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| 2. |
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| 3. |
- Abila, R., et al.
(författare)
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Oil extraction imperils Africa’s Great Lakes
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 354:6312, s. 561-562
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- As the world's demands for hydrocarbons increase (1), remote areas previously made inaccessible by technological limitations are now being prospected for oil and gas deposits. Virtually unnoticed by the public, such activities are ongoing in the East African Great Lakes region, threatening these ecosystems famed for their hyper-diverse biota, including the unique adaptive radiations of cichlid fishes (2). Countries in the region see exploitation of hydrocarbon reserves as a vital economic opportunity. In the Lake Albert region of Uganda, for example, the government foresees a $3.6 billion oil profit per year starting in 2018—a sum almost as high as the country's current annual budget (3). However, oil extraction in the East African Great Lakes region poses grave risks to the environment and local communities.
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| 4. |
- Carrieri, Daniele, et al.
(författare)
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Recontacting patients in clinical genetics services : recommendations of the European Society of Human Genetics
- 2019
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Ingår i: European Journal of Human Genetics. - : NATURE PUBLISHING GROUP. - 1018-4813 .- 1476-5438. ; 27:2, s. 169-182
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Tidskriftsartikel (refereegranskat)abstract
- Technological advances have increased the availability of genomic data in research and the clinic. If, over time, interpretation of the significance of the data changes, or new information becomes available, the question arises as to whether recontacting the patient and/or family is indicated. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with research groups from the UK and the Netherlands, developed recommendations on recontacting which, after public consultation, have been endorsed by ESHG Board. In clinical genetics, recontacting for updating patients with new, clinically significant information related to their diagnosis or previous genetic testing may be justifiable and, where possible, desirable. Consensus about the type of information that should trigger recontacting converges around its clinical and personal utility. The organization of recontacting procedures and policies in current health care systems is challenging. It should be sustainable, commensurate with previously obtained consent, and a shared responsibility between healthcare providers, laboratories, patients, and other stakeholders. Optimal use of the limited clinical resources currently available is needed. Allocation of dedicated resources for recontacting should be considered. Finally, there is a need for more evidence, including economic and utility of information for people, to inform which strategies provide the most cost-effective use of healthcare resources for recontacting.
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| 5. |
- Fernández-Calle, Rosalía, et al.
(författare)
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APOE in the bullseye of neurodegenerative diseases : impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases
- 2022
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1
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Forskningsöversikt (refereegranskat)abstract
- ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell-cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.
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| 6. |
- Joosen, R.V.L., et al.
(författare)
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Correlating gene expression to physiological parameters and environmental conditions during cold acclimation of Pinus sylvestris, identification of molecular markers using cDNA microarrays
- 2006
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Ingår i: Tree Physiology. - : Oxford University Press (OUP). - 0829-318X .- 1758-4469. ; 26:10, s. 1297-1313
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Tidskriftsartikel (refereegranskat)abstract
- Scots pine (Pinus sylvestris L.) seedlings were grown under different conditions (three field locations, two seasons and two climate room regimes), and then analyzed for freezing tolerance of shoots and roots and for transcript abundance in apical buds based on a cDNA microarray containing about 1500 expressed sequence tags (ESTs) from buds of cold-treated Scots pine seedlings. In a climate room providing long daily photoperiods and high temperatures, seedlings did not develop freezing tolerance, whereas seedlings in a climate room set to provide declining temperatures and day lengths developed moderate freezing tolerance. Control seedlings grown outside under field conditions developed full freezing tolerance. Differences in physiological behavior of the different seedling groups, combined with molecular analysis, allowed identification of a large group of genes, expression of which changed during the development of freezing tolerance. Transcript abundance of several of these genes was highly correlated with freezing tolerance in seedlings differing in provenance, field location or age, making them excellent candidate marker genes for molecular tests for freezing tolerance.
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| 7. |
- Kilander, C., et al.
(författare)
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Menopausal hormone therapy and biliary tract cancer : a population-based matched cohort study in Sweden
- 2019
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 58:3, s. 290-295
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This study tested the hypothesis that contemporary menopausal hormonal therapy (MHT) increases the risk of biliary tract cancer. The risk of cancer of the biliary tract (gallbladder and extra-hepatic bile ducts) may be increased following estrogen exposure.MATERIAL AND METHODS: This was a nationwide population-based matched cohort study in Sweden. Data from the Swedish Prescribed Drug Register identified all women exposed to systemic MHT in 2005-2012. Group-level matching (1:3 ratio) was used to select women unexposed to MHT from the same study base, matched for history of delivery, thrombotic events, hysterectomy, age, smoking- and alcohol related diseases, obesity, and diabetes. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI).RESULTS: Comparing 290,186 women exposed to MHT with 870,165 unexposed, MHT did not increase the OR of biliary tract cancer. The OR of gallbladder cancer was rather decreased in MHT users (OR 0.58, 95% CI 0.43-0.79), but this association became attenuated and statistically non-significant after adjusting for gallstone disease (OR 0.84, 95% CI 0.60-1.15). The OR of extra-hepatic bile duct cancers was 0.83 (95% CI 0.61-1.15). There were no clear differences when the analyses were stratified for estrogen or estrogen/progestogen combinations. MHT increased the risk of gallstone disease (OR 6.95, 95% CI 6.64-7.28).CONCLUSIONS: Contemporary MHT does not seem to increase the risk of biliary tract cancer. The decreased risk of gallbladder cancer may be explained by the increased use of surgery for symptomatic gallstones in MHT users.
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| 8. |
- Konings, Sabine C, et al.
(författare)
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Apolipoprotein E intersects with amyloid-β within neurons
- 2023
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Ingår i: Life Science Alliance. - 2575-1077. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein E4 (ApoE4) is the most important genetic risk factor for Alzheimer's disease (AD). Among the earliest changes in AD is endosomal enlargement in neurons, which was reported as enhanced in ApoE4 carriers. ApoE is thought to be internalized into endosomes of neurons, whereas β-amyloid (Aβ) accumulates within neuronal endosomes early in AD. However, it remains unknown whether ApoE and Aβ intersect intracellularly. We show that internalized astrocytic ApoE localizes mostly to lysosomes in neuroblastoma cells and astrocytes, whereas in neurons, it preferentially localizes to endosomes-autophagosomes of neurites. In AD transgenic neurons, astrocyte-derived ApoE intersects intracellularly with amyloid precursor protein/Aβ. Moreover, ApoE4 increases the levels of endogenous and internalized Aβ 42 in neurons. Taken together, we demonstrate differential localization of ApoE in neurons, astrocytes, and neuron-like cells, and show that internalized ApoE intersects with amyloid precursor protein/Aβ in neurons, which may be of considerable relevance to AD.
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| 9. |
- Konings, Sabine C., et al.
(författare)
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Astrocytic and Neuronal Apolipoprotein E Isoforms Differentially Affect Neuronal Excitability
- 2021
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 15, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic changes and neuronal network dysfunction are among the earliest changes in Alzheimer’s disease (AD). Apolipoprotein E4 (ApoE4), the major genetic risk factor in AD, has been shown to be present at synapses and to induce hyperexcitability in mouse knock-in brain regions vulnerable to AD. ApoE in the brain is mainly generated by astrocytes, however, neurons can also produce ApoE under stress conditions such as aging. The potential synaptic function(s) of ApoE and whether the cellular source of ApoE might affect neuronal excitability remain poorly understood. Therefore, the aim of this study was to elucidate the synaptic localization and effects on neuronal activity of the two main human ApoE isoforms from different cellular sources in control and AD-like in vitro cultured neuron models. In this study ApoE is seen to localize at or near to synaptic terminals. Additionally, we detected a cellular source-specific effect of ApoE isoforms on neuronal activity measured by live cell Ca2+ imaging. Neuronal activity increases after acute but not long-term administration of ApoE4 astrocyte medium. In contrast, ApoE expressed by neurons appears to induce the highest neuronal firing rate in the presence of ApoE3, rather than ApoE4. Moreover, increased neuronal activity in APP/PS1 AD transgenic compared to wild-type neurons is seen in the absence of astrocytic ApoE and the presence of astrocytic ApoE4, but not ApoE3. In summary, ApoE can target synapses and differentially induce changes in neuronal activity depending on whether ApoE is produced by astrocytes or neurons. Astrocytic ApoE induces the strongest neuronal firing with ApoE4, while the most active and efficient neuronal activity induced by neuronal ApoE is caused by ApoE3. ApoE isoforms also differentially affect neuronal activity in AD transgenic compared to wild-type neurons.
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| 10. |
- Konings, Sabine C., et al.
(författare)
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Neurobiological role of Alzheimer's disease genetic risk factor ApoE on early synaptic changes in Alzheimer-like models
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 17:S3, s. 1-1
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Konferensbidrag (refereegranskat)abstract
- BACKGROUND: The presence of an apolipoprotein E4 (ApoE4) genotype is the major genetic risk factor for Alzheimer's disease (AD). Astrocytes are the main source of ApoE in the brain, however ApoE can also be produced by neurons and microglia. ApoE plays a role in many cell types and processes related to AD, however, it remains unclear which mechanism(s) and cellular source of ApoE are most critical for AD. One of the earliest changes in AD are early cellular changes such as endosomal and synaptic alterations. ApoE4 has been associated with impaired endosomal trafficking and dysregulated synaptic plasticity. Neuronal hyperexcitability has been reported in mice expressing human ApoE4, a dysregulation that is also seen in AD transgenic mice. Although ApoE seems to play a crucial role in neuronal changes linked to early AD, ApoE's synaptic localization and mechanisms remain poorly understood. In this study, the aim is to determine the role of ApoE, in particular ApoE4, on synaptic alterations in AD models. METHOD: Mouse neurons and astrocytes are derived from wild-type, ApoE knock-out (KO), humanized ApoE3 and ApoE4 knock-in mice. Astrocyte-conditioned medium from mouse astrocytes expressing human ApoE and recombinant ApoE are used as a source for human ApoE to treat ApoE KO, wild-type and AD transgenic APP/PS1 neurons. Additionally, ApoE KO and humanized ApoE neurons are treated with synthetic Aβ or vehicle control. Analysis is performed using immunofluorescence, confocal and live cell imaging. RESULT: Exogenously added and endogenously produced human ApoE is shown to be present at neurites and synaptic terminals of cultured neurons. Differences in neuronal activity are observed among different ApoE conditions using Ca2+ live cell microscopy, both in the presence and absence of elevated human Aβ. Added recombinant and endogenous ApoE appear to be present in the endosome-lysosome system of neurons. CONCLUSION: ApoE appears to localize at synapses and endosomes, sites associated with early cellular changes in AD, and seems to play a role in neuronal excitability. Determining the neurobiology of ApoE, in particular in connection with cellular sites vulnerable to early changes in AD, can contribute to a better understanding of the role of ApoE in AD.
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| 11. |
- Martinsson, Isak, et al.
(författare)
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Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer’s Disease
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is increasingly seen as a disease of synapses and diverse evidence has implicated the amyloid-β peptide (Aβ) in synapse damage. The molecular and cellular mechanism(s) by which Aβ and/or its precursor protein, the amyloid precursor protein (APP) can affect synapses remains unclear. Interestingly, early hyperexcitability has been described in human AD and mouse models of AD, which precedes later hypoactivity. Here we show that neurons in culture with either elevated levels of Aβ or with human APP mutated to prevent Aβ generation can both induce hyperactivity as detected by elevated calcium transient frequency and amplitude. Since homeostatic synaptic plasticity (HSP) mechanisms normally maintain a setpoint of activity, we examined whether HSP was altered in AD transgenic neurons. Using methods known to induce HSP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and that AD transgenic neurons have an impaired adaptation of calcium transients to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we show that both APP and Aβ influence neuronal activity and that mechanisms of HSP are disrupted in primary neuron models of AD.
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| 12. |
- Martinsson, I, et al.
(författare)
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Aβ/APP-induced hyperexcitability and dysregulation of homeostatic synaptic plasticity in models of Alzheimer’s disease
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The proper function of the nervous system is dependent on the appropriate timing of neuronal firing. Synapses continually undergo rapid activity-dependent modifications that require feedback mechanisms to maintain network activity within a window in which communication is energy efficient and meaningful. Homeostatic synaptic plasticity (HSP) and homeostatic intrinsic plasticity (HIP) are such negative feedback mechanisms. Accumulating evidence implicates that Alzheimer’s disease (AD)-related amyloid precursor protein (APP) and its cleavage product amyloid-beta (Aβ) play a role in the regulation of neuronal network activity, and in particular HSP. AD features impaired neuronal activity with regional early hyper-activity and Aβ-dependent hyperexcitability has also been demonstrated in AD transgenic mice. We demonstrate similar hyper-activity in AD transgenic neurons in culture that have elevated levels of both human APP and Aβ. To examine the individual roles of APP and Aβ in promoting hyperexcitability we used an APP construct that does not generate Aβ, or elevated Aβ levels independently of APP. Increasing either APP or Aβ in wild type (WT) neurons leads to increased frequency and amplitude of calcium transients. Since HSP/HIP mechanisms normally maintain a setpoint of activity, we examined whether homeostatic synaptic/intrinsic plasticity was altered in AD transgenic neurons. Using methods known to induce HSP/HIP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and show that AD transgenic neurons have an impaired response to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we present evidence that both APP and Aβ influence neuronal activity and that mechanisms of HSP/HIP are disrupted in neuronal models of AD.Competing Interest StatementThe authors have declared no competing interest.
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| 13. |
- Prater, Craig, et al.
(författare)
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Fluorescently Guided Optical Photothermal Infrared Microspectroscopy for Protein-Specific Bioimaging at Subcellular Level
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 66:4, s. 2542-2549
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Tidskriftsartikel (refereegranskat)abstract
- Infrared spectroscopic imaging is widely used for the visualization of biomolecule structures, and techniques such as optical photothermal infrared (OPTIR) microspectroscopy can achieve <500 nm spatial resolution. However, these approaches lack specificity for particular cell types and cell components and thus cannot be used as a stand-alone technique to assess their properties. Here, we have developed a novel tool, fluorescently guided optical photothermal infrared microspectroscopy, that simultaneously exploits epifluorescence imaging and OPTIR to perform fluorescently guided IR spectroscopic analysis. This novel approach exceeds the diffraction limit of infrared microscopy and allows structural analysis of specific proteins directly in tissue and single cells. Experiments described herein used epifluorescence to rapidly locate amyloid proteins in tissues or neuronal cultures, thus guiding OPTIR measurements to assess amyloid structures at the subcellular level. We believe that this new approach will be a valuable addition to infrared spectroscopy providing cellular specificity of measurements in complex systems for studies of structurally altered protein aggregates.
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| 14. |
- Ramakrishna, Sarayu, et al.
(författare)
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APOE4 affects basal and NMDAR mediated protein synthesis in neurons by perturbing calcium homeostasis
- 2021
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Ingår i: The Journal of Neuroscience. - 1529-2401. ; 41:42, s. 8686-8709
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans - APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the pre-disposition for Alzheimer's disease. The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4 induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague-Dawley rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male Sprague-Dawley rats. APOE4 treatment also abrogates the NMDA mediated translation response indicating an alteration of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation response which is closely linked to their respective calcium signature. Acute exposure of neurons to APOE3 causes a short burst of calcium through NMDARs leading to an initial decrease in protein synthesis which quickly recovers. Contrarily, APOE4 leads to a sustained increase in calcium levels by activating both NMDARs and L-VGCCs, thereby causing sustained translation inhibition through eEF2 phosphorylation, which in turn disrupts the NMDAR response. Thus, we show that APOE4 affects basal and activity mediated protein synthesis responses in neurons by affecting calcium homeostasis.SIGNIFICANCE STATEMENTDefective protein synthesis has been shown as an early defect in familial Alzheimer's disease. However, this has not been studied in the context of sporadic Alzheimer's disease, which constitutes the majority of cases. In our study, we show that APOE4, the predominant risk factor for Alzheimer's disease, inhibits global protein synthesis in neurons. APOE4 also affects NMDA activity mediated protein synthesis response, thus inhibiting synaptic translation. We also show that the defective protein synthesis mediated by APOE4 is closely linked to the perturbation of calcium homeostasis caused by APOE4 in neurons. Thus, we propose the dysregulation of protein synthesis as one of the possible molecular mechanisms to explain APOE4 mediated synaptic and cognitive defects. Hence, the study not only suggests an explanation for the APOE4 mediated pre-disposition to Alzheimer's disease, it also bridges the gap in understanding APOE4 mediated pathology.
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| 15. |
- Smith, A. L., et al.
(författare)
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Thermodynamic assessment of the neptunium-oxygen system : Mass spectrometric studies and thermodynamic modelling
- 2016
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Ingår i: Journal of Chemical Thermodynamics. - : Elsevier. - 0021-9614 .- 1096-3626. ; 103, s. 257-275
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Tidskriftsartikel (refereegranskat)abstract
- Knudsen effusion mass spectrometry measurements on neptunium dioxide are reported in this work, which have allowed to improve the understanding of its vapourization behaviour and solved discrepancies noticed in the literature: the enthalpy of formation of NpO2(g) has been re-assessed and the composition of neptunia at congruent vapourization has been determined at 2262 K. In addition, a thermodynamic model for the neptunium-oxygen system has been developed using the CALPHAD method. The non stoichiometric NpO2-x phase is described herein using the compound energy formalism with ionic constituents (Np3+, Np4+)(1) (O2-, Va)(2), while the liquid phase is represented with the ionic two-sublattice model (Np4+)(P) (O2-, Va(Q-), O)(Q). The reliability and consistency of all optimized Gibbs energies have been verified by calculating the phase equilibria, thermodynamic data, oxygen chemical potential and equilibrium partial pressures. Finally, a number of ill-defined data in the Np-O system have been identified after critical review of the literature and comparison with the present experimental results and CALPHAD model.
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