| 1. |
- Bartoszak-Adamska, E, et al.
(författare)
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The influence of (O, N)-deuteration on the crystal and molecular structure, thermal stability and spectroscopic properties of 1,3-propanediammonium hydrogenphosphate monohydrate
- 2000
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Ingår i: POLISH JOURNAL OF CHEMISTRY. - 0137-5083. ; 74:3, s. 393-408
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Tidskriftsartikel (refereegranskat)abstract
- Exchange of mobile hydrogen atoms in 1,3-propanediammonium hydrogenphosphate for deuterium (OH-->OD, NH-->ND) affects the thermal stability of the salt. Additionally, (O,N)-deuteration induces some unexpected changes in the -CH2- vibrations in the IR spec
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| 2. |
- Kozak, M, et al.
(författare)
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Expression of a selenomethionine derivative and preliminary crystallographic studies of human cystatin C
- 1999
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Ingår i: Acta Crystallographica. Section D: Biological Crystallography. - 1399-0047. ; 55:11, s. 1939-1942
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Tidskriftsartikel (refereegranskat)abstract
- Human cystatin C, a protein with amyloidogenic properties and a potent inhibitor of papain-like mammalian proteases, has been produced in its full-length form by recombinant techniques and crystallized in two polymorphic forms: cubic and tetragonal. A selenomethionyl derivative of the protein, obtained by Escherichia coli expression and with complete Met→Se-Met substitution confirmed by mass spectrometry, amino-acid analysis and X-ray absorption spectra, was crystallized in the cubic form. A truncated variant of the protein, lacking ten N-terminal residues, has also been crystallized. The crystals of this variant are tetragonal and, like the two polymorphs of the full-length protein, contain multiple copies of the molecule in the asymmetric unit, suggesting oligomerization of the protein.
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| 3. |
- Janowski, R, et al.
(författare)
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3D domain-swapped human cystatin c with amyloidlike intermolecular beta-sheets
- 2005
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Ingår i: Proteins. - : Wiley. - 0887-3585. ; 61:3, s. 570-578
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Tidskriftsartikel (refereegranskat)abstract
- Oligomerization of human cystatin C (HCC) leads to amyloid deposits in brain arteries, and this process is greatly accelerated with a naturally occurring L68Q variant. The crystal structures of N-truncated and full-length HCC (cubic form) showed dimer formation via three-dimensional (3D) domain swapping, and this observation has led to the suggestion that an analogous domain-swapping mechanism, but propagated in an open-ended fashion, could be the basis of HCC fibril formation. Here we report that full-length HCC, when crystallized in a new, tetragonal form, dimerizes by swapping the same secondary structure elements but with a very different overall structure generated by the flexibility of the hinge linking the moveable elements. The beta-strands of the beta-cores of the two folding units of the present dimer are roughly parallel, while they formed an angle of about 100 degrees in the previous two structures. The dimers pack around a crystallographic dyad by extending their molecular beta-sheets in an intermolecular context. At the other edge of the molecular beta-sheet, side-chain-side-chain hydrogen bonds propagate the beta-structure in the same direction. In consequence, a supramolecular crystal structure is generated, with all the P-strands of the domain-swapped dimers being perpendicular to one crystallographic direction. This observation is relevant to amyloid aggregation of HCC, as X-ray diffraction studies of amyloid fibrils show them to have ordered, repeating structure, consistent with the so-called cross-beta structure, in which extended polypeptide chains are perpendicular to the fiber axis and form infinite beta-sheets that are parallel to this axis.
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| 4. |
- Nilsson, M., et al.
(författare)
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Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C. Use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C
- 2004
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 279:23, s. 24236-24245
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Tidskriftsartikel (refereegranskat)abstract
- Amyloidogenic proteins like cystatin C and prion proteins have been shown to form dimers by exchange of subdomains of the monomeric proteins. This process, called "three-dimensional domain swapping," has also been suggested to play a part in the generation of amyloid fibrils. One variant of cystatin C, L68Q cystatin C, is highly amyloidogenic, and persons carrying the corresponding gene suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adult life. The present work describes the production of two variants of wild type and L68Q cystatin C with disulfide bridges at positions selected to inhibit domain swapping without affecting the biological function of the four cystatin C variants as cysteine protease inhibitors. The capacity of the four variant proteins to form dimers was tested and compared with that of wild type and L68Q cystatin C. In contrast to the latter two proteins, all four protein variants stabilized by disulfide bridges were resistant toward the formation of dimers. The capacity of the two stabilized variants of wild type cystatin C to form amyloid fibrils was investigated and found to be reduced by 80% compared with that of wild type cystatin C. In an effort to investigate whether exogenous agents could also suppress the formation of dimers of wild type and L68Q cystatin C, a monoclonal antibody or carboxymethylpapain, an inactivated form of a cysteine protease, was added to systems inducing dimerization of wild type and L68Q cystatin C. It was observed that catalytic amounts of both the monoclonal antibody and carboxymethylpapain could suppress dimerization.
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| 5. |
- Wisniewski, K., et al.
(författare)
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Overlapping stimulation of subthalamic nucleus and dentato-rubro-thalamic tract in Parkinson's disease after deep brain stimulation
- 2024
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Ingår i: Acta Neurochirurgica. - : Springer. - 0001-6268 .- 0942-0940. ; 166:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces tremor, rigidity, and akinesia. According to the literature, the dentato-rubro-thalamic tract (DRTt) is verified target for DBS in essential tremor; however, its role in the treatment of Parkinson's disease is only vaguely described. The aim of our study was to identify the relationship between symptom alleviation in PD patients and the distance of the DBS electrode electric field (EF) to the DRTt.MethodsA single-center retrospective analysis of patients (N = 30) with idiopathic Parkinson's disease (PD) who underwent DBS between November 2018 and January 2020 was performed. DRTt and STN were visualized using diffusion-weighted imaging (DWI) and tractography protocol of magnetic resonance (MR). The EF was calculated and compared with STN and course of DRTt. Evaluation of patients before and after surgery was performed with use of UPDRS-III scale. The association between distance from EF to DRTt and clinical outcomes was examined. To confirm the anatomical variation between DRTt and STN observed in tractography, white matter dissection was performed with the Klingler technique on ten human brains.ResultsPatients with EF overlapping STN and DRTt benefited from significant motor symptoms improvement. Anatomical findings confirmed the presence of population differences in variability of the DRTt course and were consistent with the DRTt visualized by MR.ConclusionsDRTt proximity to STN, the main target in PD DBS surgery, confirmed by DWI with tractography protocol of MR combined with proper predefined stimulation parameters may improve efficacy of DBS-STN.
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| 6. |
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| 7. |
- Janowski, R, et al.
(författare)
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Domain swapping in N-truncated human cystatin C
- 2004
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 1089-8638 .- 0022-2836. ; 341:1, s. 151-160
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Tidskriftsartikel (refereegranskat)abstract
- Human cystatin C (HCC) inhibits papain-like cysteine proteases by a binding epitope composed of two beta-hairpin loops and the N-terminal segment. HCC is found in all body fluids and is present at a particularly high level in the cerebrospinal fluid. Oligomerization of HCC leads to amyloid deposits in brain arteries at advanced age but this pathological process is greatly accelerated with a naturally occurring Leu68Gln variant, resulting in fatal amyloidosis in early adult life. When proteins are extracted from human cystatin C amyloid deposits, an N-terminally truncated cystatin C (THCC) is found, lacking the first ten amino acid residues of the native sequence. It has been shown that the cerebrospinal fluid may cause this N-terminal truncation, possibly because of disintegration of the leucocytes normally present in this fluid, and the release of leucocyte proteolytic enzymes. HCC is the first disease-causing amyloidogenic protein for which oligomerization via 3D domain swapping has been observed. The aggregates arise in the crystallization buffer and have the form of 2-fold symmetric dimers in which a long alpha-helix of one molecule, flanked by two adjacent beta-strands, has replaced an identical domain of the other molecule, and vice versa. Consistent with a conformational change at one of the beta-hairpin loops of the binding epitope, the dimers (and also any other oligomers, including amyloid aggregates) are inactive as papain inhibitors. Here, we report the structure of N-truncated HCC, the dominant form of cystatin C in amyloid deposits. Although the protein crystallized under conditions that are drastically different from those for the full-length protein, the structure reveals dimerization by the same act of domain swapping. However, the new crystal structure is composed of four independent HCC dimers, none of which has the exact 2-fold symmetry of the full-length dimer. While the four dimers have the same overall topology, the exact relation between the individual domains shows a variability that reflects the flexibility at the dimer-specific open interface, which in the case of 3D domain-swapped HCC consists of beta-interactions between the open hinge loops and results in an unusually long intermolecular beta-sheet. The dimers are engaged in further quaternary interactions resulting in spherical, closed octameric assemblies that are identical to that present in the crystal of the full-length protein. The octamers interact via hydrophobic patches formed on the surface of the domain-swapped dimers as well as by extending the dimer beta-sheet through intermolecular contacts. (C) 2004 Elsevier Ltd. All rights reserved.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Rodziewicz-Motowidlo, S, et al.
(författare)
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Checking the conformational stability of cystatin C and its L68Q variant by molecular dynamics studies: Why is the L68Q variant amyloidogenic?
- 2006
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Ingår i: Journal of Structural Biology. - : Elsevier BV. - 1095-8657 .- 1047-8477. ; 154:1, s. 68-78
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Tidskriftsartikel (refereegranskat)abstract
- Human L68Q cystatin C is one of the known human amyloidogenic proteins. In its native state it is a monomer with alpha/beta structure. Experimental evidence suggests that L68Q variant associates into dimeric intermediates and that the dimers subsequently self-assemble to form amyloid deposits and insoluble fibrils. Details of the pathway of L68Q mutant amyloid formation are unclear; however, different experimental approaches with resolutions at molecular level have provided Some clues. Probably, the stability and flexibility of monomeric L68Q variant play essential roles in the early steps of amyloid formation; thus, it is necessary to characterize early conformational changes of L68Q cystatin C monomers. In this paper, we demonstrate the possibility that the differences between the monomeric forms of wild-type (wt) cystatin C and its L68Q variant are responsible for higher tendency of the L68Q cystatin C amyloidogenesis. We started our studies with the simulations of wt and L68Q cystatin C monomers. Nanosecond time scale molecular dynamics simulations at 308 K were performed using AMBER7.0 program, The results show that the structure of the L68Q monomer was changed, relative to the wt cystatin C structure. The results support earlier speculation that the L68Q point mutation would easily lead to dimer formation. (c) 2006 Published by Elsevier Inc.
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| 12. |
- Wisniewski, Karol, et al.
(författare)
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Predictors of 30-Day Mortality for Surgically Treated Patients with Spontaneous Supratentorial Intracerebral Hemorrhage and Validation of the Surgical Swedish Intracerebral Hemorrhage Score : A Retrospective Single-Center Analysis of 136 Cases
- 2024
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Ingår i: World Neurosurgery. - : Elsevier. - 1878-8750 .- 1878-8769. ; 186, s. E539-E551
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We aimed to identify independent risk factors of 30-day mortality in patients with surgically treated spontaneous supratentorial intracerebral hemorrhage (ICH), validate the Surgical Swedish ICH (SwICH) score within Polish healthcare system, and compare the SwICH score to the ICH score. METHODS: We carried out a single-center retrospective analysis of the medical data juxtaposed with computed tomography scans of 136 ICH patients treated surgically between 2008 and 2022. Statistical analysis was performed using the same characteristics as in the SwICH score and the ICH score. Backward stepwise logistic regression with both 5-fold crossvalidation and 1000x bootstrap procedure was used to create new scoring system. Finally predictive potential of these scales were compared. RESULTS: The most important predictors of 30-day mortality were: ICH volume (P < 0.01), Glasgow Coma Scale at admission (P < 0.01), anticoagulant status (P = 0.03), and age (P < 0.01). The SwICH score appears to have a better predictive potential than the ICH score, although this did not reach statistical significance [area under the curve {AUC}: 0.789 (95% confidence interval {CI}: 0.715-0.863) vs. AUC: 0.757 (95% CI: 0.677-0.837)]. Moreover, based on the analyzed characteristics, we developed our score (encompassing: age, ICH volume, anticoagulants status, Glasgow Coma Scale at admission), [AUC of 0.872 (95% CI: 0.815-0.929)]. This score was significantly better than previous ones. CONCLUSIONS: Differences in health care systems seem to affect the accuracy of prognostic scales for patients with ICH, including possible differences in indications for surgery and postoperative care. Thus, it is important to validate assessment tools before they can be applied in a new setting and develop population-specific scores. This may improve the effectiveness of risk stratification in patients with ICH.
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