| 1. |
- Berbyuk, Viktor, 1953
(author)
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Dynamics and optimal control of biotechnical systems "Man-Prosthesis"
- 1997
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In: IUTAM Symposium on Interaction Between Dynamics and Control in Advanced Mechanical Systems, Ed. D. van Campen, Kluwer Academic Publishers, 1997. - Dordrecht : Springer Netherlands. ; , s. 35-42
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Conference paper (peer-reviewed)abstract
- In the paper, a mathematical model is proposed for investigating the controlled motion of human locomotion system (HLS) with an above-knee prosthesis. To provide insight into the interaction between dynamics and control in biotechnical system Man-Prosthesis the energy optimal control problem of the HLS wearing a lower limb prosthesis has been considered. The algorithm is based on special conversion of the optimal control problem for a nonlinear dynamical system which models HLS into a standard nonlinear programming problem. A number of energy-optimal control problems of human locomotion with an artificial leg, and optimization problems for the constructive parameters of the prostheses under different boundary conditions and constraints have been solved. The numerical results obtained were compared with experimental data for normal human locomotion. The energy-optimal elastic and viscoelastic characteristics of the ankle and knee joints of the prostheses have been determined.
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| 2. |
- Berbyuk, Viktor, 1953
(author)
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Multibody systems modeling and optimization problems of lower limb prostheses
- 1996
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In: 1996 IUTAM Symposium on Optimization of Mechanical Systems. - Dordrecht : Springer Netherlands. ; , s. 25-32
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Conference paper (peer-reviewed)abstract
- To study the effect of prosthesis design on the kinematic, dynamic, energetic and other characteristics of an amputee's locomotion and to improve and create new efficient lower limb prostheses it is expendient to use mathematical modeling of a human walk process and dynamic optimization techniques. In this paper a mathematical model is proposed for investigating the dynamics of a man's skeletal system (MSS) with a below-knee prosthesis. A MSS is simulated by a plane controlled dynamic system of rigid masses. The controlled motions of the system are described by Lagrange's equations of the second kind, and for the expressions for kineto-static balance of the prosthesis under the action of ankle and metatarsal moments and the forces of reactions are derived. An algorithm is construced for solving the problem of human gait dynamics with a below-knee prosthesis. The series of dynamics problems for multibody biothechnical system "Man-Prosthesis" and optimization of structural parameters of the artificial lower extremity of a man has been solved.
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| 3. |
- Goldsteins, Gundars, et al.
(author)
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Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants
- 1999
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 96:6, s. 3108-3113
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Journal article (peer-reviewed)abstract
- The structural requirements for generation of amyloid from the plasma protein transthyretin (TTR) are not known, although it is assumed that TTR is partly misfolded in amyloid. In a search for structural determinants important for amyloid formation, we generated a TTR mutant with high potential to form amyloid. We demonstrated that the mutant represents an intermediate in a series of conformational changes leading to amyloid. Two monoclonal antibodies were generated against this mutant; each displayed affinity to ex vivo TTR and TTR mutants with amyloidogenic folding but not to wild-type TTR or mutants exhibiting the wild-type fold. Two cryptic epitopes were mapped to a domain of TTR, where most mutations associated with amyloidosis occur and which we propose is displaced at the initial phase of amyloid formation, opening up new surfaces necessary for autoaggregation of TTR monomers. The results provide direct biochemical evidence for structural changes in an amyloidogenic intermediate of TTR.
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| 4. |
- Balciunas, Darius
(author)
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Functional studies in yeast of cyclin C and the RNA polymerase II Mediator complex
- 1999
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Doctoral thesis (other academic/artistic)abstract
- Cyclin C belongs to a group of cyclins that are not cell cycle-regulated. It was first cloned from Drosophila and rat, but its role was not understood until the yeast cyclin C homologue Srb 11 was identified in several genetic screens for transcriptional repressors and subsequently was shown to be associated with the RNA polymerase II Mediator complex. The Mediator is a multisubunit complex that enables RNA polymerase II to respond to activators in vitro.In the work presented here, the yeast genes encoding cyclin C (Srb11/Gig3), its cyclin-dependent kinase (Srb10/Gig2), and a third associated protein (Srb8/Gig1) were identified in a genetic screen for negative regulators of the gluconeogenic genes. A further analysis of the cloned genes suggested that the encoded proteins function closely together.The Med1 subunit of the yeast Mediator complex was characterized. Evidence was found of a functional connection between Med1 and the cyclin C-dependent kinase. The expression of the GAL1 promoter is partly deregulated in cells lacking cyclin C, Med1, or another mediator subunit, Med2. This deregulated expression is seen also under derepressed non-inducing conditions, and is therefore not due to a failure of glucose repression.An analysis of the ability of different Mediator subunits to activate transcription when fused to a DNA binding domain indicated that Med1 and Srb7 are negatively regulated both by cyclin C and by the Sin4 subunit of the Mediator, but not by the Med2 or Gal11 subunits, even though Sin4, Med2 and Gal11 are a part of the same module within the Mediator.A screen was made for multicopy suppressors of disruptions in the SRB8, SRB10 and SRB11 genes. Since these disruptions lack selectable phenotypes in a wild type background, the failure of snf1 mig1 srb8/10/11 cells to grow on galactose was used to select suppressors. Four new genes were identified and named GISI-4. Evidence was obtained of a functional interaction between these genes and the RAS/cAMP pathway.
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| 5. |
- Blomquist, H K, et al.
(author)
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Glycerol kinase deficiency in two brothers with and without clinical manifestations.
- 1996
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In: Clinical genetics. - 0009-9163 .- 1399-0004. ; 50:5, s. 375-9
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Journal article (peer-reviewed)abstract
- We report two brothers with glycerol kinase deficiency (GKD). The older brother had serious clinical symptoms, mental and growth retardation, abnormal skeleton, spontaneous fractures and premature loss of abnormal teeth. He and his mother had low serum phosphate levels. He had elevated serum and urine glycerol levels and GKD was found in cultured fibroblasts. Prenatal diagnosis was performed in the second pregnancy. Glycerol kinase activity was considered normal in a chorionic villus sample of the foetus. After birth, it was found that the boy had elevated serum and urine glycerol levels. Enzymatic analysis in cultured fibroblasts revealed that this boy also had GKD, in spite of having no expression of the disease. Chromosomal analyses in the parents and both boys were normal. Major rearrangements or deletions were not detected in molecular studies of DNA from the two brothers. The hybridisation pattern was normal and no allelic loss was observed.
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| 6. |
- Feyzi Talarposhti, Emadoldin
(author)
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Protein recognition domains in heparan sulfate
- 1998
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Doctoral thesis (other academic/artistic)abstract
- Heparan sulfate (HS) is a sulfated glycosaminoglycan (GAG) implicated in various physiological and pathological processes such as cell proliferation, viral infection and inhibition of blood coagulation. These effects are due to interactions of HS with proteins. The first aim of the current work was to characterize HS domains recognizing the long splice variant of platelet-derived growth factor A chain (PDGF-AL) and the gC protein, the principal attachment-mediating coat protein of herpes simplex virus type 1 (HSV-1). The second aim was to study the biological regulation of the growth factor binding HS domains using human aorta as a model tissue. The third aim was to study the structural and functional aspects of heparin/HS-analogs generated by modification of the capsular polysaccharide of E. coli K5.The PDGF-AL binding HS domain is shown to comprise an N-sulfated octasaccharide sequence, entailing essential 2-O- sulfated iduronic acid (IdoA) and 6-O-sulfated glucosamine (GlcN) residues. The gC binding domain showed similar preferences for 0-sulfation, but clearly required a longer, deca/dodecasaccharide, HS domain. In both cases, the O-sulfate groups appear to be preferentially localized adjacent to each other in -IdoA(2-OSO3)-GlcNSO3(6-OSO3)- disaccharide units.Analysis of human aorta HS from subjects of various ages revealed that the binding of HS to PDGF isoforms was significantly higher in old individuals, due to age-dependent upregulation of -IdoA(2-OSO3)-GlcNSO3(6-OSO3)- disaccharide units. These findings represent a novel recognition of structural and functional regulation of a human macromolecule.Chemical N- and 0-sulfation of the E. coli K5 polysaccharide is shown to yield structures interacting with antithrombin in a fashion similar to heparin. The semisynthetic saccharide structures contained 3-0-sulfated GlcN residues, critical for the anticoagulant activity of heparin, and prolonged coagulation time in in vitro assays. These results suggest that bacterial polysaccharides can be exploited in production of pharmacologically active heparin analogs.
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| 7. |
- Hagner McWhirter, Åsa
(author)
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Glucuronyl C5-epimerases in the biosynthesis of glycosaminoglycans
- 1999
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Doctoral thesis (other academic/artistic)abstract
- This thesis is focused on two enzymes, both glucuronyl CS-epimerases, that catalyse the conversion of D-glucuronic acid (GlcA) into L-iduronic acid (IdoA) residues in the repeating disaccharide units of heparin/heparan sulphate (HS) and dermatan sulphate (DS) polymers. These glycosaminoglycans are produced as proteoglycans, in which linear polysaccharide chains are attached covalently to a protein core. Proteoglycans are widespread molecules in the body and have many important physiological functions.The reaction catalysed by the C5-epimerases occurs by reversible abstraction and readdition ofa proton at C5 of target hexuronic acid residues, through a carbanion intermediate, with or without inversion of configuration at C5. Studies on the course of C5-3H incorporation from 3H2O into the two hexuronic acid isomers led to proposals for reaction mechanisms. Different incorporation patterns for heparin/HS-epimerase and DS-epimerase implied different sets of bases in the active sites of the two types of enzymes.No significant difference was found between the kinetic behaviour of the heparin-producingmastocytoma enzyme and the heparan sulphate-producing bovine liver enzyme towards differently N-sulphated substrates, suggesting that the enzyme species are functionally similar. The Km values were unexpectedly seen to vary with the enzyme concentration. This effect of enzyme concentration on the Km was also seen for highly purified epimerase and it is likely that the phenomenon is due to the polymeric nature of the substrate.The C5-enimerase involved in the biosynthesis of heparin and HS was cloned from a bovinelung cDNA library and functionally expressed in insect cells, using the baculovirus vector. The cDNA of the cloned enzyme may lack some sequence in the 5'-end, since the cDNA sequence starts in-frame, upstream of the assigned start codon. Northern analysis implicated a ~ 9-kb and a& ~ 5-kb epimerase transcript in both lung and liver tissues, whereas only a ~ 5-kb transcript was seen in mouse mastocytoma cells.
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| 8. |
- Hjälm, Göran
(author)
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The megalin receptor
- 1998
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Doctoral thesis (other academic/artistic)abstract
- Ionized calcium is a major player in the living organism. Its importance in both intra- and extracellular mechanisms have been studied in a broad number of publications. In man, the parathyroid glands have an essential role in the maintenance of a correct Ca2+-level in the blood serum by its ability to sense extracellular free Ca2+ and to modulate parathyroid hormone secretion. With the help of anti-parathyroid antibodies, previously shown to interfere with the parathyroid Ca2+-sensing mechanism, we have purified and cloned a human 520 kDa membrane bound receptor, megalin, implicated as a Ca2+-sensor. The primary structure of the receptor is characterized. Its possible involvement in Ca2+-regulation, but also in Alzheimer's disease and vitamin B12 metabolism is discussed.The cytoplasmic domain of megalin harbors a number of amino acid sequence motifs, potentially coupling the receptor to several intracellular signaling pathways. To further elucidate the organization of the cytoplasmic domain, we identified and sequenced a human genomic DNA clone encoding for this part of the receptor. The structure of this clone is characterized and discussed. In addition, one of the intronscontain a human endogenous retrovirus-like element of the HERV-H family. We show the presence of this element in the corresponding position in the genome of chimpanzee, gorilla, and orangutan, but absence in the African green monkey.
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| 9. |
- Holmberg, Monica, et al.
(author)
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Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1
- 1995
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 4:8, s. 1441-1445
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Journal article (peer-reviewed)abstract
- We present linkage analysis on a large Swedish five-generation family of 15 affected individuals with autosomal dominant cerebellar ataxia (ADCA) associated with retinal degeneration and anticipation, Common clinical signs in this family include ataxia, dysarthria and severely impaired vision with the phenotype ADCA type II, Different subtypes of ADCA have proven difficult to classify clinically due to extensive phenotypic variability within and between families. Genetic analysis of a number of ADCA type I families shows that heterogeneity exists also genetically, During the last few years several types of ADCA type I have been localized and to date six genetically distinct forms have been identified including SCA1 (6p), SCA2 (12q), SCA3 and Machado-Joseph disease (MJD) (14q), SCA4 (16q), and finally SCA5 (11), We performed a genome-wide search of the Swedish ADCA type II family using a total of 270 microsatellite markers, Positive lod scores were obtained with a number of microsatellite markers located on chromosome 3p12-p21.1. Three markers gave lod scores over 3 with a maximum lod score of 4.53 achieved with the marker D3S1600. The ADCA type II gene could be restricted to a region of 32 cM by the markers D3S1547 and D3S1274.
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| 10. |
- Johansson, Jenni, et al.
(author)
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Expanded CAG repeats in Swedish Spinocerebellar ataxia type 7 (SCA7) patients : effect of repeat length on the clinical manifestation
- 1998
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 7:2, s. 171-176
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Journal article (peer-reviewed)abstract
- Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. The gene responsible for SCA7, located on chromosome 3p, recently was cloned and shown to contain a CAG repeat in the coding region of the gene, that is expanded in SCA7 patients of French origin, We examined the SCA7 repeat region in four Swedish SCA7 families as well as in 57 healthy controls, All Swedish SCA7 patients exhibited expanded CAG repeats with a strong negative correlation between repeat size and age of onset, The repeat length in SCA7 patients ranged from 40 to >200 repeats, The largest expansion was observed in a juvenile case with an age of onset of 3 months, and represents the longest polyglutamine stretch ever reported, In patients with 59 repeats or more, visual impairment was the most common initial symptom observed, while ataxia predominates in patients with <59 repeats. Two of the Swedish SCA7 families analysed in this study were shown to be related genealogically, The other two SCA7 families could not be traced back to a common ancestor, All four families shared the same allele on the disease chromosome at a locus closely linked to SCA7, suggesting the possibility of a founder effect in the Swedish population.
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