| 1. |
- Godoy, Patricio, et al.
(författare)
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
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Forskningsöversikt (refereegranskat)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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| 2. |
- Kurilshikov, Alexander, et al.
(författare)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 3. |
- Andersson, John, et al.
(författare)
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Double Obstacle Problems with Obstacles Given by Non-C-2 Hamilton-Jacobi Equations
- 2012
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Ingår i: Archive for Rational Mechanics and Analysis. - : Springer Science and Business Media LLC. - 0003-9527 .- 1432-0673. ; 206:3, s. 779-819
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Tidskriftsartikel (refereegranskat)abstract
- We prove optimal regularity for double obstacle problems when obstacles are given by solutions to Hamilton-Jacobi equations that are not C (2). When the Hamilton-Jacobi equation is not C (2) then the standard Bernstein technique fails and we lose the usual semi-concavity estimates. Using a non-homogeneous scaling (different speeds in different directions) we develop a new pointwise regularity theory for Hamilton-Jacobi equations at points where the solution touches the obstacle. A consequence of our result is that C (1)-solutions to the Hamilton-Jacobi equation , are, in fact, C (1,alpha/2), provided that . This result is optimal and, to the authors' best knowledge, new.
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| 4. |
- Andersson, John, et al.
(författare)
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Equilibrium points of a singular cooperative system with free boundary
- 2015
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Ingår i: Advances in Mathematics. - : Elsevier BV. - 0001-8708 .- 1090-2082. ; 280, s. 743-771
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we initiate the study of maps minimising the energy integral(D)(vertical bar del u vertical bar(2) + 2 vertical bar u vertical bar) dx, which, due to Lipschitz character of the integrand, gives rise to the singular Euler equations Delta u = u / vertical bar u vertical bar chi({vertical bar u vertical bar >0}), u = (u(1,) ... ,u(m)) Our primary goal in this paper is to set up a road map for future developments of the theory related to such energy minimising maps. Our results here concern regularity of the solution as well as that of the free boundary. They are achieved by using monotonicity formulas and epiperimetric inequalities, in combination with geometric analysis.
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| 5. |
- Andersson, John, et al.
(författare)
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On the singularities of a free boundary through Fourier expansion
- 2012
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Ingår i: Inventiones Mathematicae. - : Springer Science and Business Media LLC. - 0020-9910 .- 1432-1297. ; 187:3, s. 535-587
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we are concerned with singular points of solutions to the unstable free boundary problem Delta u = -chi({u>0}) in B-1. The problem arises in applications such as solid combustion, composite membranes, climatology and fluid dynamics. It is known that solutions to the above problem may exhibit singularities-that is points at which the second derivatives of the solution are unbounded-as well as degenerate points. This causes breakdown of by-now classical techniques. Here we introduce new ideas based on Fourier expansion of the non-linearity chi({u>0}). The method turns out to have enough momentum to accomplish a complete description of the structure of the singular set in R-3. A surprising fact in R-3 is that although u(rx)/sup(B1) vertical bar u(rx)vertical bar can converge at singularities to each of the harmonic polynomials xy, x(2) + y(2)/2 - z(2) and z(2) - x(2) + y(2)/2, it may not converge to any of the non-axially-symmetric harmonic polynomials alpha((1 + delta)x(2) + (1 - delta)y(2) - 2z(2)) with delta not equal 1/2. We also prove the existence of stable singularities in R-3.
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| 6. |
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| 7. |
- Andersson, John, et al.
(författare)
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Uniform Regularity Close to Cross Singularities in an Unstable Free Boundary Problem
- 2010
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Ingår i: Communications in Mathematical Physics. - : Springer Science and Business Media LLC. - 0010-3616 .- 1432-0916. ; 296:1, s. 251-270
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Tidskriftsartikel (refereegranskat)abstract
- We introduce a new method for the analysis of singularities in the unstable problem Delta u = chi{u> 0}, which arises in solid combustion as well as in the composite membrane problem. Our study is confined to points of "supercharacteristic" growth of the solution, i.e. points at which the solution grows faster than the characteristic/invariant scaling of the equation would suggest. At such points the classical theory is doomed to fail, due to incompatibility of the invariant scaling of the equation and the scaling of the solution. In the case of two dimensions our result shows that in a neighborhood of the set at which the second derivatives of u are unbounded, the level set {u = 0} consists of two C-1-curves meeting at right angles. It is important that our result is not confined to the minimal solution of the equation but holds for all solutions.
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| 8. |
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| 9. |
- Eberle, Simon, et al.
(författare)
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On Global Solutions of the Obstacle Problem
- 2023
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Ingår i: Duke mathematical journal. - : Duke University Press. - 0012-7094 .- 1547-7398. ; 172:11, s. 2149-2193
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Tidskriftsartikel (refereegranskat)abstract
- Assuming a lower bound on the dimension, we prove a long-standing conjecture concerning the classification of global solutions of the obstacle problem with unbounded coincidence sets.
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| 10. |
- Eberle, Simon, et al.
(författare)
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The structure of the regular part of the free boundary close to singularities in the obstacle problem
- 2023
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Ingår i: Journal of Differential Equations. - : Elsevier BV. - 0022-0396 .- 1090-2732. ; 377, s. 873-887
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Tidskriftsartikel (refereegranskat)abstract
- We prove the –to the best knowledge of the authors– first result on the fine asymptotic behavior of the regular part of the free boundary of the obstacle problem close to singularities. The result is motivated by a recent answer to a long standing conjecture concerning the classification of global solutions of the obstacle problem.
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