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- Ge, Changrong P, et al.
(författare)
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Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
- 2017
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Ingår i: JCI INSIGHT. - : AMER SOC CLINICAL INVESTIGATION INC. - 2379-3708. ; 2:13
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Tidskriftsartikel (refereegranskat)abstract
- Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.
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| 4. |
- Andersson, Maria L.E., et al.
(författare)
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Autoantibodies to Disease-Related Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis
- 2023
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 75:7, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- Objective. This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints.Methods. We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE).Results. Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE.Conclusion. A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA.
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| 7. |
- Axelsson, Susanne, et al.
(författare)
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Psychotherapy students' experiences of supervisee-centred supervision based on deliberate practice, feedback-informed treatment and self-compassion
- 2024
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Ingår i: Counselling and Psychotherapy Research. - : John Wiley & Sons. - 1473-3145 .- 1746-1405. ; 24:2, s. 719-733
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Tidskriftsartikel (refereegranskat)abstract
- Objective: There are few methods that focus on therapists' experiences of supervision. To facilitate the development of psychologist students, a supervisee-centred supervision, based on deliberate practice, feedback informed treatment and self-compassion, was introduced.Methods: This study examines six supervisees’ experiences of a supervisee-centred supervision. A semi- structured interview was used for the collection of the data, which identified two main themes: Learning and Development and five associated sub-themes: structure and purposesfulness, prerequisites, experience-based learning, therapeutic skills and personal development.Conclusion: The experience- and feedback-based approach was perceived as efficient, structured and goal oriented. This created high-focused activity and participation, a strong group dynamic and a good alliance with the supervisors, providing a good climate for learning and development. Focusing on performance and feedback was perceived as a potential obstacle that could create stress and anxiety.
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| 10. |
- Geschwindner, Stefan, et al.
(författare)
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Characterisation of de novo mutations in the C-terminal domain of proprotein convertase subtilisin/kexin type 9.
- 2015
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Ingår i: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134.
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Tidskriftsartikel (refereegranskat)abstract
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the hepatic low-density lipoprotein receptor (LDL-R) and is therefore a prominent therapeutic target for reducing LDL-cholesterol. The C-terminal domain of PCSK9 is unlikely to be involved in a direct extracellular interaction with the LDL-R. We probed the importance of the C-terminus for the degradation of the LDL-R by designing seven de novo mutants of PCSK9 that fill potential druggable cavities. The mutants were tested for their ability to diminish LDL uptake in human HepG2 cells and for affinity towards a calcium independent mutant of the EGF(A) domain of the human LDL-R. The later was done by a newly developed surface plasmon resonance-based assay format. We identified three mutant proteins (G517R, V610R and V644R) with decreased ability to block LDL uptake into HepG2 cells. These mutations define areas outside the direct interaction area between PCSK9 and the LDL-R that could be targeted to inhibit the PCSK9 triggered degradation of the LDL-R. We also describe the mechanistic rationalisation of the affinity changes seen with the natural occurring human D374Y (gain of function) mutation causing severe hypercholesterolaemia. The action of this mutant is due to a significantly decreased dissociation rate constant, whereas the mutation does not affect the association rate constant.
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| 11. |
- Karimi, F, et al.
(författare)
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[C-11]/(C-13)Carbon monoxide in palladium-mediated synthesis of imides
- 2001
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Ingår i: JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1. - : ROYAL SOC CHEMISTRY. - 1472-7781. ; :13, s. 1528-1531
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Tidskriftsartikel (refereegranskat)abstract
- [C-11]Carbon monoxide in low concentration with palladium(0) complexes (in the range of 5 mu mol) and aryl halides (about 10 mu mol) were used in the synthesis of the C-11-labelled imides, thalidomide, N-phthaloyl-L-glutamic acid, N-phthaloylhexane and an
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| 17. |
- Lidstrom, P, et al.
(författare)
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[C-11]Carbon monoxide in the palladium-mediated synthesis of C-11-labelled ketones
- 1997
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Ingår i: JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1. - : ROYAL SOC CHEMISTRY. ; :18
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- [C-11]Carbon monoxide has been used in the palladium-mediated synthesis of [carbonyl-C-11]ketones. Methyl iodide, vinylic and arylic halides and trifluoromethanesulfonates (triflates) have been coupled with tin reagents with insertion of [C-11]carbon mon
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| 22. |
- Marcos, Nuno T., et al.
(författare)
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Role of the Human ST6GalNAc-I and ST6GalNAc-II in the Synthesis of the Cancer-Associated Sialyl-Tn Antigen
- 2004
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Ingår i: CANCER RESEARCH. - 0008-5472. ; 64:19, s. 7050-7
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Tidskriftsartikel (refereegranskat)abstract
- The Sialyl-Tn antigen (Neu5Acalpha2-6GaINAc-O-Ser/Thr) is highly expressed in several human carcinomas and is associated with carcinoma aggressiveness and poor prognosis. We characterized two human sialyltransferases,(CMP)-C-.-Neu5Ac:GaINAc-R alpha2,6-sialyltransferase (ST6GaINAc)-I and ST6GaINAc-II, that are candidate enzymes for Sialyl-Tn synthases. We expressed soluble recombinant hST6GaINAc-I and hST6GaINAc-II and characterized the substrate specificity of both enzymes toward a panel of glycopeptides, glycoproteins, and other synthetic glycoconjugates. The recombinant ST6GaINAc-I and ST6GaINAc-II showed similar substrate specificity toward glycoproteins and GaINAcalpha-O-Ser/Thr glycopeptides, such as glycopeptides derived from the MUC2 mucin and the HIVgp120. We also observed that the amino acid sequence of the acceptor glycopeptide contributes to the in vitro substrate specificity of both enzymes. We additionally established a gastric cell line, MKN45, stably transfected with the full length of either ST6GaINAc-I or ST6GaINAc-II and evaluated the carbohydrate antigens expression profile induced by each enzyme. MKN45 transfected with ST6GaINAc-I showed high expression of Sialyl-Tn, whereas MKN45 transfected with ST6GaINAc-II showed the biosynthesis of the Sialyl-6T structure [GaIbeta1-3 (Neu5Acalpha2-6)GaINAc-O-Ser/Thr].In conclusion, although both enzymes show similar in vitro activities when Tn antigen alone is available, whenever both Tn and T antigens are present, ST6GaINAc-I acts preferentially on Tn antigen, whereas the ST6GaINAc-II acts preferentially on T antigen. Our results show that ST6GaINAc-I is the major Sialyl-Tn synthase and strongly support the hypothesis that the expression of the Sialyl-Tn antigen in cancer cells is due to ST6GaINAc-I activity.
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| 23. |
- Matricon, Pierre, et al.
(författare)
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Structure-based virtual screening discovers potent and selective adenosine A1 receptor antagonists
- 2023
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 257
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Tidskriftsartikel (refereegranskat)abstract
- Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A1 and A2A adenosine receptors (A1R and A2AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. A library of 4.6 million compounds was screened computationally against both receptors using molecular docking and 20 A1R selective ligands were predicted. Of these, seven antagonized the A1R with micromolar activities and several compounds displayed slight selectivity for this subtype. Twenty-seven analogs of two discovered scaffolds were designed, resulting in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. Our results show the potential of structure-based virtual screening to guide discovery and optimization of subtype-selective ligands, which could facilitate the development of safer drugs.
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| 24. |
- Moller, T, et al.
(författare)
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Job enlargement and mechanical exposure variability in cyclic assembly work
- 2004
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Ingår i: Ergonomics. - : Informa UK Limited. - 0014-0139 .- 1366-5847. ; 47:1, s. 19-40
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Tidskriftsartikel (refereegranskat)abstract
- Cyclic assembly work is known to imply a high risk for musculoskeletal disorders. To have operators rotate between work tasks is believed to be one way of decreasing this risk, since it is expected to increase variation in mechanical and psychological exposures (physical and mental loads). This assumption was investigated by assessing mechanical exposure variability in three assembly tasks in an electronics assembly plant, each on a separate workstation, as well as in a 'job enlargement' scenario combining all three stations. Five experienced operators worked for 1 h on each station. Data on upper trapezius and forearm extensor muscle activity were obtained by means of electromyography (EMG), and working postures of the head and upper arms were assessed by inclinometry. The cycle-to-cycle variance of parameters representing the three exposure dimensions: level , frequency and duration was estimated using ANOVA algorithms for each workstation separately as well as for a balanced combination of all three. For a particular station, the variability of trapezius EMG activity levels relative to the mean was higher than for extensor EMG: between-cycles coefficients of variation (CV) about 0.15 and 0.10, respectively. A similar relationship between CV applied to the parameter describing frequency of EMG activity. Except for head inclination levels, the between-cycles CV was larger for posture parameters than for EMG. The between-cycles variance increased up to six fold in the job enlargement scenario, as compared to working at only one station. The difference in mean exposure between workstations was larger for trapezius EMG parameters than for forearm extensor EMG and postures, and hence the effect of job enlargement on exposure variability was more pronounced for the trapezius. For some stations, job enlargement even implied less cycle-to-cycle variability in forearm extensor EMG parameters than working at that station only. Whether the changes in exposure variability associated with job enlargement were sufficient to imply a decreased risk for musculoskeletal disorders is not known.
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| 25. |
- Neu, H, et al.
(författare)
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Synthesis of [18-C-11/(C-13)]linoleic acid
- 1997
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Ingår i: JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS. - : JOHN WILEY & SONS LTD. ; 39:7
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A method for the preparation of [18-C-11]linoleic acid is described. A highly reactive zerovalent copper complex was prepared from lithium (2-thienyl)iodocuprate reduced by lithium naphtalenide. This copper complex was used in a coupling reaction between
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| 26. |
- Neu, H, et al.
(författare)
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Synthesis of saturated fatty acids C-11 (C-13)-labelled in the omega-methyl position
- 1997
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Ingår i: JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS. - : JOHN WILEY & SONS LTD. ; 39:6
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A method for the preparation of saturated fatty acids C-11 (C-13)-labelled in the omega-methyl position is described. A highly reactive zerovalent copper complex was prepared from lithium naphtalenide reduced lithium(2-thienyl)iodocuprate. The labelling
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