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- Berg, Sven
(author)
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Ultra high-pressure compaction of powder
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Sintering at high-pressure improves the properties of the material, either through new sintering aids becoming available or through improving intergranular bonding. This gives the manufactured products potential advantages like faster cut rates, and more precise and cleaner production methods that add up to cost efficiency and competitive edge. The production of synthetic diamond products demands tooling that can achieve high pressures and deliver it with a high degree of certainty. The common denominator for almost all high-pressure systems is to use capsules where a powder material encloses the core material. Numerical analysis of manufacturing processes with working conditions that reach ultra high pressure (above 10 GPa) requires a constitutive model that can handle the specific behaviours of the powder from a low density to solid state. The work in this thesis deals with characterization and simulation of the material behaviour during high-pressure compaction in powder pressing. Some of the work was focused on investigating the material when used as compressible gasket in high-pressure systems. The aim was to increase the knowledge of the high-pressure pressing process. This includes a better understanding of how mean stress develops in the compact during pressing and an insight into the development material models concerning highpressure materials. Both experimental and numerical investigations were made to gain knowledge in these fields. The mechanical behaviour of a CaCO3 powder mix was investigated using the Brazilian disc test, uniaxial compression testing and closed die experiments. The aim of the experimental work was to provide a foundation for numerical simulation of CaCO3 powder compaction at higher pressures. Friction measurements of the powder were also conducted. From the experimental investigations, density dependent material parameters were found. An elasto-plastic Cap model was developed for ultra high-pressure powder pressing. To improve the material model, density dependent constitutive parameters were included. The model was implemented as a user-defined material subroutine in a nonlinear finite element program. The model was validated against pressure measurements using phase transitions of Bismuth. The measurements were conducted in a Bridgman anvil apparatus. The simulations showed that thin discs with small radial extrusion generate a plateau at a low-pressure level, while thick discs with large radial extrusion generate a pressure peak at a high-pressure level. The results showed that FE-results can be used to engineer pressure peaks needed to seal HPHT-systems. For compressible gaskets, it was found that diametral support increases the phase transformation load. Higher initial density of the powder compact and diametral support generate higher pressure per unit thickness. The results from the validation using pressure measurements showed that the simulation model was indeed capable of reproducing load–thickness curves and pressure profiles, up to 9 GPa, close to the experimental curves.
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| 2. |
- Martrat, Griselda, et al.
(author)
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Exploring the link between MORF4L1 and risk of breast cancer
- 2011
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:2
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Journal article (peer-reviewed)abstract
- Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
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| 3. |
- Maxwell, Christopher A., et al.
(author)
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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- 2011
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In: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 9:11
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Journal article (peer-reviewed)abstract
- Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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