| 1. |
- Brännström, Kristoffer, et al.
(författare)
-
Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner
- 2013
-
Ingår i: Biochemical Journal. - : Portland Press. - 0264-6021 .- 1470-8728. ; 450, s. 189-197
-
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.
|
|
| 2. |
- Arnqvist, Anders, et al.
(författare)
-
En kunskapsbas : Sätt att organisera för att individanpassa skolgången
- 2010
-
Ingår i: I rättan tid. - Stockholm : Fritzes. - 9789138234471 ; , s. 67-87
-
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.
|
|
| 3. |
- Björklund, Emmelie, et al.
(författare)
-
Involvement of Fatty Acid Amide Hydrolase and Fatty Acid Binding Protein 5 in the Uptake of Anandamide by Cell Lines with Different Levels of Fatty Acid Amide Hydrolase Expression: A Pharmacological Study
- 2014
-
Ingår i: PLOS ONE. - : PLoS ONE. - 1932-6203. ; 9:7, s. e103479-
-
Tidskriftsartikel (refereegranskat)abstract
- Background:The endocannabinoid ligand anandamide (AEA) is removed from the extracellular space by a process ofcellular uptake followed by metabolism. In many cells, such as the RBL-2H3 cell line, inhibition of FAAH activity reduces theobserved uptake, indicating that the enzyme regulates uptake by controlling the intra- : extracellular AEA concentrationgradient. However, in other FAAH-expressing cells, no such effect is seen. It is not clear, however, whether these differencesare methodological in nature or due to properties of the cells themselves. In consequence, we have reinvestigated the roleof FAAH in gating the uptake of AEA.Methodology/Principal Findings: The effects of FAAH inhibition upon AEA uptake were investigated in four cell lines: AT1rat prostate cancer, RBL-2H3 rat basophilic leukaemia, rat C6 glioma and mouse P19 embryonic carcinoma cells. SemiquantitativePCR for the cells and for a rat brain lysate confirmed the expression of FAAH. No obvious expression of atranscript with the expected molecular weight of FLAT was seen. FAAH expression differed between cells, but all four couldaccumulate AEA in a manner inhibitable by the selective FAAH inhibitor URB597. However, there was a difference in thesensitivities seen in the reduction of uptake for a given degree of FAAH inhibition produced by a reversible FAAH inhibitor,with C6 cells being more sensitive than RBL-2H3 cells, despite rather similar expression levels and activities of FAAH. Thefour cell lines all expressed FABP5, and AEA uptake was reduced in the presence of the FABP5 inhibitor SB-FI-26, suggestingthat the different sensitivities to FAAH inhibition for C6 and RBL2H3 cells is not due to differences at the level of FABP-5.Conclusions/Significance: When assayed using the same methodology, different FAAH-expressing cells display differentsensitivities of uptake to FAAH inhibition.
|
|
| 4. |
- Brännström, Kristoffer, et al.
(författare)
-
A Generic Method for Design of Oligomer-Specific Antibodies
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3, s. e90857-
-
Tidskriftsartikel (refereegranskat)abstract
- Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specific antibodies. The method takes a two-step approach where discrimination between oligomers and fibrils is first accomplished through identification of cryptic epitopes exclusively buried within the structure of the fibrillar form. The second step discriminates between monomers and oligomers based on differences in avidity. We show here that a simple divalent mode of interaction, as within e. g. the IgG isotype, can increase the binding strength of the antibody up to 1500 times compared to its monovalent counterpart. We expose how the ability to bind oligomers is affected by the monovalent affinity and the turnover rate of the binding and, importantly, also how oligomer specificity is only valid within a specific concentration range. We provide an example of the method by creating and characterising a spectrum of different monoclonal antibodies against both the A beta peptide and alpha-synuclein that are associated with Alzheimer's and Parkinson's diseases, respectively. The approach is however generic, does not require identification of oligomer-specific architectures, and is, in essence, applicable to all polypeptides that form oligomeric and fibrillar assemblies.
|
|
| 5. |
- Burza, Matthias, et al.
(författare)
-
Hollow microspheres as targets for staged laser-driven proton acceleration
- 2011
-
Ingår i: New Journal of Physics. - : Institute of Physics Publishing (IOPP). - 1367-2630. ; 13, s. 013030-
-
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.
|
|
| 6. |
- Burza, Matthias, et al.
(författare)
-
Laser wakefield acceleration using wire produced double density ramps
- 2013
-
Ingår i: Physical Review Special Topics. Accelerators and Beams. - 1098-4402. ; 16:1
-
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
|
|
| 7. |
- Enochsson, Lars, et al.
(författare)
-
The Swedish Registry of Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks) : A nationwide registry for quality assurance of gallstone surgery.
- 2013
-
Ingår i: JAMA Surgery. - : American Medical Association (AMA). - 2168-6254 .- 2168-6262. ; 148:5, s. 471-8
-
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.
|
|
| 8. |
- Fowler, Christopher J, et al.
(författare)
-
Targeting the endocannabinoid system for the treatment of cancer : a practical view
- 2010
-
Ingår i: Current Topics in Medicinal Chemistry. - : Bentham Science Publishers. - 1568-0266 .- 1873-4294. ; 10:8, s. 814-827
-
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.
|
|
| 9. |
- Hedblom, Andreas, et al.
(författare)
-
CDK1 interacts with RARγ and plays an important role in treatment response of acute myeloid leukemia
- 2013
-
Ingår i: Cell Cycle. - : Taylor & Francis. - 1538-4101 .- 1551-4005. ; 12:8, s. 1251-1266
-
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.
|
|
| 10. |
- Lindhagen-Persson, Malin, et al.
(författare)
-
Amyloid-β oligomer specificity mediated by the IgM isotype : implications for a specific protective mechanism exerted by endogenous auto-antibodies
- 2010
-
Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 5:11, s. e13928-
-
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.
|
|
