| 1. |
- Graslund, S, et al.
(author)
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Protein production and purification
- 2008
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In: Nature methods. - : Springer Science and Business Media LLC. - 1548-7105 .- 1548-7091. ; 5:2, s. 135-146
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Journal article (peer-reviewed)
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| 26. |
- Behravan, G., et al.
(author)
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THE INTERACTION OF ELLIPTICINE DERIVATIVES WITH NUCLEIC-ACIDS STUDIED BY OPTICAL AND H-1-NMR SPECTROSCOPY - EFFECT OF SIZE OF THE HETEROCYCLIC RING
- 1994
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In: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 34:5, s. 599-609
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Journal article (peer-reviewed)abstract
- The DNA interaction of derivatives of ellipticine with heterocyclic ring systems with three, four, or five rings and a dimethylaminoethyl side chain was studied. Optical spectroscopy of drug complexes with calf thymus DNA, poly [(dA-dT).(dA-dT)], or poly [(dG-dC).(dG-dC)] showed a 10 nm bathochromic shift of the light absorption bands of the pentacyclic and tetracyclic compounds upon binding to the nucleic acids, which indicates binding by intercalation. For the tricyclic compound a smaller shift of 1-3 nm was observed upon binding to the nucleic acids. Flow linear dichroism studies show that the geometry of all complexes is consistent with intercalation of the ring system, except for the DNA and poly [(dG-dC).(dG-dC)] complexes of the tricyclic compound, where the average angle between the drug molecular plane and the DNA helix axis was found to be 65 degrees. One-dimensional H-1-nmr spectroscopy was used to study complexes between d(CGCGATCGCG)(2) and the tricyclic and pentacyclic compounds. The results on the pentacyclic compound show nonselective broadening due to intermediate chemical exchange of most oligonucleotide resonances upon drug binding. The imino proton resonances are in slow chemical exchange, and new resonances with upheld shifts approaching 1 ppm appear upon drug binding, which supports intercalative binding of the pentacyclic compound. The results on the tricyclic compound show more rapid binding kinetics and very selective broadening of resonances. The data suggest that the tricyclic compound is in an equilibrium between intercalation and minor groove binding, with a preference to bind close to the AT base pairs with the side chain residing in the minor groove. (C) 1994 John Wiley and Sons, Inc.
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| 27. |
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| 28. |
- Cho, K. B., et al.
(author)
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The substrate reaction mechanism of class III anaerobic ribonucleotide reductase
- 2001
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In: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1089-5647 .- 1520-6106 .- 1520-5207. ; 105:27, s. 6445-6452
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Journal article (peer-reviewed)abstract
- The substrate mechanism of class III anaerobic ribonucleotide reductase has been studied using quantum chemical methods. The study is based on the previously suggested mechanism for the aerobic class I enzyme, together with the recently determined X-ray structure of the anaerobic enzyme. The initial steps are similar in the mechanisms of these enzymes, but for the suggested rate-limiting steps there are key differences. In the class I enzyme, the 3 ' -keto group of the substrate is protonated in a step involving formation of a sulfur-sulfur bond between two cysteines, One of these cysteines is not present in the anaerobic enzyme. Instead, carbon dioxide is formed in this step from formate, which is present as a cofactor. In line with previous suggestions from experimental observations, the formate first forms a formyl radical. The next step, where the formyl radical protonates the 3 ' -keto group of the substrate, is suggested to be rate limiting with a calculated total barrier of 19.9 kcal/mol, in reasonable agreement with the experimental rate-limiting barrier of 17 kcal/mol. Zero-point and entropy effects are found to be quite significant in lowering the barrier. The mechanism for the entire cycle is discussed in relation to known experimental facts.
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| 38. |
- Demirdal, D, et al.
(author)
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CHARACTERISATION OF SWEDISH MYOSITIS PATIENTS WITH ANTI-MDA5 AUTOANTIBODIES AND CORRELATION OF CLINICAL FEATURES WITH AUTOANTIBODY LEVELS
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 751-752
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Conference paper (other academic/artistic)abstract
- The association between anti-melanoma differentiation association protein 5 autoantibodies (aMDA5) and rapidly progressive interstitial lung disease (RP-ILD) in clinically amyopathic dermatomyositis is well established in Asian population cohorts. In western cohorts, ILD has been strongly associated with aMDA5 but data regarding RP-ILD have been more conflicting. It is also suggested that western cohorts have more pronounced myopathic features than Asian.ObjectivesTo characterise the disease manifestations of a Swedish aMDA5 positive idiopathic inflammatory myositis (IIM) cohort and to explore antigen reactivity of the MDA5 protein.MethodsFirst available serum samples collected from 28 consecutive patients with IIM and positive aMDA5 ever tested by ELISA, Line Blot (LB) or Immunoprecipitation, attending Karolinska University Hospital between 1999 and 2021, were included. Clinical data including presence of anti-SSA autoantibodies by ELISA or LB was retrieved retrospectively. An in-house ELISA was used to screen serum samples for reactivity against a recombinant MDA5 protein (rMDA5, aa A110-D1025, UniProt ID Q9BYX4) and seven MDA5-derived constructs containing different domains. Correlations between aMDA5 reactivity levels and clinical data were explored.ResultsNine patients showed no reactivity to any of the rMDA5 constructs by ELISA and were excluded from further analysis.Reactivity against rMDA5 was confirmed by ELISA in 19 patients (median 184.7 µg/mL (interquartile range (IQR) 277.07). The cohort included 13 male and 6 female patients, 94% Caucasian, with mean age at diagnosis of 41.05 years (standard deviation (SD) 10.5). Median disease duration at time of sampling was 0 months (IQR 1). All patients except one had signs of muscle involvement (muscle weakness, elevated muscle enzymes, muscle oedema or muscle biopsy consistent with myositis). At diagnosis 63.2% of patients reported muscle weakness (21.1 % had a manual muscle test 8 score <75). Dermatological findings were observed in 17/19 (89.7 %). During disease course nine patients (47.4%) had confirmed arthritis.ILD was diagnosed in 16/19 patients (84.2%), four of these (25%) developed a RP-ILD. One patient passed away due to RP-ILD and one required a lung transplant. Patients with ILD had a statistically significant higher mean age at diagnosis than those without (42.8.5 (SD 10.3) vs 31.3 (SD 4.7) years, p=0.02). Patients developing RP-ILD were not significantly older than patients with chronic ILD. Respiratory symptoms were reported by 75% of patients with ILD at time of diagnosis. The mean total lung capacity (TLC) of the ILD cohort was 68% (SD 17), mean diffusion capacity of carbon monoxide (DLCO) was 59% (SD 15) and mean forced vital capacity (FVC) was 62% (SD 19). There was a higher proportion of patients with CRP ≥ 3 times the reference range at diagnosis amongst patients with FVC <70 % than patients with FVC >70 % (88.9 % vs 16.7 %, p= 0.01).Ten patients (52.6%) had anti-SSA autoantibodies, all had ILD. Anti-SSA positive patients had a statistically significant lower TLC than those without (62% vs 79% respectively, p=0.04) and a lower FVC (57% vs 76% respectively, p=0.05).We found a weak non-statistically significant negative correlation between titres of aMDA5 and TLC, DLCO and FVC (Pearson coefficients -0.187, -0.289, -0.130 respectively). Frequency of ILD was higher in patients with aMDA5 titres >100 µg/mL than those with titers <100, but not statistically significant (81.3% vs 18.8%, respectively).ConclusionIn this Caucasian cohort of aMDA5 positive IIM patients, ILD was present in over 80% of patients, of these, one quarter had RP-ILD. Older patients were more likely to present with ILD. Anti-SSA positivity and higher CRP levels were associated with worse lung function. We found a weak negative correlation between aMDA5 titres and lung function tests, as well as a trend of higher frequency of ILD in patients with higher aMDA5 titres. Muscle and skin involvement were found in a high proportion of patients.AcknowledgementsD. Demirdal & E. Van Gompel contributed equally to this abstract.Disclosure of InterestsDeniz Demirdal: None declared, Eveline Van Gompel: None declared, Edvard Wigren: None declared, Maryam Dastmalchi: None declared, Begum Horuluoglu: None declared, Angeles Shunashy Galindo-Feria: None declared, Susanne Gräslund: None declared, Karine Chemin: None declared, Ingrid E. Lundberg Shareholder of: Roche and Novartis., Consultant of: Consulting fees from Corbus Pharmaceuticals Inc, Astra Zeneca, Bristol Myer´s Squibb, Corbus Pharmaceutical, EMD Serono Research & Development Institute, Argenx, Octapharma, Kezaar, Orphazyme, and Janssen, Grant/research support from: Research grants from Astra Zeneca, Antonella Notarnicola Speakers bureau: compensation for lecture at conference sponsored by Boehringer Ingelheim.
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| 39. |
- Doglia, S. M., et al.
(author)
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QUINACRINE - SPECTROSCOPIC PROPERTIES AND INTERACTIONS WITH POLYNUCLEOTIDES
- 1993
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In: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 33:9, s. 1431-1442
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Journal article (peer-reviewed)abstract
- The acridine dye quinacrine and its interactions with calf thymus DNA, poly(dA-dT).poly(dA-dT), and poly(dG-dC).poly(dG-dC) were studied by light absorption, linear dichroism, and fluorescence spectroscopy. The transition moments of quinacrine give rise to absorption bands polarized along the short axis (400-480-nm band), and the long axis (345-nm and 290-nm bands) of the molecule, respectively. Linear dichroism studies show that quinacrine intercalates into calf thymus DNA as well as into the polynucleotides, displaying fairly homogeneous binding to poly (dA-dT).poly(dA-dT), but more than one type of intercalation site for calf thymus DNA and poly(dG-dC).poly(dG-dC). Fluorescence spectroscopy shows that for free quinacrine the pK = 8.1 between the mono- and diprotonated states also remains unchanged in the excited state. Quinacrine bound to calf thymus DNA and polynucleotides exhibits light absorption typical for the intercalated diprotonated form. The fluorescence enhancement of quinacrine bound to poly (dA-dT).poly(dA-dT) may be due to shielding from water interactions involving transient H-bond formation. The fluorescence quenching in poly (dG-dC).poly (dG-dC) may be due to excited state electron transfer from guanine to quinacrine. (C) 1993 John Wiley & Sons, Inc.
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| 40. |
- Engstrom, Maria, et al.
(author)
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Hydrogen bonding to tyrosyl radical analyzed by ab initio g-tensor calculations
- 2000
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In: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 104:21, s. 5149-5153
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Journal article (peer-reviewed)abstract
- Hydrogen bonding to the tyrosyl radical in ribonucleotide reductase (RNR) has been simulated by a complex between the phenoxyl radical and a water molecule. Multiconfigurational self-consistent field linear response theory was used to calculate the g-tensor of the isolated phenoxyl radical and of the phenoxyl-water model. The relevance of the model was motivated by the fact that spin density distributions and electron paramagnetic resonance (EPR) spectra of the phenoxyl and tyrosyl radicals are very similar. The calculated g-tensor anisotropy of the phenoxyl radical was comparable with experimental findings for tyrosyl in those RNRs where the H-bond is absent: g(x) = 2.0087(2.0087), g(y) = 2.0050(2.0042), and g(z) = 2.0025(2.0020), where the tyrosyl radical EPR data from Escherichia coli RNR are given in parentheses. The hydrogen bonding models reproduced a shift toward a lower g(x) value that was observed experimentally for mouse and herpes simplex virus RNR where the H-bond was detected by electron-nuclear double resonance after deuterium exchange. This decrease could be traced to lower angular momentum and spin-orbit coupling matrix elements between the ground B-2(1) and the first excited B-2(2) states (oxygen lone-pair n to pi(SOMO) excitation) upon hydrogen bonding in a linear configuration. The g(x) value was further decreased by hydrogen bonding in bent configurations due to a blue shift of this excitation.
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| 43. |
- Eriksson, Magdalena, 1962, et al.
(author)
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Binding geometry of benzo[a] pyrene diol epoxide covalently bound to DNA. A flow linear dichroism study
- 1986
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In: Journal of the Chemical Society - Series Chemical Communications. - : Royal Society of Chemistry (RSC). - 0022-4936. ; :21, s. 1613-1615
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Journal article (peer-reviewed)abstract
- Flow linear dichroism (LD) provides new structural information on 7β,8α-dihydroxy-9α, 10α-epoxy-7,8,9,10-tetrahydrobenzo[a] pyrene (anti-BPDE) covalently bound to DNA: by resolving the LD spectrum with respect to the polarized absorption components of the pyrenyl chromophore, we have determined the orientations of the in-plane symmetry axes of the bound compound relative to the helix axis of DNA [they are on average oriented at 70°(short axis) and 30°(long axis)]; for both (+)- and (–)-anti-BPDE adducts the flexibility of the DNA is increased.
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| 44. |
- Eriksson, M., et al.
(author)
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BINDING OF DELTA- RU(PHEN)(3) (2+) AND LAMBDA- RU(PHEN)(3) (2+) TO D(CGCGATCGCG) (2) STUDIED BY NMR
- 1994
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In: Biochemistry. - : American Chemical Society (ACS). - 1520-4995 .- 0006-2960. ; 33:17, s. 5031-5040
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Journal article (peer-reviewed)abstract
- The interactions of the Delta and Delta enantiomers of the chiral metal complex [Ru(phen)(3)](2+) (phen = 1,10-phenanthroline) with the oligonucleotide duplex [d(CGCGATCGCG)](2) have been studied with NMR and CD spectroscopy. From NOESY data it is shown that the interaction primarily takes place in the minor groove of the oligonucleotide which remains in a B-like conformation. The observed NOEs also provide evidence that the metal complexes preferentially bind to the central AT region. The observed AT specificity is more pronounced with the Delta as compared to the Delta enantiomer, which interacts with a larger part of the oligonucleotide. Furthermore, the NOESY data show that neither of the enantiomers binds by classical intercalation. This is also supported by a comparison study of the analogue [Ru(phen)(2)DPPZ](2+) (DPPZ = dipyrido[ 3,2-a:2',3'-c] phenazine) which intercalates in DNA. The NMR as well as the CD results show that the Delta and Delta enantiomers of [Ru(phen)(3)](2+) bind in different modes to [d(CGCGATCGCG)](2). Comparison of CD spectra of the metal complex in the presence of [d(CGCGATCGCG)](2), poly(dAdT).poly(dAdT), poly(dGdC).poly(dGdC), and calf thymus DNA suggests that these binding modes are independent of DNA sequence. The results are found to be compatible with binding of Delta-[Ru(phen)(3)](2+) by insertion of two phenanthroline ligands into the minor groove, causing minor distortions of the DNA structure, whereas the Delta enantiomer binds in a mode that leaves the DNA structure unaffected.
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| 45. |
- Eriksson, M., et al.
(author)
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LOCATION OF EXCIMER-FORMING ADDUCTS OF (+)-ANTI-BENZO A PYRENE DIOL EPOXIDE IN DNA
- 1993
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 115:5, s. 1639-1644
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Journal article (peer-reviewed)abstract
- Covalent adducts of the carcinogenic polycyclic aromatic hydrocarbon (+)-anti-benzo[a]pyrene 7,8-dihydrodiol 9,10-epoxide ((+)-anti-BPDE) in polynucleotides have been studied by fluorescence spectroscopy. The pyrenyl chromophores of the BPDE adducts, linked by the C10 atom to the exocyclic nitrogen of guanine, interact in the photoexcited state, as evidenced by excimer fluorescence. Strong BPDE excimer fluorescence is observed in the alternating poly(dGdC).poly(dGdC) sequence, whereas it is weak in the homopolymeric poly(dG).poly(dC) and in calf thymus DNA. No excimer fluorescence is observed for the BPDE adducts in poly(dAdC).poly(dGdT) or poly(dAdG).poly(dCdT). It is concluded that the formation of BPDE excimers in polynucleotides requires binding to guanines on different strands on consecutive basepairs. The experimental results are supported by graphics modeling and energy minimization of BPDE adducts in various oligonucleotide sequences. The results show that the most favorable arrangement for excimer formation of the BPDE-dG adducts is in a 5'(dCdG-BPDE).5'(dCdG-BPDE) sequence, where the pyrenyl chromophores interact in the minor groove.
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