| 1. |
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| 2. |
- Aldrin-Kirk, Patrick, et al.
(författare)
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Chemogenetic modulation of cholinergic interneurons reveals their regulating role on the direct and indirect output pathways from the striatum
- 2018
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 109, s. 148-162
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Tidskriftsartikel (refereegranskat)abstract
- The intricate balance between dopaminergic and cholinergic neurotransmission in the striatum has been thoroughly difficult to characterize. It was initially described as a seesaw with a competing function of dopamine versus acetylcholine. Recent technical advances however, have brought this view into question suggesting that the two systems work rather in concert with the cholinergic interneurons (ChIs) driving dopamine release. In this study, we have utilized two transgenic Cre-driver rat lines, a choline acetyl transferase ChAT-Cre transgenic rat and a novel double-transgenic tyrosine hydroxylase TH-Cre/ChAT-Cre rat to further elucidate the role of striatal ChIs in normal motor function and in Parkinson's disease. Here we show that selective and reversible activation of ChIs using chemogenetic (DREADD) receptors increases locomotor function in intact rats and potentiate the therapeutic effect of L-DOPA in the rats with lesions of the nigral dopamine system. However, the potentiation of the L-DOPA effect is accompanied by an aggravation of L-DOPA induced dyskinesias (LIDs). These LIDs appear to be driven primarily through the indirect striato-pallidal pathway since the same effect can be induced by the D2 agonist Quinpirole. Taken together, the results highlight the intricate regulation of balance between the two output pathways from the striatum orchestrated by the ChIs.
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| 3. |
- Aldrin-Kirk, Patrick, et al.
(författare)
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DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor
- 2016
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273. ; 90:5, s. 955-968
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.
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| 4. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 5. |
- Butler, Simon, et al.
(författare)
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An Investigation of Work Practices Used by Companies Making Contributions to Established OSS Projects
- 2018
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Ingår i: ICSE-SEIP '18 Proceedings of the 40th International Conference on Software Engineering: Software Engineering in Practice. - New York : Association for Computing Machinery (ACM). - 9781450356596 ; , s. 201-210
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Konferensbidrag (refereegranskat)abstract
- Professionals contribute to open source software (OSS) projects aspart of their employment. Previous research has addressed motivationsof individuals and the ways they engage with OSS projects.However, there is a lack of research which examines and explainswork practices used by companies in their engagement with projects.Work practices used by companies to contribute to five establishedOSS projects are investigated through examination of the actions ofemployees in public communication channels and draw on our experienceswhen analysing engagement with the same projects. Wefind that companies utilise work practices for contributing whichare congruent with the circumstances and their capabilities thatsupport their short and long term needs. We find that companiescontribute to OSS projects in different ways, such as employing coreproject developers, making donations, and joining project steeringcommittees in order to advance strategic interests.
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| 6. |
- Lundell, Björn, et al.
(författare)
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Addressing Lock-in, Interoperability, and Long-Term Maintenance Challenges Through Open Source : How Can Companies Strategically Use Open Source?
- 2017
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Ingår i: Open Source Systems. - Cham : Springer. - 9783319577340 - 9783319577357 ; , s. 80-88
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Konferensbidrag (refereegranskat)abstract
- This industry paper reports on how strategic use of open source in company contexts can provide effective support for addressing the fundamental challenges of lock-in, interoperability, and longevity of software and associated digital assets. The fundamental challenges and an overview of an ongoing collaborative research project are presented. Through a conceptual model for open source usage in company contexts we characterise how companies engage with open source and elaborate on how the fundamental challenges can be effectively addressed through open source usage in company contexts.
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| 7. |
- Mattsson, Niklas, et al.
(författare)
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18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease
- 2017
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 9, s. 1212-1223
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the relationship between cerebrospinal fluid (CSF) total-tau (T-tau) and phosphorylated tau (P-tau) with the tau PET ligand 18F-AV-1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T-tau and P-tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F-AV-1451, and mainly in demented AD patients. 18F-AV-1451, but not CSF T-tau or P-tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F-AV-1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F-AV-1451 retention was always increased at this disease stage. We conclude that CSF T-tau and P-tau mainly behave as biomarkers of "disease state", since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F-AV-1451 is a biomarker of "disease stage", since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.
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| 8. |
- Mattsson, Niklas, et al.
(författare)
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Comparing 18F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease
- 2018
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Ingår i: Neurology. - 0028-3878. ; 90:5
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Tidskriftsartikel (refereegranskat)abstract
- To compare PET imaging of tau pathology with CSF measurements (total tau [t-tau] and phosphorylated tau [p-tau]) in terms of diagnostic performance for Alzheimer disease (AD).We compared t-tau and p-tau and 18F-AV-1451 in 30 controls, 14 patients with prodromal AD, and 39 patients with Alzheimer dementia, recruited from the Swedish BioFINDER study. All patients with AD (prodromal and dementia) were screened for amyloid positivity using CSF β-amyloid 42. Retention of 18F-AV-1451 was measured in a priori specified regions, selected for known associations with tau pathology in AD.Retention of 18F-AV-1451 was markedly elevated in Alzheimer dementia and moderately elevated in prodromal AD. CSF t-tau and p-tau was increased to similar levels in both AD dementia and prodromal AD. 18F-AV-1451 had very good diagnostic performance for Alzheimer dementia (area under the receiver operating characteristic curve [AUROC] ∼1.000), and was significantly better than t-tau (0.876), p-tau (0.890), hippocampal volume (0.824), and temporal cortical thickness (0.860). For prodromal AD, there were no significant AUROC differences between CSF tau and 18F-AV-1451 measures (0.836-0.939), but MRI measures had lower AUROCs (0.652-0.769).CSF tau and 18F-AV-1451 have equal performance in early clinical stages of AD, but 18F-AV-1451 is superior in the dementia stage, and exhibits close to perfect diagnostic performance for mild to moderate AD.This study provides Class III evidence that CSF tau and 18F-AV-1451 PET have similar performance in identifying early AD, and that 18F-AV-1451 PET is superior to CSF tau in identifying mild to moderate AD.
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| 9. |
- Mattsson, Niklas, et al.
(författare)
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Greater tau load and reduced cortical thickness in APOE ε4-negative Alzheimer’s disease : a cohort study
- 2018
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer’s disease is characterized by aggregated β-amyloid and tau proteins, but the clinical presentations and patterns of brain atrophy vary substantially. A part of this heterogeneity may be linked to the risk allele APOE ε4. The spread of tau pathology is related to atrophy and cognitive decline, but little data exist on the effects of APOE ε4 on tau. The objective of this preliminary study was therefore to test if tau load and brain structure differ by APOE ε4 in Alzheimer’s disease. Methods: Sixty-five β-amyloid-positive patients at the prodromal and dementia stages of Alzheimer’s disease were enrolled, including APOE ε4-positive (n = 46) and APOE ε4-negative (n = 19) patients. 18F-AV-1451 positron emission tomography was used to measure tau and brain magnetic resonance imaging (MRI) was used to measure cortical thickness. Results: Compared with their APOE ε4-positive counterparts, APOE ε4-negative patients had greater tau load and reduced cortical thickness, with the most pronounced effects for both in the parietal cortex. Relative to the overall cortical tau load, APOE ε4-positive patients had greater tau load in the entorhinal cortex. APOE ε4-positive patients also had slightly greater cortical β-amyloid load. There was an interaction between APOE ε4 and 18F-AV-1451 on cortical thickness, with greater effects of 18F-AV-1451 on cortical thickness in APOE ε4-negative patients. APOE ε4 and 18F-AV-1451 were independent predictors of cognition, but showed distinct associations with different cognitive tests. Conclusions: APOE genotype may be associated with differences in pathways in Alzheimer’s disease, potentially through differential development and spread of tau, as well as through effects on cognitive outcomes involving non-tau-related mechanisms.
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| 10. |
- Mattsson, Niklas, et al.
(författare)
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Predicting diagnosis and cognition with 18F-AV-1451 tau PET and structural MRI in Alzheimer's disease
- 2019
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:4, s. 570-580
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The relative importance of structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) to predict diagnosis and cognition in Alzheimer's disease (AD) is unclear. Methods: We tested 56 cognitively unimpaired controls (including 27 preclinical AD), 32 patients with prodromal AD, and 39 patients with AD dementia. Optimal classifiers were constructed using the least absolute shrinkage and selection operator with 18F-AV-1451 (tau) PET and structural MRI data (regional cortical thickness and subcortical volumes). Results: 18F-AV-1451 in the amygdala, entorhinal cortex, parahippocampal gyrus, fusiform, and inferior parietal lobule had 93% diagnostic accuracy for AD (prodromal or dementia). The MRI classifier involved partly the same regions plus the hippocampus, with 83% accuracy, but did not improve upon the tau classifier. 18F-AV-1451 retention and MRI were independently associated with cognition. Discussion: Optimized tau PET classifiers may diagnose AD with high accuracy, but both tau PET and structural brain MRI capture partly unique information relevant for the clinical deterioration in AD.
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| 11. |
- Mutvei, Ann, 1958-, et al.
(författare)
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Evolution, Teaching and Assessment of Students in Pre-Service Primary School Teacher Education
- 2015
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Ingår i: Conference proceedings. New perspectives in science education, 4<sup>th</sup> ed.. - : Libreriauniversitaria.it. - 9788862926003 ; , s. -3
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Konferensbidrag (refereegranskat)abstract
- This project aims at assessment of learning outcome of teaching evolutionary theory to pre-service primary school teacher students. The quality of the students understanding and use of evolutionary theory after their participation in seminars and lectures was made by analysing written reflections of the students. The texts were primarily written by students to show that the knowledge requirements of the course were accomplished but they were here used to analyse their ability to communicate the content but also to evaluate the depth of their understanding of evolutionary theory. For this assessment two different methods were used aiming at the two different targets. One was focused on the students’ use of evolutionary terminology and to what extent they used the language of an evolutionist. Here, we also analysed whether the students gave accurate explanations or descriptions without using the traditional evolutionary terminology. Thus, mainly the students´ ability in their own writing to present evolutionary reflections in an everyday language was here investigated. This ability may be useful when teaching young students without using a theoretical framework. For the assessment of quality of the students’ own understanding of the theory Doll’s criteria, the four R´s, richness, recursion, relations, and rigor, were used. Richness refers to the depth, the layers of meaning in their texts. Recursion is here referring to the students’ use of making thoughts loop back on themselves and earlier experiences. The use of relations are important when developing thinking in different areas. Here, both the students’ references to relations to other persons as well as to objects, theories, places etc. were recorded. Rigor means in this context to purposely look for different alternatives, relations, connections, new combinations, interpretations and patterns. The results may briefly be summarized as follows: 1) most of the students use evolutionary terminology and 2) are fairly good at presenting their thoughts within the theoretical framework in everyday language, although 3) they often show problems in distinguishing processes on molecular, individual, and population levels.
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| 12. |
- Mörner, Torsten, et al.
(författare)
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Thiamine deficiency impairs common eider (Somateria mollissima) reproduction in the field
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The Baltic Sea population of the common eider (Somateria mollissima) has declined dramatically during the last two decades. Recently, widespread episodic thiamine (vitamin B1) deficiency has been demonstrated in feral birds and suggested to contribute significantly to declining populations. Here we show that the decline of the common eider population in the Baltic Sea is paralleled by high mortality of the pulli a few days after hatch, owing to thiamine deficiency and probably also thereby associated abnormal behaviour resulting in high gull predation. An experiment with artificially incubated common eider eggs collected in the field revealed that thiamine treatment of pulli had a therapeutic effect on the thiamine status of the brain and prevented death. The mortality was 53% in untreated specimens, whereas it was only 7% in thiamine treated specimens. Inability to dive was also linked to brain damage typical for thiamine deficiency. Our results demonstrate how thiamine deficiency causes a range of symptoms in the common eider pulli, as well as massive die-offs a few days after hatch, which probably are the major explanation of the recent dramatic population declines.
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| 13. |
- Ossenkoppele, Rik, et al.
(författare)
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Associations between tau, Aβ, and cortical thickness with cognition in Alzheimer disease
- 2019
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Ingår i: Neurology. - 1526-632X. ; 92:6, s. 601-612
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the cross-sectional associations between regional tau, β-amyloid (Aβ), and cortical thickness and neuropsychological function across the preclinical and clinical spectrum of Alzheimer disease (AD). METHODS: We included 106 participants from the Swedish Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study, of whom 33 had preclinical AD (Aβ-positive cognitively normal individuals), 25 had prodromal AD (Aβ-positive mild cognitive impairment), and 48 had probable AD dementia. All underwent [18F]flortaucipir (tau) and structural MRI (cortical thickness), and 88 of 106 underwent [18F]flutemetamol (Aβ) PET. Linear regression models adjusted for age, sex, and education were performed to examine associations between 7 regions of interest and 7 neuropsychological tests for all 3 imaging modalities. RESULTS: In preclinical AD, [18F]flortaucipir, but not [18F]flutemetamol or cortical thickness, was associated with decreased global cognition, memory, and processing speed (range standardized β = 0.35-0.52, p < 0.05 uncorrected for multiple comparisons). In the combined prodromal AD and AD dementia group, both increased [18F]flortaucipir uptake and reduced cortical thickness were associated with worse performance on a variety of neuropsychological tests (most regions of interest survived correction for multiple comparisons at p < 0.05), while increased [18F]flutemetamol uptake was specifically associated with lower scores on a delayed recall memory task (p < 0.05 uncorrected for multiple comparisons). The strongest effects for both [18F]flortaucipir and cortical thickness on cognition were found in the lateral and medial parietal cortex and lateral temporal cortex. The effect of [18F]flutemetamol on cognition was generally weaker and less region specific. CONCLUSION: Our findings suggest that tau PET is more sensitive than Aβ PET and measures of cortical thickness for detecting early cognitive changes in preclinical AD. Furthermore, both [18F]flortaucipir PET and cortical thickness show strong cognitive correlates at the clinical stages of AD.
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| 14. |
- Prigge, Justin R., et al.
(författare)
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Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase
- 2017
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 19:13, s. 2771-2781
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Tidskriftsartikel (refereegranskat)abstract
- Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP(+) ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triplenull) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.
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| 15. |
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| 16. |
- Vagovič, Patrik, et al.
(författare)
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Megahertz x-ray microscopy at x-ray free-electron laser and synchrotron sources
- 2019
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Ingår i: Optica. - 2334-2536. ; 6:9, s. 1106-1109
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Tidskriftsartikel (refereegranskat)abstract
- Modern emerging technologies, such as additive manufacturing, bioprinting, and new material production, require novel metrology tools to probe fundamental high-speed dynamics happening in such systems. Here we demonstrate the application of the megahertz (MHz) European X-ray Free-Electron Laser (EuXFEL) to image the fast stochastic processes induced by a laser on water-filled capillaries with micrometer-scale spatial resolution. The EuXFEL provides superior contrast and spatial resolution compared to equivalent state-of-the-art synchrotron experiments. This work opens up new possibilities for the characterization of MHz stochastic processes on the nanosecond to microsecond time scales with object velocities up to a few kilometers per second using XFEL sources.
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| 17. |
- Vallot, Dorothée, 1984-
(författare)
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Modelling calving and sliding of Svalbard outlet glaciers : Spatio-temporal changes and interactions
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Future sea level rise associated to global warming is one of the greatest societal and environmental challenges of tomorrow. A large part of the contribution comes from glaciers and ice sheets discharging ice and meltwater into the ocean and the recent worldwide increase is worrying. Future predictions of sea level rise try to encompass the complex processes of ice dynamics through glacier modelling but there are still large uncertainties due to the lack of observations or too coarse parameterisation, particularly for processes occurring at the glacier interfaces with the bed (sliding) and with the ocean (calving). This thesis focuses on modelling these processes from two marine-terminating glaciers in Svalbard, Kronebreen and Tunabreen. By inverting three years of high temporal resolution time-series of surface velocities on Kronebreen, basal properties are retrieved with the ice flow model Elmer/Ice in Paper I. Results suggest that surface melt during the summer greatly influences the dynamics of the following season and that sliding laws for such glaciers should be adapted to local and global processes changing in space and time. The subglacial drainage system, fed by the surface melt, is modelled in Paper II during two melting seasons. Results show different configurations of efficient and inefficient drainage systems between years and the importance of using a sliding law dependent on spatio-temporal changes in effective pressure. The interaction with the ocean is incorporated in Paper III by combining a series of models, including an ice flow model, a plume model and a particle model for discrete calving and compares the output with observations. Results show the importance of glacier geometry, sliding and undercutting on calving rate and location. However, more observations and analytic methods are needed. Time-lapse imagery placed in front of Tunabreen have been deployed and a method of automatic detection for iceberg calving is presented in Paper IV. Results show the influence of the rising plume in calving and the front destabilisation of the local neighbourhood.
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