| 1. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 2. |
- Allern, Sigurd, 1946-, et al.
(författare)
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Introduction: New Nordic Journalism Research
- 2013
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Ingår i: Nordicom Review. - : Walter de Gruyter GmbH. - 1403-1108 .- 2001-5119. ; 34, s. 7-10
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Paul, M., et al.
(författare)
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Clopidogrel Administration Impairs Post-Stroke Learning and Memory Recovery in Mice
- 2023
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Ingår i: International Journal of Molecular Sciences. - 1661-6596. ; 24:14
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Tidskriftsartikel (refereegranskat)abstract
- Clopidogrel, which is one of the most prescribed antiplatelet medications in the world, is given to stroke survivors for the prevention of secondary cardiovascular events. Clopidogrel exerts its antiplatelet activity via antagonism of the P2Y12 receptor (P2RY12). Although not widely known or considered during the initial clinical trials for clopidogrel, P2RY12 is also expressed on microglia, which are the brain's immune cells, where the receptor facilitates chemotactic migration toward sites of cellular damage. If microglial P2RY12 is blocked, microglia lose the ability to migrate to damaged sites and carry out essential repair processes. We aimed to investigate whether administering clopidogrel to mice post-stroke was associated with (i) impaired motor skills and cognitive recovery; (ii) physiological changes, such as survival rate and body weight; (iii) changes in the neurovascular unit, including blood vessels, microglia, and neurons; and (iv) changes in immune cells. Photothrombotic stroke (or sham surgery) was induced in adult male mice. From 24 h post-stroke, mice were treated daily for 14 days with either clopidogrel or a control. Cognitive performance (memory and learning) was assessed using a mouse touchscreen platform (paired associated learning task), while motor impairment was assessed using the cylinder task for paw asymmetry. On day 15, the mice were euthanized and their brains were collected for immunohistochemistry analysis. Clopidogrel administration significantly impaired learning and memory recovery, reduced mouse survival rates, and reduced body weight post-stroke. Furthermore, clopidogrel significantly increased vascular leakage, significantly increased the number and appearance of microglia, and significantly reduced the number of T cells within the peri-infarct region post-stroke. These data suggest that clopidogrel hampers cognitive performance post-stroke. This effect is potentially mediated by an increase in vascular permeability post-stroke, providing a pathway for clopidogrel to access the central nervous system, and thus, interfere in repair and recovery processes.
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| 4. |
- Pollack, Martin, et al.
(författare)
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Zero-flux approximations for multivariate quadrature-based moment methods
- 2019
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Ingår i: Journal of Computational Physics. - : Elsevier BV. - 1090-2716 .- 0021-9991. ; 398
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of polydisperse systems is governed by population balance equations. A group of efficient solution approaches are the moment methods, which do not solve for the number density function (NDF) directly but rather for a set of its moments. While this is computationally efficient, a specific challenge arises when describing the fluxes across a boundary in phase space for the disappearance of elements, the so-called zero-flux. The main difficulty is the missing NDF-information at the boundary, which most moment methods cannot provide. Relevant physical examples are evaporating droplets, soot oxidation or particle dissolution. In general, this issue can be solved by reconstructing the NDF close to the boundary. However, this was previously only achieved with univariate approaches, i.e. considering only a single internal variable. Many physical problems are insufficiently described by univariate population balance equations, e.g. droplets in sprays often require the temperature or the velocity to be internal coordinates in addition to the size. In this paper, we propose an algorithm, which provides an efficient multivariate approach to calculate the zero-fluxes. The algorithm employs the Extended Quadrature Method of Moments (EQMOM) with Beta and Gamma kernel density functions for the marginal NDF reconstruction and a polynomial or spline for the other conditional dimensions. This combination allows to reconstruct the entire multivariate NDF and based on this, expressions for the disappearance flux are derived. An algorithm is proposed for the whole moment inversion and reconstruction process. It is validated against a suite of test cases with increasing complexity. The influence of the number of kernel density functions and the configuration of the polynomials and splines on the accuracy is discussed. Finally, the associated computational costs are evaluated.
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| 5. |
- Zaitlen, Noah, et al.
(författare)
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Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low-BMI cases are larger than those estimated from high-BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-controlcovariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled falsepositive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1x10(-9)). The improvement varied across diseases with a 16% median increase in chi(2) test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
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| 6. |
- Zhukova, Nataliya, et al.
(författare)
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WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
- 2014
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
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