| 1. |
- Abrahamsson, L., et al.
(författare)
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Behöver arbetslinjen inte forskning?
- 2007
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Ingår i: Svenska Dagbladet Brännpunkt (debattinlägg). ; :2007-11-28
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 2. |
- Aili, Margareta, et al.
(författare)
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Functional analysis of the YopE GTPase-activating protein (GAP) activity of Yersinia pseudotuberculosis
- 2006
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Ingår i: Cellular Microbiology. - : Wiley. - 1462-5814 .- 1462-5822. ; 8:6, s. 1020-1033
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Tidskriftsartikel (refereegranskat)abstract
- YopE of Yersinia pseudotuberculosis inactivates three members of the small RhoGTPase family (RhoA, Rac1 and Cdc42) in vitro and mutation of a critical arginine abolishes both in vitro GTPase-activating protein (GAP) activity and cytotoxicity towards HeLa cells, and renders the pathogen avirulent in a mouse model. To understand the functional role of YopE, in vivo studies of the GAP activity in infected eukaryotic cells were conducted. Wild-type YopE inactivated Rac1 as early as 5 min after infection whereas RhoA was down regulated about 30 min after infection. No effect of YopE was found on the activation state of Cdc42 in Yersinia-infected cells. Single-amino-acid substitution mutants of YopE revealed two different phenotypes: (i) mutants with significantly lowered in vivo GAP activity towards RhoA and Rac1 displaying full virulence in mice, and (ii) avirulent mutants with wild-type in vivo GAP activity towards RhoA and Rac1. Our results show that Cdc42 is not an in vivo target for YopE and that YopE interacts preferentially with Rac1, and to a lesser extent with RhoA, during in vivo conditions. Surprisingly, we present results suggesting that these interactions are not a prerequisite to establish infection in mice. Finally, we show that avirulent yopE mutants translocate YopE in about sixfold higher amount compared with wild type. This raises the question whether YopE's primary function is to sense the level of translocation rather than being directly involved in downregulation of the host defence.
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| 3. |
- Aili, Margareta, et al.
(författare)
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Regulation of Yersinia Yop-effector delivery by translocated YopE
- 2008
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Ingår i: International Journal of Medical Microbiology. - : Elsevier. - 1438-4221 .- 1618-0607. ; 298:3-4, s. 183-192
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Tidskriftsartikel (refereegranskat)abstract
- The bacterial pathogen Yersinia pseudotuberculosis uses a type III secretion (T3S) system to translocate Yop effectors into eukaryotic cells. Effectors are thought to gain access to the cytosol via pores formed in the host cell plasma membrane. Translocated YopE can modulate this pore formation through its GTPase-activating protein (GAP) activity. In this study, we analysed the role of translocated YopE and all the other known Yop effectors in the regulation of effector translocation. Elevated levels of Yop effector translocation into HeLa cells occurred by YopE-defective strains, but not those defective for other Yop effectors. Only Yersinia devoid of YopK exhibits a similar hyper-translocation phenotype. Since both yopK and yopE mutants also failed to down-regulate Yop synthesis in the presence of eukaryotic cells, these data imply that translocated YopE specifically regulates subsequent effector translocation by Yersinia through at least one mechanism that involves YopK. We suggest that the GAP activity of YopE might be working as an intra-cellular probe measuring the amount of protein translocated by Yersinia during infection. This may be a general feature of T3S-associated GAP proteins, since two homologues from Pseudomonas aeruginosa, exoenzyme S (ExoS) and exoenzyme T (ExoT), can complement the hyper-translocation phenotypes of the yopE GAP mutant.
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| 4. |
- Anderot, Maria, et al.
(författare)
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Determination of dissociation constants between polyelectrolytes and proteins by affinity capillary electrophoresis
- 2009
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 877:10, s. 892-896
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Tidskriftsartikel (refereegranskat)abstract
- In this manuscript we report the binding affinity between two model proteins, human serum albumin (HSA) and ribonuclease A (RNase A), and negatively charged polyelectrolytes, two different heparin fractions and dextran sulfate, by means of partial filling and affinity capillary electrophoresis. The apparent dissociation constants, K-d, obtained by use of the partial-filling method, between HSA and heparin (17 kDa), heparin (3 kDa) and dextran sulfate (8 kDa) were 33 and 307 mu M, respectively. A new method was developed to determine affinities that take in account different migration directions between the protein and the polyelectrolyte, which was required to study RNase A. By use of this affinity capillary electrophoresis two K-d values were observed for the interaction between RNase A and heparin 17 kDa, yielding a high affinity binding with K-d1 0.0075 mu M, and a lower affinity binding with K-d2 8.7 mu M. For dextran sulfate 8 kDa these K-d values were 0.027 and 10.4 mu M, respectively. Heparin 3 kDa only showed a single K-d value of 0.52 mu M. The results show that the magnitude of the binding affinity depends on the type of polyelectrolyte and its molecular weight. (C) 2009 Elsevier B.V. All rights reserved.
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| 5. |
- Bauden, Monika, et al.
(författare)
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Novel anti-adhesive barrier Biobarrier reduces growth of colon cancer cells.
- 2014
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 191:1, s. 196-202
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Tidskriftsartikel (refereegranskat)abstract
- Postoperative peritoneal carcinomatosis together with adhesion formation are considered as two major clinical complications after resection of malignant abdominal tumors, jeopardizing the beneficial effect of the curative surgery. Biobarrier is a novel anti-adhesive barrier fulfilling the criteria for a good adhesion preventive agent, possessing biochemical properties that may enable it to function as a dual efficient device, reducing both adhesion and tumor development. This study aims to evaluate the effect of novel anti-adhesive device Biobarrier on intra-abdominal tumor progression.
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| 6. |
- Bergström, Maria, et al.
(författare)
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Lectin affinity capillary electrophoresis in glycoform analysis applying the partial filling technique
- 2004
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 809:2, s. 323-329
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Tidskriftsartikel (refereegranskat)abstract
- The study of protein glycosylation and its significance in biological interactions is a field of growing interest. This work demonstrates a lectin-based separation of protein glycoforms of α1-acid glycoprotein (AGP or orosomucoid) with capillary electrophoresis. Glycoform analysis was performed with a "partial filling technique" with the lectin Concanavalin A (Con A) as affinity ligand. Con A separated human AGP into two peaks, the first peak included AGP glycoforms without biantennary glycans, and the second peak represented the fraction that had one or more biantennary glycans. The applicability of the method was demonstrated with the analysis of AGP from clinical samples and AGP treated with N-glycosidase F. The AGP separation was also used as a reporter system to estimate the dissociation constant (KD) between Con A and a competing sugar. © 2004 Elsevier B.V. All rights reserved.
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| 7. |
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| 8. |
- Björling, Marcus, et al.
(författare)
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The influence of DLC coating on EHL friction coefficient
- 2012
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Ingår i: Tribology letters. - : Springer Science and Business Media LLC. - 1023-8883 .- 1573-2711. ; 47:2, s. 285-294
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Tidskriftsartikel (refereegranskat)abstract
- High hardness, high elastic modulus, low friction characteristics, high wear and corrosion resistance, chemical inertness, and thermal stability are factors that make diamond-like carbon (DLC) coatings the subject of many studies. For the same reasons they also seem suitable for use in, amongst others, machine components and cutting tools. While most studies in the literature focus on the influence of coatings on wear and friction in boundary lubrication and pure sliding contacts, few studies can be found concerning rolling and sliding elastohydrodynamic lubrication (EHL) friction, especially in the mixed and full film regime. In this article tests are carried out in a Wedeven Associates Machine tribotester where an uncoated ball and disc pair is compared to the case of coated ball against uncoated disc, coated disc against uncoated ball, and coated disc against coated ball. The tests are conducted at two different temperatures and over a broad range of slide-to-roll ratios and entrainment speeds. The results are presented as friction maps as introduced in previous work (Björling et al. in J Eng Tribol 225(7):671, 2011). Furthermore a numerical simulation model is developed to investigate if there is a possibility that the hard, thin DLC coating is affecting the friction coefficient in an EHL contact due to thermal effects caused by the different thermal properties of the coating compared to the substrate. The experimental results show a reduction in friction coefficient in the full film regime when DLC-coated surfaces are used. The biggest reduction is found when both surfaces are coated, followed by the case when either ball or disc is coated. The thermal simulation model shows a substantial increase of the lubricant film temperature compared to uncoated surfaces when both surfaces are coated with DLC. The reduction in friction coefficient when coating either only the ball or the disc are almost the same, lower than when coating both the surfaces but still higher than the uncoated case. The findings above indicate that it is reasonable to conclude that thermal effects are a likely cause for the decrease in coefficient of friction when operating under full film conditions, and in the mixed lubrication regime when DLC-coated surfaces are used
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| 9. |
- Boija, Elisabet, et al.
(författare)
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Bilayer disk capillary electrophoresis : a novel method to study drug partitioning into membranes
- 2008
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Ingår i: Electrophoresis. - : Wiley. - 0173-0835 .- 1522-2683. ; 29:16, s. 3377-3383
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Tidskriftsartikel (refereegranskat)abstract
- CE in the presence of lipid bilayer disks was introduced as a new approach in membrane partitioning studies. The disks were used as a pseudostationary phase in the partial-filling mode of CE and the partitioning of cationic drugs was determined. The migration times of the analytes increased linearly with the lipid amount in the system. An appropriate algorithm for the calculation of a partition coefficient is presented. In the disk-shaped bilayers, which have excellent stability and shelf life, all of the lipids are readily available for interaction and the disks can be used as realistic cell membrane models.
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| 10. |
- Chevul, Stefan, et al.
(författare)
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Network Selection Box : An Implementation of Seamless Communication
- 2006
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Konferensbidrag (refereegranskat)abstract
- In recent years it has become evident that mobility support will have profound impact on current and future wireless networks. Users expect service connectivity at any place at anytime without having to think about the underlying communication systems used in that particular moment in time. On this background, this paper presents a ready to deploy implementation of a mobility framework that supports seamless communication and represents an important enabler for adaptive applications through its simple QoS feedback mechanism. The framework selects the best available network through a decision algorithm that takes advantage of a link performance monitoring concept. The performance evaluation of the proposed framework is also presented in this paper.
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| 11. |
- Duong-Thi, Minh-Dao, et al.
(författare)
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High-Throughput Fragment Screening by Affinity LC-MS
- 2013
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Ingår i: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 18:2, s. 160-171
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Tidskriftsartikel (refereegranskat)abstract
- Fragment screening, an emerging approach for hit finding in drug discovery, has recently been proven effective by its first approved drug, vemurafenib, for cancer treatment. Techniques such as nuclear magnetic resonance, surface plasmon resonance, and isothemal titration calorimetry, with their own pros and cons, have been employed for screening fragment libraries. As an alternative approach, screening based on high-performance liquid chromatography separation has been developed. In this work, we present weak affinity LC/MS as a method to screen fragments under high-throughput conditions. Affinity-based capillary columns with immobilized thrombin were used to screen a collection of 590 compounds from a fragment library. The collection was divided into 11 mixtures (each containing 35 to 65 fragments) and screened by MS detection. The primary screening was performed in < 4 h (corresponding to > 3500 fragments per day). Thirty hits were defined, which subsequently entered a secondary screening using an active site-blocked thrombin column for confirmation of specificity. One hit showed selective binding to thrombin with an estimated dissociation constant (K-D) in the 0.1 mM range. This study shows that affinity LC/MS is characterized by high throughput, ease of operation, and low consumption of target and fragments, and therefore it promises to be a valuable method for fragment screening.
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| 12. |
- Duong-Thi, Minh-Dao, et al.
(författare)
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Weak affinity chromatography as a new approach for fragment screening in drug discovery
- 2011
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Ingår i: Analytical Biochemistry. - : Elsevier. - 0003-2697 .- 1096-0309. ; 414:1, s. 138-146
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Tidskriftsartikel (refereegranskat)abstract
- Fragment-based drug design (FBDD) is currently being implemented in drug discovery, creating a demand for developing efficient techniques for fragment screening. Due to the intrinsic weak or transient binding of fragments (mM–uM in dissociation constant (KD)) to targets, methods must be sensitive enough to accurately detect and quantify an interaction. This study presents weak affinity chromatography (WAC) as an alternative tool for screening of small fragments. The technology was demonstrated by screening of a selected 23 compound fragment collection of documented binders, mostly amidines, using trypsin and thrombin as model target protease proteins. WAC was proven to be a sensitive, robust, and reproducible technique that also provides information about affinity of a fragment in the range of 1 mM–10uM. Furthermore, it has potential for high throughput as was evidenced by analyzing mixtures in the range of 10 substances by WAC–MS. The accessibility and flexibility of the technology were shown as fragment screening can be performed on standard HPLC equipment. The technology can further be miniaturized and adapted to the requirements of affinity ranges of the fragment library. All these features of WAC make it a potential method in drug discovery for fragment screening.
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| 13. |
- Duong-Thi, Minh-Dao, et al.
(författare)
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Weak Affinity Chromatography for Evaluation of Stereoisomers in Early Drug Discovery
- 2013
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Ingår i: Journal of Biomolecular Screening. - : Sage Publications. - 1087-0571 .- 1552-454X. ; 18:6, s. 748-755
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Tidskriftsartikel (refereegranskat)abstract
- In early drug discovery (e.g. in fragment screening), recognition of stereoisomeric structures is valuable and guides medicinal chemists to focus only on useful configurations. In this work, we concurrently screened mixtures of stereoisomers and estimated their affinities to a protein target (thrombin) using weak affinity chromatography-mass spectrometry (WAC-MS). Affinity determinations by WAC showed that minor changes in stereoisomeric configuration could have major impact on affinity. The ability of WAC-MS to provide instant information about stereoselectivity and binding affinities directly from analyte mixtures is a great advantage in fragment library screening and drug lead development.
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| 14. |
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| 15. |
- Fagerström, Alexandra, et al.
(författare)
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Chiral recognition mechanism of cellobiohydrolase Cel7A for ligands based on the β‐blocker propranolol : The effect of explicit water molecules on binding and selectivities
- 2023
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Ingår i: Natural Sciences. - : John Wiley & Sons. - 2698-6248 .- 2698-6248. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- Proteins are useful chiral selectors. In order to understand the recognition mechanism and chiral discrimination, the binding of the (R)- and (S)-enantiomers of a series of designed amino alcohol inhibitors based on propranolol to cellobiohydrolase Cel7A (Trichoderma reesei) has been studied more closely. X-ray crystal structures were determined of the protein complex with the (R)- and (S)-enantiomers of the strongest binding propranolol analogue. The combination of the structural data, thermodynamic data from capillary electrophoresis and microcalorimetry experiments and computational modelling give a clearer insight into the origin of the enantioselectivity and its opposite thermodynamic signature. The new crystal structures were used in computational molecular flexible dockings of the propranolol analogues using the program Glide. The results indicated that several water molecules in the active site were essential for the docking of the (R)-enantiomers but not for the (S)-enantiomers. The results are discussed in relation to the enantiomeric discrimination of the enzyme. Both dissociation constants (Kd values) and thermodynamical data are included to show the effects of the structural modifications in the ligand on enthalpy and entropy in relation to the enantioselectivity.
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| 16. |
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| 17. |
- Fagerström, Alexandra, et al.
(författare)
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New propranolol analogues: binding and chiral discrimination by cellobiohydrolase Cel7A
- 2006
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Ingår i: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0539. ; 4:16, s. 3067-3076
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Tidskriftsartikel (refereegranskat)abstract
- Novel propranolol analogues have been designed and synthesised and their enantioselective binding to the cellulose degrading enzyme, Cel7A, has been evaluated. Affinity and enantioselectivity have been determined by capillary electrophoresis experiments. Ligands with significantly improved affinity and selectivity have been obtained and an analysis of the results has led to insights concerning the relation between the changes in ligand structure and selectivity as well as affinity to the protein.
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| 18. |
- Fagerström, Alexandra, et al.
(författare)
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pH dependency of ligand binding to cellobiohydrolase 1 (Cel7A) - Affinity, selectivity and inhibition for designed propranolol analogues
- 2007
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Ingår i: Journal of Chromatography A. - : Elsevier BV. - 0021-9673. ; 1138:1-2, s. 276-283
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Tidskriftsartikel (refereegranskat)abstract
- The affinity and enantioselectivity have been determined for designed propranolol derivatives as ligands for Cel7A by capillary electrophoresis (CE) at pH 7.0. These results have been compared to measurements at pH 5.0. In agreement with previous studies, the affinity increased at the higher pH. However, the affinity was not as dependent of the ligand structure at pH 7.0 as at pH 5.0, and the selectivity was generally decreased. Instead, at pH 7.0, the changes in binding were mainly dependent on the presence of additional dihydroxyl groups, indicating an increased importance of the electrostatic interactions. To evaluate the pH dependent variations in binding, changes in both the ligand and in the enzyme had to be taken into account. To ensure that the ligands had the same charge in all measurements, pKa-values of all compounds were determined. The ligand-protein interaction has also been studied by inhibition experiments at both pHs to evaluate the specific binding to the active site when competing with the substrate p-nitrophenyl lactoside (pNPL). With support of docking computations we propose a hypothesis on the effect of the ligand structure and pH dependency of the binding and selectivity of amino alcohols to Cel7A. (c) 2006 Elsevier B.V. All rights reserved.
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| 19. |
- Haataja, Topi, et al.
(författare)
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Enzyme kinetics by GH7 cellobiohydrolases on chromogenic substrates is dictated by non-productive binding : insights from crystal structures and MD simulation
- 2023
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Ingår i: The FEBS Journal. - : John Wiley & Sons. - 1742-464X .- 1742-4658. ; 290:2, s. 379-399
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Tidskriftsartikel (refereegranskat)abstract
- Cellobiohydrolases (CBHs) in the glycoside hydrolase family 7 (GH7) (EC3.2.1.176) are the major cellulose degrading enzymes both in industrial settings and in the context of carbon cycling in nature. Small carbohydrate conjugates such as p-nitrophenyl-beta-d-cellobioside (pNPC), p-nitrophenyl-beta-d-lactoside (pNPL) and methylumbelliferyl-beta-d-cellobioside have commonly been used in colorimetric and fluorometric assays for analysing activity of these enzymes. Despite the similar nature of these compounds the kinetics of their enzymatic hydrolysis vary greatly between the different compounds as well as among different enzymes within the GH7 family. Through enzyme kinetics, crystallographic structure determination, molecular dynamics simulations, and fluorometric binding studies using the closely related compound o-nitrophenyl-beta-d-cellobioside (oNPC), in this work we examine the different hydrolysis characteristics of these compounds on two model enzymes of this class, TrCel7A from Trichoderma reesei and PcCel7D from Phanerochaete chrysosporium. Protein crystal structures of the E212Q mutant of TrCel7A with pNPC and pNPL, and the wildtype TrCel7A with oNPC, reveal that non-productive binding at the product site is the dominating binding mode for these compounds. Enzyme kinetics results suggest the strength of non-productive binding is a key determinant for the activity characteristics on these substrates, with PcCel7D consistently showing higher turnover rates (k(cat)) than TrCel7A, but higher Michaelis-Menten (K-M) constants as well. Furthermore, oNPC turned out to be useful as an active-site probe for fluorometric determination of the dissociation constant for cellobiose on TrCel7A but could not be utilized for the same purpose on PcCel7D, likely due to strong binding to an unknown site outside the active site.
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| 20. |
- Harang, Valérie, et al.
(författare)
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A statistical experimental design to study factors affecting enantioseparation of propranolol by capillary electrophoresis with cellobiohydrolase (Cel7A) as chiral selector.
- 2002
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Ingår i: Electrophoresis. - 0173-0835 .- 1522-2683. ; 23:14, s. 2306-2319
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Tidskriftsartikel (refereegranskat)abstract
- The capillary electrophoretic enantioseparation of rac-propranolol using cellobiohydrolase Tr Cel7A as selector was optimized by an unbiased statistical experimental design. A set of pre-experiments was performed in order to identify critical experimental factors. In the definitive chemometric design pH, ranging from 5 to 7, ionic strength ranging between 0.01 and 0.02 and organic solvent additive in concentration from 1 to 19% v/v were studied. The response surface plot revealed a separation optimum in the pH interval studied. When all parameters were taken into account, a background electrolyte consisting of 0.016 M bistris-acetate buffer with pH 6.5 and 17% v/v acetonitrile gave the optimum separation. The significance of the statistical design was confirmed by the generally good agreement obtained between predicted response and actual experimental data.
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| 21. |
- Henriksson, Hongbin, et al.
(författare)
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Cellobiohydrolase 58 (P.c. Cel 7D) is complementary to the homologous CBHI (T.r. Cel 7A) in enantioseparations
- 2000
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Ingår i: Journal of Chromatography A. - 0021-9673 .- 1873-3778. ; 898:1, s. 63-74
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Tidskriftsartikel (refereegranskat)abstract
- Cellobiohydrolase 58 (EC 3.2.1.91, pc. Cel 7D) from Phanerochaete chrysosporium was immobilized on silica and the resulting material, CBH 58-silica, was then used as a chiral stationary phase (CSP) in liquid chromatographic separations of enantiomers. The enantioselectivities obtained on CBH 58-silica were compared with those on CBH I-silica (a phase based on a corresponding cellulase from Trichoderma reesei). CBH 58-silica displayed higher selectivity than CBH I-silica for the more hydrophilic compounds, such as atenolol and metoprolol, although great similarities in chiral separation of beta -adrenergic antagonists were found between the two phases. None of the acidic compounds tested could be resolved on the CBH 58 phase. Moreover, the solutes were retained more on the CBH 58 phase in general, indicating an improved application potential in bioanalysis. Addition of cellobiose or lactose, both of which are inhibitors of cellulases, To the mobile phase impaired the enantioselectivity, indicating an overlap of the enantioselective and catalytic sites. The chiral analytes also functioned as competitive inhibitors and their inhibition constants were determined.
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| 22. |
- Isaksson, Elin L, et al.
(författare)
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The membrane localization domain is required for intracellular localization and autoregulation of YopE in Yersinia pseudotuberculosis.
- 2009
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Ingår i: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 77:11, s. 4740-4749
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Tidskriftsartikel (refereegranskat)abstract
- Recent work has shown that a domain of YopE of Yersinia pseudotuberculosis ranging from amino acids 54 to 75 (R. Krall, Y. Zhang, and J. T. Barbieri, J. Biol. Chem. 279:2747-2753, 2004) is required for proper localization of YopE after ectopic expression in eukaryotic cells. This domain, called the membrane localization domain (MLD), has not been extensively studied in Yersinia. Therefore, an in cis MLD deletion mutant of YopE was created in Y. pseudotuberculosis. The mutant was found to secrete and translocate YopE at wild-type levels. However, the mutant was defective in the autoregulation of YopE expression after the infection of HeLa cells. Although the mutant translocated YopE at wild-type levels, it showed a delayed HeLa cell cytotoxicity. This delay was not caused by a change in GTPase activating protein (GAP) activity, since the mutant showed wild-type YopE GAP activity toward Rac1 and RhoA. The MLD mutant displayed a changed intracellular localization pattern of YopE in HeLa cells after infection, and the YopEDeltaMLD protein was found to be dispersed within the whole cell, including the nucleus. In contrast, wild-type YopE was found to localize to the perinuclear region of the cell and was not found in the nucleus. In addition, the yopEDeltaMLD mutant was avirulent. Our results suggest that YopE must target proteins other than RhoA and Rac1 and that the MLD is required for the proper targeting and hence virulence of YopE during infection. Our results raise the question whether YopE is a regulatory protein or a "true" virulence effector protein.
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| 23. |
- Isaksson, Karolin, et al.
(författare)
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In vivo toxicity and biodistribution of intraperitoneal and intravenous poly-L-lysine and poly-L-lysine/poly-L-glutamate in rats.
- 2014
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Ingår i: Journal of Materials Science: Materials in Medicine. - : Springer Science and Business Media LLC. - 1573-4838 .- 0957-4530. ; 25:5, s. 1293-1299
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Tidskriftsartikel (refereegranskat)abstract
- The combination of two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), has shown excellent postsurgical antiadhesive properties. However, the high molecular, positively charged PL is toxic in high doses, proposed as lysis of red blood cells. This study aims to elucidate the in vivo toxicity and biodistribution of PL and complex bound PLPG comparing intravenous and intraperitoneal administration. Fifty-six Sprague-Dawley rats were used in a model with repeated blood samples within 30 min examining blood gases and blood smears. Similarly, FITC labelled PL were used to track bio distribution and clearance of PL, given as single dose and complex bound to PG after intravenous and intraperitoneal administration. Tissue for histology and immunohistochemistry was collected. Blood gases and blood smears as well as histology points to a toxic effect of high dose PL given intravenously but not after intraperitoneal administration. The toxic effect is exerted through endothelial disruption and subsequent bleeding in the lungs, provoking sanguineous lung edema. FITC-labelled PL experiments reveal a rapid clearance with differences between routes and complex binding. This study advocates a new theory of the toxic effects in vivo of high molecular PL. PLPG complex is safe to use as antiadhesive prevention based on this toxicity study given that PL is always intraperitoneally administered in combination with PG and that the dose is adequate.
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| 24. |
- Isaksson, Karin, 1984-
(författare)
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Logistics Service Providers Going Green : A Framework for Developing Green Service Offerings
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Environmental impact has increasingly become a “buzzword” and an important topic. This topic has been integrated into the agenda of many companies worldwide, and this dissertation focuses on the transportation and logistics industry. Environmental concerns have gained increased attention among many logistic service providers (LSPs) due to the environmental impact from their operations, and they have been identified of having a significant role in reducing the environmental burden in the supply chain. An environmental approach of the LSPs' business has also been identified as a way to achieve competitive advantage and provide market opportunities where the development and marketing of new products and services associated with green issues are suggested as important aspects for future growth. However, considering the scarcity of research regarding this topic, a study that reveals potential aspects in the development of green service offerings can bridge the knowledge gap and provide opportunities for further research within this field. The purpose of this dissertation is therefore to develop and explain a framework for LSPs’ development of green service offerings. The purpose is addressed by first investigating LSPs' service development from a general perspective in order to, in a second stage, reach a better understanding of the implications when integrating green aspects in LSPs' service development efforts.Theoretically, this dissertation departed from service marketing literature or more specifically new service development (NSD) research. This resulted in a conceptual framework including key dimensions and aspects regarding a company’s NSD efforts and activities. From this foundation, the theoretical framework was developed further based on research regarding LSPs' service development and innovation management. Finally the framework was extended with green logistics literature as well as research regarding LSPs' green development and influences on their service offerings.Empirically, this research is mainly based on qualitative data from an in-depth case study on a large LSP active on the Swedish market. In addition, empirical data from a multiple case study and a questionnaire survey conducted for the Licentiate thesis were used in order to enrich the analysis regarding the LSPs' development of green service offerings. The analysis followed a stepwise approach where literature and empirical data were analysed.One of the main results in this dissertation is the framework for LSPs' new service development, consisting of five dimensions: NSD culture, NSD strategy, NSD process focus, IT use and expertise and NSD knowledge and skills. The NSD framework presents a holistic view of the LSPs’ NSD efforts by revealing different dimensions, their roles and relations to each other as well as the pre-requisites to take into consideration in the development of new services. Thus, the different NSD dimensions should not solely be viewed as isolated dimensions; instead, there is a need for LSPs to have a holistic view and understanding of the NSD activities’ reciprocity.Another main result concerns the adaption of the NSD framework to green service development. The results reveal some pre-requisites relevant for LSPs to consider in their efforts to develop green service offerings and are summarised in the following main dimensions:Creating green awareness in the NSD culture – encourage participation regarding green initiatives within the organisation, defining a “common picture” in order to facilitate collaboration efforts and knowledge exchange concerning green expertise. The support from top management was also identified of having an influencing impact. Defining the strategic approach of green service offerings – integrate a green concern in the overall business strategy and to define the strategic role and incentives for developing green service offerings. The results also suggest LSPs to adapt green NSD efforts to different business contexts and market possibilities to match existing resources and skills with customers’ green requirements, and to perform a segmentation of customers’ environmental work and ambitions to increase the understanding of customers’ green attitudes and requirements.Create processes and routines to facilitate spreading of green knowledge – highlights the relevance of a process focus for spreading green knowledge both from an external and internal perspective. It involves e.g. adoption of certifications, procedures for environmental calculations and documentation as well as routines to spread and integrate green knowledge among employees as well as identification of customers’ green requirements.Improve green internal knowledge and build green collaborations – provide training and education to increase the level of green awareness and knowledge among employees as well as customers and strive for collaboration efforts both internally and externally to utilise each other’s knowledge and resources towards the development of green service offerings.Increase transparency of green information both internally and externally – improve green information transparency to build both internal and external trust and increase possibilities to effectively use other actors’ knowledge and resources to develop environmental improvements in the supply chain. Integration of IT expertise and synchronisations of IT systems to facilitate and support environmental work and development of green service offerings.
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| 25. |
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| 26. |
- Isaksson, Karolin, et al.
(författare)
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Small bowel obstruction: early parameters predicting the need for surgical intervention
- 2011
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Ingår i: European Journal of Trauma and Emergency Surgery. - : Springer Science and Business Media LLC. - 1863-9933 .- 1863-9941. ; 37:2, s. 155-159
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Tidskriftsartikel (refereegranskat)abstract
- To study and identify early clinical and radiological findings that could help to predict operative intervention for small bowel obstruction. One hundred and nine consecutive patients with small bowel obstruction who underwent small bowel follow-through examination with Gastrografin(A (R)) during 2005-2006. The patients were divided into an operative group and a non-operative group, n = 44 and 65, respectively. Findings primarily noted were those which were possible to register within 1-4 h from hospital arrival. In univariate analyses, factors found to be significantly associated with surgical intervention were no prior abdominal surgery, the presence of radiological differential air fluid levels, and absence of flatulence 24 h prior to admission, CRP > 10 mg/L and dehydration at admission. In multivariate analyses, the presence of dehydration and radiological differentiated air fluid levels were independent predictive factors of significance. Absence of all factors significantly favored non-operative treatment, while operative treatment was significantly favored when two or more factors were present. The presence of two or more early predictive factors as defined above, available at admission, significantly correlates with a likelihood of complete obstruction and the need of surgical intervention.
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| 27. |
- Isaksson, Karolin, et al.
(författare)
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Toxicity and Dose Response of Intra-Abdominally Administered Poly-L-alpha-Lysine and Poly-L-Glutamate for Postoperative Adhesion Protection.
- 2010
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Ingår i: European Surgical Research. - : S. Karger AG. - 0014-312X .- 1421-9921. ; 44:1, s. 17-22
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: Two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), have previously been shown to reduce postoperative intra-abdominal adhesions. This study aims to investigate the possible toxic effects and to establish a lowest effective antiadhesive dose. Methods: 152 mice were investigated with a well-known adhesion model and given different concentrations of the two differently charged polypeptides as well as only the cationic PL. Results: For the first time, a probable toxic level of PL given intraperitoneally (40 mg/kg) and the lowest significant concentration of PL and PG for antiadhesive purposes (1.6 mg/kg) could be established. Conclusion: The gap between the possible toxicity level of PL and the lowest efficient antiadhesive dose is probably too narrow, and the shape and charge of PL warrant continuous research for another polycation in the concept of differently charged polypeptides used as antiadhesive agents.
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| 28. |
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| 29. |
- Isaksson, Patrik, et al.
(författare)
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Elasto-hydrodynamic simulation of complex geometries in hydraulic motors
- 2008
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Ingår i: Proceedings of NORDTRIB 2008, 13th Nordic Symposium on Tribology. - Tampere : Tampere University of Technology. - 9789521519598
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Konferensbidrag (refereegranskat)abstract
- As many other machines, the radial piston hydraulic motor contains a lot of tribological interfaces. One important area is the piston assembly and the journal bearing contact between the piston and cam roller. There exists good models to describe the performance of simpler geometries such as journal bearings, but when put into a system or when having a more complex geometry, the models do not apply very well. To be able to predict the tribological performance of such components, it is important to have a model that is able to include the real geometry and the properties of the system. A simulation model of the piston assembly in Hägglunds Compact hydraulic motor was built using FE software which made it easy to include the complex geometries. The model includes the deformation of the piston. The hydrodynamics is solved by using Reynolds equation. Density/pressure and viscosity/pressure dependency for the oil are included. The whole model was solved with the built in solvers in the software. Simulation results such as friction, hydrodynamic pressure and oil leakage was compared with test results. Good agreement between simulation and tests shows that this kind of model can be a useful tool in development and optimization of tribological systems.
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| 30. |
- Isaksson, Patrik, et al.
(författare)
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Elasto-hydrodynamic simulation of complex geometries in hydraulic motors
- 2009
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Ingår i: Tribology International. - : Elsevier BV. - 0301-679X .- 1879-2464. ; 42:10, s. 1418-1423
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Tidskriftsartikel (refereegranskat)abstract
- As many other machines, the radial piston hydraulic motor contains a lot of tribological interfaces. One important area is the piston assembly and the journal bearing contact between the piston and cam roller. There exists good models to describe the performance of simpler geometries such as journal bearings, but when put into a system or when having a more complex geometry, the models do not apply very well. To be able to predict the tribological performance of such components, it is important to have a model that is able to include the real geometry and the properties of the system.A simulation model of the piston assembly in Hägglunds Compact hydraulic motor was built using FE software which made it easy to include the complex geometries. The model includes the deformation of the piston. The hydrodynamics is solved by using Reynolds equation.Density/pressure and viscosity/pressure dependency for the oil are included.Simulation results such as friction, hydrodynamic pressure and oil leakage was compared with test results. Good agreement between simulation and tests shows that this kind of model can be a useful tool in development and optimization of tribological systems.
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| 31. |
- Isaksson, Patrik, et al.
(författare)
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The influence of surface roughness on friction in a flexible hybrid bearing
- 2011
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Ingår i: Proceedings of the Institution of mechanical engineers. Part J, journal of engineering tribology. - : SAGE Publications. - 1350-6501 .- 2041-305X. ; 225:J10, s. 975-985
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Tidskriftsartikel (refereegranskat)abstract
- The effect of surface roughness on friction in all lubrication regimes is studied for a flexible hybrid bearing of a radial piston hydraulic motor. The effect is studied by performing experiments in a specially designed test rig and numerical simulations of the real measured surface topographies of the bearings. The simulations are performed with a two-scale model where surface roughness is treated on a local asperity level by homogenized flow factors and a global scale where the bearing structure is included. Three bearings with different surface topographies are included in the study and both experimentally measured and simulated friction are analysed for each of them. Comparison of friction predicted by the model and experimentally measured friction is performed and it reveals that the model is a valuable tool for analysing the effect of surface roughness in this type of bearing
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| 32. |
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| 33. |
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| 34. |
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| 35. |
- Lindberg, Peter, et al.
(författare)
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Seamless Communication for ITS Applications
- 2006
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Konferensbidrag (refereegranskat)abstract
- In order to meet user expectations in an ITS environment, services need efficient support from the underlying communication systems. Seamless communication is an important functionality in these systems. The PIITSA project, a research and demonstration project mainly funded by Vinnova the Swedish Agency for Innovation Systems, aims at a communication concept that delivers this seamless functionality. A framework for seamless communication has been outlined and during 2006 this concept has been evaluated. This paper presents the framework, results from the evaluation, and outlines the demonstration ahead.
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| 36. |
- Movérare-Skrtic, Sofia, et al.
(författare)
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Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
- 2014
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:11, s. 1279-88
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Tidskriftsartikel (refereegranskat)abstract
- The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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| 37. |
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| 38. |
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| 39. |
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| 40. |
- Nilsson, Mikael, et al.
(författare)
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Thermodynamics studies of designed ligands binding to Cel7A using partial-filling capillary electrophoresis
- 2008
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Ingår i: Electrophoresis. - : Wiley. - 0173-0835 .- 1522-2683. ; 29:2, s. 358-362
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Tidskriftsartikel (refereegranskat)abstract
- A convenient experimental method for thermodynamical studies based on partial-filling affinity CE is presented. The advantages of this approach are the possibility to determine binding energies from relatively weak interactions as well as the small amounts of samples consumed. In order to explore the affinity and selectivity of the cellobiolrydrolase Cel7A, a number of propranolol analogues were recently designed. The affinities of a selection of these ligands were determined in the temperature interval 15-40 degrees C, and Delta G degrees, Delta H degrees and Delta S degrees were obtained by means of Van't Hoff plots. Through these experiments, the importance of the entropy contribution in the complexation between the ligands and Cel7A has been demonstrated.
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| 41. |
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| 42. |
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| 43. |
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| 44. |
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| 45. |
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| 46. |
- Ohlson, Sten, et al.
(författare)
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Toward high-throughput drug screening on a chip-based parallell affinity separation platform
- 2010
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Ingår i: Journal of Separation Science. - : Wiley. - 1615-9306 .- 1615-9314. ; 33:17-18, s. 2575-2581
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Tidskriftsartikel (refereegranskat)abstract
- High-throughput screening of compound libraries, including the study of fragments, has become one of the cornerstones in modern drug discovery research. During this process hits are defined that may be developed into valuable leads and eventually into possible drug candidates. In this paper, we have demonstrated that parallel zonal weak affinity chromatography in microcolumns on a chip offers a possible screening format for weakly binding ligands toward a protein target. We used albumin as a model system because this transport protein is well established as a binder (both weak and strong) for drug substances. Bovine serum albumin was immobilized on microparticulate diolsilica particles and then packed into a 24-channel cartridge, which served as the separation platform. Analysis of the obtained chromatograms yielded information about affinity even in the millimolar range. Employing this approach, thousands of substances can be screened in just a day. We feel confident that zonal affinity chromatography will provide a useful technology in the future for performing high-throughput screening.
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| 47. |
- Raudberget, Dag, 1967, et al.
(författare)
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Supporting design platforms by identifying flexible modules
- 2017
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Ingår i: Proceedings of the International Conference on Engineering Design, ICED. - : The Design Society. - 2220-4334 .- 2220-4342. ; 3:DS87-3, s. 191-200, s. 191-200
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Konferensbidrag (refereegranskat)abstract
- One way for firms to stay competitive is to adapt a platform approach. In product platforms, modules are used as exchangeable design blocks to create a variety in product performance. This is a proven way to get advantages of scale in production by reusing physical parts and investments in manufacturing. To ensure exchangeability between modules, interfaces between modules must be well defined. Hence, from this point of view, there is no such thing as flexible modules. In this research, flexibility refers to the idea of identifying strategic portions of the platform where flexibility is needed and to create the modular division in a way that the assigned modules are de-coupled in theses areas. The presented approach shows how the Design platform concept can be extended by the introduction of flexible modules. These support the Design Platforms by allowing areas of strategic importance to be more flexible and thereby enable room for uncertainties such as fluctuating requirements and future technical development.
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| 48. |
- Spelt, Lidewij, et al.
(författare)
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Tumour growth after portal vein embolization with pre-procedural chemotherapy for colorectal liver metastases.
- 2015
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Ingår i: HPB. - : Elsevier BV. - 1477-2574 .- 1365-182X. ; 17:6, s. 529-535
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Tidskriftsartikel (refereegranskat)abstract
- For resection of colorectal cancer (CRC) liver metastases, pre-operative portal vein embolization (PVE) is used to increase the size of the future liver remnant (FLR) prior to advanced liver resection when indicated. PVE is speculated to cause tumour progression, but only a limited number of studies have analysed tumour growth after PVE in the context of pre-procedural chemotherapy, which was the aim of this retrospective study.
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| 49. |
- Stolt, Roland, 1970-
(författare)
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CAD-Model Parsing for Automated Design and Design Evaluation
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Product development has both innovative and analytic sides. Starting from the requirements, a design suggestion is generated. In order to assess how well the envisioned design fulfils the requirements, it is sometimes necessary to build a computer model of it for the analysis. The overall motivation of the work presented is to reduce the time spent on creating the model by reusing knowledge gained from developing similar products by suggesting, building and evaluating IT-systems. To verify the systems real design examples, obtained from companies that have participated in the research projects have been used. The work is based on two major application examples. The first, involving the automated geometrical idealisation of die-cast parts (Paper I-III), and the second involving manufacturability of powder metallurgy pressed and sintered parts (Paper IV-VI). The work starts from the point in the product development process where it exists a design suggestion represented as an arbitrary format CAD-model. In the powder metallurgy case the object is to secure that the geometry is suitable for the production process. In the die-casting case the object is to automatically create an idealised version of the model for shell elements meshing. These two tasks have previously been treated as two separate cases, addressed by completely different software. This thesis suggests a common method for addressing the two cases. The method is based on converting the CAD-models, using the geometrical restrictions of the production processes, into a format with a specialised feature structure, parameterisation and construction history using a feature recognition approach. The features are then automatically reconstructed in a target CAD-system. The resulting, specialised CAD-model can be used for automated design and design evaluation purposes, demonstrated in the thesis. The models are therefore called DAR (Design Automation Ready)-models. The DAR-models are useful in that they separate the conversion from the subsequent treatment of the models providing modularisation, flexibility and user insight in the model structure. In that a construction history and parameterisation have be constructed in the target CAD-system, the advanced geometry manipulation and means for knowledge management often provided in modern CAD-systems can be accessed in a transparent and user manageable way. This extends the usefulness of the CAD-systems from involving only interactive work to managing all components sharing the same production process.
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| 50. |
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