| 1. |
- Borgegard, Tomas, et al.
(författare)
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Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.
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| 2. |
- Borgegård, Tomas, et al.
(författare)
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Alzheimer's Disease : Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.
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| 3. |
- Sehgelmeble, Fernando, et al.
(författare)
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Sulfonimidamides as Sulfonamides Bioisosteres : Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with γ-Secretase Inhibitors
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 396-399
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Tidskriftsartikel (refereegranskat)abstract
- The proof of the pudding: A proof-of-concept study using γ-secretase inhibitors as a model has shown that sulfonimidamides act as bioisosteres for sulfonamides. Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility. Our data support a wider use of this unique functional group in the design of new pharmacologically active agents.
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| 4. |
- Bokhorst, Stef, et al.
(författare)
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Changing Arctic snow cover : A review of recent developments and assessment of future needs for observations, modelling, and impacts
- 2016
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 45:5, s. 516-537
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Forskningsöversikt (refereegranskat)abstract
- Snow is a critically important and rapidly changing feature of the Arctic. However, snow-cover and snowpack conditions change through time pose challenges for measuring and prediction of snow. Plausible scenarios of how Arctic snow cover will respond to changing Arctic climate are important for impact assessments and adaptation strategies. Although much progress has been made in understanding and predicting snow-cover changes and their multiple consequences, many uncertainties remain. In this paper, we review advances in snow monitoring and modelling, and the impact of snow changes on ecosystems and society in Arctic regions. Interdisciplinary activities are required to resolve the current limitations on measuring and modelling snow characteristics through the cold season and at different spatial scales to assure human well-being, economic stability, and improve the ability to predict manage and adapt to natural hazards in the Arctic region.
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| 5. |
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| 6. |
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| 7. |
- Ingvander, Susanne, 1979-, et al.
(författare)
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Method study : Grain size sampling and digital object oriented image analysis for explanation of snow grain size, shape and distribution
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Ingår i: Journal of Glaciology. - 0022-1430 .- 1727-5652.
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a digital image processing method for snow particle size and shape analysis suitable for quick and reliable analysis in the eld. Snow particle size is an important parameter strongly aecting snow cover albedo from seasonally snow covered areas and ice sheets. It is also important in remote sensing analysis because it influences the reflectance and scattering properties of the snow. Alternatively traditional methods based on visual inspection of samples can be used but they do not yield quantitative data. Our method provides an additional alternative to both simpler and more complex methods by providinga tool that limits the subjective eect of the visual analysis and provides a quantitativeparticle size distribution. The method involves image analysis software and field efficient instrumentation in order to develop a complete process-chain easily implemented under field conditions. The results from the analysis are a two dimensional analysis of particle size, shape and distributions for each sample. The developed method improves snow particle analysis being quantitative, reproducible and applicable for dierent types of eld sites.
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| 8. |
- Ingvander, Susanne, et al.
(författare)
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Particle Size Sampling and Object-Oriented Image Analysis for Field Investigations of Snow Particle Size, Shape, and Distribution
- 2013
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Ingår i: Arctic, Antarctic and Alpine research. - : Informa UK Limited. - 1523-0430 .- 1938-4246. ; 45:3, s. 330-341
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Tidskriftsartikel (refereegranskat)abstract
- Snow particle size is an important parameter strongly affecting snow cover broadband albedo from seasonally snow covered areas and ice sheets. It is also important in remote sensing analyses because it influences the reflectance and scattering properties of the snow. We have developed a digital image processing method for the capture and analysis of data of snow particle size and shape. The method is suitable for quick and reliable data capture in the field. Traditional methods based on visual inspection of samples have been used but do not yield quantitative data. Our method provides an alternative to both simpler and more complex methods by providing a tool that limits the subjective effect of the visual analysis and provides a quantitative particle size distribution. The method involves image analysis software and field efficient instrumentation in order to develop a complete process-chain easily implemented under field conditions. The output from the analysis is a two-dimensional analysis of particle size, shape, and distributions for each sample. The results of the segmentation process were validated against manual delineation of snow particles. The developed method improves snow particle analysis because it is quantitative, reproducible, and applicable for different types of field sites.
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| 9. |
- Ingvander, Susanne, et al.
(författare)
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Seasonal and interannual variability of elemental carbon in the snowpack of Storglaciaren, northern Sweden
- 2013
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Ingår i: Annals of Glaciology. - 0260-3055 .- 1727-5644. ; 54:62, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- We studied the variability of elemental carbon (EC) over 3 years (2009-11) in the winter snowpack of Storglaciaren, Sweden. The goal of this study was to relate the seasonal variation in EC to specific snow accumulation events in order to improve understanding of how different atmospheric circulation patterns control the deposition of EC. Specifically, we related meteorological parameters (e.g. wind direction, precipitation) to snow physical properties, EC content, stable-isotope 8180 ratios and anion concentrations in the snowpack. The distribution of EC in the snowpack varied between years. Low EC contents corresponded to a predominance of weather systems originating in the northwest, i.e. North Atlantic. Analysis of single layers within the snowpacks showed that snow layers enriched in heavy isotopes coincided predominantly with low EC contents but high chloride and sulfate concentration. Based on this isotopic and geochemical evidence, snow deposited during these events had a strong oceanic, i.e. North Atlantic, imprint. In contrast, snow layers with high EC content coincided with snow layers depleted in heavy isotopes but high anion concentrations, indicating a more continental source of air masses and origin of EC from industrial emissions.
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| 10. |
- Rosqvist, Kristina, et al.
(författare)
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Dopaminergic effect on non-motor symptoms in late stage Parkinson's disease
- 2018
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Ingår i: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 8:3, s. 409-420
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Tidskriftsartikel (refereegranskat)abstract
- Background: Non-motor symptoms (NMS) are common in late stage Parkinson's disease (PD), as the frequency and severity of most of these symptoms increase with advancing disease. Objective: To assess effect of dopaminergic therapy on NMS in late stage PD and to investigate relationships between dopaminergic effect on NMS and on motor function. Method: Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in "on" were included. Dopaminergic effect on non-motor symptomatology was assessed by the modified version of the Non-Motor Symptoms Scale (NMSS) in the "off" and the "on" state during a standardized L-dopa test, in parallel also assessing motor function. Results: NMS were common and many of the symptoms occurred in>80% of the individuals. The highest NMSS scores were seen within the NMSS domains 3: mood/apathy and 7: urinary in both the "off" and the "on" state. There was a statistically significant (p<0.001) improvement in the modified NMSS total score (median) from 79 in "off" to 64 in "on". There were statistically significant differences between the "off" and the "on" state for domains 2: sleep/fatigue, 3: mood/apathy, 5: attention/memory, 6: gastrointestinal and 7: urinary. The differences in the NMSS score between the "off" and the "on" state were in general larger for motor responders than for motor non-responders. In motor non-responders, differences of the NMSS score between the "off" and the "on" state were found for the total score, domain 3: mood/apathy and its item 11-flat moods. Conclusion: There is an effect of dopaminergic medication on NMS in late stage PD, to some extent also for those with a non-significant response on motor function during L-dopa test. It is therefore of importance to optimize dopaminergic therapy in order to give the most effective symptomatic treatment possible.
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