| 1. |
- Brännström, Kristoffer, et al.
(författare)
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Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner
- 2013
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Ingår i: Biochemical Journal. - : Portland Press. - 0264-6021 .- 1470-8728. ; 450, s. 189-197
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Tidskriftsartikel (refereegranskat)abstract
- Identifying factors that affect the self-assembly of the amyloid-β peptide (Aβ) is of utmost importance in the quest to understand the molecular mechanisms causing Alzheimer's disease (AD). Ca2+ has previously been shown to accelerate both Aβ fibril nucleation and maturation, and a dysregulated Ca2+ homeostasis frequently correlates with development of AD. The mechanisms regarding Ca2+ binding as well as its effect on fibril kinetics are not fully understood. Using a polymerization assay we show that Ca2+ in a dynamic and reversible manner enhances both the elongation rate and fibrillar stability, where specifically the "dock and lock" phase mechanism is enhanced. Through NMR analysis we found that Ca2+ affects the fibrillar architecture. In addition, and unexpectedly, we found that Ca2+ does not bind the free Aβ monomer. This implies that Ca2+ binding requires an architecture adopted by assembled peptides, and consequently is mediated through intermolecular interactions between adjacent peptides. This gives a mechanistic explanation to the enhancing effect on fibril maturation and indicates structural similarities between prefibrillar structures and mature amyloid. Taken together we expose how Ca2+ levels affect the delicate equilibrium between the monomeric and assembled Aβ and how fluctuations in vivo may contribute to development and progression of the disease.
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| 2. |
- Arnqvist, Anders, et al.
(författare)
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En kunskapsbas : Sätt att organisera för att individanpassa skolgången
- 2010
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Ingår i: I rättan tid. - Stockholm : Fritzes. - 9789138234471 ; , s. 67-87
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- De överväganden och förslag som redovisas i detta betänkande har tagits fram med utgångspunkt i en kunskapsbas. Kunskapsbasen består av dels översikter över aktuella forskningsresultat inom ett antal områden som har bäring på frågan om flexibel skolstart i grundskolan, dels några internationella utblickar. Vetenskapligt förankrade kunskapsöversikter har för utredningens räkning sammanställts av fyra forskare, nämligen professor Anders Arnqvist, Karlstads universitet, professor Sven Persson, Malmö högskola, fil dr Monika Vinterek, Umeå universitet och fil lic Helena Ackesjö, Linnéuniversitetet. Var och en har haft i uppdrag att inom respektive område redogöra för resultat inom svensk och internationell forskning från mitten av 1990-talet och senare. I uppdraget har ingått att uppmärksamma eventuella skillnader mellan olika elevgrupper samt effekter på både elevers kunskapsutveckling och sociala utveckling. I detta kapitel redovisas forskarnas egna sammanfattningar av forskningsöversikterna. Dessa återges i sin helhet i bilagorna 2–5. Av dem framgår också de frågeställningar och områden med bäring på flexibel skolstart som forskarna finner behov av att följa upp, utvärdera och beforska. Kunskapsbasen innehåller även en internationell utblick. I den återges hur barn på Nya Zeeland börjar skolan successivt på sin födelsedag och hur barn i England kan börja skolan vid fler tillfällen under läsåret. Lite mer utförligt redovisas dessutom diskussionen inför och införandet av rullande skolstart i Danmark och flexibel skolstart i Norge.
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| 3. |
- Burza, Matthias, et al.
(författare)
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Hollow microspheres as targets for staged laser-driven proton acceleration
- 2011
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Ingår i: New Journal of Physics. - : Institute of Physics Publishing (IOPP). - 1367-2630. ; 13, s. 013030-
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Tidskriftsartikel (refereegranskat)abstract
- A coated hollow core microsphere is introduced as a novel targetin ultra-intense laser–matter interaction experiments. In particular, it facilitates staged laser-driven proton acceleration by combining conventional target normal sheath acceleration (TNSA), power recycling of hot laterally spreading electrons and staging in a very simple and cheap target geometry. During TNSA of protons from one area of the sphere surface, laterally spreading hot electrons form a charge wave. Due to the spherical geometry, this wave refocuses on the opposite side of the sphere, where an opening has been laser micromachined.This leads to a strong transient charge separation field being set up there, which can post-accelerate those TNSA protons passing through the hole at the right time. Experimentally, the feasibility of using such targets is demonstrated. A redistribution is encountered in the experimental proton energy spectra, as predicted by particle-in-cell simulations and attributed to transient fields set up by oscillating currents on the sphere surface.
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| 4. |
- Burza, Matthias, et al.
(författare)
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Laser wakefield acceleration using wire produced double density ramps
- 2013
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Ingår i: Physical Review Special Topics. Accelerators and Beams. - 1098-4402. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- A novel approach to implement and control electron injection into the accelerating phase of a laser wakefield accelerator is presented. It utilizes a wire, which is introduced into the flow of a supersonic gas jet creating shock waves and three regions of differing plasma electron density. If tailored appropriately, the laser plasma interaction takes place in three stages: Laser self-compression, electron injection, and acceleration in the second plasma wave period. Compared to self-injection by wave breaking of a nonlinear plasma wave in a constant density plasma, this scheme increases beam charge by up to 1 order of magnitude in the quasimonoenergetic regime. Electron acceleration in the second plasma wave period reduces electron beam divergence by approximate to 25%, and the localized injection at the density downramps results in spectra with less than a few percent relative spread. DOI: 10.1103/PhysRevSTAB.16.011301
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| 5. |
- Enochsson, Lars, et al.
(författare)
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The Swedish Registry of Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks) : A nationwide registry for quality assurance of gallstone surgery.
- 2013
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Ingår i: JAMA Surgery. - : American Medical Association (AMA). - 2168-6254 .- 2168-6262. ; 148:5, s. 471-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To describe the process of initiating and organizing a nationwide validated web-based quality registry of gallstone surgery and endoscopic retrograde cholangiopancreatography (ERCP) and to present some clinical data and the impact the registry has had on the clinical treatment of gallstones.DESIGN: Observational, population-based registry study.SETTING: Data from the nationwide Swedish Registry of Gallstone Surgery and ERCP (GallRiks).PATIENTS: From May 1, 2005, to December 31, 2011, 63 685 cholecystectomies (laparoscopic and open) and 37 860 ERCPs have been prospectively registered in GallRiks.INTERVENTIONS: Cholecystectomies, laparoscopic or conventional, as well as ERCP in a population-based setting.MAIN OUTCOME MEASURES: Registrations of all cholecystectomies and ERCPs are performed online by the surgeon or endoscopist. Thirty-day follow-up of both gallstone surgery and ERCP is mandatory, as is an additional 6-month follow-up of the cholecystectomies. Scores on the 36-Item Short Form Health Survey are registered preoperatively and 6 months postoperatively in elective cholecystectomies at selected units.RESULTS: The 30-day overall complication rate is 6.1% in elective cholecystectomy, 11.2% in urgent cholecystectomy, and 12.0% following ERCP. The use of antibiotic and thromboembolic prophylaxis in elective laparoscopic cholecystectomy in Sweden has decreased by 8.7% and 17.8% (2006-2011), respectively, mainly owing to presentation of GallRiks data both at meetings and published in peer-reviewed publications. The large database has also enabled several research projects, including one demonstrating that the intention to perform intraoperative cholangiography reduced the risk of death after cholecystectomy. The database has reached greater than 90% national coverage and is continuously validated.CONCLUSIONS: GallRiks is a validated national quality registry for gallstone surgery and ERCP, serving as a base for audit of gallstone disease treatment. It also provides a database for clinical research.
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| 6. |
- Fowler, Christopher J, et al.
(författare)
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Targeting the endocannabinoid system for the treatment of cancer : a practical view
- 2010
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Ingår i: Current Topics in Medicinal Chemistry. - : Bentham Science Publishers. - 1568-0266 .- 1873-4294. ; 10:8, s. 814-827
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Forskningsöversikt (refereegranskat)abstract
- In recent years, considerable interest has been generated by findings that cannabinoids not only have useful palliative effects, but also can affect the viability and invasivity of a variety of different cancer cells. In the present review, the potential of targeting the cannabinoid system for the treatment of cancer is considered from a practical, rather than a mechanistic viewpoint, addressing questions such as whether human tumour cells express CB receptors; whether the potencies of action of cannabinoids in vitro match the potencies expected on the base of receptor theory; what is known about the in vivo effects of cannabinoids and cancer, and how relevant the experiments undertaken are to the clinical situation; and finally, what approaches can be taken to minimise unwanted effects of cannabinoid treatment. It is concluded that cannabinoids (or agents modulating the endogenous cannabinoid system) are an attractive target for drug development in the cancer area, but that more in vivo studies, particularly those investigating the potential of cannabinoids as an addition to current treatment strategies, are needed.
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| 7. |
- Hedblom, Andreas, et al.
(författare)
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CDK1 interacts with RARγ and plays an important role in treatment response of acute myeloid leukemia
- 2013
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Ingår i: Cell Cycle. - : Taylor & Francis. - 1538-4101 .- 1551-4005. ; 12:8, s. 1251-1266
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in cell cycle pathways and retinoic acid signaling are implicated in leukemogenesis. However, little is known about the roles of cyclin-dependent kinases (CDKs) in treatment response of leukemia. In this study, we observed that CDK1 expression was significantly higher in bone marrow from 42 patients with acute myeloid leukemia (AML) at recurrence than that at first diagnosis (p = 0.04). AML patients had higher level of nuclear CDK1 in their leukemic blasts tended to have poorer clinical outcome compared with those with lower levels. We showed that CDK1 function is required for all-trans retinoic acid (ATRA) to achieve the optimal effect in U-937 human leukemic cells. CDK1 modulates the levels of P27(kip) and AKT phosphorylation in response to ATRA treatment. Further, we show, for the first time, that RARγ in concert with ATRA regulates protein levels of CDK1 and its subcellular localization. The regulation of the subcellular content of CDK1 and RARγ by ATRA is an important process for achieving an effective response in treatment of leukemia. RARγ and CDK1 form a reciprocal regulatory circuit in the nucleus and influence the function and protein stability of each other and the level of P27(kip) protein. In addition, expression of wee1 kinase and Cdc25A/C phosphatases also coincide with CDK1 expression and its subcellular localization in response to ATRA treatment. Our study reveals a novel mechanism by which CDK1 and RARγ coordinate with ATRA to influence cell cycle progression and cellular differentiation.
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| 8. |
- Lindhagen-Persson, Malin, et al.
(författare)
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Amyloid-β oligomer specificity mediated by the IgM isotype : implications for a specific protective mechanism exerted by endogenous auto-antibodies
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 5:11, s. e13928-
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Tidskriftsartikel (refereegranskat)abstract
- Background Alzheimers disease (AD) has been strongly linked to an anomalous self-assembly of the amyloid-β peptide (Aβ). The correlation between clinical symptoms of AD and Aβ depositions is, however, weak. Instead small and soluble Aβ oligomers are suggested to exert the major pathological effects. In strong support of this notion, immunological targeting of Aβ oligomers in AD mice-models shows that memory impairments can be restored without affecting the total burden of Aβ deposits. Consequently a specific immunological targeting of Aβ oligomers is of high therapeutic interest. Methodology/Principal Findings Previously the generation of conformational-dependent oligomer specific anti-Aβ antibodies has been described. However, to avoid the difficult task of identifying a molecular architecture only present on oligomers, we have focused on a more general approach based on the hypothesis that all oligomers expose multiple identical epitopes and therefore would have an increased binding to a multivalent receptor. Using the polyvalent IgM immunoglobulin we have developed a monoclonal anti-Aβ antibody (OMAB). OMAB only demonstrates a weak interaction with Aβ monomers and dimers having fast on and off-rate kinetics. However, as an effect of avidity, its interaction with Aβ-oligomers results in a strong complex with an exceptionally slow off-rate. Through this mechanism a selectivity towards Aβ oligomers is acquired and OMAB fully inhibits the cytotoxic effect exerted by Aβ(1-42) at highly substoichiometric ratios. Anti-Aβ auto-antibodies of IgM isotype are frequently present in the sera of humans. Through a screen of endogenous anti-Aβ IgM auto-antibodies from a group of healthy individuals we show that all displays a preference for oligomeric Aβ. Conclusions/Significance Taken together we provide a simple and general mechanism for targeting of oligomers without the requirement of conformational-dependent epitopes. In addition, our results suggest that IgM anti-Aβ auto-antibodies may exert a more specific protective mechanism in vivo than previously anticipated.
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| 9. |
- Lindhagen Persson, Malin, 1982-
(författare)
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Targeting cytotoxic species in amyloid diseases
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyloid diseases are a world-wide problem causing great human suffer and large economical costs. Although amyloid deposits, a common denominator in all amyloid disorders, are detrimental to the surrounding tissue, there is a poor correlation between total amyloid burden and clinical symptoms. Soluble oligomers are much more potent to exert a tissue damaging effect. Alzheimer’s disease (AD) is strongly linked to self-assembly of the amyloid-β (Aβ) peptide. Antibodies selectively targeting cytotoxic Aβ-species are useful both for understanding oligomer formation and for their therapeutic abilities. We hypothesized that the effect of avidity would compensate for a low single site affinity and be enough to selectively target oligomers. To evaluate this hypothesis, we focused on the IgM isotype having ten antigen-binding sites. In accordance with the hypothesis, the IgM isotype effectively bound oligomeric Aβ also in presence of a vast excess of its monomeric counterpart, clearly illustrating the potentiating effect of avidity. As a continuation of this work, we have shown that the avidity effect from a bivalent binding is enough to induce oligomer specificity. This finding facilitates a direct application on the clinically more useful IgG isotype, where the binding properties now can be controlled in detail. The method is general and we have, using this technique, also designed oligomer specific antibodies targeting α-synuclein. Transthyretin (TTR) is an amyloidogenic protein involved in both hereditary and sporadic amyloidosis. The cytotoxicity of TTR is intriguing since studies have shown cytotoxic potential from oligomers, tetramers and even monomers. Elucidation of the molecular properties associated with TTR cytotoxicity is hence of interest. By preventing tetramer dissociation, TTR aggregation and TTR-induced cytotoxicity is abolished. Based on this rationale, a current therapeutic strategy is to stabilize the TTR tetramer with small molecules. The kinetic stability within the spectra of known TTR mutations spans more than three orders of magnitude. However, although the most stable mutants are inert, a poor correlation within the group of cytotoxic variants exists where the cytotoxic effect is not potentiated in proportion to their kinetic stability. Through analysis of a large spectra of TTR variants, our results indicate that TTR induced cytotoxicity requires an intermediate stability of the TTR molecule. The kinetic stability should be low enough to permit tetramer dissociation and the thermodynamic stability high enough to prevent instant aggregation and to allow formation of the cytotoxic fold.
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| 10. |
- Lundström, Jan O, et al.
(författare)
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The geographic distribution of mosquito species in Sweden
- 2013
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Ingår i: Journal of the European Mosquito Control Association. - 2054-930X .- 1460-6127. ; 31, s. 21-35
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Tidskriftsartikel (refereegranskat)abstract
- Surveillance of the actual distribution of mosquito species in Northern Europe is fundamental for evaluating risk for emerging pathogens, and for research on potential vectors. The Swedish mosquito fauna composition and geographic distribution, originally described by Professor Christine Dahl in the 1970´s, included 43 species. We have compiled the information published from 1978 to 2012, and our own surveillance data from 2001 to 2013, and compared this with the species list and geographic distribution provided in "Taxonomy and geographic distribution of Swedish Culicidae" by Dahl (1977). New species detected during these 36 years were Culiseta (Culicella) ochroptera (Peus, 1935) published 1984, Aedes (Aedes) rossicus Dolbeskin, Goritzkaja & Mitrofanova, 1930 published 1986, Anopheles (Anopheles) beklemishevi published 1986, Aedes (Ochlerotatus) euedes (Howard, Dyar & Knab, 1912) published 2001, Aedes (Ochlerotatus) nigrinus (Eckstein, 1918) first recorded in 2012, and Anopheles (Anopheles) algeriensis Theobald, 1903, first recorded in 2013. We provide maps with the distribution by province for each species, including historic information up until 1977, and new records from 1978 to 2013, showing the similarities and differences between the old and the new records. Important findings in recent years include the wide distribution of the Sindbis virus enzootic vector Culex (Culex) torrentium Martinii, 1925, and the more limited distribution of the potential West Nile virus vector Culex (Culex) pipiens Linnaeus, 1758. The updated list of mosquito species in Sweden now includes 49 species.
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