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| 2. |
- Ayoglu, Burcu, et al.
(författare)
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Anoctamin 2 identified as an autoimmune target in multiple sclerosis
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences of the USA. - 0027-8424 .- 1091-6490. ; 113:8, s. 2188-2193
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
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| 3. |
- Bredenberg, Johan, et al.
(författare)
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Conformational states of the glucocorticoid receptor DNA-binding domain from molecular dynamics simulations
- 2002
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Ingår i: Proteins. - : Wiley. - 0887-3585 .- 1097-0134. ; 49:1, s. 24-36
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Tidskriftsartikel (refereegranskat)abstract
- Molecular dynamics simulations (MD) have been performed on variant crystal and NMR-derived structures of the glucocorticoid receptor DNA-binding domain (GR DBD). A loop region five residues long, the so-called D-box, exhibits significant flexibility, and transient perturbations of the tetrahedral geometry of two structurally important Cys4 zinc finger are seen, coupled to conformational changes in the D-box. In some cases, one of the Cys ligands to zinc exchanges with water, although no global distortion of the protein structure is observed. Thus, from MD simulation, dynamics of the D-box could partly be explained by solvent effects in conjunction with structural reformation of the zinc finger.
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| 4. |
- Bredenberg, Johan, et al.
(författare)
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Modeling zinc sulfhydryl bonds in zinc fingers
- 2001
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Ingår i: International Journal of Quantum Chemistry. - : Wiley. - 0020-7608 .- 1097-461X. ; 83:3-4, s. 230-244
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Tidskriftsartikel (refereegranskat)abstract
- Molecular dynamics simulations have been carried out employing three different model descriptions of the zinc sulfhydryl interactions in class II fingers. One bonded and two nonbonded models were studied. Two variant structures of the glucocorticoid receptor DNA-binding; domain and a NMR structure from a fragment of methionyl-tRNA synthetase were subjected to long-time MD simulations with these models. Our analysis is focused on comparison with experimental and quantum mechanical data, concerning the local Zn-finger and overall structural and dynamic properties for these models. All models performed M ell, but the nonbonded models appeared to reproduce the protein dynamics in better agreement with experimental data than does the bonded description.
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| 5. |
- Bredenberg, Johan
(författare)
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Modelling biomolecular interactions
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Computational approaches for understanding and aiding in molecular biology has increased in significance over the last decades, where a wealth of biochemical experiments have provided a solid ground for developing computer models that can be used to predict unresolved issues within biology. Molecular dynamics (MD) is one of these methods, based on classical laws, and suitable for handling large macromolecules in their natural environment, water. A detailed picture at the atomic level can be obtained, and given that the formulation of the computer model is correct, new strategies for experiments and interpretation of real-world results are feasible. An important target group for treating various diseases is found within the nuclear receptor super family, which is the largest known group of transcription regulators. They are ligand induced and promote gene regulation by recognising a specific DNA-sequence. This recognition is performed by a discrete functional DNA-binding domain (DBD), which consists of two perpendicularly packed amphipathic helix loop regions with eight out of nine invariant cysteine residues formed in two Cys4-zinc fingers. This thesis is mainly based on molecular dynamics simulations performed on the glucocorticoid receptor DNA-binding domain (GR DBD) and follows two main topics: Develop and evaluate methods for describing metals within the framework of classical laws and resolve some of the biology behind recognition of protein-DNA assemblies. Non-bonded models that only include the Coulomb electrostatic and van der Waals interactions between Zn to its ligands were in better agreement with experimental data. Being satisfied with the non-bonded metal description, MD was conducted variant structures of GR DBD. One ligand (C496) in the second zinc finger appeared less rigid than the other ligands in conjunction with conformational changes in this region. In some cases ligand exchange with water was observed, which led to the speculation that P493 acts as a regulator for the conformational switch of C476. A virtual alanine-scan was done on variant DNA-DBD complexes and on the free GR DBD monomer for defining putative mutations that may be done in vivo and/or in vivo. In particular, P493 mutants appeared to stabilise the free protein monomer GR DBD as well as the dimer GR DBD associated with DNA. MD simulations on variant P493-mutants, suggest that P493 regulates the relative positions of secondary structure elements within the GR DBD, and that mutations involving side-chains with hydrogen bonding capabilities recovers the loss of steric isomerisation that is encountered in the wild type protein. The methods and results presented in this study are readily applied to other DBDs free or associated with DNA.
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| 6. |
- Forsgren, Johan, et al.
(författare)
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A ceramic drug delivery vehicle for oral administration of highly potent opioids.
- 2010
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Ingår i: Journal of pharmaceutical sciences. - : Elsevier BV. - 1520-6017 .- 0022-3549. ; 99:1, s. 219-26
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Tidskriftsartikel (refereegranskat)abstract
- Pellets composed of the ceramic material Halloysite and microcrystalline cellulose were synthesized with the aim of producing a drug delivery vehicle for sustained release of the opioid Fentanyl with low risk for dose dumping at oral intake of the highly potent drug. Drug release profiles of intact and crushed pellets, to simulate swallowing without or with chewing, in pH 6.8, pH 1, and in 48% ethanol were recorded in order to replicate the conditions in the small intestines, in the stomach, as well as cointake of the drug with alcohol. The drug release was analyzed by employing the Weibull equation, which showed that the release profiles were either governed by fickian diffusion (intact pellets in pH 6.8 and in ethanol) or by diffusion in a fractal or disordered pore network (intact pellets in pH 1 and crushed pellets in all solutions). A sustained release for approximately 3-4 h was obtained in all studied solutions from intact pellets, whereas crushed pellets released the drug content during approximately 2-3 h. The finding that a sustained release profile could be obtained both in alcohol and after crushing of the pellets, shows that the ceramic carrier under investigation, at least to some extent, hampers dose dumping, and may thus be a promising material in future developments of new opioid containing oral dosage forms.
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| 7. |
- Forsgren, Johan, 1981-
(författare)
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Functional Ceramics in Biomedical Applications : On the Use of Ceramics for Controlled Drug Release and Targeted Cell Stimulation
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ceramics are distinguished from metals and polymers by their inorganic nature and lack of metallic properties. They can be highly crystalline to amorphous, and their physical and chemical properties can vary widely. Ceramics can, for instance, be made to resemble the mineral phase in bone and are therefore an excellent substitute for damaged hard tissue. They can also be made porous, surface active, chemically inert, mechanically strong, optically transparent or biologically resorbable, and all these properties are of interest in the development of new materials intended for a wide variety of applications. In this thesis, the focus was on the development of different ceramics for use in the controlled release of drugs and ions. These concepts were developed to obtain improved therapeutic effects from orally administered opioid drugs, and to reduce the number of implant-related infections as well as to improve the stabilization of prosthetic implants in bone.Geopolymers were used to produce mechanically strong and chemically inert formulations intended for oral administration of opioids. The carriers were developed to allow controlled release of the drugs over several hours, in order to improve the therapeutic effect of the substances in patients with severe chronic pain. The requirement for a stable carrier is a key feature for these drugs, as the rapid release of the entire dose, due to mechanical or chemical damage to the carrier, could have lethal effects on the patient because of the narrow therapeutic window of opioids. It was found that it was possible to profoundly retard drug release and to achieve almost linear release profiles from mesoporous geopolymers when the aluminum/silicon ratio of the precursor particles and the curing temperature were tuned.Ceramic implant coatings were produced via a biomimetic mineralization process and used as carriers for various drugs or as an ion reservoir for local release at the site of the implant. The formation and characteristics of these coatings were examined before they were evaluated as potential drug carriers. It was demonstrated that these coatings were able to carry antibiotics, bisphosphonates and bone morphogenetic proteins to obtain a sustained local effect, as they were slowly released from the coatings.
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| 8. |
- Jämstorp, Erik, et al.
(författare)
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Mechanically strong geopolymers offer new possibilities in treatment of chronic pain
- 2010
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 146:3, s. 370-377
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Tidskriftsartikel (refereegranskat)abstract
- We propose that a clay derived class of materials, known as geopolymers, may solve the problem of finding materials for controlled release with the right combination of properties necessary for a safe and sustained oral delivery of highly potent opioids. We show that the opioid Fentanyl, and its structurally similar sedative Zolpidem, can be embedded into metakaolin based geopolymer pellets to provide prolonged release dosage forms with mechanical strengths of the same order of magnitude as that of human teeth. The results presented in the current work may open up new opportunities for future development of drug delivery for high potency drugs employing high-strength and variable-pore-structure geopolymers and materials alike.
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