| 571. |
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| 572. |
- Parkash, Vimal, et al.
(författare)
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Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase epsilon
- 2019
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The most frequently recurring cancer-associated DNA polymerase epsilon (Pol epsilon) mutation is a P286R substitution in the exonuclease domain. While originally proposed to increase genome instability by disrupting exonucleolytic proofreading, the P286R variant was later found to be significantly more pathogenic than Pol epsilon proofreading deficiency per se. The mechanisms underlying its stronger impact remained unclear. Here we report the crystal structure of the yeast orthologue, Pol epsilon-P301R, complexed with DNA and an incoming dNTP. Structural changes in the protein are confined to the exonuclease domain, with R301 pointing towards the exonuclease site. Molecular dynamics simulations suggest that R301 interferes with DNA binding to the exonuclease site, an outcome not observed with the exonuclease-inactive Pol epsilon-D290A, E292A variant lacking the catalytic residues. These results reveal a distinct mechanism of exonuclease inactivation by the P301R substitution and a likely basis for its dramatically higher mutagenic and tumorigenic effects.
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| 573. |
- Pasti, Igor A., et al.
(författare)
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Atomic adsorption on pristine graphene along the Periodic Table of Elements - From PBE to non-local functionals
- 2018
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Ingår i: Applied Surface Science. - : ELSEVIER SCIENCE BV. - 0169-4332 .- 1873-5584. ; 436, s. 433-440
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Tidskriftsartikel (refereegranskat)abstract
- The understanding of atomic adsorption on graphene is of high importance for many advanced technologies. Here we present a complete database of the atomic adsorption energies for the elements of the Periodic Table up to the atomic number 86 (excluding lanthanides) on pristine graphene. The energies have been calculated using the projector augmented wave (PAW) method with PBE, long-range dispersion interaction corrected PBE (PBE+D2, PBE+D3) as well as non-local vdW-DF2 approach. The inclusion of dispersion interactions leads to an exothermic adsorption for all the investigated elements. Dispersion interactions are found to be of particular importance for the adsorption of low atomic weight earth alkaline metals, coinage and s-metals (11th and 12th groups), high atomic weight p-elements and noble gases. We discuss the observed adsorption trends along the groups and rows of the Periodic Table as well some computational aspects of modelling atomic adsorption on graphene.
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| 574. |
- Pasti, Igor A., et al.
(författare)
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Tunable reactivity of supported single metal atoms by impurity engineering of the MgO(001) support
- 2018
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 20:9, s. 6337-6346
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Tidskriftsartikel (refereegranskat)abstract
- Development of novel materials may often require a rational use of high price components, like noble metals, in combination with the possibility to tune their properties in a desirable way. Here we present a theoretical DFT study of Au and Pd single atoms supported by doped MgO(001). By introducing B, C and N impurities into the MgO(001) surface, the interaction between the surface and the supported metal adatoms can be adjusted. Impurity atoms act as strong binding sites for Au and Pd adatoms and can help to produce highly dispersed metal particles. The reactivity of metal atoms supported by doped MgO(001), as probed by CO, is altered compared to their counterparts on pristine MgO(001). We find that Pd atoms on doped MgO(001) are less reactive than on perfect MgO(001). In contrast, Au adatoms bind CO much more strongly when placed on doped MgO(001). In the case of Au on N-doped MgO(001) we find that charge redistribution between the metal atom and impurity takes place even when not in direct contact, which enhances the interaction of Au with CO. The presented results suggest possible ways for optimizing the reactivity of oxide supported metal catalysts through impurity engineering.
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| 575. |
- Patel, Ami V, et al.
(författare)
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Fatty acid synthase is a metabolic oncogene targetable in malignant peripheral nerve sheath tumors
- 2015
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 17:12, s. 1599-1608
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas with minimal therapeutic opportunities. We observed that lipid droplets (LDs) accumulate in human MPNST cell lines and in primary human tumor samples. The goal of this study was to investigate the relevance of lipid metabolism to MPNST survival and as a possible therapeutic target.METHODS: Based on preliminary findings that MPNSTs accumulate LDs, we hypothesized that a deregulated lipid metabolism supports MPNST cell survival/proliferation rate. To test this, we examined respiration, role of fatty acid oxidation (FAO), and the enzyme fatty acid synthase involved in de novo fatty acid synthesis in MPNSTs using both genetic and pharmacological tools.RESULTS: We demonstrate that LDs accumulate in MPNST cell lines, primary human and mouse MPNST tumors, and neural crest cells. LDs from MPNST cells disappear on lipid deprivation, indicating that LDs can be oxidized as a source of energy. Inhibition of FAO decreased oxygen consumption and reduced MPNST survival, indicating that MPNST cells likely metabolize LDs through active FAO. FAO inhibition reduced oxygen consumption and survival even in the absence of exogenous lipids, indicating that lipids synthesized de novo can also be oxidized. Consequently, inhibition of de novo fatty acid synthesis, which is overexpressed in human MPNST cell lines, effectively reduced MPNST survival and delayed induction of tumor growth in vivo.CONCLUSION: Our results show that MPNSTs depend on lipid metabolic pathways and suggest that disrupting lipid metabolism could be a potential new strategy for the development of MPNST therapeutics.
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| 576. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 577. |
- Plym, Anna, et al.
(författare)
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Causes of sick leave, disability pension, and death following a breast cancer diagnosis in women of working age
- 2019
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Ingår i: Breast. - : CHURCHILL LIVINGSTONE. - 0960-9776 .- 1532-3080. ; 45, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Women diagnosed with breast cancer during working age are at increased risk of permanent absence from work, but the underlying medical causes have rarely been studied. We examined the risk of cause-specific sick leave, disability pension, and the competing event death after a breast cancer diagnosis in a population-based cohort study.Materials and methods: From the Breast Cancer Data Base Sweden, we identified 16,603 women diagnosed with stage I-III breast cancer between 2000 and 2012, and 63,773 control women. Using multi-state modelling, we calculated probabilities and durations of sick leave, disability pension, and death by registered cause, together with cause-specific hazard ratios.Results: Five years after diagnosis, causes other than cancer accounted for around half of all sick leave (3.5% out of 6.8% of women) and disability pension (1.4% out of 2.6%) in women with breast cancer. Compared with control women, women with breast cancer were at increased risk of sick leave and disability pension due to mental disorders (HR 1.24, 95% CI 1.15-1.33 and HR 1.54, 95% CI 1.29-1.85, respectively) and disability pension due to inflammatory diseases (HR 1.46, 95% CI 1.05-2.03). The risk of sick leave and disability pension due to cardiovascular disease was also elevated, although only statistically significant for disability pension in women diagnosed after 2005 (HR 2.24, 95% CI 1.22-4.13).Conclusion: Follow-up, support, and rehabilitation programs for women diagnosed with breast cancer must address a wide range of psychological and physical conditions to limit the consequences on working life.
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| 578. |
- Pouransari, Zeinab, et al.
(författare)
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DNS Analysis of Wall Heat Transfer and Combustion Regimes in a Turbulent Non-premixed Wall-jet Flame
- 2016
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Ingår i: Flow Turbulence and Combustion. - : Springer Netherlands. - 1386-6184 .- 1573-1987. ; , s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the heat-release effects on the wall heat transfer in turbulent reacting flows, i.e. heat transfer with or without significant density variation, is essential for a wide variety of industrial flows, especially combustion problems. The present study focuses on the wall heat transfer and the near-wall reaction characteristics. The heat-release effects on the wall heat transfer and skin-friction coefficients are investigated using three-dimensional direct numerical simulations of a turbulent reacting wall-jet flow with and without heat release. Reductions in the skin-friction coefficient are observed in the exothermic case, compared to the isothermal one, and the underlying mechanism is explained. The absolute wall heat flux also increases, while the corresponding Nusselt number decreases with increasing heat release. Furthermore, the wall effects on the near-wall average burning rate are assessed. It is found that the isothermal cold wall results in an appreciable decrease of the burning rate in the exothermic cases. We observed indications that the wall increases the chances for the development of the premixed mode and its occurrence is very fast in the wall-normal direction.
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| 579. |
- Pouransari, Zeinab, 1982-
(författare)
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Numerical studies of turbulent flames in wall-jet flows
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present thesis deals with the fundamental aspects of turbulent mixing and non-premixed combustion in the wall-jet flow, which has a close resemblance to many industrial applications. Direct numerical simulations (DNS) of turbulent wall-jets with isothermal and exothermic reactions are performed. In the computational domain, fuel and oxidizer enter separately in a nonpremixed manner and the flow is compressible, fully turbulent and subsonic. The triple “turbulence-chemistry-wall” interactions in the wall-jet flow have been addressed first by focusing on turbulent flow effects on the isothermal reaction, and then, by concentrating on heat-release effects on both turbulence and flame characteristics in the exothermic reaction. In the former, the mixing characteristics of the flow, the key statistics for combustion and the near-wall effects in the absence of thermal effects are isolated and studied. In the latter, the main target was to identify the heat-release effects on the different mixing scales of turbulence. Key statistics such as the scalar dissipation rates, time scale ratios, two-point correlations, one and two-dimensional premultiplied spectra are used to illustrate the heat release induced modifications. Finer small mixing scales were observed in the isothermal simulations and larger vortical structures formed after adding significant amounts of heat-release. A deeper insight into the heat release effects on three-dimensional mixing and reaction characteristics of the turbulent wall-jet flow has been gained by digging in different scales of DNS datasets. In particular, attention has been paid to the anisotropy levels and intermittency of the flow by investigating the probability density functions, higher order moments of velocities and reacting scalars and anisotropy invariant maps for different reacting cases. To evaluate and isolate the Damkohler number effects on the reaction zone structure from those of the heat release a comparison between two DNS cases with different Damkohler numbers but a comparable temperature rise is performed. Furthermore, the wall effects on the flame and flow characteristics, for instance, the wall heat transfer; the near-wall combustion effects on the skin-friction, the isothermal wall cooling effects on the average burning rates and the possibility of formation of the premixed mode within the non-premixed flame are addressed. The DNS datasets are also used for a priori analysis, focused on the heat release effects on the subgrid-scale (SGS) statistics. The findings regarding the turbulence small-scale characteristics, gained through the statistical analysis of the flow have many phenomenological parallels with those concerning the SGS statistics. Finally, a DNS of turbulent reacting wall-jet at a substantially higher Reynolds number is performed in order to extend the applicability range for the conclusions of the present study and figuring out the possible differences.
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| 580. |
- Pouransari, Zeinab, et al.
(författare)
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Statistical analysis of the velocity and scalar fields in reacting turbulent wall-jets
- 2015
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Ingår i: Physics of fluids. - : American Institute of Physics (AIP). - 1070-6631 .- 1089-7666. ; 27:2, s. 025102-
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Tidskriftsartikel (refereegranskat)abstract
- The concept of local isotropy in a chemically reacting turbulent wall-jet flow is addressed using direct numerical simulation (DNS) data. Different DNS databases with isothermal and exothermic reactions are examined. The chemical reaction and heat release effects on the turbulent velocity, passive scalar, and reactive species fields are studied using their probability density functions (PDFs) and higher order moments for velocities and scalar fields, as well as their gradients. With the aid of the anisotropy invariant maps for the Reynolds stress tensor, the heat release effects on the anisotropy level at different wall-normal locations are evaluated and found to be most accentuated in the near-wall region. It is observed that the small-scale anisotropies are persistent both in the near-wall region and inside the jet flame. Two exothermic cases with different Damkohler numbers are examined and the comparison revealed that the Damkohler number effects are most dominant in the near-wall region, where the wall cooling effects are influential. In addition, with the aid of PDFs conditioned on the mixture fraction, the significance of the reactive scalar characteristics in the reaction zone is illustrated. We argue that the combined effects of strong intermittency and strong persistency of anisotropy at the small scales in the entire domain can affect mixing and ultimately the combustion characteristics of the reacting flow.
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