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- Larsson, Mårten, et al.
(författare)
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Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins
- 2003
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 373:2, s. 381-391
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Tidskriftsartikel (refereegranskat)abstract
- Megalin is an integral membrane receptor belonging to the low-density lipoprotein receptor family. In addition to its role as an endocytotic receptor, megalin has also been proposed to have signalling functions. Using interaction cloning in yeast, we identified the membrane-associated guanylate kinase family member postsynaptic density-95 (PSD-95) as an interaction partner for megalin. PSD-95 and a truncated version of megalin were co-immunoprecipitated from HEK-293 cell lysates overexpressing the two proteins, which confirmed the interaction. The two proteins were found to be co-localized in these cells by confocal microscopy. Immunocytochemical studies showed that cells in the parathyroid, proximal tubuli of the kidney and placenta express both megalin and PSD-95. We found that the interaction between the two proteins is mediated by the binding of the C-terminus of megalin, which has a type I PSD-95/ Drosophila discs-large/zona occludens 1 (PDZ)-binding motif, to the PDZ2 domain of PSD-95. The PSD-95-like membrane-associated guanylate kinase ('MAGUK') family contains three additional members: PSD-93, synapse-associated protein 97 (SAP97) and SAP102. We detected these proteins, apart from SAP102, in parathyroid chief cells, a cell type having a marked expression of megalin. The PDZ2 domains of PSD-93 and SAP102 were also shown to interact with megalin, whereas no interaction was detected for SAP97. The SAP97 PDZ2 domain differed at four positions from the other members of the PSD-95 subfamily. One of these residues was Thr(389), located in the alphaB-helix and part of the hydrophobic pocket of the PDZ2 domain. Surface plasmon resonance experiments revealed that mutation of SAP97 Thr(389) to alanine, as with the other PSD-95-like membrane-associated guanylate kinases, induced binding to megalin.
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- Buciuto, Robert
(författare)
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Treatment of unstable trochanteric hip fractures : A clinical, mechanical and radiographic evaluation of the RAB-plate
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The problems associated with the management of proximal femoral fractures gain more attention as the elderly population continue to increase. It has been estimated that the total number of hip fractures in the world will increase from 1.7 million per year in 1990 to 6.3 million per year in 2050 (Cooper et al 1992). Operative treatment of these fractures is a challenge for the orthopaedic surgeon mainly due to poor bone quality, which increases the risk of fixation failure.More than 50% of the total number of hip fractures are extracapsular fractures. Mortality, morbidity and costs as a result of trochanteric fracture are higher than those for a cervical fracture. The consequence is increased resource consumption in the national health-care system. The estimated total cost of treatment increase 3-fold in case of a complication. Therefore, a variety of different devices have been designed in order to decrease the ratio of complications. However, in spite of this, the reported ratio of fixation failure continues be high and may reach 25% following treatment of unstable trochanteric fractures. We evaluated a new type of fixation device, the RAB-plate (Rigidity Augmentation Baixauli), for the treatment of unstable trochanteric hip fractures. The RAB-plate is a fixed 120-degree angle blade-plate with a buttress rod.We performed three clinical trials where 391 unstable trochanteric fractures were stabilised with the RAB-plate or a Sliding Hip Screw (SHS). The results showed a statistically significant lower number of complications in fractures stabilised with the RAB-plate.The fatigue resistance of the RAB-plate was evaluated in a cyclic loading test model. The RAB-plate had a statistically significant higher fatigue strength than two different designs of the SHS.Stability of the fixation and modes of failure were radiographically analysed in a series of 218 unstable trochanteric fractures treated with the RAB-plate or the SHS. The RAB-plate provided a more stable fixation especially with regard to maintained postoperative alignment. However, positive predictors for fixation failure e.g.implant position within the femoral head, varus reduction in anteroposterior projection and screw/neck angle deviation in the lateral projection were identical for both devices.Spontaneous femoral neck fracture after removal of the fixation device in healed unstable trochanteric fractures was investigated in a series of 7 patients. Our results indicate that implant-induced osteoporosis (stress protection) is a possible cause of subsequent fracture.Our conclusions are that the RAB-plate is a safe implant for fixation of unstable trochanteric hip fractures and results in lower incidence of complications compared to SHS. Therefore, the RAB can be recommended for fixation of unstable trochanteric fractures.
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- Irobi, Edward, et al.
(författare)
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Structural basis of actin sequestration by thymosin β4 : implications for WH2 proteins
- 2004
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Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 23:18, s. 3599-608
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Tidskriftsartikel (refereegranskat)abstract
- The WH2 (Wiscott-Aldridge syndrome protein homology domain 2) repeat is an actin interacting motif found in monomer sequestering and filament assembly proteins. We have stabilized the prototypical WH2 family member, thymosin-beta4 (Tbeta4), with respect to actin, by creating a hybrid between gelsolin domain 1 and the C-terminal half of Tbeta4 (G1-Tbeta4). This hybrid protein sequesters actin monomers, severs actin filaments and acts as a leaky barbed end cap. Here, we present the structure of the G1-Tbeta4:actin complex at 2 A resolution. The structure reveals that Tbeta4 sequesters by capping both ends of the actin monomer, and that exchange of actin between Tbeta4 and profilin is mediated by a minor overlap in binding sites. The structure implies that multiple WH2 motif-containing proteins will associate longitudinally with actin filaments. Finally, we discuss the role of the WH2 motif in arp2/3 activation.
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| 8. |
- Kronstrand, Robert, et al.
(författare)
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Quantitative Analysis of Desmethylselegiline, Methamphetamine, and Amphetamine in Hair and Plasma from Parkinson Patients on Long-Term Selegiline Medicatio
- 2003
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Ingår i: Journal of Analytical Toxicology. - : Oxford University Press (OUP). - 0146-4760 .- 1945-2403. ; 27:3, s. 135-141
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Tidskriftsartikel (refereegranskat)abstract
- Hair and plasma from patients on long-term selegiline medication were analyzed to evaluate the relationships between plasma and hair melanin concentrations and the incorporation of the selegiline metabolites methamphetamine and amphetamine in hair, and to evaluate hair analyses for determining compliance in medication. Analyses were performed on both the whole hairs, as well as pigmented and non-pigmented hairs from gray-haired patients. Melanin was quantitated by spectrophotometry, and metabolites were quantitated by gas chromatography-mass spectrometry. Concentrations in pigmented and non-pigmented hairs differed significantly for both methamphetamine (p < 0.01) and amphetamine (p < 0.02), with mean concentration ratios being 3.69 ± 1.88 and 2.95 ± 1.16 for methamphetamine and amphetamine, respectively. Segmental analysis indicated that some patients had not been compliant with medication. We concluded that the incorporation of methamphetamine and amphetamine into hair of single individuals shows a preference for pigmented hairs over white hairs and that segmental analysis of hair may he useful when measuring compliance with medication.
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| 9. |
- Larsson, Robert, et al.
(författare)
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Styrsystem för ändamålsstyrd torkning : förutsättningar och industriförsök
- 2002
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Del A: Inledningsvis behandlas allmänna principer för adaptiv reglering av torkprocessen vad gäller solitt trä. De grundläggande meknaismerna som ligger bakom fukttransporten i trä vid artificiell torkning beskrivs även. På basis av denna fundamentala kunskap kan exempelvis parameterstyrning utvecklas för industriella satstorksystem. Ett antal principer för sådan styrning har implementerats i en laboratorietork. Del B: Ett antal industriförsök i full skala har genomförts för att undersöka hur en dynamisk återkoppling i styrsystemet kan ske. Exempelvis finns tydliga samband mellan vireksstapelns krympning och dess medelfuktkvot, vilket tillsammans med andra signaler från torkningen kan ge återkoppling i styrsystemet. En multivariat ansats kan vara en möjlig utveckling till ett styrsystem som även innefattar ett integrerat expertsystem för färgstyrning bl a.
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