| 1. |
- Danielsson, Olof, et al.
(författare)
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Expression of apoptosis related proteins in normal and diseased muscle : A possible role for Bcl-2 in protection of striated muscle
- 2009
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Ingår i: NEUROMUSCULAR DISORDERS. - : Elsevier BV. - 0960-8966. ; 19:6, s. 412-417
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Tidskriftsartikel (refereegranskat)abstract
- The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle. we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.
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| 2. |
- Gennemark, Peter, et al.
(författare)
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An oral antisense oligonucleotide for PCSK9 inhibition
- 2021
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:593
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
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| 3. |
- Hoffman, Tove, et al.
(författare)
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Co-Occurrence of Francisella, Spotted Fever Group Rickettsia, and Midichloria in Avian-Associated Hyalomma rufipes
- 2022
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Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- The migratory behavior of wild birds contributes to the geographical spread of ticks and their microorganisms. In this study, we aimed to investigate the dispersal and co-occurrence of Francisella and spotted fever group Rickettsia (SFGR) in ticks infesting birds migrating northward in the African-Western Palaearctic region (AWPR). Birds were trapped with mist nests across the Mediterranean basin during the 2014 and 2015 spring migration. In total, 575 ticks were collected from 244 birds. We screened the ticks for the species Francisella tularensis, the genus Francisella, and SFGR by microfluidic real-time PCR. Confirmatory analyses and metagenomic sequencing were performed on tick samples that putatively tested positive for F. tularensis during initial screenings. Hyalomma rufipes was the most common tick species and had a high prevalence of Francisella, including co-occurrence of Francisella and SFGR. Metagenomic analysis of total DNA extracted from two H. rufipes confirmed the presence of Francisella, Rickettsia, and Midichloria. Average nucleotide identity and phylogenetic inference indicated the highest identity of the metagenome-assembled genomes to a Francisella-like endosymbiont (FLE), Rickettsia aeschlimannii, and Midichloria mitochondrii. The results of this study suggest that (i) FLE- and SFGR-containing ticks are dispersed by northbound migratory birds in the AWPR, (ii) H. rufipes likely is not involved in transmission of F. tularensis in the AWPR, and (iii) a dual endosymbiosis of FLEs and Midichloria may support some of the nutritional requirements of H. rufipes.
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| 4. |
- Maria Psonka-Antonczyk, Katarzyna, et al.
(författare)
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Nanoscopic and Photonic Ultrastructural Characterization of Two Distinct Insulin Amyloid States
- 2012
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG, POSTFACH, CH-4005 BASEL, SWITZERLAND. - 1661-6596 .- 1422-0067. ; 13:2, s. 1461-1480
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Tidskriftsartikel (refereegranskat)abstract
- Two different conformational isoforms or amyloid strains of insulin with different cytotoxic capacity have been described previously. Herein these filamentous and fibrillar amyloid states of insulin were investigated using biophysical and spectroscopic techniques in combination with luminescent conjugated oligothiophenes (LCO). This new class of fluorescent probes has a well defined molecular structure with a distinct number of thiophene units that can adopt different dihedral angles depending on its binding site to an amyloid structure. Based on data from surface charge, hydrophobicity, fluorescence spectroscopy and imaging, along with atomic force microscopy (AFM), we deduce the ultrastructure and fluorescent properties of LCO stained insulin fibrils and filaments. Combined total internal reflection fluorescence microscopy (TIRFM) and AFM revealed rigid linear fibrous assemblies of fibrils whereas filaments showed a short curvilinear morphology which assemble into cloudy deposits. All studied LCOs bound to the filaments afforded more blue-shifted excitation and emission spectra in contrast to those corresponding to the fibril indicating a different LCO binding site, which was also supported by less efficient hydrophobic probe binding. Taken together, the multi-tool approach used here indicates the power of ultrastructure identification applying AFM together with LCO fluorescence interrogation, including TIRFM, to resolve structural differences between amyloid states.
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| 5. |
- Nilsson, Susanna, et al.
(författare)
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Cross-Organizational Collaboration Supported by Augmented Reality
- 2011
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Ingår i: IEEE Transactions on Visualization and Computer Graphics. - : Institute of Electrical and Electronics Engineers (IEEE). - 1077-2626 .- 1941-0506. ; 17:10, s. 1380-1392
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a study where Augmented Reality (AR) technology has been used as a tool for supporting collaboration between the rescue services, the police and military personnel in a crisis management scenario. There are few studies on how AR systems should be designed to improve cooperation between actors from different organizations while at the same time supporting individual needs. In the present study, an AR system was utilized for supporting joint planning tasks by providing organization specific views of a shared map. The study involved a simulated emergency event conducted in close to real settings with representatives from the organizations for which the system is developed. As a baseline, a series of trials without the AR system was carried out. Results show that the users were positive toward the AR system and would like to use it in real work. They also experience some performance benefits of using the AR system compared to their traditional tools. Finally, the problem of designing for collaborative work as well as the benefits of using an iterative design processes is discussed.
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| 6. |
- Nilsson, Susanna, et al.
(författare)
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Cross-Organizational Collaboration Supported by Augmented Reality
- 2011
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Ingår i: IEEE Transactions on Visualization and Computer Graphics. - : Institute of Electrical and Electronics Engineers (IEEE). - 1077-2626 .- 1941-0506. ; 17:10, s. 1380-1392
-
Tidskriftsartikel (refereegranskat)abstract
- This paper presents a study where Augmented Reality (AR) technology has been used as a tool for supporting collaboration between the rescue services, the police and military personnel in a crisis management scenario. There are few studies on how AR systems should be designed to improve cooperation between actors from different organizations while at the same time supporting individual needs. In the present study, an AR system was utilized for supporting joint planning tasks by providing organization specific views of a shared map. The study involved a simulated emergency event conducted in close to real settings with representatives from the organizations for which the system is developed. As a baseline, a series of trials without the AR system was carried out. Results show that the users were positive toward the AR system and would like to use it in real work. They also experience some performance benefits of using the AR system compared to their traditional tools. Finally, the problem of designing for collaborative work as well as the benefits of using an iterative design processes is discussed.
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| 7. |
- Nyström, Sofie, et al.
(författare)
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Evidence for Age-Dependent in Vivo Conformational Rearrangement within A beta Amyloid Deposits
- 2013
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Ingår i: ACS Chemical Biology. - : American Chemical Society. - 1554-8929 .- 1554-8937. ; 8:6, s. 1128-1133
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Tidskriftsartikel (refereegranskat)abstract
- Deposition of aggregated A beta peptide in the brain is one of the major hallmarks of Alzheimers disease. Using a combination of two structurally different, but related, hypersensitive fluorescent amyloid markers, LCOs, reporting on separate ultrastructural elements, we show that conformational rearrangement occurs within A beta plaques of transgenic mouse models as the animals age. This important mechanistic insight should aid the design and evaluation of experiments currently using plaque load as readout.
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