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Träfflista för sökning "AMNE:(MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi) srt2:(1990-1999)"

Sökning: AMNE:(MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi) > (1990-1999)

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1.
  • Berbyuk, Viktor, 1953 (författare)
  • Dynamics and optimal control of biotechnical systems "Man-Prosthesis"
  • 1997
  • Ingår i: 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
  • Konferensbidrag (refereegranskat)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 (författare)
  • Multibody systems modeling and optimization problems of lower limb prostheses
  • 1996
  • Ingår i: 1996 IUTAM Symposium on Optimization of Mechanical Systems. - Dordrecht : Springer Netherlands. ; , s. 25-32
  • Konferensbidrag (refereegranskat)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. (författare)
  • Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants
  • 1999
  • Ingår i: 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
  • Tidskriftsartikel (refereegranskat)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 (författare)
  • Functional studies in yeast of cyclin C and the RNA polymerase II Mediator complex
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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. (författare)
  • Glycerol kinase deficiency in two brothers with and without clinical manifestations.
  • 1996
  • Ingår i: Clinical genetics. - 0009-9163 .- 1399-0004. ; 50:5, s. 375-9
  • Tidskriftsartikel (refereegranskat)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 (författare)
  • Protein recognition domains in heparan sulfate
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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 (författare)
  • Glucuronyl C5-epimerases in the biosynthesis of glycosaminoglycans
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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 (författare)
  • The megalin receptor
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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. (författare)
  • Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1
  • 1995
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 4:8, s. 1441-1445
  • Tidskriftsartikel (refereegranskat)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. (författare)
  • Expanded CAG repeats in Swedish Spinocerebellar ataxia type 7 (SCA7) patients : effect of repeat length on the clinical manifestation
  • 1998
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 7:2, s. 171-176
  • Tidskriftsartikel (refereegranskat)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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11.
  • Onyango, Isaac G. (författare)
  • Intracellular components involved in parathyroid sensing of extracellular calcium
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Parathyroid glands are the primary regulator of extracellular calcium ([Ca2+]e). Ca2+ plays a key role in many fundamental biological processes and is also an essential structural component of the skeleton. The parathyroid chief cells detect small changes in [Ca2+]e and respond by altering the secretion of parathyroid hormone (PTH). This thesis details studies towards the identification of intracellular components involved in the parathyroid sensing mechanism of [Ca2+]e.Src family members c-Src, c-Yes, Fyn, Lyn, Lck and PKC isozymes (α, βI, βII, ε, ζ and ι) were found to be expressed in bovine parathyroid cells. Increase in [Ca2+]e to 3.0 mM caused activation of c-Src and c-Yes that was maximal at 5 min of incubation of the parathyroid cells. This activation was still evident after 30 min. Parathyroid caveolin along with 62, 38, 36, and 32 kDa proteins were found to be phosphorylated in high [Ca2+]e. Inhibition of Src kinases blocked tyrosine phosphorylation of caveolin and the 38 kDa protein and uncoupled the inhibition of PTH secretion seen at high [Ca2+]e. ERK was found to be strongly activated at 3 mM and also, but more weakly at 0.5 mM compared to at 1.25 mM [Ca2+]e. Inhibition of ERK blocked PTH secretion at low [Ca2+]e.Increase of [Ca2+]e to 3.0 mM also elicited translocation of PKCβI, -ε, -ζ and -ι to the cell periphery. In contrast, at 0.5 mM [Ca2+]e PKCα was translocated to the cell periphery and PI 3-kinase was found to be activated. Inhibition of PI 3-kinase activity blocked the dissociation of the cortical actin ring of parathymid cells evident at low [Ca2+]e and inhibited the subcellular translocation of PKCε, -ζ, and -ι in cells exposed to high [Ca2+]e. Moreover, the secretion of PTH induced at low [Ca2+]e was blocked by inhibition of PI 3-kinase. These results suggestthat c-Src, c-Yes, ERK, PI 3-kinase and several PKC isozymes are involved in the mechanism that couples the [Ca2+]e stimulus to secretion in the parathyroid cell.
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12.
  • Rong, Jianhui (författare)
  • Novel chemical and enzymatic routes to the generation of heparin- related polysaccarides
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Heparin and heparan sulphate (HS) are structurally related polysaccharides influencing various biological processes. The biological functions of heparin/HS largely depend on interactions between the negatively charged polysaccharide chains and a variety of proteins. Heparin/HS is generated through a complex biosynthetic process, which apparently requires a coordinated action of several enzymes. This thesis aimed to address two questions: 1) how 2-O-sulphation of L-iduronic acid (IdoA) and D-glucuronic acid (GlcA) residues is accomplished in the biosynthesis of heparin/HS; 2) how different saccharide domains must be organised in order to generate biologically active polysaccharides.Using a DNA probe generated from a Chinese hamster ovary (CHO) cell HS 2-OST clone, we isolated a highly similar 2-OST from a mouse mastocytoma cDNA library. Northern-blotting analysis showed a predominant mRNA transcript of ~3 kb in adult mouse tissues, and in addition, ~5 kb and ~7 kb transcripts in some tissues.Overexpression of 2-OST id a mammalian cell line resulted in GlcA 2-O-sulphation. Incubation of different polysaccharide acceptors with cell extract of either 2-OST transfected cells or control cells in the presence of the active sulphate donor adenosine 3'-phosphate 5'-phospho[35S]sulphate revealed that 2-OST prefers to act on IdoA residues. However, the enzyme is capable of sulphating GlcA residues in polysaccharides lacking IdoA residues. Moreover, the activity of 2-OST requires the presence of N-sulphated glucosamine residues. Our data suggest that 2-O-sulphation of GlcA and IdoA residues is catalysed by the same 2-OST.To facilitate the studies on the domain organisation and its biological importance, we developed a novel strategy to generate biologically active neo-glycosaminoglycan (neo-GAG) conjugates by chemical conjugation of two heparin-oligosaccharides. Heparin prevents blood coagulation by binding to, and thus activating antithrombin (AT). An in vitro assay of thrombin inactivation by AT was performed in the presence of heparin with high affinity (HA) to AT or neo-GAG conjugates. Strikingly, the neo-GAG conjugates with the low affinity (LA)-HA (non-reducing end-reducing end) arrangement showed better efficacy to promote the inactivation of thrombin by AT than that of HA-heparin whereas the conjugates with the LA-LA arrangement were virtually inactive.
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13.
  • Rönn, Ola (författare)
  • DNA and protein interactions of mouse polyomavirus large T antigen
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Polyomaviruses require dividing cells to multiply. The regulatory genes express proteins, theT-antigens, necessary for this to occur. Large T-antigen (LT), is a phosphoprotein withmultiple intrinsic activities, e.g. ATPase, helicase, and interaction with cellular factors. Crucial for the regulatory role of LT is its ability to specifically bind DNA containing GRGGC-motifs located in the non-coding regulatory region of the viral genome. This thesis focuses on the characteristics of LT-DNA interactions. Also, it addresses some important questions regarding the role of LT-protein interactions in initiation of DNA synthesis.The DNA binding specificity of LT was investigated using a binding site selection protocolbased on the polymerase chain reaction. A pool of polynucleotides with randomised sequences was probed with LT. Molecules that bound to LT were selected. All obtained polynucleotides contained tandemly repeated GRGGC-motifs in a head-to-tail arrangement, with a relatively uniform spacing. Experiments with a DNA binding deficient LT produced evidence for an alternative lower affinity binding site.LT binding to different types of sites was studied using surface plasmon resonance(BIAcore). Both association and dissociation rates were related to motif configuration. LTcomplexed with the origin of replication site was particularly unstable. Comparison betweensites containing one to four motifs in tandem, showed a preference for non-cooperative dimerbinding. Sodium chloride stabilised the complexes. A pH above 7.0 increased dissociationrate.An enhancer-less polyomavirus (PyV) can be rescued by inserting binding sites for bovinepapillomavirus (BPV) E2 protein, and supplying E2. In BPV, E2 is a transcriptional activatorthat is, together with E1, required for DNA replication. Using a set of E2 mutants, a correlationbetween transcriptional activation and replication of PyV, but not BPV, was found, suggestingdifferent mechanisms for activation. Interaction assays found evidence of a cellular factoracting as a mediator between E2 and LT.An LT with an amino acid substitution close to the DNA-binding domain could rescueviability in a PyV with a base substitution in the origin of replication. BIAcore analysisshowed no great differences between mutant and wild type interactions. The mutant LT wascomparable to wild type in other selected activities.
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14.
  • Safaiyan, Fariba (författare)
  • Cellular regulation of heparan sulfate structure and function
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Heparan sulfate (HS) is a sulfated glycosaminoglycan found on cell surfaces and in the extracellular matrix as HS proteoglycans. HS is synthesized as a polymer of alternating glucuronic acid and N-acetylglucosamine units. Parts of the polymer are subsequently modified by N-deacetylation/N-sulfation of the glucosamine units, C-5 epimerization of glucuronic acid to iduronic acid and O-sulfation at various positions.We studied whether the HS biosynthesis is affected by malignant transformation and cell differentiation using established cell culture models for the two processes. Structural analysis of HS indicated that transformation anddifferentiation were accompanied by structural alterations in HS, particularly with regard to 6-O-sulfation. Reduced 6-O-sulfation resulted in decreased binding of HS to the platelet derived growth factor.The biosynthesis of the sulfate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) can be inhibited by treatment of cells with sodium chlorate. We studied the effects of decreased PAPS availability on HS biosynthesis. The sulfation reactions were affected in the order of 6-O-sulfation>2-O-sulfation>>N-sulfation, suggesting that the various sulfotransferase species have different affinities to PAPS. Moreover, we found that 6-O-sulfation of HS was affected in a domain selective fashion. We also studied the influence of the length of N-sulfated HS domains on their further polymer modification. The domain length had distinct effects on the various polymer modifications reactions. The efficiency of 2-O-sulfation was increased along with increasing domain length, whereas 6-O-sulfation was not affected by the domain length. N-sulfated domains from different HS species displayed marked structural diversity, perhaps due to the specialized functions of HS in different tissues.
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15.
  • Sandbäck Pikas, Dagmar (författare)
  • Enzymes involved in biosynthesis and degradation of heparin-related polysaccharides
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Heparin and heparan sulphate (HS) are structurally related polysaccharides of the glycosaminoglycan type. As the glycan moiety of proteoglycans, they exist covalently linked to various core proteins. Highly sulphated, the polysaccharide chains are prone to interact with proteins at the cell surface and in the extracellular matrix, affecting various biological processes. This thesis focuses on two enzymes involved in biosynthesis and degradation of heparin/HS, with the long-term goal to further understand the physiological functions of these polysaccharides.Heparanases are endoglycosidases that cleave HS at a few sites, generating polysaccharide fragments. The substrate specificity of heparanases from human hepatoma and platelets was characterised. We used a bacterial polysaccharide from E. coli K5, identical to the HS "back-bone" structure, as starting material to generatespecifically modified substrates that were tested for heparanase susceptibility. It is concluded that the heparanases from both sources cleave the polysaccharide at the reducing end of a glucuronic acid (GlcA) residue, provided that a 2-O-sulphate group is located two monosaccharide units from the cleavage site.The specific structures recognised by HS interacting proteins, such as the heparanase, are generated by the concerted action of a number of biosynthetic enzymes. The N-acetylglucosamine N-deacetylase/N-sulphotransferase (NDST) holds a key role during biosynthesis. This enzyme N-sulphates certain regions of the polysaccharide, which can then undergo subsequent modifications (GlcA C5-epimerization and O-sul-phation), resulting in highly heterogenous structures. However, the mechanisms for regulation of HS structure are poorly known.Two isoforms of the enzyme, NDST-1 and -2, were cloned from mouse. They are encoded by two separate genes, which are both expressed in a number of tissues. Functional studies of purified NDST-2 indicated its dependence on a polycationic factor to express N-deacetylase activity. The two catalytic activities of this bifunctionalprotein are tightly coupled to each other. Overexpression of the NDST isoforms in a mammalian cell line illustrated their different characteristics, resulting in different HSN-sulphation patterns. These results suggest specific roles for the NDST isoforms in heparin/HS biosynthesis.
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16.
  • Sokolowski, Marcus (författare)
  • Control of human papillomavirus type 1 late mRNA stability and translation by an AU-rich RNA element
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Human Papillomaviruses (HPVs) infect the epithelial tissues in humans and infection with certain high-risk types is associated with cancer. The expressionof the HPV late capsid genes is dependent on cell differentiation. This may be one reason for the lack of HPV replication in vitro.Here we have studied an AU-rich sequence in the 3´ untranslated region (UTR) on the HPV type 1 (HPV-1) late mRNAs that acts in cis to posttranscriptionally inhibit HPV late gene expression in undifferentiated cells. Mapping revealed that the minimal AU-rich element (ARE) was 57 nts long, 93% AU-rich and that point mutations in two AUUUA- and three UUUUU-motifs inactivated the ARE. Analysis of the mRNA stability in HeLa cells showed that mRNAs containing the HPV-1 ARE (h1ARE) had reduced half life. The h1ARE also acted by suppressing translation independently of the effect on mRNA stability. Inhibition of translation appeared to occur by suppressing a function mediated by the 3´-poly(A) tails.Analysis of RNA-protein interactions in vitro revealed that both cytoplasmic and nuclear proteins interacted specifically with the h1ARE. Three cellular proteins were identified as the heterogeneous nuclear ribonucleoproteins (hnRNPs) C1 and C2 and the HuR protein. Recombinant HuR protein bound specifically to the AUUUA- and UUUUU-sites within the h1ARE and the apparent Kd value of HuR binding to the h1ARE or the inactive mutants thereof differed more than 50 fold. Binding of HuR and hnRNPC1/C2 to the AUUUA- and UUUUU-motifs suggested their importance for the function of the h1ARE. The h1ARE was the major negative element on HPV-1 late mRNAs whereas HPV-16 late mRNAs contained multiple negative elements. The number of negative elements correlated with the levels of virions produced by these HPV types in vivo.
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17.
  • Ström, Anne-Christine (författare)
  • Transcriptional activation by Sp1 and the adenovirus E1A transactivator protein
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Transcription is a key step in the regulation of gene expression. Activation of transcriptionrequires that the RNA polymerase receive both, regulatory signals from transcription factors,and initiate transcription at the correct location in the genome, at the promoter. A key issuedescribed in this thesis is the understanding of how transcription factors function to achievethe specificity required to regulate the complex pattern of gene expression. In particular,transcriptional regulation by the human Sp1 factor and the adenovirus encoded E1A proteinhave been studied.Sp1 is a ubiquitously expressed human transcription factor which regulatestranscription of several genes by synergistically interacting with a variety of transcriptionfactors, coactivators and TAFs. This thesis addresses whether Sp1 requires different regions,to mediate activation from two different RNA polymerase II promoters. Genetic studiesrevealed that overlapping but not identical parts of Sp1 were required for stimulation of aTATA box containing promoter and a U2 snRNA promoter. Moreover, this work describes the nature of the cooperativity between the transcription factors Sp1 and Oct-l. These factorswere found to cooperatively bind the U2 enhancer, as well as psychically interact, both in astandard in vitro binding approach, and in the yeast two hybrid system in vivo. The part ofSpl that bound to Oct-1 was found be located in a region necessary for transcriptionalstimulation of U2 transcription. Since there was a correlation between the in vitro interaction and the in vivo transcriptional activation, these results suggest that the physical interaction between these factors is of functional importance.Adenoviruses are small DNA viruses that use the mammalian transcriptionalmachinery to activate transcription of their own genes. This thesis describes the structuralfeatures of a novel region, termed auxiliary region 1 (AR1), located in the adenovirus encodedE1A protein. Genetic dissection of the AR1 region revealed, that E1A mediatedtranscriptional activation required the AR1 element in addition to the classicaltransactivation domain (CR3) for efficient activation of all early viral adenovirus promoters.Since the AR1 region is an essential element for viral transcription and located next to theCR3 region, this thesis suggest that the CR3 activation domain should be extended to alsoinclude AR1.
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18.
  • Svineng, Gunbjørg (författare)
  • Characterisation of integrin splice variants and the interaction between integrins and the urokinase receptor
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Integrins are a family of receptors involved in adhesion to extracellular matrix proteins and in cell-cell contacts. Each integrin consists of one a and one β subunit. Our main interest has been the β1 subunit and its splice variants.The new splice variant, named β1C-2, was identified and its transcript found to be generated as a result of utilisation of a more 3' splice acceptor-site in exon C. Hence, β1C-2 has an internal deletion of six amino acids compared to β1C-1. Exon C is part of a retrotransposable Alu element, and is thus primate specific. Low levels of β1C-1 and β1C-2 transcripts were found in all human cells and cell lines tested. Expression of β1A, β1C-1 and β1C-2 cDNAs in the mouse β1-deficient GD25 cells demonstrated that β1A integrins localised at the cell surface, while β1C-1 and β1C-2 were retained and finally degraded intracellularly. This suggests that the ER quality control system is able to recognise and prevent cell surface localisation of the β1C-1 and β1C-2 subunits.The β1B splice variant has been reported to have dominant negative effects on β1A-integrin functions. Since β1A and β3 cytoplasmic tails are highly homologous, we investigated if expression of β1B had a similar effect on αVβ3 integrin functions by expressing β1B in GD25 cells. The presence of β1B did not interfere with a Vβ3 mediated adhesion or signalling.The urokinase receptor (uPAR) has been shown to modulate integrin function. To study the effect of uPAR on αVβ3 and β1-integrins separately, GD25 and GD25Tβ1A cells were transfected with the human uPAR cDNA. Although stimulation of uPAR with its ligand (uPA) resulted in increased adhesion to vitronectin, but not to fibronectin, phosphorylation of FAK and paxillin was unchanged, while phosphorylation of p 130Cas was reduced. However, the absence or presence of β1A did not alter the intracellular signals generated by stimulation of uPAR.
  •  
19.
  • Söderbärg, Karin (författare)
  • Effects of polyomavirus T antigens on cellular signal transduction pathways
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The early viral proteins, the tumor (T) antigens, of mouse polyomavirus,stimulate cell growth by interaction with cellular growth regulating proteins.The viral interference with cellular growth regulation may, eventually, alsoresult in effects on cellular apoptosis (programmed cell death) mechanisms.The aim of this work has been to contribute to the understanding ofpolyomavirus T antigens effect on cellular growth regulation and apoptosis.Large T antigen stimulates host cell DNA synthesis, and it has theability to immortalize primary cells. it is also required for initiation of viralDNA replication, and regulation of viral transcription. We found that mutantlarge T antigens, with deletions in the conserved retinoblastoma proteinbinding-site, had defects in the immortalizing activity. Furthermore, themutants could no longer stimulate viral DNA replication in slowly growingcells. Thus, Rb-binding by large T antigen is probably important for viralreplication in quiescent cells.Middle T antigen is the main transforming protein of polyomavirus. Itinteracts with a number of cellular proteins, involved in signal transduction.In this work we demonstrate that middle T antigen induces sensitivity to TNF-α- and H2O2- induced apoptosis. This induced sensitivit is dependent on the ability of middle T antigen to interact with the cellular proteinsphosphatidylinositol 3-kinase and Shc.Small T antigen stimulate viral DNA synthesis, and cooperates withmiddle T antigen in transformation. We show here, that small T antigen alsohas a protective effect against cytotoxicity induced by TNF-α and H2O2.Furthermore, we demonstrate two possible mechanisms for the anti-apoptoticeffect, induction of NF-κB activity and increased expression of heat shockprotein 27.The protective effect of small T antigen appears to be important forpolyomavirus induced tumor formation. Middle T antigen expression has anegative effect on the development of tumors by FM3A cells in mice.However, expression of small T antigen overcame this negative effect, leading to increased tumor formation.
  •  
20.
  • Thuveson, Maria (författare)
  • Intracellular processing of pre-a-inhibitor
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Pre-α-inhibitor (PαI) is a plasma protein consisting of a 25 and a 75 kDa polypeptide: bikunin and heavy chain 3 (H3), respectively. Both these polypeptides are made by hepatocytes and while passing through the Golgi complex, bikunin, which carries a chondroitin sulfate chain, becomes covalently linked to the C-terminal amino acid residue of H3 via its polysaccharide. Both bikunin and H3 are made as precursors which are proteolytically cleaved during their intracellular transport. In this thesis, the intracellular processing of these precursors, as well as their assembly to PαI were studied in more detail.When H3 and bikunin were co-expressed in COS-1 cells, the two polypeptide became coupled. Furthermore, another chondroitin sulfate bearing protein, decorin, was found to form a linkage when co-expressed with H3. These results show that cells other than hepatocytes are capable of forming the protein-glycosaminoglycan link and that the bikunin polypeptide is not required for this coupling to occur. Thus it is possible that non-hepatic cells may produce proteins with similar structures.Heavy chain 3 is synthesized with a 30 kDa C-terminal extension which is released in the Golgi complex; the cleavage of this propeptide occurs between an Asp and a Pro residue. Transfected COS-1 cells were found to secrete partially cleaved H3. Incubation of this recombinant protein at pH 6.0 or below, led to further cleavage. The reaction seemed to be intramolecular since dilution or immobilization of the protein did not affect the cleavage rate. Mutation or deletionsof the C-terminal extension abolished cleavage suggesting that it is mediated by this part of the polypeptide.
  •  
21.
  • Åhlén, Karina (författare)
  • Collagen-binding integrin α2β1 activity in vivo and in vitro : Effects of platelet-derived growth factor-BB
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The expression of integrins by two cell clones from a rat colon carcinoma was investigated. Cloned cells that gave rise to regressive tumors, but not cells that gave rise to progressive, lethal, tumors, adhered to interstitial collagens through the integrin α2β1, although both cell types expressed it. These data suggest that the apparent activity of α2β1 is important for tumorinvasiveness.Inhibition of the α2β1 integrin in rat paw skin lead to a lowering of the interstitial fluid pressure (PIF). an effect that could be overcome by platelet-derived growth factor-BB (PDGF-BB).PDGF-BB could stimulate the synthesis of the α2, but not α1, α3 or β1 integrin chains in human AG1518 fibroblasts.PDGF-BB also stimulated cell spreading and induced a rapid and transientrelocalization of α2β1 in AG1518 fibroblasts. The relocalization was dependent on phosphatidylinositol 3-kinase (PI3-K) and protein kinase C (PKC), and involved disassembly of focal adhesions as seen in interference reflection microscopy (IRM). The mobility of β1-integrins in the cell membrane was increased in cells stimulated with PDGF-BB.PDGF-BB-stimulated collagen gel contraction, as well as the induction of a rise in cytoplasmic free calcium [Ca2+]i were shown to depend on PI3-K. The experimental anti-inflamatory drug α-trinositol induced an increase in [Ca2+]i and could restore PI3-K-dependent chemotaxis towards PDGF-BB as well as the lowering of PIF induced bv inhibitors of PI3K. In conclusion: α2β1 is implicated in invasiveness of tumor cells in vivo, and in the maintenance of interstitial fluid pressure (PIF). PDGF-BB is shown to regulate PIF, to stimulate synthesis of the integrin α2 chain, and to modulate cytoskeletal interactions of α1- integrins. The maintenance of PIF, as well as PDGF-BB-stimulation of collagen gel contraction, induction of integrin reorganization from focal adhesions, and induction of a calcium response, was dependent on an activation of PI3-K. PI3-K is hypothesized to mediate these effects at least in part through induction of a rise in [Ca2+]i.
  •  
22.
  • Baeckström, Dan, 1956 (författare)
  • Post-translational fate of a mucin-like leukocyte sialoglycoprotein (CD43) aberrantly expressed in a colon carcinoma cell line.
  • 1997
  • Ingår i: The Journal of biological chemistry. - 0021-9258. ; 272:17, s. 11503-9
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper describes the biosynthesis of L-CanAg, a mucin-like glycoprotein which carries the carcinoma-associated carbohydrate epitope sialyl-Lewis a and is secreted by the colon adenocarcinoma cell line COLO 205. Recently, it has been shown that L-CanAg is a novel glycoform of CD43, a surface sialoglycoprotein normally found only on hematopoietic cells. Immunoprecipitation with alpha-GPEP18, a novel antiserum against the cytoplasmic domain of CD43, detected a transmembrane form of L-CanAg carrying sialyl-Lewis a. Cell surface biotinylation experiments demonstrated the presence of transmembrane L-CanAg at the plasma membrane and that COLO 205, unlike the leukocyte cell line HL-60, contained significant amounts of glycosylated intracellular CD43. Immunoprecipitation of phosphate-labeled COLO 205 cells revealed that membrane-bound L-CanAg, like leukocyte CD43, is a phosphoprotein. Interestingly, both surface- and phosphate-labeled L-CanAg were eluted earlier from a gel filtration column than their unlabeled counterparts, indicating that this method could separate membrane-bound L-CanAg from its soluble form. Immunoprecipitations of pulse-chase-labeled COLO 205 lysates fractionated by gel filtration showed that decrease in membrane-bound L-CanAg was concomitant with an increase in the intracellular soluble form. Together, these data indicate that transmembrane L-CanAg is fully glycosylated and phosphorylated before the extracellular domain is cleaved off and stored inside the cell before exocytosis.
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23.
  • Johanson, U, et al. (författare)
  • A new mutation in 16S rRNA of Escherichia coli conferring spectinomycin resistance
  • 1995
  • Ingår i: Nucleic Acids Research. - 0305-1048. ; 23:3, s. 6-464
  • Tidskriftsartikel (refereegranskat)abstract
    • We report a novel mutation, C1066U in 16S rRNA which was selected for resistance to spectinomycin, an antibiotic which inhibits ribosomal translocation. The minimal inhibitory concentration (MIC) of spectinomycin determined for this mutant (15 micrograms/ml) is greater than with the wild-type plasmid (5 micrograms/ml) but lower than with the well known C1192U mutation (> 80 micrograms/ml). The C1066U mutation also increases the cells sensitivity to fusidic acid, another antibiotic which inhibits translation at the translocation stage, whereas C1192U is unchanged relative to the wild type. We discuss why the acquisition of resistance to one of these drugs is often associated with hypersensitivity to the other.
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24.
  • Källtorp, Mia, et al. (författare)
  • In vivo cell recruitment, cytokine release and chemiluminescence response at gold, and thiol functionalized surfaces.
  • 1999
  • Ingår i: Biomaterials. - 0142-9612. ; 20:22, s. 2123-37
  • Tidskriftsartikel (refereegranskat)abstract
    • Hydroxylated and methylated surfaces were prepared by the self-assembled monolayer technique (SAM) of alkane thiols on gold. The surfaces were used to evaluate the influence of implant surface chemistry on protein deposition and inflammatory cell response. Implants were inserted subcutaneously in the rat for 3 and 24 h. The surface chemical properties influenced the in vitro rat plasma protein adsorption (ellipsometry/antibody) with few exceptions (albumin not found and fibrinogen always found). The number of recruited cells and their distribution (DNA from implant versus from exudate) was influenced by the different chemistries at 24 h, but not at 3 h. HIS48+, ED1+, ED2+ and small numbers of CD5+ cells were present in the exudate at both time periods (flow cytometry). The cellular oxidative metabolism was low, although cells on -OH surfaces responded with the highest phorbol ester-stimulated chemiluminescence (CL)/DNA. The levels of cytokines IL-1alpha, IL-1beta and TNFalpha (ELISA) were not influenced by material surface chemistry. Sham operated sites had a higher cytokine concentration/DNA compared with exudates from an implant milieu. The results of this study show that surface chemical functionalization modifies specific events in the inflammatory response around implants in soft tissues.
  •  
25.
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26.
  • Karlsson, Niclas G., 1966, et al. (författare)
  • Analysis of monosaccharide composition of mucin oligosaccharide alditols by high-performance anion-exchange chromatography.
  • 1995
  • Ingår i: Analytical biochemistry. - : Elsevier BV. - 0003-2697. ; 224:2, s. 538-41
  • Tidskriftsartikel (refereegranskat)abstract
    • A simple one-step method for the analysis of monosaccharides including galactosaminitol after acidic hydrolysis is described. The hydrolyzate was re-N-acetylated and analyzed by high-performance anion-exchange chromatography and the sugars were detected by a pulsed amperometric detector. The method was applied on a mixture of neutral oligosaccharides released from mucin glycopeptides of rat small intestine by alkaline borohydride. Sugars were detected down to the nanomole range and the results were compared with monosaccharide compositional analysis performed by gas chromatography of acetylated alditols.
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27.
  • Björkqvist, Susan, 1967, et al. (författare)
  • Isoprene from expired air inside a private car
  • 1997
  • Ingår i: The science of the total environment. ; 207, s. 63-67
  • Tidskriftsartikel (refereegranskat)abstract
    • The concentration of isoprene inside a small-sized parked private car with one person was found to be of the order of 20 g/m3. Isoprene was then the major non-methane volatile hydrocarbon except in strongly traffic-polluted parking places. On driving, with intermediate fan ventilation, the isoprene levels were one order of magnitude lower. In the empty car, the concentrations were still much lower, proving that isoprene originates predominantly from expired air. Air samples were taken on triple-layer adsorbent cartridges and were analysed for volatile hydrocarbons by gas chromatography after thermal desorption. The analytical aluminium oxide column permitted simultaneous determination of a range of reported traffic-emitted hydrocarbons including the carcinogenic 1,3-butadiene and benzene.
  •  
28.
  • Goldsteins, Gundars, et al. (författare)
  • Characterisation of two highly amyloidogenic mutants of transthyretin
  • 1997
  • Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 36:18, s. 5346-5352
  • Tidskriftsartikel (refereegranskat)abstract
    • The plasma protein transthyretin (TTR) has the potential to form amyloid under certain conditions. More than 50 different point mutations have been associated with amyloid formation that occurs only in adults. It is not known what structural changes are introduced into the structure of this otherwise stable molecule that results in its aggregation into insoluble amyloid fibrils. On the basis of calculations of the frequency of known mutations over the polypeptide, we have constructed two mutants in the D-strand of the polypeptide. These molecules, containing either a deletion or a substitution at amino acid positions 53−55, were unstable and spontaneously formed aggregates upon storage in TBS (pH 7.6). The precipitates were shown to be amyloid by staining with thioflavin T and Congo Red. Their ultrastructure was very similar to that of amyloid fibrils deposited in the vitreous body of patients with familial amyloidotic polyneuropathy type 1 with an amino acid replacement in position 30 (TTRmet30). Like amyloid isolated from the vitreous body of the eye, the amyloid precipitates generated from the TTR mutants exposed a trypsin cleavage site between amino acid residues 48 and 49, while plasma TTRmet30 isolated from amyloidosis patients as well as wild-type TTR only showed minor trypsin sensitivity. Our data indicate that the mutants we have constructed are similar to amyloid precursors or may share structural properties with intermediates on a pathway leading to amyloid deposits of plasma TTR.
  •  
29.
  •  
30.
  • Zuccarello, Guido, et al. (författare)
  • HIV-1 protease inhibitors based on acyclic carbohydrates
  • 1998
  • Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 63:15, s. 4898-4906
  • Tidskriftsartikel (refereegranskat)abstract
    • A series of acyclic C2-symmetric HIV protease inhibitors readily accessible from D-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.
  •  
31.
  • Johannsson, Gudmundur, 1960, et al. (författare)
  • Effects of 1 year of growth hormone therapy on serum lipoprotein levels in growth hormone-deficient adults. Influence of gender and Apo(a) and ApoE phenotypes.
  • 1995
  • Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1079-5642. ; 15:12, s. 2142-50
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated the influence of gender and apoE and apo(a) phenotypes as well as the effect of the metabolic effects of growth hormone (GH) on the effect of GH therapy on serum lipoprotein concentrations in GH-deficient (GHD) adults. Forty-four consecutive patients, 30 men and 14 women aged 46.5 (range, 19 to 76) years with GHD due mainly to pituitary tumors, were treated with recombinant human GH for 12 months. Serum concentrations of lipoproteins, insulin, thyroxine, and insulin-like growth factor-I were determined, body composition was assessed by bioelectrical impedance, and apo(a) and apoE phenotypes were analyzed. Lipoprotein(a) [Lp(a)] concentrations in the GHD subjects were compared with a gender- and apo(a) phenotype-matched control group. After 12 months of GH treatment, the total cholesterol, LDL cholesterol, and apoB concentrations decreased, the HDL cholesterol and apoE concentrations increased, and the apoA-I and triglyceride concentrations were unchanged. Before treatment, the Lp(a) concentration was similar to that in the control group. However, after 12 months of treatment, the Lp(a) concentration had increased by 44% and 101% above baseline and the control group, respectively. Men and women responded differently to GH, with a more marked increase in Lp(a) concentration and fat-free mass and a more pronounced decrease in body-fat mass in men. Apo(a) phenotypes had no major influence on the effect of GH therapy. The only significant difference between apoE phenotypes was a higher baseline Lp(a) concentration among apoE4 heterozygotes.(ABSTRACT TRUNCATED AT 250 WORDS)
  •  
32.
  • Berbyuk, Viktor, 1953, et al. (författare)
  • Modeling of human locomotion with artificial lower extremities
  • 1994
  • Ingår i: Biomechanics Seminar. - 1100-2247. ; 8, s. 167-178
  • Konferensbidrag (refereegranskat)abstract
    • To solve the problems of improvement of the existent and creation of new efficient lower limb prostheses, and to stu­dy effect of prosthesis design, as a special technical devi­ce, on kinematical dynamical energetical and other characte­ristics of amputee locomotion it is expedient to use wide ca­pabilities of mathematical modelling of a human walk process on a prosthetic limb. There was proposed earlier mathemati­cal models of biped walk having different degrees of adequa­cy in multitude of works. These models were used for diffe­rent purposes: investigation of kinematical dynamical and energetical characteristics of human gait, working out and creation of antropomorphic walking machines, etc. In the given paper a mathematical model has been proposed for investigation of dynamics of an amputee's locomotor sys­tem with a below-knee prosthesis. Based on this model computer program has been composed. The series of problems of dynamics of a two-leggal walking, calculation of consumption of energy on motion and optimization of elastic parameters of the prosthetic foot design have been solved.
  •  
33.
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34.
  • Platz-Christensen, Jens Jörgen, et al. (författare)
  • Endotoxin and interleukin-1 alpha in the cervical mucus and vaginal fluid of pregnant women with bacterial vaginosis.
  • 1993
  • Ingår i: American journal of obstetrics and gynecology. - : Elsevier BV. - 0002-9378. ; 169:5, s. 1161-6
  • Tidskriftsartikel (refereegranskat)abstract
    • The purpose of our study was to determine the concentrations of endotoxin and interleukin-1 alpha in the cervical mucus and vaginal fluid of pregnant women who either did or did not have bacterial vaginosis.Samples of cervical mucus and vaginal fluid were collected from women in early pregnancy who had signs of bacterial vaginosis and from healthy control subjects. The samples were analyzed for the concentrations of endotoxin and interleukin-1 alpha. In addition, wet mounts were examined for signs of inflammation indicated by increased numbers of leukocytes.Both endotoxin and interleukin-1 alpha occurred in much higher concentrations (p < 0.0001, p < 0.0002) in both the cervical mucus and the vaginal fluid of women with signs of bacterial vaginosis than they did in healthy control subjects. A correlation was found between the interleukin-1 alpha concentrations in the vaginal fluid and the number of leukocytes as judged by a semi-quantitative evaluation of wet mounts (p = 0.0365). The concentrations of endotoxin correlated with those of interleukin-1 alpha in both fluids (vaginal fluid, p < 0.01; cervical mucus, p < 0.01).Our study shows that concentrations of endotoxin and interleukin-1 alpha in cervical mucus and vaginal fluid of women in early pregnancy who have bacterial vaginosis are significantly higher than the corresponding levels in control subjects.
  •  
35.
  • Asker, Noomi, 1968, et al. (författare)
  • Dimerization of the human MUC2 mucin in the endoplasmic reticulum is followed by a N-glycosylation-dependent transfer of the mono- and dimers to the Golgi apparatus.
  • 1998
  • Ingår i: The Journal of biological chemistry. - 0021-9258. ; 273:30, s. 18857-63
  • Tidskriftsartikel (refereegranskat)abstract
    • Pulse-chase experiments in the colon cell line LS 174T combined with subcellular fractionation by sucrose density gradient centrifugation showed that the initial dimerization of the MUC2 apomucin started directly after translocation of the apomucin into the rough endoplasmic reticulum as detected by calnexin reactivity. As the mono- and dimers were chased, O-glycosylated MUC2 mono- and dimers were precipitated using an O-glycosylation-insensitive antiserum against the N-terminal domain of the MUC2 mucin. These O-glycosylated species were precipitated from the fractions that comigrated with the galactosyltransferase activity during the subcellular fractionation, indicating that not only MUC2 dimers but also a significant amount of monomers are transferred into the Golgi apparatus. Inhibition of N-glycosylation with tunicamycin treatment slowed down the rate of dimerization and introduced further oligomerization of the MUC2 apomucin in the endoplasmic reticulum. Results of two-dimensional gel electrophoresis demonstrated that these oligomers (putative tri- and tetramers) were stabilized by disulfide bonds. The non-N-glycosylated species of the MUC2 mucin were retained in the endoplasmic reticulum because no O-glycosylated species were precipitated after inhibition by tunicamycin. This suggests that N-glycans of MUC2 are necessary for the correct folding and dimerization of the MUC2 mucin.
  •  
36.
  • Asker, Noomi, 1968, et al. (författare)
  • Human MUC5AC mucin dimerizes in the rough endoplasmic reticulum, similarly to the MUC2 mucin.
  • 1998
  • Ingår i: The Biochemical journal. - 0264-6021. ; 335:2, s. 381-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Biosynthetic studies on the human MUC5AC mucin were performed by immunoprecipitations with antisera recognizing only the non-O-glycosylated apomucin in the colon adenocarcinoma cell line LS 174T. Pulse-chase studies and subcellular fractionations showed that MUC5AC formed dimers in the rough endoplasmic reticulum within 15 min of the initiation of biosynthesis. No non-O-glycosylated species larger than dimers were identified. The dimerization was N-glycosylation-dependent, because tunicamycin treatment significantly lowered the rate of dimerization. When the biosynthesis of MUC5AC apomucin was compared with that of MUC2 apomucin, also produced in the LS 174T cell line, both apomucins were assembled in similar ways with respect to their rates of dimerization with and without inhibition of N-glycosylation. No heterodimerization was observed between the human MUC5AC and the MUC2 apomucins despite the extensive sequence similarities in the positions of the cysteine residues in the C-termini proposed to be involved in mucin dimerization.
  •  
37.
  • Asker, Noomi, 1968, et al. (författare)
  • The human MUC2 mucin apoprotein appears to dimerize before O-glycosylation and shares epitopes with the 'insoluble' mucin of rat small intestine.
  • 1995
  • Ingår i: The Biochemical journal. - 0264-6021. ; 308:3, s. 873-80
  • Tidskriftsartikel (refereegranskat)abstract
    • Rabbit antiserum against a synthetic peptide corresponding to a tandemly repeated amino acid sequence in the human intestinal mucin apoprotein MUC2 was used in immunoprecipitation to study the biosynthesis of MUC2 in the colon-carcinoma cell line LS 174T. Under non-reducing conditions, two bands were precipitated, the smaller with an apparent size of about 700 kDa on SDS/PAGE. When analysed by two-dimensional electrophoresis after reduction, the larger band migrated to the same position as the smaller band and was interpreted as a putative disulphide-bond-stabilized dimer. Pulse-chase experiments showed only the monomer after 5 min and the appearance of the putative dimer after 30 min. The MUC2 apoprotein was also precipitated by antisera against the HF-deglycosylated peptides of the two highly glycosylated domains of the 'insoluble' mucin complex of rat small intestine [Carlstedt, Herrmann, Karlsson, Sheehan, Fransson and Hansson (1993) J. Biol. Chem. 268, [18771-18781]. Endoprotease Lys-C cleavage of the immunopurified apoprotein gave a large fragment of about 250 kDa that was detected by both the antiserum against the MUC2 tandem repeat and one of the glycopeptide antisera. This supports the view that the 'insoluble' mucin of rat small intestine is encoded by the Muc2 gene, as recently indicated by a partial cDNA sequence [Hansson, Baeckström, Carlstedt and Klinga-Levan (1994) Biochem. Biophys. Res. Commun. 198, 181-190] and that parts of the apoprotein are conserved between the species. A lectin from the snail Helix pomatia that detects terminal alpha-GalNAc residues did not bind to the monomer or putative dimer, suggesting that O-glycosylation starts after dimerization. The results indicate that the biosynthetic pathway of the MUC2 mucin may be similar to that of the von Willebrand factor with which MUC2 shares sequence similarities at its C- and N-termini.
  •  
38.
  • Axelsson, Magnus A. B., et al. (författare)
  • Deglycosylation by gaseous hydrogen fluoride of mucus glycoproteins immobilized on nylon membranes and in microtiter wells.
  • 1998
  • Ingår i: Glycoconjugate journal. - 0282-0080. ; 15:8, s. 749-55
  • Tidskriftsartikel (refereegranskat)abstract
    • Strongly reacting antibodies specific for defined mucin gene products are often directed against the mucin protein backbone of the heavily glycosylated serine/threonine rich regions. A prerequisite for the use of such antibodies is often the complete removal of the oligosaccharides from the protein. This paper describes an efficient one-step deglycosylation method using gaseous hydrogen fluoride on nylon blotting membranes and microtiter wells.
  •  
39.
  • Axelsson, Magnus A. B., et al. (författare)
  • O-glycosylated MUC2 monomer and dimer from LS 174T cells are water-soluble, whereas larger MUC2 species formed early during biosynthesis are insoluble and contain nonreducible intermolecular bonds.
  • 1998
  • Ingår i: The Journal of biological chemistry. - 0021-9258. ; 273:30, s. 18864-70
  • Tidskriftsartikel (refereegranskat)abstract
    • The MUC2 mucin is the major gel-forming mucin in the small and large intestine. Due to its sequence similarities with the von Willebrand factor, it has been suggested to dimerize in the endoplasmic reticulum and polymerize in the trans-Golgi network. Using an O-glycosylation-sensitive MUC2 antiserum, a dimerization has been shown to occur in the endoplasmic reticulum of LS 174T cells (Asker, N., Axelsson, M. A. B., Olofsson, S.-O., and Hansson, G. C. (1998) J. Biol. Chem. 273, 18857-18863). Using an antiserum immunoprecipitating O-glycosylated MUC2 mucin, monomers and dimers were shown to occur in soluble form in the lysate of LS 174T cells. The amount of O-glycosylated dimer was small, and no larger species were found even after long chase periods. However, most of the labeled MUC2 mucin was found in pelleted debris of the cell lysate. This insoluble MUC2 mucin was recovered by immunoprecipitation after reduction of disulfide bonds. Analysis by agarose gel electrophoresis revealed two bands, of which the smaller migrated as the O-glycosylated monomer and the larger migrated as the O-glycosylated dimer of the cell lysis supernatant. Mucins insoluble in 6 M guanidinium chloride could also be obtained from LS 174T cells. Such mucins have earlier been found in the small intestine (Carlstedt, I., Herrmann, A., Karlsson, H., Sheehan, J., Fransson, L. -A., and Hansson, G. C. (1993) J. Biol. Chem. 268, 18771-18781). Reduction of the mucins followed by purification by isopycnic density gradient ultracentrifugation and analysis by agarose gel electrophoresis revealed two bands reacting with an anti-MUC2 tandem repeat antibody after deglycosylation. These bands migrated identically to the bands shown by metabolic labeling, and they could also be separated by rate zonal ultracentrifugation. These results suggest that the MUC2 mucin is forming nonreducible intermolecular bonds early in biosynthesis, but after initial O-glycosylation.
  •  
40.
  • Baeckström, Dan, 1956, et al. (författare)
  • Purification and characterization of sialyl-Le(a)-carrying mucins of human bile; evidence for the presence of MUC1 and MUC3 apoproteins.
  • 1994
  • Ingår i: The Journal of biological chemistry. - 0021-9258. ; 269:20, s. 14430-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Purification of sialyl-Le(a)-carrying mucins from primary human bile by trichloroacetic acid precipitation, delipidation, and gel filtration in guanidinium chloride gave three separable fractions, one of which was further purified by affinity chromatography. These fractions, named SBG1 (for soluble bile glycoprotein), SBG2, and SBG3 had molecular masses of > 1100, 800-950, and 100-250 kDa, respectively, as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Their mucin characteristics were indicated by a high carbohydrate content, ranging from 74 to 95%. The carbohydrate compositions indicated the presence of very long fucosylated polylactosamine chains. Amino acid analyses showed high abundance of serine and threonine in all three fractions (19-36%), confirming their mucin-like nature. Immunochemical analyses of deglycosylated samples detected the MUC1 mucin apoprotein in SBG2 and the MUC3 protein in SBG1. To our knowledge, this is the first report of a MUC3 mucin being purified. This mucin showed no significant reduction in size upon trypsin treatment or disulfide bond reduction and alkylation. Gel filtration of three samples of secondary bile showed that the size distribution of sialyl-Le(a)-carrying glycoproteins was similar to that found in primary bile, and immunochemical analysis showed that the MUC1 protein was present in all three samples. In one sample an additional fraction was isolated, which was insoluble in 6 M guanidinium chloride, but was solubilized upon reduction and alkylation. mRNAs from gallbladder epithelia were analyzed in Northern blot hybridizations showing that the MUC1 and MUC3 but not the MUC2 mucin apoprotein genes were expressed.
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41.
  • Baeckström, Dan, 1956, et al. (författare)
  • The transcripts of the apomucin genes MUC2, MUC4, and MUC5AC are large and appear as distinct bands.
  • 1996
  • Ingår i: Glycoconjugate journal. - 0282-0080. ; 13:5, s. 833-7
  • Tidskriftsartikel (refereegranskat)abstract
    • RNA from four colorectal carcinoma cell lines was prepared and analysed in Northern blots using probes for the MUC2, MUC4, and MUC5AC mucin apoprotein genes. The sizes of the transcripts were very large, in the order of at least 12-16 kb. The presence of distinct bands is in contrast to earlier reports, where these transcripts showed extensive polydispersity. RNA from rat small intestine was also prepared and probed with cDNA for the rat Muc2 mucin gene. This analysis also showed a large and discrete hybridizing band, indicating that apomucin mRNA of well-defined size can be obtained also from a tissue with high endogenous RNase activity.
  •  
42.
  • Bouhours, Danièle, et al. (författare)
  • Structure and genetic polymorphism of blood group A-active glycosphingolipids of the rat large intestine.
  • 1995
  • Ingår i: Biochimica et biophysica acta. - 0006-3002. ; 1255:2, s. 131-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Study of blood group A- and B-active glycosphingolipid content of the epithelium of the large intestine of 16 strains of inbred rats led to the discovery of two related strains, SHR and WKY, devoid of A-active glycolipids, whereas all strains expressed B-active glycolipids. This finding evidenced a new A/non-A genetic polymorphism in the rat. Blood group A-active glycolipids were isolated from the large intestine of F344 rats and purified by affinity chromatography on immobilized Helix pomatia lectin. Three glycolipid fractions were separated by preparative thin-layer chromatography and characterized by electron-impact mass spectrometry of their permethylated and permethylated-LiAlH4-reduced derivatives. They were identified as a tetraglycosylceramide (A-4), a hexaglycosylceramide (A-6), and a difucosylated heptaglycosylceramide (A-7) with small amounts of monofucosylated octaglycosylceramide (A-8). Methylation analysis and fragmentation indicated that A6 and A-8 had a lacto- and A-7 a neolactotetraosylceramide core, respectively, identical to the core structures of B-6 and B-7 previously characterized in the large intestine of WF rats (Angström et al. (1987) Biochim. Biophys. Acta 926, 79-86). Upon methylation analysis, B-6 and B-7 purified from SHR (A-deficient) and F344 (A-expressing) were found identical to those of WF rats. This result indicated that precursor substrates for the synthesis of A-active glycolipids were available in SHR rats and thus the genetic deficiency of A-active glycolipid expression probably originated in a defect of the termination of the blood group A determinant by the alpha-3-N-acetylgalactosaminyltransferase.
  •  
43.
  • Bridge, Eileen, et al. (författare)
  • Spliced exons of adenovirus late RNAs colocalize with snRNP in a specific nuclear domain
  • 1996
  • Ingår i: Journal of Cell Biology. - 0021-9525 .- 1540-8140. ; 135:2, s. 303-314
  • Tidskriftsartikel (refereegranskat)abstract
    • Posttranscriptional steps in the production of mRNA include well characterized polyadenylation and splicing reactions, but it is also necessary to understand how RNA is transported within the nucleus from the site of its transcription to the nuclear pore, where it is translocated to the cytoplasmic compartment. Determining the localization of RNA within the nucleus is an important aspect of understanding RNA production and may provide clues for investigating the trafficking of RNA within the nucleus and the mechanism for its export to the cytoplasm. We have previously shown that late phase adenovirus-infected cells contain large clusters of snRNP and non-snRNP splicing factors; the presence of these structures is correlated with high levels of viral late gene transcription. The snRNP clusters correspond to enlarged interchromatin granules present in late phase infected cells. Here we show that polyadenylated RNA and spliced tripartite leader exons from the viral major late transcription unit are present in these same late phase snRNP-containing structures. We find that the majority of the steady state viral RNA present in the nucleus is spliced at the tripartite leader exons. Tripartite leader exons are efficiently exported from the nucleus at a time when we detect their accumulation in interchromatin granule clusters. Since the enlarged interchromatin granules contain spliced and polyadenylated RNA, we suggest that viral RNA may accumulate in this late phase structure during an intranuclear step in RNA transport.
  •  
44.
  • Calles-Escandon, Jorge, et al. (författare)
  • The membrane-associated 40 KD fatty acid binding protein(Berk's protein), a putative fatty acid transporter is present in human skeletal muscle
  • 1995
  • Ingår i: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 58:1, s. 19-28
  • Tidskriftsartikel (refereegranskat)abstract
    • Muscle tissue (1.1 +/- 0.1 grams) was obtained from seven healthy individuals (3 males, 4 females) using an open incision approach before and after ingestion of either 75 grams of dextrose (N=5) or water (N=2). Purified sarcolemmal membranes from the muscle were prepared using a sucrose step gradient. A polyclonal antibody raised against the purified (99%) rat hepatocyte 40 KD membrane fatty acid binding protein (mFABP-L) was used to probe for this putative transporter in the muscle membranes using Western blot. A single band at the 40 KD MW band was identified which reacted antigenically with the proteinpurified from rat livers. These response of Berk's protein 60-75 minutes after dextrose ingestion (or water) was erratic and no specific trend could be identified. Our data demonstrate that the 40 KD mFABP-L originally isolated from rat liver is also present in human skeletal muscle membrane. This protein may be involved in transport of fatty acids across the membrane of skeletal muscle, however its physiological role in human fatty acidmetabolism remains to be established.
  •  
45.
  • Carlstedt, I, et al. (författare)
  • Characterization of two different glycosylated domains from the insoluble mucin complex of rat small intestine.
  • 1993
  • Ingår i: The Journal of biological chemistry. - 0021-9258. ; 268:25, s. 18771-81
  • Tidskriftsartikel (refereegranskat)abstract
    • The highly glycosylated domains of rat small intestinal mucins were isolated after reduction and trypsin digestion and separated into two populations (A and B) by gel chromatography. The molecular mass values were 650 and 335 kDa, respectively, and the relative yields suggest that the two glycopeptides occur in equimolar proportions. Electron microscopy revealed linear structures with weight average lengths of 230 nm (A) and 110 nm (B) corresponding to a mass/unit length of about 3 kDa/nm. The protein cores (17-19%) contain large amounts of threonine (over 40%), serine (17-24%), and proline (18-19%). Carbohydrate and sulfate account for approximately 80 and 0.5%, respectively, and gas chromatography-mass spectrometry showed that the patterns of neutral and sialic acid-containing glycans are very similar in the two glycopeptides. Both contain a significant amount (7-10 mol %) of single GalNAc residues, the average oligosaccharide is about 4 sugar residues long, and the largest species observed are heptasaccharides. The major neutral and sialic acid-containing oligosaccharides are Fuc1-2Gal1-3GalNAcol and GlcNAc1-6(NeuGc2-Gal1-3)GalNAcol, respectively. Sialic acid is present as both N-acetyl- and N-glycoloyl-neuraminic acid. Repeated extractions of the tissue with guanidinium chloride left approximately 80% of the mucus glycoproteins as an insoluble glycoprotein complex whereas exposure to dithiothreitol or high speed homogenization accomplished complete solubilization. The "subunits" obtained after reduction with dithiothreitol are larger than glycopeptides A and B, and fragments corresponding in size to the latter are obtained after cleavage with trypsin. Most of the mucins from rat small intestine thus occurs as an insoluble glycoprotein complex composed of subunits joined with disulfide bonds. The subunits contain two highly glycosylated regions with different lengths substituted with very similar oligosaccharides.
  •  
46.
  •  
47.
  • Gustafsson, Claes M, 1966, et al. (författare)
  • The DNA ligands influence the interactions between the herpes simplex virus 1 origin binding protein and the single strand DNA-binding protein, ICP-8.
  • 1995
  • Ingår i: The Journal of biological chemistry. - 0021-9258. ; 270:32, s. 19028-34
  • Tidskriftsartikel (refereegranskat)abstract
    • The herpes simplex virus type 1 (HSV-1) origin binding protein, OBP, is a DNA helicase specifically stimulated by the viral single strand DNA-binding protein, ICP-8. The stimulation is dependent on direct protein-protein interactions between the C-terminal domain of OBP, delta OBP, and ICP 8 (Boehmer, P.E., Craigie, M.C., Stow, N.D., and Lehman, I.R. (1994) J. Biol. Chem. 269, 29329-29334). We have now observed that this interaction is dramatically influenced by the nature of the DNA ligand. Stable complexes between delta OBP, ICP 8, and double-stranded DNA, presented either as a specific duplex oligonucleotide or a restriction fragment containing the HSV-1 origin of replication, oriS, can be detected by gel chromatography and gel electrophoresis. In contrast, a single-stranded oligonucleotide, oligo(dT)65, will completely disrupt the complex between delta OBP and ICP 8. We therefore suggest that the interaction between delta OBP and ICP 8 serves to position the single strand DNA-binding protein with high precision onto single-stranded DNA at a replication fork or at an origin of DNA replication.
  •  
48.
  • Hansson, Gunnar C., 1951, et al. (författare)
  • Molecular cloning of a cDNA coding for a region of an apoprotein from the 'insoluble' mucin complex of rat small intestine.
  • 1994
  • Ingår i: Biochemical and biophysical research communications. - 0006-291X. ; 198:1, s. 181-90
  • Tidskriftsartikel (refereegranskat)abstract
    • The major part of rat small intestinal mucins occurs as an 'insoluble' glycoprotein complex unextractable in 6 M guanidinium chloride unless disulfide bonds are cleaved. One of the trypsin-resistant high-glycosylated domains of this complex (glycopeptide A) was recently isolated. We have now deglycosylated it with HF, injected it into rabbits and the obtained antiserum was used for expression cloning providing a cDNA clone (VR-1A). This clone contained an open reading frame of 235 amino acids composed of two regions. The deduced N-terminal 53 amino acids included seven Cys residues and only one Ser, followed by a region of 182 residues with 64% Ser and Thr but devoid of Cys residues. Analysis of mRNA revealed a transcript of about 12 kb, identical in size to a band labelled with a probe based on the rat mucin-like protein (MLP/Muc2) cDNA. Pulsed-field gel electrophoresis of genomic rat DNA showed identical bands (380 and 500 kb) when blots were sequentially probed with the MLP/Muc2 probe and VR-1A. A panel of mouse x rat hybrids was used to localize the gene corresponding to both VR-1A and Muc2 to rat chromosome 1. The results strongly suggest that the 'insoluble' mucin complex of the rat small intestine is encoded by the Muc2 gene.
  •  
49.
  • Helander, A, et al. (författare)
  • Binding of enterotoxigenic Escherichia coli to isolated enterocytes and intestinal mucus.
  • 1997
  • Ingår i: Microbial pathogenesis. - : Elsevier BV. - 0882-4010. ; 23:6, s. 335-46
  • Tidskriftsartikel (refereegranskat)abstract
    • Binding of human enterotoxigenic Escherichia coli (ETEC) to the small intestine is a prerequisite for colonization and is mediated by colonization factor (CF) antigens. Coli surface antigen 6 (CS6) is considered a CF but binding to isolated enterocytes has not been established. In this study bacteria expressing CS6 were analysed for binding to enterocytes from human and rabbit small intestine, isolated using either an EDTA-containing buffer or a buffer devoid of EDTA. We found that the bacteria bound to enterocytes from rabbit ileum and human duodenum, but only when the cells had been isolated in the absence of EDTA. Pretreatment of rabbit enterocytes with meta-periodate resulted in a decreased proportion of cells with bound bacteria. Purified CS6, and for comparison other ETEC CFs, were also tested for binding to different human and rabbit mucus fractions. These analyses showed that purified CS6 bound to mucus from rabbit duodenum and ileum as well as from human duodenum, jejunum and ileum and that this binding was abolished by pretreatment of the mucus material with meta-periodate or Proteinase K. CFA/I, CS1 to CS5, CS7, CS17, putative CF (PCF) O159 (CS12), PCFO166 (CS14), and CFA/III (CS8) also bound to the rabbit mucus material although with different patterns; the binding of CS2 and CS5 was abolished by meta-periodate treatment. Thus, ETEC bacteria expressing CS6 might bind to carbohydrate-containing structure(s) in the apical membrane of isolated rabbit ileal and human duodenal enterocytes that could probably be released by EDTA treatment. In addition, CS6 and other ETEC CFs bind to component(s), in some instances protein-associated carbohydrate structures, in mucus fractions from small intestine.
  •  
50.
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