analyses were the residual stress distributions. Theresults are compared to experimental data from the literature.
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| 17. |
- Loberg, Bengt, et al.
(författare)
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High critical currents in Bi-2223 phase bars
- 1993
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Ingår i: Cryogenics (Guildford). - 0011-2275 .- 1879-2235. ; 33:5, s. 475-476
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Tidskriftsartikel (refereegranskat)abstract
- The critical current Ic and the critical current density Jc of Bi-2223 phase bars have been found to depend on the mass density of the bars. Bars densified using a cold isostatic pressing (CIPing) process have been obtained with transport critical currents of gt;150 A with Jc levels up to approximately equals 103 A cm-2 at 77 K in the absence of an applied magnetic field. Bending or kinking of the grains may promote densification during CIPing of a sintered bar.
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| 18. |
- Loberg, Bengt, et al.
(författare)
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HIPing of rapidly solidified high-carbon steel powder
- 1988
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Ingår i: HIP. - Luleå : CENTEK. - 918699834X ; , s. 205-208
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Konferensbidrag (refereegranskat)abstract
- The investigated alloy had a nominal composition of Fe--1.6C--1Cr. HIP-parameteres used: T = 750, 650, 550 deg C, p = 200 MPa, t = 2 h. Even though densification is relatively easily achieved due to the small grain size, the surface contaminants (especially oxides) play a key roll in the bulk properties and create problems which increase as the HIP temperature decreases. The oxide solubility is too low for dissolution mechanisms to work, with the result that the fragmented oxide layer stays in the vicinity of the prior particle boundaries, influences the area of metallic bonding and thus decreases material performance (e.g. ductility). Photomicrographs
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| 19. |
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| 20. |
- Mihalic, Filip, et al.
(författare)
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Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs
- 2022
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Ingår i: Nature Communications. - : Cold Spring Harbor Laboratory. - 2041-1723.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Viruses mimic host short linear motifs (SLiMs) to hijack and deregulate cellular functions. Studies of motif-mediated interactions therefore provide insight into virus-host dependencies, and reveal targets for therapeutic intervention. Here, we describe the pan-viral discovery of 1,712 SLiM-based virus-host interactions using a phage peptidome tiling the intrinsically disordered protein regions of 229 RNA viruses. We find mimicry of host SLiMs to be a ubiquitous viral strategy, reveal novel host proteins hijacked by viruses, and identify cellular pathways frequently deregulated by viral motif mimicry. Using structural and biophysical analyses, we show that viral mimicry-based interactions have similar binding strength and bound conformations as endogenous interactions. Finally, we establish polyadenylate-binding protein 1 as a potential target for broad-spectrum antiviral agent development. Our platform enables rapid discovery of mechanisms of viral interference and the identification of potential therapeutic targets which can aid in combating future epidemics and pandemics.
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| 21. |
- Mihalič, Filip, et al.
(författare)
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Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Viruses mimic host short linear motifs (SLiMs) to hijack and deregulate cellular functions. Studies of motif-mediated interactions therefore provide insight into virus-host dependencies, and reveal targets for therapeutic intervention. Here, we describe the pan-viral discovery of 1712 SLiM-based virus-host interactions using a phage peptidome tiling the intrinsically disordered protein regions of 229 RNA viruses. We find mimicry of host SLiMs to be a ubiquitous viral strategy, reveal novel host proteins hijacked by viruses, and identify cellular pathways frequently deregulated by viral motif mimicry. Using structural and biophysical analyses, we show that viral mimicry-based interactions have similar binding strength and bound conformations as endogenous interactions. Finally, we establish polyadenylate-binding protein 1 as a potential target for broad-spectrum antiviral agent development. Our platform enables rapid discovery of mechanisms of viral interference and the identification of potential therapeutic targets which can aid in combating future epidemics and pandemics.
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| 22. |
- Nätt, Daniel, et al.
(författare)
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Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
- 2012
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Ingår i: BMC Genomics. - : BioMed Central. - 1471-2164. ; 13:59
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Tidskriftsartikel (refereegranskat)abstract
- Variations in gene expression, mediated by epigenetic mechanisms, may cause broad phenotypic effects in animals. However, it has been debated to what extent expression variation and epigenetic modifications, such as patterns of DNA methylation, are transferred across generations, and therefore it is uncertain what role epigenetic variation may play in adaptation. Here, we show that in Red Junglefowl, ancestor of domestic chickens, gene expression and methylation profiles in thalamus/hypothalamus differ substantially from that of a domesticated egg laying breed. Expression as well as methylation differences are largely maintained in the offspring, demonstrating reliable inheritance of epigenetic variation. Some of the inherited methylation differences are tissue-specific, and the differential methylation at specific loci are little changed after eight generations of intercrossing between Red Junglefowl and domesticated laying hens. There was an over-representation of differentially expressed and methylated genes in selective sweep regions associated with chicken domestication. Hence, our results show that epigenetic variation is inherited in chickens, and we suggest that selection of favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation states which are inherited independently of sequence differences, may have been an important aspect of chicken domestication.
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| 23. |
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| 24. |
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| 25. |
- Rubin, Carl-Johan, et al.
(författare)
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Differential gene expression in femoral bone from red junglefowl and domestic chicken, differing for bone phenotypic traits
- 2007
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 8, s. 208-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Osteoporosis is frequently observed among aging hens from egg-producing strains (layers) of domestic chicken. White Leghorn (WL) has been intensively selected for egg production and it manifests striking phenotypic differences for a number of traits including several bone phenotypes in comparison with the wild ancestor of chicken, the red junglefowl (RJ). Previously, we have identified four Quantitative Trait Loci (QTL) affecting bone mineral density and bone strength in an intercross between RJ and WL. With the aim of further elucidating the genetic basis of bone traits in chicken, we have now utilized cDNA-microarray technology in order to compare global RNA-expression in femoral bone from adult RJ and WL (five of each sex and population). Results: When contrasting microarray data for all WL-individuals to that of all RJ-individuals we observed differential expression (False discovery rate adjusted p-values < 0.015) for 604 microarray probes. In corresponding male and female contrasts, differential expression was observed for 410 and 270 probes, respectively. Altogether, the three contrasts between WL and RJ revealed differential expression of 779 unique transcripts, 57 of which are located to previously identified QTL-regions for bone traits. Some differentially expressed genes have previously been attributed roles in bone metabolism and these were: WNT inhibitory factor I (WIFI), WD repeat-containing protein 5 (WDR5) and Syndecan 3 (SDC3). Among differentially expressed transcripts, those encoding structural ribosomal proteins were highly enriched and all 15 had lower expression in WL. Conclusion: We report the identification of 779 differentially expressed transcripts, several residing within QTL-regions for bone traits. Among differentially expressed transcripts, those encoding structural ribosomal proteins were highly enriched and all had lower expression levels in WL. In addition, transcripts encoding four translation initiation and translation elongation factor proteins also had lower expression levels in WL, possibly indicating perturbation of protein biosynthesis pathways between the two populations. Information derived from this study could be relevant to the bone research field and may also aid in further inference of genetic changes accompanying animal domestication.
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| 26. |
- Rubin, Carl-Johan, et al.
(författare)
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Quantitative trait loci for BMD and bone strength in an intercross between domestic and wildtype chickens.
- 2007
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 0884-0431. ; 22:3, s. 375-84
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Tidskriftsartikel (refereegranskat)abstract
- With chicken used as a model species, we used QTL analysis to examine the genetic contribution to bone traits. We report the identification of four QTLs for femoral traits: one for bone strength, one for endosteal circumference, and two affecting mineral density of noncortical bone. INTRODUCTION: BMD is a highly heritable phenotype, governed by elements at numerous loci. In studies examining the genetic contribution to bone traits, many loci have been identified in humans and in other species. The goal of this study was to identify quantitative trait loci (QTLs) controlling BMD and bone strength in an intercross between wildtype and domestic chickens. MATERIALS AND METHODS: A set of 164 markers, covering 30 chromosomes (chr.), were used to genotype 337 F2-individuals from an intercross of domesticated white Leghorn and wildtype red junglefowl chicken. DXA and pQCT were used to measure BMD and bone structure. Three-point bending tests and torsional strength tests were performed to determine the biomechanical strength of the bone. QTLs were mapped using forward selection for loci with significant marginal effects. RESULTS: Four QTLs for femoral bone traits were identified in QTL analysis with body weight included as a covariate. A QTL on chr. 1 affected female noncortical BMD (LOD 4.6) and is syntenic to human 12q21-12q23. Also located on chr. 1, a locus with synteny to human 12q13-14 affected endosteal circumference (LOD 4.6). On chr. 2, a QTL corresponding to human 5p13-p15, 7p12, 18q12, 18q21, and 9q22-9q31 affected BMD in females; noncortical (LOD 4.0) and metaphyseal (LOD 7.0) BMD by pQCT and BMD by DXA (LOD 5.9). A QTL located on chr. 20 (LOD 5.2) affected bone biomechanical strength and had sex-dependent effects. In addition to the significant QTLs, 10 further loci with suggestive linkage to bone traits were identified. CONCLUSIONS: Four QTLs were identified: two for noncortical BMD, one for endosteal circumference, and one affecting bone biomechanical strength. The future identification of genes responsible for these QTLs will increase the understanding of vertebrate skeletal biology.
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| 27. |
- Rubin, Carl-Johan, et al.
(författare)
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Quantitative Trait Loci for BMD and Bone Strength in an Intercross Between Domestic and Wildtype Chickens
- 2007
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 22:3, s. 375-384
-
Tidskriftsartikel (refereegranskat)abstract
- With chicken used as a model species, we used QTL analysis to examine the genetic contribution to bone traits. We report the identification of four QTLs for femoral traits: one for bone strength, one for endosteal circumference, and two affecting mineral density of noncortical bone. Introduction: BMD is a highly heritable phenotype, governed by elements at numerous loci. In studies examining the genetic contribution to bone traits, many loci have been identified in humans and in other species. The goal of this study was to identify quantitative trait loci (QTLs) controlling BMD and bone strength in an intercross between wildtype and domestic chickens. Materials and Methods: A set of 164 markers, covering 30 chromosomes (chr.), were used to genotype 337 F 2-individuals from an intercross of domesticated white Leghorn and wildtype red junglefowl chicken. DXA and pQCT were used to measure BMD and bone structure. Three-point bending tests and torsional strength tests were performed to determine the biomechanical strength of the bone. QTLs were mapped using forward selection for loci with significant marginal effects. Results: Four QTLs for femoral bone traits were identified in QTL analysis with body weight included as a covariate. A QTL on chr. 1 affected female noncortical BMD (LOD 4.6) and is syntenic to human 12q21-12q23. Also located on chr. 1, a locus with synteny to human 12q 13-1.4 affected endosteal circumference (LOD 4.6). On chr. 2, a QTL corresponding to human 5p13-p15, 7p12, 18q12, 18q21, and 9q22-9q31 affected BMD in females; noncortical (LOD 4.0) and metaphyseal (LOD 7.0) BMD by pQCT and BMD by DXA (LOD 5.9). A QTL located on chr. 20 (LOD 5.2) affected bone biomechanical strength and had sex-dependent effects. In addition to the significant QTLs, 10 further loci with suggestive linkage to bone traits were identified. Conclusions: Four QTLs were identified: two for noncortical BMD, one for endosteal circumference, and one affecting bone biomechanical strength. The future identification of genes responsible for these QTLs will increase the understanding of vertebrate skeletal biology.
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| 28. |
- Rubin, Carl-Johan, et al.
(författare)
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Whole genome resequencing reveals loci under selection during chicken domestication
- 2010
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Ingår i: Nature. - London : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7288, s. 587-591
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Tidskriftsartikel (refereegranskat)abstract
- Domestic animals are excellent models for genetic studies of phenotypic evolution. They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.
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| 29. |
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| 30. |
- Rubin, Jenny, et al.
(författare)
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Asparagine-linked glycans determine the cytotoxic capacity of eosinophil cationic protein (ECP)
- 2013
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 55:3-4, s. 372-380
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophil cationic protein (ECP) is a toxic, granule-stored protein of the eosinophil granulocyte. It is a heterogeneous protein; molecular weights can differ from 15 to 22 kDa, due to glycosylations. We purified high molecular weight ECP from blood donors with the ECP434GG (rs2073342) genotype, with the aim of examining whether removal of carbohydrates could enhance the cytotoxic capacity. The cytotoxic activity of the ECP pools was tested against the NCI-H69 cell line, before and after enzymatic deglycosylation. ECP was also analysed by SELDI-TOF MS to monitor the changes in molecular mass after deglycosylation. Five high molecular weight pools of ECP (HMW-ECP I-V) with decreasing degrees of glycosylation were tested at concentrations ranging from 0.02 to 0.6 mu M. The activity ranged from EC50 of >0.6 mu M to 0.04 mu M; HMW-ECP II had the lowest activity and HMW-ECP V the highest. After deglycosylation with N-glycosidase F, pools HMW-ECP I-III were reduced to the same molecular weight of 15.78 kDa and acquired potent cytotoxic activities. HMW-ECP IV and V with molecular species at 163 and 16.1 kDa were highly cytotoxic as such and were only partially deglycosylated, with slight enhancement of the toxic properties. The results suggest the presence of several HMW-ECP molecular species with differences in their post-translational modifications and cytotoxic properties. We conclude that a fraction of native ECP is stored in a non-cytotoxic form, which can be converted into a cytotoxic form by N-deglycosylation, whereas another fraction is stored as a highly cytotoxic form carrying different post-translational modifications.
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| 31. |
- Rubin, Jenny, et al.
(författare)
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The coding ECP 434(G>C) gene polymorphism determines the cytotoxicity of ECP but has minor effects on fibroblast-mediated gel contraction and no effect on RNase activity
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:1, s. 445-451
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophil cationic protein (ECP) is a secretory protein of the eosinophil granulocyte, a cell involved in innate immunity. Functional studies have implicated ECP in numerous processes, such as tissue remodeling in allergic inflammation and cytotoxicity toward a variety of pathogens. Recent genetic studies have suggested that the ECP 434(G>C) polymorphism resulting in an arg97thr substitution would alter the function of ECP in vivo. Functional (in vitro) studies of ECP up until now have either been conducted with native preparations containing an unknown mixture of the ECP(97arg) and ECP(97thr) variants, or with recombinant proteins. Therefore, we have now for the first time extracted the native ECP(97arg) and ECP(97thr) variants from healthy blood donors and tested them functionally in vitro. Our results show that the arg97thr shift dramatically alters the cytotoxic capacity of ECP in vitro; the tested ECP(97arg) variants were cytotoxic toward the small-cell lung cancer cell line NCI-H69, whereas ECP(97thr) was noncytotoxic. RNase activity was unaffected by the arg97thr substitution. Both ECP(97arg) and ECP(97thr) stimulated fibroblast-mediated collagen gel contraction, an experimental model, which depicts wound healing, in a dose-dependent manner. In conclusion, our results demonstrate that the ECP 434(G>C) gene polymorphism affects the functional properties of native ECP, but also that there is a dissociation between different biological activities; the arg97thr substitution impairs the cytotoxic potential of ECP but less the gel contraction and not at all the RNase activity.
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| 32. |
- Rubin, Per, et al.
(författare)
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Graphite Formation and Dissolution in Ductile Irons and Steels Having High Silicon Contents: Solid-State Transformations
- 2018
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Ingår i: Metallography, Microstructure, and Analysis. - New York : Springer. - 2192-9262 .- 2192-9270. ; 7:5, s. 587-595
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Tidskriftsartikel (refereegranskat)abstract
- Graphite formation in the solid state is both in ductile cast irons and in steels strongly promoted by high silicon contents above 3 wt.% Si. The matrix microstructure in austempered ductile iron can be further refined by secondary graphite if the austenitization, quench, and isothermal transformation into ausferrite are preceded by an austenitization at a slightly higher temperature followed by quench to martensite, resulting in higher carbon content than being soluble at the second austenitization temperature. Hypoeutectoid steels with high silicon contents can be rapidly graphitized, causing recrystallization of surrounding ferrite due to plastic deformation making room for less dense graphite. In rolled steels, the interface between manganese sulfide and steel matrix is the most common nucleation site. Voids are formed when graphite is partly or completely dissolved during austenitization in succeeding hardening heat treatments, but the mechanical properties can still be good if the graphite particles dissolved into voids are below 20 µm. Graphitized Si-solution strengthened ferritic steels may perform similar to free-cutting steels but with improved mechanical properties.
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| 33. |
- Rubin, Per, et al.
(författare)
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Novel Cost-Efficient Method of Producing Ausferritic Steels Displaying Excellent Combination of Mechanical Properties
- 2020
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Ingår i: Metallography and Fractography XVII. - : Trans Tech Publications. ; , s. 11-18
-
Konferensbidrag (refereegranskat)abstract
- ound bars Ø 53 mm were hot-rolled from a 1.4 tonne ingot forged to 165 × 165 mm. The composition of the steel was 0.45 wt. % C and 3.33 wt. % Si plus alloying elements for hardenability. Microstructure after air cooling from 1010 °C on the cooling bed was predominantly ausferritic. Tensile testing of as-rolled bars resulted in yield strength 846 ± 22 MPa, ultimate tensile strength 1169 ± 99 MPa and A5-elongation of 1.7 ± 0.8 % (without prior necking). When as-rolled steel was baked in air at T = {Ms initial -30 K} for six hours, the yield stress raised to 1121 ± 4 MPa, the ultimate tensile stress raised to 1447 ± 5 MPa and the elongation raised to 22.6 ± 1.6 % (with necking > 18 %). For as-rolled bars during continuous cooling, the exposure time within the temperature range 460 – 320 °C was estimated to be about 10 minutes. The microstructure of as-rolled “semi-finished” bars is stable at room temperature. The first baking was done six months after hot-rolling. Optical and scanning electron microscopy showed that remaining areas of austenite, not transformed during continuous cooling but stable at room temperature, transforms to ausferrite when properly baked.
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| 34. |
- Rubin, Per, et al.
(författare)
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The effect of normalizing, intercritical annealing, and manganese partitioning, respectively, on the recrystallization behaviour of ferrite in a cold rolled carbon manganese structural steel
- 1990
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Ingår i: Recrystallization '90. - Warrendale, Pa : Minerals, Metals & Materials Society. - 0873391241 ; , s. 211-218
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Konferensbidrag (refereegranskat)abstract
- A commercial 0.16% carbon, 1.5% Mn structural steel was heat treated in three different ways, cold rolled and then recrystallized at temperatures between 500-600 deg C. The heat treatments were: normalizing at 920 deg C, 30 min, air cool; Mn partitioning treatment at 715 deg C, 112 h, air cool; dual-phase treatment, i.e. a short intercritical anneal at 750 deg C followed by quenching in water. All treatments produced massive two-phase structures, in which the second constituent was pearlite, Mn enriched martensite, and non-partitioned martensite, respectively. It is shown that the recrystallization rates of the ferrite in the steel samples, deformed 54%, differ significantly. The recrystallization temperature of the normalized and or the dual-phase steel is considerably higher than that of the Mn-partitioned dual-phase steel. The results of the experiments are discussed and some explanations of the steels' different recrystallization behaviours are suggested. Photomicrographs, Graphs. 7 ref.--AA
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| 35. |
- Salazar, Vivian A., et al.
(författare)
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Protein post-translational modification in host defense : the antimicrobial mechanism of action of human eosinophil cationic protein native forms
- 2014
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 281:24, s. 5432-5446
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge on the contribution of protein glycosylation in host defense antimicrobial peptides is still scarce. We have studied here how the post-translational modification pattern modulates the antimicrobial activity of one of the best characterized leukocyte granule proteins. The human eosinophil cationic protein (ECP), an eosinophil specific granule protein secreted during inflammation and infection, can target a wide variety of pathogens. Previous work in human eosinophil extracts identified several ECP native forms and glycosylation heterogeneity was found to contribute to the protein biological properties. In this study we analyze for the first time the antimicrobial activity of the distinct native proteins purified from healthy donor blood. Low and heavy molecular weight forms were tested on Escherichiacoli cell cultures and compared with the recombinant non-glycosylated protein. Further analysis on model membranes provided an insight towards an understanding of the protein behavior at the cytoplasmic membrane level. The results highlight the significant reduction in protein toxicity and bacteria agglutination activity for heavy glycosylated fractions. Notwithstanding, the lower glycosylated fraction mostly retains the lipopolysaccharide binding affinity together with the cytoplasmic membrane depolarization and membrane leakage activities. From structural analysis we propose that heavy glycosylation interferes with the protein self-aggregation, hindering the cell agglutination and membrane disruption processes. The results suggest the contribution of post-translational modifications to the antimicrobial role of ECP in host defense.
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| 36. |
- Steinmetz, Julia, et al.
(författare)
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Descriptive Proteome Analysis to Investigate Context-Dependent Treatment Responses to OXPHOS Inhibition in Colon Carcinoma Cells Grown as Monolayer and Multicellular Tumor Spheroids
- 2020
-
Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:28, s. 17242-17254
-
Tidskriftsartikel (refereegranskat)abstract
- We have previously identified selective upregulation of the mevalonate pathway genes upon inhibition of oxidative phosphorylation (OXPHOS) in quiescent cancer cells. Using mass spectrometry-based proteomics, we here investigated whether these responses are corroborated on the protein level and whether proteomics could yield unique insights into context-dependent biology. HCT116 colon carcinoma cells were cultured as monolayer cultures, proliferative multicellular tumor spheroids (P-MCTS), or quiescent (Q:MCTS) multicellular tumor spheroids and exposed to OXPHOS inhibitors: nitazoxanide, FCCP, oligomycin, and salinomycin or the HMG-CoA-reductase inhibitor simvastatin at two different doses for 6 and 24 h. Samples were processed using an in-depth bottom-up proteomics workflow resulting in a total of 9286 identified protein groups. Gene set enrichment analysis showed profound differences between the three cell systems and confirmed differential enrichment of hypoxia, OXPHOS, and cell cycle progression-related protein responses in P-MCTS and QMCTS. Treatment experiments showed that the observed drug-induced alterations in gene expression of metabolically challenged cells are not translated directly to the protein level, but the results reaffirmed OXPHOS as a selective vulnerability of quiescent cancer cells. This work provides rationale for the use of deep proteome profiling to identify context-dependent treatment responses and encourages further studies investigating metabolic processes that could be co-targeted together with OXPHOS to eradicate quiescent cancer cells.
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| 37. |
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| 38. |
- Wild, Philipp S., et al.
(författare)
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A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease
- 2011
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Ingår i: Circulation: Cardiovascular Genetics. - : American Heart Association/Lippincott, Williams & Wilkins. - 1942-325X .- 1942-3268. ; 4:4, s. 203-403
-
Tidskriftsartikel (refereegranskat)abstract
- Background-eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results-In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)). Conclusions-The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.)
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| 39. |
- Woschnagg, Charlotte, et al.
(författare)
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Eosinophil cationic protein (ECP) is processed during secretion
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:6, s. 3949-3954
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Tidskriftsartikel (refereegranskat)abstract
- The eosinophil granulocyte is an inflammatory cell involved in allergic diseases such as asthma and rhinitis. Eosinophil cationic protein (ECP) is a basic and potentially cytotoxic granule protein that is released from the eosinophil upon activation. The aim was to study secretion of molecular variants of ECP from blood eosinophils with the hypothesis that the stored noncytotoxic ECP is altered into cytotoxic species upon release from the cell. Eosinophil granulocytes were purified to >95% from venous blood from birch pollen allergic subjects, with symptoms of rhinitis, and from healthy control subjects during the birch pollen season. The cells were stimulated with IL-5, GM-CSF, or serum-opsonized Sephadex particles. Concentration of ECP in cells or supernatants was measured by means of a fluoroenzyme immunoassay, and ECP heterogeneity was studied using an affinity capture assay with the surface-enhanced laser desorption/ionization-time of flight mass spectrometry technique. Extracts of unstimulated eosinophils contained 10 major ECP variants, with molecular masses ranging from 16.1 to 17.7 kDa. Stimulation with particles mainly induced the secretion of two molecular variants at 16.1 and 16.3 kDa, while cytokine stimulation gave rise to a different secretion profile. ECP variants in the pellet extracts remained unaffected by cell activation. The modifications of secreted ECP were partly explained by differences in N-linked glycosylations. Secretion of ECP from eosinophils involves protein modification. The molecular masses of released ECP have acquired the masses of the cytotoxic species.
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| 40. |
- Wright, Dominic, et al.
(författare)
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Onset of Sexual Maturity in Female Chickens is Genetically Linked to Loci Associated with Fecundity and a Sexual Ornament
- 2012
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Ingår i: Reproduction in domestic animals. - : Blackwell Publishing. - 0936-6768 .- 1439-0531. ; 47:SI, s. 31-36
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Tidskriftsartikel (refereegranskat)abstract
- Onset of sexual maturation is a trait of extreme importance both evolutionarily and economically. Unsurprisingly therefore, domestication has acted to reduce the time to sexual maturation in a variety of animals, including the chicken. In comparison with wild progenitor chickens [the Red Junglefowl (RJF)], domestic layer hens attain maturity approximately 20% earlier. In addition, domestic layers also possess larger combs (a sexual ornament), produce more eggs and have denser bones. A large quantitative trait loci (QTL) analysis (n = 377) was performed using an F2 intercross between a White Leghorn layer breed and a RJF population, with onset of sexual maturity measured and mapped to three separate loci. This cross has already been analysed for comb mass, egg production and bone allocation. Onset of sexual maturity significantly correlated with comb mass, whilst the genetic architecture for sexual maturity and comb mass overlapped at all three loci. For two of these loci, the QTL for sexual maturity and comb mass were statistically indistinguishable from pleiotropy, suggesting that the alleles that increase comb mass also decrease onset of sexual maturity.
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| 41. |
- Wright, Dominic, 1977-, et al.
(författare)
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The genetic architecture of domestication in the chicken: effects of pleiotropy and linkage
- 2010
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Ingår i: Molecular Ecology. - Oxford : Blackwell Publishing Ltd. - 0962-1083 .- 1365-294X. ; 19, s. 5140-5156
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Tidskriftsartikel (refereegranskat)abstract
- The extent of pleiotropy and epistasis in quantitative traits remains equivocal. In the caseof pleiotropy, multiple quantitative trait loci are often taken to be pleiotropic if theirconfidence intervals overlap, without formal statistical tests being used to ascertain ifthese overlapping loci are statistically significantly pleiotropic. Additionally, the degreeto which the genetic correlations between phenotypic traits are reflected in thesepleiotropic quantitative trait loci is often variable, especially in the case of antagonisticpleiotropy. Similarly, the extent of epistasis in various morphological, behavioural andlife-history traits is also debated, with a general problem being the sample sizes requiredto detect such effects. Domestication involves a large number of trade-offs, which arereflected in numerous behavioural, morphological and life-history traits which haveevolved as a consequence of adaptation to selective pressures exerted by humans andcaptivity. The comparison between wild and domestic animals allows the geneticanalysis of the traits that differ between these population types, as well as being ageneral model of evolution. Using a large F2 intercross between wild and domesticatedchickens, in combination with a dense SNP and microsatellite marker map, bothpleiotropy and epistasis were analysed. The majority of traits were found to segregate in11 tight ‘blocks’ and reflected the trade-offs associated with domestication. These blockswere shown to have a pleiotropic ‘core’ surrounded by more loosely linked loci. Incontrast, epistatic interactions were almost entirely absent, with only six pairs identifiedover all traits analysed. These results give insights both into the extent of such blocks inevolution and the development of domestication itself.
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