| 41. |
- 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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| 42. |
- Boushel, R, et al.
(författare)
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Editorial
- 2015
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Ingår i: Scandinavian journal of medicine & science in sports. - : Wiley. - 1600-0838 .- 0905-7188. ; 25 Suppl 4, s. 1-6
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 43. |
- Cadieux-Dion, M, et al.
(författare)
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Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy
- 2020
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Ingår i: The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. - : Cambridge University Press (CUP). - 0317-1671 .- 2057-0155. ; 47:6, s. 800-809
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Our purpose was to determine the role of CHRNA4 and CHRNB2 in insular epilepsy.Method:We identified two patients with drug-resistant predominantly sleep-related hypermotor seizures, one harboring a heterozygous missense variant (c.77C>T; p. Thr26Met) in the CHRNB2 gene and the other a heterozygous missense variant (c.1079G>A; p. Arg360Gln) in the CHRNA4 gene. The patients underwent electrophysiological and neuroimaging studies, and we performed functional characterization of the p. Thr26Met (c.77C>T) in the CHRNB2 gene.Results:We localized the epileptic foci to the left insula in the first case (now seizure-free following epilepsy surgery) and to both insulae in the second case. Based on tools predicting the possible impact of amino acid substitutions on the structure and function of proteins (sorting intolerant from tolerant and PolyPhen-2), variants identified in this report could be deleterious. Functional expression in human cell lines of α4β2 (wild-type), α4β2-Thr26Met (homozygote), and α4β2/β2-Thr26Met (heterozygote) nicotinic acetylcholine receptors revealed that the mutant subunit led to significantly higher whole-cell nicotinic currents. This feature was observed in both homo- and heterozygous conditions and was not accompanied by major alterations of the current reversal potential or the shape of the concentration-response relation.Conclusions:This study suggests that variants in CHRNB2 and CHRNA4, initially linked to autosomal dominant nocturnal frontal lobe epilepsy, are also found in patients with predominantly sleep-related insular epilepsy. Although the reported variants should be considered of unknown clinical significance for the moment, identification of additional similar cases and further functional studies could eventually strengthen this association.
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| 44. |
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| 45. |
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| 46. |
- Dahlgren, Hanna, et al.
(författare)
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Energy and flux variations across thin auroral arcs
- 2011
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Ingår i: Annales Geophysicae. - : Copernicus GmbH. - 0992-7689 .- 1432-0576. ; 29:10, s. 1699-1712
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Tidskriftsartikel (refereegranskat)abstract
- Two discrete auroral arc filaments, with widths of less than 1 km, have been analysed using multi-station, multi-monochromatic optical observations from small and medium field-of-view imagers and the EISCAT radar. The energy and flux of the precipitating electrons, volume emission rates and local electric fields in the ionosphere have been determined at high temporal (up to 30 Hz) and spatial (down to tens of metres) resolution. A new time-dependent inversion model is used to derive energy spectra from EISCAT electron density profiles. The energy and flux are also derived independently from optical emissions combined with ion-chemistry modelling, and a good agreement is found. A robust method to obtain detailed 2-D maps of the average energy and number flux of small scale aurora is presented. The arcs are stretched in the north-south direction, and the lowest energies are found on the western, leading edges of the arcs. The large ionospheric electric fields (250 mV m(-1)) found from tristatic radar measurements are evidence of strong currents associated with the region close to the optical arcs. The different data sets indicate that the arcs appear on the boundaries between regions with different average energy of diffuse precipitation, caused by pitch-angle scattering. The two thin arcs on these boundaries are found to be related to an increase in number flux (and thus increased energy flux) without an increase in energy.
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| 47. |
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| 48. |
- Dreilich, M., et al.
(författare)
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High-risk human papilloma virus (HPV) and survival in patients with esophageal carcinoma : a pilot study
- 2006
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 6, s. 94-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Human papilloma virus (HPV) in patients with esophageal carcinoma has previously been studied with an average detection rate of 15%, but the role of HPV in relation to survival is less clear. In cervical cancer, lung cancer and tonsil cancer HPV viral load is a predictive factor for survival and outcome of treatment. The primary aim was to study the spectrum of high-risk HPV types in esophageal tumors. Secondary, as a pilot study we investigated the association between HPV status and the survival rates. METHODS: We compared both the presence and the viral load of high-risk HPV types 16, 18, 31, 33, 39, 45, 52, 58, and 67 in relation to clinical data from patients with esophageal carcinoma. Survival data and tumor samples were retrieved from 100 patients receiving treatment at the Department of Oncology, Uppsala Hospital, Uppsala, Sweden. The tumor samples were investigated for HPV viral load using real-time PCR. RESULTS: HPV 16 was detected in 16% of the patients; no other HPV type was detected. HPV 16 infection had no significant effect on survival (p = 0.72). Also, HPV 16 did not improve survival after treatment (radiotherapy or chemotherapy). CONCLUSION: Only HPV 16 was detected among the patients. HPV 16 in esophageal carcinoma patients did not influence survival or improve therapy response. However, given the size of the study there is a need to examine a larger cohort in order to understand in more detail the effect of high risk HPV types in esophageal carcinoma.
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| 49. |
- Edlund, Petra, et al.
(författare)
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The room temperature crystal structure of a bacterial phytochrome determined by serial femtosecond crystallography
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Phytochromes are a family of photoreceptors that control light responses of plants, fungi and bacteria. A sequence of structural changes, which is not yet fully understood, leads to activation of an output domain. Time-resolved serial femtosecond crystallography (SFX) can potentially shine light on these conformational changes. Here we report the room temperature crystal structure of the chromophore-binding domains of the Deinococcus radiodurans phytochrome at 2.1 angstrom resolution. The structure was obtained by serial femtosecond X-ray crystallography from microcrystals at an X-ray free electron laser. We find overall good agreement compared to a crystal structure at 1.35 angstrom resolution derived from conventional crystallography at cryogenic temperatures, which we also report here. The thioether linkage between chromophore and protein is subject to positional ambiguity at the synchrotron, but is fully resolved with SFX. The study paves the way for time-resolved structural investigations of the phytochrome photocycle with time-resolved SFX.
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| 50. |
- Ekholm, Jennifer, et al.
(författare)
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Full-scale aerobic granular sludge for municipal wastewater treatment – granule formation, microbial succession, and process performance
- 2022
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Ingår i: Environmental Science: Water Research & Technology. - 2053-1419. ; :8, s. 3138-3154
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Tidskriftsartikel (refereegranskat)abstract
- Aerobic granular sludge (AGS) plants have gained growing interest and application due to their low energy demand, small footprint, and low operational costs. However, the fulfilment of strict discharge limits for nitrogen and phosphorus, vast seasonal temperature variations, and large peaks in influent flows may pose challenges to the implementation of AGS. Moreover, the knowledge about microbial community assembly and process performance under varying environmental conditions in full-scale reactors is still limited. In this study, the first implementation of the AGS process in the Nordic countries was assessed. In two full-scale AGS reactors with different seeding sludges, the start-up was associated with rapid changes in microbial community composition in both, but only successful granulation in one. As a consequence, the non-granulated reactor was eventually reseeded with biomass from the better granulated reactor. This resulted in a convergence of the microbial communities in the two reactors with the maintenance of stable sludge concentrations (6–8 g L−1) with large granules (50–80% with diameter >2 mm) and fast settling of biomass (SVI30/SVI10 of 0.9–1). Immigration from the influent wastewater was a minor factor affecting the microbial community once the granules had formed, while the seasonal variations in environmental factors were identified as important. Key guilds of AOB (Nitrosomonas), NOB (mainly Ca. Nitrotoga), PAOs (mainly Tetrasphaera), and GAOs (mainly Ca. Competibacter) varied considerably in abundance throughout the study period. After 15 months, stable organic matter, nitrogen, and phosphorus removal were attained with low effluent concentrations. During the start-up, the BOD7/N ratio, influent flow, and temperature were important factors influencing the performance of the AGS.
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