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| 2. |
- 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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| 3. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 4. |
- Wan, Lu Ming, et al.
(författare)
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Heparanase Facilitates PMA-Induced Megakaryocytic Differentiation in K562 Cells via Interleukin 6/STAT3 Pathway
- 2020
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Ingår i: Thrombosis and Haemostasis. - : GEORG THIEME VERLAG KG. - 0340-6245 .- 2567-689X. ; 120:4, s. 647-657
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Tidskriftsartikel (refereegranskat)abstract
- Heparanase (HPSE) is an endo-beta-D-glucuronidase that cleaves heparan sulfate and hence participates in remodeling of the extracellular matrix, leading to release of cytokines that are immobilized by binding to heparan sulfate proteoglycans (HSPGs), and consequently activating signaling pathways. This function of HPSE is correlated to its expression level that is normally very low in majority of the tissues. Exceptionally, human platelets express high level of HPSE, suggesting a unique physiological role in this cell. Using K562 cell line, we found a progressive increase of HPSE during the megakaryocytic differentiation. Analysis of a series of megakaryocytic differentiation-related heparin-binding proteins (HBPs) in the cell culture medium revealed an exclusive positive correlation between the level of interleukin 6 (IL-6) and HPSE expression. IL-6 modulated megakaryocytic differentiation through activation of STAT3. Further, we demonstrated that overexpression of HPSE potentiates megakaryocytic differentiation, whereas elimination of HPSE led to a delayed differentiation. This function of HPSE is associated with its activity, as overexpression of inactive HPSE had no effect on IL-6 production and megakaryocytic differentiation. The role of HPSE is further supported by the observation in an umbilical cord blood CD34+ cells megakaryocytic differentiation model. Our data propose a novel role for HPSE in platelets production by a HPSE/IL-6/STAT3 positive feedback loop that specifically regulates megakaryocytes maturation.
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| 6. |
- Wei, Kun, et al.
(författare)
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Intergranular microstructure in magnesium based die cast AE alloys
- 2012
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Ingår i: Materials Science and Technology. - : Maney Publishing. - 0267-0836 .- 1743-2847. ; 28:3, s. 311-320
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Tidskriftsartikel (refereegranskat)abstract
- A systematic investigation of the microstructures of a series of magnesium based die cast magnesium‐aluminium‐rare earth (RE) alloys has been performed using X-ray diffraction analysis, scanning electron microscopy and transmission electron microscopy. The alloys had an aluminium content of 3‐4 wt-% and RE content of between 0·6 and 3·5 wt-%. The alloys were studied in the as cast condition and after aging at 200 and 250°C. Three kinds of binary aluminium‐RE phases were found in the alloys existing intergranularly. Al11RE3 was the predominant intergranular phase. In addition, Al3RE and Al2RE phases were found in the alloys with high RE content. The Al3RE phase became unstable when the alloy was aged at 200°C, while the Al11RE3 phase remained stable at 250°C. In alloys with a RE/aluminium weight ratio of <0·6, primary Al12Mg17 and aluminium enriched zones existed at the grain boundaries beside the Al11RE3 phase, both of which are considered to contribute to the reduction in creep resistance. The aluminium enriched zone transformed into Al12Mg17 precipitates when the alloys were aged. Therefore, to achieve improved creep resistance in Mg‐Al‐RE alloys, the RE/Al ratio should exceed 0·6.
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| 7. |
- Wei, Kun, et al.
(författare)
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The Intergranular Microstructure of Magnesium Based Die-Cast AE Alloys
- 2009
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Ingår i: Magnesium Technology 2009. - : The Minerals, Metals & Materials Society (TMS). - 9780873397308 ; , s. 261-266
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Konferensbidrag (refereegranskat)abstract
- A systematic investigation on microstructures of magnesium based die-cast Mg-Al-RE alloys (AE alloys) has been performed by XRD, SEM and TEM. The alloys are with content of Al around 4wt% and various content of rare earth (RE). Samples of these alloys are in as-cast condition as well as in aged condition at 200°C and 250°C. The intergranular microstructure of the alloys has been studied in details. Three type binary Al-RE phases were found intergranularly. Al11RE3 is predominant intergranular phase in the as cast alloys. Al3RE particles and small amount of Al2RE phase were found in alloys with high RE content. Thermal stability of the Al-RE phases in AE alloys was suggested to decrease in sequence: Al2RE→ Al11RE3 →Al3RE. The Al/RE ratio of the die cast alloys determined their phase constitutions. Promising AE alloys for creep resistance is suggested to have an Al/RE ratio not higher than 1.8.
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| 8. |
- Wei, Liu-Ying, et al.
(författare)
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A TEM study of microstructural change in Mg alloys during creep
- 2007
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Ingår i: 8th Multinational Congress on Microscopy.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- M5-10 A TEM Study of Microstructural Change in Mg Alloys during Creep Wei L.-Y. Wei K. and Warren R. Division of Materials Science, School of Technology and Society Malmö University, 205 06 Malmö Sweden liu-ying.wei@ts.mah.se Due to their low densities and a good combination of castability and different properties, magnesium alloys have been attractive materials for automotive industry for weight saving. Die-cast AZ91 is one of the most widely used alloys. It exhibits excellent die castability, good strength properties and a fair ductility but its mechanical properties, especially the creep resistance, decrease on exposure at temperature above 120ºC [1]. Softening and coarsening of the interdendritic phase β-Al12Mg17 in AZ91 can readily occur at elevated temperatures due to its low melting temperature (Tm = 437°C) [2]. Rare earth in magnesium alloys usually brings about alloy strengthening through the formation of thermally stable intergranular phases and the complete suppression of the β-Al12Mg17 phase formation. In the present work tensile creep behavior of the die-cast magnesium alloys AZ91 and AE42 and their microstructural change during plastic deformation in creep have been studied. The objective of the work is to study the active creep mechanisms on the basis of the creep data in combination with the microstructural investigations. The SEM micrographs in Fig. 1 (a-b) illustrate the as-cast microstructures of the two die cast alloys showing a typical dendritic solidification structure with a fine-scale grain size. Segregation of Al adjacent to the dendrite boundaries can be seen clearly in AZ91D. Phases with a bright contrast and surrounded by high Al-segregated eutectic α-Mg are β-Al12Mg17 phase. Segregation of Al seems not obvious in AE42. The dominant interdendritic phase is Al11RE3. Mn-containing phases also formed during solidification in both AZ91 and AE42. The TEM micrographs in Fig. 2 (a-c) illustrate the structural changes during creep in AZ91 and AE42. Fig. 2 (a) shows the formation of denuded zones around the dendrite boundaries and the formation of discontinuous precipitates Al12Mg17. TEM/XEDS revealed that the Al content in the denuded zones decreased after creep test, from the original 5.5% to 2.5% (wt%). Fig. 2 (b-c) illustrates the formation of dislocation sources in the (0001) basal planes under a relatively high stress and the movement of dislocations from the sources towards the dendrite boundaries. The existence of the supersaturated Al-segregated zones adjacent to the dendrite boundaries is the main reason for the recovery of AZ91 at operating temperatures above 100ºC. Under loading plastic deformation occurred by the diffusion of Al atoms along the boundaries from compressive to tensile grain boundaries that caused the formation of the denuded grain boundaries and as a consequence the formation of the discontinuous precipitates Al12Mg17. Dislocation climb process also operated and tended to become a dominant process at stress above 60MPa.The low level of Al in AE42 suppresses the formation of Al supersaturated zones adjacent to the dendrite boundaries that, combining with the formation of the thermally stable interdendritic phase Al11RE3 (Tm~640ºC), provides AE42 a much better creep performance. Diffusion accompanying with the dislocation climb also occurred and became more dominant at a relatively high stress. Figure 1 SEM micrographs of the die cast alloys (a) AZ91D; (b) AE42. Fig. 2 TEM micrographs of the crept samples, (a-b) AZ91 after creep test at 100ºC/100MPa (n=3), (c) AE42 after creep at 175ºC/60MPa (n=2-7). References: 1. I.J. Polmer, 2nd Mg conference, DGM Informationsgesellschaft, Germany (1992), 201 2. M.S. Dargush, G.L. Dunlop, K. Pettersen, in: W. Higgins (Ed.), Trans. of 19th Intern. Die Casting Cong., North American Die Casting Association, Rosemont, IL, 1997, 131–137. Acknowledgements: Norsk Hydro ASA is gratefully acknowledged for providing the test bars
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| 9. |
- Wei, Liu-Ying, et al.
(författare)
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Creep behaviour and microstructure of magnesium die cast alloys AZ91 and AE42
- 2007
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Ingår i: Materials Science Forum. - : Trans Tech Publications. ; 546-549, s. 73-76
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Tidskriftsartikel (refereegranskat)abstract
- Tensile creep behaviour of the die-cast magnesium alloys AZ91 and AE42 has been studied at temperatures between 85oC and 200oC and at stresses in the range from 30 to 100 MPa. Microstructural investigations, mainly by TEM, have been performed on the selected crept samples to characterise the microstructural change during the plastic deformation, which reveals several phenomena related to the creep process including formation of dislocation sources, denuded zones around grain boundaries and microvoids, and changes in the nature of intermetallic phases. The active creep mechanisms have been discussed on the basis of the creep data in combination with the microstructural change during creep.
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