| 131. |
- Nikolaou, Nikolaos, et al.
(författare)
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AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease.
- 2019
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Ingår i: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 99, s. 67-80
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroid hormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes a fundamental step in bile acid synthesis.Human liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels were measured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver cell lines. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clinical biochemistry, and enzyme immunoassays.In human liver biopsies, AKR1D1 expression decreased with advancing steatosis, fibrosis and inflammation. Expression was decreased in patients with type 2 diabetes. In human liver cell lines, AKR1D1 knockdown decreased primary bile acid biosynthesis and steroid hormone clearance. RNA-sequencing identified disruption of key metabolic pathways, including insulin action and fatty acid metabolism. AKR1D1 knockdown increased hepatocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increased de novo lipogenesis and decreased β-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bile acid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the observed metabolic phenotype is driven through bile acid rather than steroid hormone availability.Genetic manipulation of AKR1D1 regulates the metabolic phenotype of human hepatoma cell lines, driving steatosis and inflammation. Taken together, the observation that AKR1D1 mRNA is down-regulated with advancing NAFLD suggests that it may have a crucial role in the pathogenesis and progression of the disease.
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| 132. |
- Nilsson, Jonas A, et al.
(författare)
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Id2 is dispensable for myc-induced lymphomagenesis.
- 2004
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Ingår i: Cancer Res. - 0008-5472. ; 64:20, s. 7296-301
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Tidskriftsartikel (refereegranskat)abstract
- The Emu-Myc transgenic mouse appears to be an accurate model of human Burkitt's lymphoma that bears MYC/Immunoglobulin gene translocations. Id2, a negative regulator of basic helix-loop-helix transcription factors, has also been proposed as a Myc target gene that drives the proliferative response of Myc by binding to and overriding the checkpoint functions of the retinoblastoma tumor suppressor protein. Targeted deletion of Id2 in mice results in defects in B-cell development and prevents the development of peripheral lymphoid nodes. In precancerous B cells and lymphomas that arise in Emu-Myc transgenic mice and in Burkitt's lymphomas, Id2 is overexpressed, suggesting that it plays a regulatory role in lymphoma development. Surprisingly, despite these connections, Emu-Myc mice lacking Id2 succumb to lethal B-cell lymphoma at rates comparable with wild-type Emu-Myc transgenics. Furthermore, precancerous splenic B cells lacking Id2 do not exhibit any significant defects in Myc-induced target gene transactivation and proliferation. However, due to their lack of secondary lymph nodes, Emu-Myc mice lacking Id2 rather succumb to disseminated lymphoma with an associated leukemia, with pronounced infiltrates of the bone marrow and other major organs. Collectively these findings argue that targeting Id2 functions may be ineffective in preventing Myc-associated malignancies.
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| 133. |
- Nilsson, Jonas A, et al.
(författare)
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Mnt loss triggers Myc transcription targets, proliferation, apoptosis, and transformation.
- 2004
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Ingår i: Mol Cell Biol. - 0270-7306. ; 24:4, s. 1560-9
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Tidskriftsartikel (refereegranskat)abstract
- Myc oncoproteins are overexpressed in most cancers and are sufficient to accelerate cell proliferation and provoke transformation. However, in normal cells Myc also triggers apoptosis. All of the effects of Myc require its function as a transcription factor that dimerizes with Max. This complex induces genes containing CACGTG E-boxes, such as Ornithine decarboxylase (Odc), which harbors two of these elements. Here we report that in quiescent cells the Odc E-boxes are occupied by Max and Mnt, a putative Myc antagonist, and that this complex is displaced by Myc-Max complexes in proliferating cells. Knockdown of Mnt expression by stable retroviral RNA interference triggers many targets typical of the "Myc" response and provokes accelerated proliferation and apoptosis. Strikingly, these effects of Mnt knockdown are even manifest in cells lacking c-myc. Moreover, Mnt knockdown is sufficient to transform primary fibroblasts in conjunction with Ras. Therefore, Mnt behaves as a tumor suppressor. These findings support a model where Mnt represses Myc target genes and Myc functions as an oncogene by relieving Mnt-mediated repression.
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| 134. |
- Nilsson, Jonas A, et al.
(författare)
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Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.
- 2005
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Ingår i: Cancer Cell. - 1535-6108. ; 7:5, s. 433-44
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Tidskriftsartikel (refereegranskat)abstract
- Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.
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| 135. |
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| 136. |
- Oster, Michael, et al.
(författare)
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Bridging gaps in the agricultural phosphorus cycle from an animal husbandry perspective: The case of pigs and poultry
- 2018
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Ingår i: Sustainability. - Basel, Switzerland : MDPI. - 2071-1050. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Since phosphorus (P) is an essential element for life, its usage and application across agricultural production systems requires great attention. Monogastric species such as pigs and poultry can significantly contribute to global food security but these animals remain highly dependent on the supply of mineral inorganic P in their feeds. Pig and poultry, which represent 70% of the global meat production, are also major P excretors and thus represent important sources of environmental P inputs. Balancing the P cycle within farming systems is crucial to achieve P sustainable and resilient livestock production. Therefore, the interconnection of animal feed, livestock farming, manure, and soil/aquatic ecosystems requires multidisciplinary approaches to improve P management. With regard to a sustainable agricultural P cycle, this study addresses aspects of feeding strategies and animal physiology (e.g., phase feeding, P conditioning, liquid feeding, phytase supplementation, genetics), soil agroecosystems (e.g., P cycling, P losses, P gains), reuse and recycling (e.g., manure, slaughter waste), measures of farmers' economic performance (e.g., bio-economic models), and P governance/policy instruments (e.g., P quota, P tax). To reconcile the economic and ecological sustainability of animal husbandry, the strategic objective of future research will be to provide solutions for a sufficient supply of high-quality animal products from resource-efficient and economically competitive agro-systems which are valued by society and preserve soil and aquatic ecosystems.
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| 137. |
- Respondek, Gesine, et al.
(författare)
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Which ante mortem clinical features predict progressive supranuclear palsy pathology?
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 32:7, s. 995-1005
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Forskningsöversikt (refereegranskat)abstract
- Background: Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. Objective: To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. Methods: We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Results: Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Conclusions: Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP.
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| 138. |
- Rutter, Nick, et al.
(författare)
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Evaluation of forest snow processes models (SnowMIP2)
- 2009
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Ingår i: Journal of Geophysical Research. - : American Geophysical Union (AGU). - 0148-0227 .- 2156-2202. ; 114:6
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Tidskriftsartikel (refereegranskat)abstract
- Thirty-three snowpack models of varying complexity and purpose were evaluated across a wide range of hydrometeorological and forest canopy conditions at five Northern Hemisphere locations, for up to two winter snow seasons. Modeled estimates of snow water equivalent (SWE) or depth were compared to observations at forest and open sites at each location. Precipitation phase and duration of above-freezing air temperatures are shown to be major influences on divergence and convergence of modeled estimates of the subcanopy snowpack. When models are considered collectively at all locations, comparisons with observations show that it is harder to model SWE at forested sites than open sites. There is no universal "best'' model for all sites or locations, but comparison of the consistency of individual model performances relative to one another at different sites shows that there is less consistency at forest sites than open sites, and even less consistency between forest and open sites in the same year. A good performance by a model at a forest site is therefore unlikely to mean a good model performance by the same model at an open site (and vice versa). Calibration of models at forest sites provides lower errors than uncalibrated models at three out of four locations. However, benefits of calibration do not translate to subsequent years, and benefits gained by models calibrated for forest snow processes are not translated to open conditions.
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| 139. |
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| 140. |
- Schmale, Julia, et al.
(författare)
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Long-term cloud condensation nuclei number concentration, particle number size distribution and chemical composition measurements at regionally representative observatories
- 2018
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 18:4, s. 2853-2881
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Tidskriftsartikel (refereegranskat)abstract
- Aerosol-cloud interactions (ACI) constitute the single largest uncertainty in anthropogenic radiative forcing. To reduce the uncertainties and gain more confidence in the simulation of ACI, models need to be evaluated against observations, in particular against measurements of cloud condensation nuclei (CCN). Here we present a data set - ready to be used for model validation - of long-term observations of CCN number concentrations, particle number size distributions and chemical composition from 12 sites on 3 continents. Studied environments include coastal background, rural background, alpine sites, remote forests and an urban surrounding. Expectedly, CCN characteristics are highly variable across site categories. However, they also vary within them, most strongly in the coastal background group, where CCN number concentrations can vary by up to a factor of 30 within one season. In terms of particle activation behaviour, most continental stations exhibit very similar activation ratios (relative to particles 20nm) across the range of 0.1 to 1.0% supersaturation. At the coastal sites the transition from particles being CCN inactive to becoming CCN active occurs over a wider range of the supersaturation spectrum. Several stations show strong seasonal cycles of CCN number concentrations and particle number size distributions, e.g. at Barrow (Arctic haze in spring), at the alpine stations (stronger influence of polluted boundary layer air masses in summer), the rain forest (wet and dry season) or Finokalia (wildfire influence in autumn). The rural background and urban sites exhibit relatively little variability throughout the year, while short-term variability can be high especially at the urban site. The average hygroscopicity parameter, calculated from the chemical composition of submicron particles was highest at the coastal site of Mace Head (0.6) and lowest at the rain forest station ATTO (0.2-0.3). We performed closure studies based on -Köhler theory to predict CCN number concentrations. The ratio of predicted to measured CCN concentrations is between 0.87 and 1.4 for five different types of . The temporal variability is also well captured, with Pearson correlation coefficients exceeding 0.87. Information on CCN number concentrations at many locations is important to better characterise ACI and their radiative forcing. But long-term comprehensive aerosol particle characterisations are labour intensive and costly. Hence, we recommend operating migrating-CCNCs to conduct collocated CCN number concentration and particle number size distribution measurements at individual locations throughout one year at least to derive a seasonally resolved hygroscopicity parameter. This way, CCN number concentrations can only be calculated based on continued particle number size distribution information and greater spatial coverage of long-term measurements can be achieved.
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