| 1. |
- Kihlberg, Steve, et al.
(författare)
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Arbete och Hälsa
- 2005
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- En ergonomisk och teknisk utvärdering genomfördes av en förändring av produktionssystemet i ett elektronikföretag som innebar en ökad automatisering. Själva förändringsprocessen utvärderades också.Automatiseringen av den manuella monteringen och transporten minskade exponeringstiden för manuell montering på systemnivå samt ökade produktiviteten. För den kvarstående manuella monteringen ökade dock repetitiviteten och ensidigheten. Montörerna upplevde också att den psykiska arbetsbelastningen var större i det nya systemet jämfört med det gamla. De ansåg också att de manuella monteringsstationerna som helhet var dåliga arbetsuppgifter.I den studerade förändringsprocessen var bristen på kontinuitet i arbetsledning ett av avdelningens huvudproblem. Arbetsledaren fick också sätta sin prägel på hur produktionsmålen skulle uppfyllas och hur arbetsförhållandena skulle utformas. Därigenom blev det arbetsledaren och inte den handlingsplan med arbetsrotation som en arbetsorganisationsgrupp utformade som avgjorde hur arbetsorganisationen utformades.
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| 2. |
- Kihlberg, Steve, et al.
(författare)
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Ett produktionssystem under förändring - ergonomisk och teknisk utvärdering
- 2005
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- En ergonomisk och teknisk utvärdering genomfördes av en förändring av produktionssystemet i ett elektronikföretag som innebar en ökad automatisering. Själva förändringsprocessen utvärderades också. Automatiseringen av den manuella monteringen och transporten minskade exponeringstiden för manuell montering på systemnivå samt ökade produktiviteten. För den kvarstående manuella monteringen ökade dock repetitiviteten och ensidigheten. Montörerna upplevde också att den psykiska arbetsbelastningen var större i det nya systemet jämfört med det gamla. De ansåg också att de manuella monteringsstationerna som helhet var dåliga arbetsuppgifter. I den studerade förändringsprocessen var bristen på kontinuitet i arbetsledning ett av avdelningens huvudproblem. Arbetsledaren fick också sätta sin prägel på hur produktionsmålen skulle uppfyllas och hur arbetsförhållandena skulle utformas. Därigenom blev det arbetsledaren och inte den handlingsplan med arbetsrotation som en arbetsorganisationsgrupp utformade som avgjorde hur arbetsorganisationen utformades.
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| 3. |
- Andersson, Ida E., 1982-, et al.
(författare)
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Probing Molecular Interactions within Class II MHC A(q)/Glycopeptide/T-Cell Receptor Complexes Associated with Collagen-Induced Arthritis.
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 50:23, s. 5627-5643
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Tidskriftsartikel (refereegranskat)abstract
- T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment from rat type II collagen (CII) bound to the class II major histocompatibility complex A(q) molecule. We report a comparative model of A(q) in complex with the glycopeptide CII260-267. This model was used in a structure-based design approach where the amide bond between Ala(261) and Gly(262) in the glycopeptide was selected for replacement with psi[COCH2], psi[CH2NH2+], and psi[(E)-CH=CH] isosteres. Ala-Gly isostere building blocks were then synthesized and introduced in CII260-267 and CII259-273 glycopeptides. The modified glycopeptides were evaluated for binding to the A(q) molecule, and the results were interpreted in view of the A(q)/glycopeptide model. Moreover, recognition by a panel of T-cell hybridomas revealed high sensitivity for the backbone modifications. These studies contribute to the understanding of the interactions in the ternary A(q)/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.
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| 4. |
- Berggren, Kristina, 1971, et al.
(författare)
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Synthesis and biological evaluation of reversible inhibitors of IdeS, a bacterial cysteine protease and virulence determinant
- 2009
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 17:9, s. 3463-3470
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Tidskriftsartikel (refereegranskat)abstract
- Analogues of the irreversible protease inhibitors TPCK and TLCK have been synthesized and tested as inhibitors of the bacterial cysteine protease IdeS excreted by Streptococcus pyogenes. Eight compounds were identified as inhibitors of IdeS in an in vitro assay. The most potent compounds contained an aldehyde function, thus acting as efficient reversible inhibitors, nitrile and azide derivatives showed moderate activity. (C) 2009 Elsevier Ltd. All rights reserved.
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| 5. |
- Blomberg, David, et al.
(författare)
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Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold
- 2007
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry. - 1477-0520 .- 1477-0539. ; 5:16, s. 2599-2605
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Tidskriftsartikel (refereegranskat)abstract
- A series of 2,4- disubstituted pyridine derivatives has been designed, synthesised and evaluated as thrombin inhibitors. A Grignard exchange reaction was used to introduce various benzoyl substituents in position 4 of the pyridine ring, where they serve as P3 residues in binding to thrombin. In position 2 of the pyridine ring, a para-amidinobenzylamine moiety was incorporated as P1 residue by an SNAr reaction using ammonia as nucleophile followed by a reductive amination. A crystal structure obtained for one of the compounds in the active site of thrombin revealed that the basic amidine group of the inhibitor was anchored to Asp 189 at the bottom of the S1 pocket. A comparison with melagatran, bound in the active site of thrombin, revealed a good shape match but lack of hydrogen bonding possibilities in the S2 - S3 region for the thrombin inhibitors reported in this study.
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| 6. |
- Blomberg, David, et al.
(författare)
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Synthesis and biological evaluation of leucine enkephalin turn mimetics
- 2006
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 4:3, s. 416-423
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Tidskriftsartikel (refereegranskat)abstract
- A cyclic Leu-enkephalin mimetic containing a 7-membered ring, and two linear analogues, has been prepared on solid phase. In the cyclic mimetic the intramolecular (1–4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted. The two linear analogues both contain the methylene ether isostere instead of the Tyr1-Gly2 amide bond and the shorter of the two lacks Gly3. The three compounds, and a β-turn mimetic analogous to the 7-membered turn mimetic but with Gly3 included, were evaluated for specific binding to µ- and δ-opioid receptors in rat brain membranes. With the exception of the β-turn mimetic the three other Leu-enkephalin analogues all bound with varying affinity to the µ- and δ-opioid receptors. From the results it could be concluded that Leu-enkephalin binds in a turn conformation to the opiate receptors, but that this conformation is not a (1–4) β-turn.
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| 7. |
- Blomberg, David, et al.
(författare)
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Synthesis of a β-strand mimetic based on a pyridine scaffold
- 2006
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 62:47, s. 10937-10944
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Tidskriftsartikel (refereegranskat)abstract
- A synthetic route to a 2,4-disubstituted pyridine as a potential β-strand mimetic has been developed and applied in the synthesis of a tripeptidomimetic of Leu-Gly-Gly. The pyridine scaffold replaces the central glycine, and is substituted with analogues of leucine and glycine in positions 4 and 2, respectively. 2-Fluoro-4-iodopyridine was chosen as the functionalized scaffold and was substituted with protected leucinal in position 4 via a Grignard exchange reaction using iso-propyl magnesium chloride. The glycine moiety was introduced in position 2 via a nucleophilic aromatic substitution reaction (SNAr) facilitated by microwave irradiation. The synthetic sequence involved 12 steps with an overall yield of 7%.
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| 8. |
- Blomberg, David, 1971-
(författare)
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Synthesis of β-turn and pyridine based peptidomimetics
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics. First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM. Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented. Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.
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| 9. |
- Dzhambazov, Balik, et al.
(författare)
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The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans
- 2005
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Ingår i: EUROPEAN JOURNAL OF IMMUNOLOGY. - : Wiley. - 0014-2980 .- 1521-4141. ; 35:2, s. 357-66
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Tidskriftsartikel (refereegranskat)abstract
- Type II collagen (CII) is a target for autoreactive T cells in both rheumatoid arthritis and the murine model collagen-induced arthritis. The determinant core of CII has been identified as CII260-270, and the alteration of this T cell epitope by posttranslational modifications is known to be critical for development of arthritis in mice. Using CII-specific T cell hybridomas we have now shown that the immunodominant T cell epitope in the normal (healthy) human and rat joint cartilage is O-glycosylated at the critical T cell receptor recognition position 264 with a mono- or di-saccharide attached to a hydroxylysine. In contrast, in the arthritic human and rat joint cartilage there are both glycosylated and non-glycosylated CII forms. Glycosylated CII from normal cartilage could not be recognized by T cells reactive to peptides having only lysine or hydroxylysine at position 264, showing that antigen-presenting cells could not degrade the O-linked carbohydrate. Thus, the variable forms of the glycosylated epitope are determined by the structures present in cartilage, and these vary during the disease course. We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states.
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| 10. |
- Dzhambazov, Balik, et al.
(författare)
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Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide in complex with MHC class II molecules
- 2006
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Ingår i: Journal of Immunology. - Rockville, MD : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 176, s. 1525-33
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Tidskriftsartikel (refereegranskat)abstract
- In both collagen-induced arthritis (CIA) and rheumatoid arthritis, T cells recognize a galactosylated peptide from type II collagen (CII). In this study, we demonstrate that the CII259-273 peptide, galactosylated at lysine 264, in complex with Aq molecules prevented development of CIA in mice and ameliorated chronic relapsing disease. In contrast, nonglycosylated CII259-273/Aq complexes had no such effect. CIA dependent on other MHC class II molecules (Ar/Er) was also down-regulated, indicating a bystander vaccination effect. T cells could transfer the amelioration of CIA, showing that the protection is an active process. Thus, a complex between MHC class II molecules and a posttranslationally modified peptide offers a new possibility for treatment of chronically active autoimmune inflammation such as rheumatoid arthritis. © 2006 by The American Association of Immunologists, Inc.
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