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  • 251.
    Grubbström, Olivia
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Biomedicinprogrammet.
    In vitro study of drugs against mammalian ribonucleotide reductase2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
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  • 252.
    Grubbström, Olivia
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The Mechanisms of Aβ self-assembly2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
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  • 253. Gruden, M A
    et al.
    Davudova, T B
    Malisauskas, Mantas
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Zamotin, Vladimir
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Sewell, R D E
    Voskresenskaya, N I
    Kostanyan, I A
    Sherstnev, V V
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Autoimmune responses to amyloid structures of Abeta(25-35) peptide and human lysozyme in the serum of patients with progressive Alzheimer's disease.2004In: Dementia and geriatric cognitive disorders, ISSN 1420-8008, Vol. 18, no 2, p. 165-71Article in journal (Refereed)
  • 254. Gruden, M. A.
    et al.
    Davydova, T. V.
    Fomina, V. G.
    Vetrile, L. A.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sewell, R. D. E.
    Antibodies to Glutamate Reversed the Amnesic Effects of Proinflammatory S100A9 Protein Fibrils in Aged C57Bl/6 Mice2017In: Bulletin of experimental biology and medicine, ISSN 0007-4888, E-ISSN 1573-8221, Vol. 162, no 4, p. 430-432Article in journal (Refereed)
    Abstract [en]

    Chronic intranasal administration of fibrillar structures of proinflammatory S100A9 protein impaired passive avoidance learning in old C57Bl/6 mice. Combined treatment with S100A9 fibrils and antibodies to glutamate was followed by an increase in horizontal locomotor activity of animals in the open-field test and did not disturb spatial memory.

  • 255. Gruden, MA
    et al.
    Davidova, TB
    Malisauskas, Mantas
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Sewell, RD
    Voskresenskaya, NI
    Wilhelm, Kristina
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Elistratova, EI
    Sherstnev, VV
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Differential neuroimmune markers to the onset of Alzheimer's disease neurodegeneration and dementia: autoantibodies to Abeta((25-35)) oligomers, S100b and neurotransmitters.2007In: Journal of Neuroimmunology, ISSN 0165-5728, Vol. 186, no 1-2, p. 181-92Article in journal (Refereed)
  • 256. Gruden, Marina A.
    et al.
    Davidova, Tatiana V.
    Yanamandra, Kiran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kucheryanu, Valery G.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sherstnev, Vladimir V.
    Sewell, Robert D. E.
    Nasal inoculation with a-synuclein aggregates evokes rigidity, locomotor deficits and immunity to such misfolded species as well as dopamine2013In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 243, p. 205-212Article in journal (Refereed)
    Abstract [en]

    Animal models of Parkinson's disease (PD) have been widely used to investigate the pathogenesis of this neurodegenerative disorder which is typically associated with the specific and largely disordered protein alpha-synuclein (alpha-syn). In the current study, the nasal vector was used to deliver alpha-syn aggregates to the brain. Both alpha-syn oligomers and its fibrils were firstly characterized using atomic force microscopy and the thioflavin T binding assay. The toxic oligomers alone (0.48 mg/kg) or their 50:50 combination with fibrils (in a total dose of 0.48 mg/kg) were then given intranasally for ten days in mice and PD-mimetic symptoms as well as humoral immunity to these species and dopamine (DA) were evaluated simultaneously. Open-field behavioral deficits indicated by rigidity and reduced locomotor activity were induced by the dual administration of alpha-syn oligomers plus fibrils but not the oligomers by themselves under the 10-day dosing regimen. In contrast, using ELISA, high levels of serum autoantibodies to alpha-syn monomeric, oligomeric and fibrillar conformers as well as DA were observed in both treatment groups reflecting immune system activation and this substantiates previous clinical studies in Parkinson's disease patients. Thus, nasal administration of alpha-syn amyloidogenic species may be a potential experimental PD model which results not only in motor deficits but also incitement of humoral protection to mimic the disease. Such a paradigm may be exploitable in the quest for potential therapeutic strategies and further studies are warranted.

  • 257. Gruden, Marina A
    et al.
    Davydova, Tatiana V
    Narkevich, Victor B
    Fomina, Valentina G
    Wang, Chao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kudrin, Vladimir S
    Morozova-Roche, Ludmilla A
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sewell, Robert D E
    Noradrenergic and serotonergic neurochemistry arising from intranasal inoculation with α-synuclein aggregates which incite parkinsonian-like symptoms2015In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 279, p. 191-201Article in journal (Refereed)
    Abstract [en]

    Alpha-synuclein (α-syn) toxic aggregates delivered by the nasal vector have been shown to modify the neurochemistry of dopamine (DA) which is associated with parkinsonian-like motor symptoms. The aim was therefore to study the intranasal effects of α-syn oligomers, fibrils or their combination on the motor behavior of aged mice in relation to possible noradrenergic and serotonergic correlates. In vitro generated α-syn oligomers and fibrils were verified using atomic force microscopy and the thioflavin T binding assay. Levels of noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected using HPLC with electrochemical detection in the substantia nigra (SN) and striatum. The oligomers or fibrils administered alone or in a 50:50 combination (total dose of 0.48mg/kg) were given intranasally for 14 days and "open-field" behaviour was tested on days 0, 15 and 28 of the protocol, at which time brain structures were sampled. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e. 14 days after treatment completion) induced hypokinesia and immobility whilst the aggregate combination additionally produced rigidity. The α-Syn oligomer/fibril mixture also instigated PD-like motor symptoms which correlated heterochronically with elevated NA levels in the striatum but then later in the SN while intranasal fibrils alone augmented 5-HT and 5-HIAA nigral concentrations throughout the protocol. In contrast, α-syn oligomers displayed a delayed serotonin upsurge in the SN. Neurodegenerative and/or actions on neurotransmitter transporters (such as NET, SERT and VMAT2) are discussed as being implicated in these α-syn amyloid induced neurochemical and motoric disturbances.

  • 258. Gruden, Marina A
    et al.
    Davydova, Tatiana V
    Narkevich, Victor B
    Fomina, Valentina G
    Wang, Chao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kudrin, Vladimir S
    Morozova-Roche, Ludmilla A
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sewell, Robert DE
    Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates2014In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 263, p. 158-168Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is a neurodegenerative disorder in which both alpha-synuclein (alpha-syn) and dopamine (DA) have a critical role. Our previous studies instigated a novel PD model based on nasal inoculation with alpha-syn aggregates which expressed parkinsonian-like behavioral and immunological features. The current study in mice substantiated the robustness of the amyloid nasal vector model by examining behavioral consequences with respect to DA-ergic neurochemical corollaries. In vitro generated alpha-syn oligomers and fibrils were characterized using atomic force microscopy and the thioflavin T binding assay. These toxic oligomers or fibrils administered alone (0.48 mg/kg) or their 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behavior was tested on days 0, 15 and 28 of the protocol. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e., 14 days after treatment completion) induced rigidity, hypokinesia and immobility. This was accompanied by elevated nigral but not striatal DA, DOPAC and HVA concentrations in response to dual administration of alpha-syn oligomers plus fibrils but not the oligomers by themselves. alpha-Syn fibrils intensified not only the hypokinesia and immobility 14 days post treatment, but also reduced vertical rearing and enhanced DA levels in the substantia nigra. Only nigral DA turnover (DOPAC/DA but not HVA/DA ratio) was augmented in response to fibril treatment but there were no changes in the striatum. Compilation of these novel behavioral and neurochemical findings substantiate the validity of the alpha-syn nasal vector model for investigating parkinsonian-like symptoms.

    (C) 2014 Elsevier B.V. All rights reserved.

  • 259. Gruden, Marina A.
    et al.
    Davydova, Tatiana V.
    Wang, Chao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Narkevich, Victor B.
    Fomina, Valentina G.
    Kudrin, Vladimir S.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sewell, Robert D. E.
    The misfolded pro-inflammatory protein S100A9 disrupts memory via neurochemical remodelling instigating an Alzheimer's disease-like cognitive deficit2016In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 306, p. 106-116Article in journal (Refereed)
    Abstract [en]

    Memory deficits may develop from a variety of neuropathologies including Alzheimer's disease dementia. During neurodegenerative conditions there are contributory factors such as neuroinflammation and amyloidogenesis involved in memory impairment. In the present study, dual properties of S100A9 protein as a pro-inflammatory and amyloidogenic agent were explored in the passive avoidance memory task along with neurochemical assays in the prefrontal cortex and hippocampus of aged mice. S100A9 oligomers and fibrils were generated in vitro and verified by AFM, Thioflavin T and All antibody binding. Native S100A9 as well as S100A9 oligomers and fibrils or their combination were administered intranasally over 14 days followed by behavioral and neurochemical analysis. Both oligomers and fibrils evoked amnestic activity which correlated with disrupted prefrontal cortical and hippocampal dopaminergic neurochemistry. The oligomer-fibril combination produced similar but weaker neurochemistry to the fibrils administered alone but without passive avoidance amnesia. Native S100A9 did not modify memory task performance even though it generated a general and consistent decrease in monoamine levels (DA, 5-HT and NA) and increased metabolic marker ratios of DA and 5-HT turnover (DOPAC/DA, HVA/DA and 5-HIAA) in the prefrontal cortex. These results provide insight into a novel pathogenetic mechanism underlying amnesia in a fear-aggravated memory task based on amyloidogenesis of a pro-inflammatory factor leading to disrupted brain neurochemistry in the aged brain. The data further suggests that amyloid species of S100A9 create deleterious effects principally on the dopaminergic system and this novel finding might be potentially exploited during dementia management through a neuroprotective strategy.

  • 260. Gruden, Marina A.
    et al.
    Sewell, Robert D. E.
    Yanamandra, Kiran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Davidova, Tatyana V.
    Kucheryanu, Valery G.
    Bocharov, Evgeny V.
    Bocharova, Olga A.
    Poleschuk, Vsevolod V.
    Sherstnev, Vladimir V.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression (vol 233, pg 221, 2011)2014In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 268, no 1-2, p. 99-99Article in journal (Refereed)
  • 261. Gruden, Marina A
    et al.
    Sewell, Robert D E
    Yanamandra, Kiran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Davidova, Tatyana V
    Kucheryanu, Valery G
    Bocharov, Evgeny V
    Bocharova, Olga R
    Polyschuk, Vsevolod V
    Sherstnev, Vladimir V
    Morozova-Roche, Ludmilla A
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression2011In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 233, no 1-2, p. 221-227Article in journal (Refereed)
    Abstract [en]

    The aim was to ascertain any possible linkage between humoral immune responses to principal biomarkers (α-synuclein monomers, its toxic oligomers or fibrils, dopamine and S100B) and cellular immunity in Parkinson's disease development. There were elevated autoantibody titers to α-synuclein monomers, oligomers plus fibrils in 72%, 56%, and 17% of Parkinsonian patients respectively with a 5-year disease duration. Additionally, there were increased titers to dopamine and S100B (96% and 89%) in the 5-year patient group. All of these values subsided in 10-year sufferers. Furthermore, CD3+, CD4+, CD8+ T-lymphocyte and B-lymphocyte subsets declined in the patient cohort during Parkinsonism indicating disease associated reductions in these lymphocyte subsets.

  • 262. Gruden, Marina A.
    et al.
    Yanamandra, Kiran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kucheryanu, Valery G.
    Bocharova, Olga R.
    Sherstnev, Vladimir V.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sewell, Robert D. E.
    Correlation between Protective Immunity to alpha-Synuclein Aggregates, Oxidative Stress and Inflammation2012In: Neuroimmunomodulation, ISSN 1021-7401, E-ISSN 1423-0216, Vol. 19, no 6, p. 334-342Article in journal (Refereed)
    Abstract [en]

    Objective: Protein aggregation leading to central amyloid deposition is implicated in Parkinson's disease (PD). During disease progression, inflammation and oxidative stress may well invoke humoral immunity against pathological aggregates of PD-associated alpha-synuclein. The aim was to investigate any possible concurrence between autoimnnune responses to alpha-synuclein monomers, oligomers or fibrils with oxidative stress and inflammation.

    Methods: The formation of alpha-synuclein amyloid species was assessed by thioflavin-T assay and atomic force microscopy was employed to confirm their morphology. Serum autoantibody titers to alpha-synuclein conformations were determined by ELISA. Enzyme activity and concentrations of oxidative stress/inflammatory indicators were evaluated by enzyme and ELISA protocols.

    Results: In PD patient sera, a differential increase in autoantibody titers to alpha-synuclein monomers, toxic oligomers or fibrils was associated with boosted levels of the pro-inflammatory cytokine interleukin-6 and tumour necrosis factor-alpha, but a decrease in interferon-gamma concentration. In addition, levels of malondialdehyde were elevated whilst those of glutathione were reduced along with decrements in the activity of the antioxidants: superoxide dismutase, catalase and glutathione transferase.

    Conclusions: It is hypothesized that the generation of alpha-synuclein amyloid aggregates allied with oxidative stress and inflammatory reactions may invoke humoral immunity protecting against dopaminergic neuronal death. Hence, humoral immunity is a common integrative factor throughout PD progression which is directed towards prevention of further neurodegeneration, so potential treatment strategies should attempt to maintain PD patient immune status. Copyright (c) 2012 S. Karger AG, Basel

  • 263.
    Grundström, Robert
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Is DNA polymerase ε a new driver in cancer development?: Functional studies of cancer associated mutations2015Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
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  • 264.
    Guittet, Olivier
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Håkansson, Pelle
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Voevodskaya, Nina
    Fridd, Susan
    Gräslund, Astrid
    Arakawa, Hirofumi
    Nakamura, Yusuke
    Thelander, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 44, p. 40647-40651Article in journal (Refereed)
  • 265.
    Gunnarsson, David
    et al.
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Leffler, Per
    Umeå University, Faculty of Science and Technology, European CBRNE Center.
    Ekwurtzel, Emelie
    Martinsson, Gunilla
    Liu, Kui
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Selstam, Gunnar
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes2008In: Reproduction, ISSN 1470-1626, E-ISSN 1476-3990, Vol. 135, no 5, p. 693-703Article in journal (Refereed)
    Abstract [en]

    Phthalates are widely used as plasticizers in a number of daily-life products. In this study, we investigated the influence of mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of the frequently used plasticizer di-(2-ethylhexyl) phthalate (DEHP), on gonadal steroidogenesis in vitro. MEHP (25–100 µM) stimulated basal steroid synthesis in a concentration-dependent manner in immortalized mouse Leydig tumor cells (MLTC-1). The stimulatory effect was also detected in KK-1 granulosa tumor cells. MEHP exposure did not influence cAMP or StAR protein levels and induced a gene expression profile of key steroidogenic proteins different from the one induced by human chorionic gonadotropin (hCG). Simultaneous treatment with MEHP and a p450scc inhibitor (aminoglutethimide) indicated that MEHP exerts its main stimulatory effect prior to pregnenolone formation. MEHP (10–100 µM) up-regulated hormone-sensitive lipase and 3-hydroxy-3-methylglutaryl coenzyme A reductase, suggesting that MEHP increases the amount of cholesterol available for steroidogenesis. Our data suggest that MEHP, besides its known inhibitory effect on hCG action, can directly stimulate gonadal steroidogenesis in both sexes through a cAMP- and StAR-independent mechanism. The anti-steroidogenic effect of DEHP has been proposed to cause developmental disorders such as hypospadias and cryptorchidism, whereas a stimulation of steroid synthesis may prematurely initiate the onset of puberty and theoretically affect the hypothalamic–pituitary–gonadal axis.

  • 266.
    Guo, Betty P
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Teneberg, Susann
    Münch, Robert
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Terunuma, Daiyo
    Hatano, Ken
    Matsuoka, Koji
    Angström, Jonas
    Borén, Thomas
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Relapsing fever Borrelia binds to neolacto glycans and mediates rosetting of human erythrocytes.2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 46, p. 19280-19285Article in journal (Refereed)
    Abstract [en]

    A hallmark of acute relapsing fever borreliosis is severe bacteremia. Some Borrelia species, such as B. duttonii and B. crocidurae, associate with erythrocytes and induce aggregation recognized as erythrocyte rosetting. Erythrocyte rosettes contribute to disease severity by increased tissue invasiveness (such as invasion of CNS and encephalitis), hemorrhaging, and reduced blood flow in affected microcapillaries. Here we report that relapsing fever Borrelia binds to neolacto (Galbeta4GlcNAcbeta3Galbeta4Glcbeta1)-carrying glycoconjugates that are present on human erythrocytes. This interaction is of low affinity but is compensated for by the multivalency of neo-lacto-oligosaccharides on the erythrocyte cell surface. Hence, the protein-carbohydrate interaction is dependent on multivalent neolacto-glycans to mediate binding.

  • 267.
    Guo, Yongzhi
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Plasmin: a potent pro-inflammatory factor2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Plasmin, the central molecule of the plasminogen activator system, is a broad-spectrum serine protease. Plasmin is important for the degradation of fibrin and other components of the extracellular matrix (ECM) during a number of physiological and pathological processes. The aim of this thesis was to elucidate the functional roles of plasmin during pathological inflammation and infection in autoimmune and non-autoimmune diseases. For this purpose, mouse models of rheumatoid arthritis (RA), bacterial arthritis, infection, and sepsis have been used.

    Previous studies from our laboratory have shown that plasminogen-deficient mice are resistant to the development of collagen type II-induced arthritis (CIA). In contrast, others have shown that plasmin plays a protective role in antigen-induced arthritis (AIA). To investigate the contrasting roles of plasminogen deficiency in models of CIA and AIA, a new animal model of arthritis called local injection-induced arthritis (LIA) was developed. In this model, we replaced methylated bovine serum albumin, which is normally used as an immunogen in the AIA model, with collagen type II (CII) to induce arthritis. When wild-type and plasminogen-deficient mice were injected intra-articularly with CII or 0.9% NaCl following CIA induction, plasminogen-deficient mice developed typical CIA, but the disease was less severe than in wild-type mice and was restricted to the injected joints. When the AIA model was used, plasminogen-deficient mice developed a much more severe arthritis than the wild-type mice. These results indicate that both the antigen and joint trauma caused by the local injection are critical to explaining the contrasting roles of plasminogen deficiency in CIA and AIA. This indicates that CIA and AIA have distinct pathogenic mechanisms and plasmin plays contrasting roles in different types of arthritis models.

    To study the functional roles of plasmin in the host inflammatory response during infectious arthritis, a Staphylococcus aureus-induced bacterial arthritis model was established. When wild-type mice were injected intra-articularly with 1 × 106 colony-forming units (CFU) of S. aureus per joint, all the bacteria were completely eliminated from the injected joints in 28 days. However, in the plasminogen-deficient mice, the S. aureus counts were 27-fold higher at day 28 than at day 0. When human plasminogen was given to the plasminogen-deficient mice daily for 7 days, the bacterial clearance was greatly improved and the necrotic tissue in the joint cavity was also completely eliminated. Supplementation of plasminogen-deficient mice with plasminogen also restored the expression level of interleukin-6 (IL-6) in the arthritic joints. In summary, plasmin has protective roles during S. aureus-induced arthritis by enhancing cytokine expression, removing necrotic tissue, and mediating bacterial killing and inflammatory cell activation.

    The functional roles of plasmin during infection and sepsis were also studied in mice. Infection was induced by injecting 1 × 107 CFU of S. aureus intravenously and the sepsis model was induced by injecting 1.6 × 108 CFU of S. aureus. In the infection model, the wild-type mice had a 25-day survival rate of 86.7%, as compared to 50% in the plasminogen-deficient group. However, when sepsis was induced, the average survival for plasminogen-deficient mice was 3 days longer than for wild-type mice. Twenty-four hours after the induction of sepsis, the serum levels of IL-6 and IL-10 as well as the bacterial counts in all organs investigated were significantly higher in wild-type mice than in plasminogen-deficient mice. In wild-type mice, blockade of IL-6 by intravenous injection of anti-IL-6 antibodies significantly prolonged the onset of mortality and improved the survival rate during sepsis. These data indicate that plasmin plays different roles during infection and sepsis. Furthermore, plasmin appears to be involved in the regulation of inflammatory cytokine expression during sepsis.

    Taken together, our data indicate that plasmin plays multifunctional pro-inflammatory roles in different autoimmune and non-autoimmune diseases. The pro-inflammatory roles of plasmin include activation of inflammatory cells, regulation of cytokine expression, and enhancement of the bacterial killing ability of the host.

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  • 268.
    Guo, Yong-Zhi
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Li, Jinan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hagstrom, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Beneficial and detrimental effects of plasmin(ogen) during infection and sepsis in mice2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e24774-Article in journal (Refereed)
    Abstract [en]

    Plasmin has been proposed to be an important mediator during inflammation/infection. In this study, by using mice lacking genes for plasminogen, tissue-type plasminogen activator (tPA), and urokinase-type PA (uPA), we have investigated the functional roles of active plasmin in infection and sepsis. Two models were used: an infection model by intravenous injection of 1x10(7) CFU of S. aureus, and a sepsis model by intravenous injection of 1.6x10(8) CFU of S. aureus. We found that in the infection model, wild-type (WT) mice showed significantly higher survival rates than plasminogen-deficient (plg(-/-)) mice. However, in the sepsis model, plg(-/-) or tPA(-/-)/uPA(-/-) mice showed the highest survival rate whereas WT and tPA(+/-)/uPA(+/-) mice showed the lowest survival rate, and plg(+/-), tPA(-/-), and uPA(-/-) mice had an intermediate survival rate. These results indicate that the levels of active plasmin are critical in determining the survival rate in the sepsis, partly through high levels of inflammatory cytokines and enhanced STAT3 activation. We conclude that plasmin is beneficial in infection but promotes the production of inflammatory cytokines in sepsis that may cause tissue destruction, diminished neutrophil function, and an impaired capacity to kill bacteria which eventually causes death of these mice.

  • 269.
    Guo, Yongzhi
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Li, Jinan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hagström, Elin
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Beneficial and detrimental effects of plasmin(ogen) during infection and sepsisArticle in journal (Refereed)
  • 270.
    Guo, Yongzhi
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Li, Jinan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hagström, Elin
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus-induced arthritis2008In: Arthritis and rheumatism, ISSN 0004-3591, Vol. 58, no 3, p. 764-772Article in journal (Refereed)
    Abstract [en]

    Objective: To assess the functional roles of plasmin in a murine model of Staphylococcus aureus-induced bacterial arthritis. Methods: Bacterial arthritis was induced in plasminogen-deficient (Plg-/-) and wild-type (Plg+/+) littermates by local injection of 1 × 106 colony-forming units of S aureus into the knee joints. Human plasminogen was administered to Plg-/- mice on days 0-7 or days 7-14. Antibiotic treatment was administered to Plg-/- mice on days 7-14. Bacteria counts and histologic, immunohistochemical, and Western blot analyses were performed. Results: In Plg+/+ mice, S aureus counts had declined within 2 days, and by day 28 the bacteria had been completely eliminated. However, S aureus was still detectable in all injected joints from Plg-/- mice, and bacteria counts were 27 times higher than the amount injected on day 0. The extent of macrophage and neutrophil recruitment to the infected joints was comparable for Plg+/+ and Plg-/- mice on days 1, 7, and 14. The activation of these inflammatory cells appeared to be impaired in Plg-/- mice, however. Treatment of Plg-/- mice with antibiotic (cloxacillin) resulted in successful killing of the bacteria, but the necrotic tissue remained in the infected joints. When human plasminogen was given intravenously to Plg-/- mice daily for 7 days, bacterial clearance was greatly improved as compared with their untreated counterparts, and the amount of necrotic tissue in the joint cavity was dramatically reduced. The expression of interleukin 6 (IL-6) and IL-10 was higher in Plg+/+ mice than in Plg-/- mice during bacterial arthritis. Conclusion: Our findings indicate that plasmin plays a pluripotent role in protecting against S aureus-induced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine expression.

  • 271. Gupta, Amitabha
    et al.
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reichenbach, Patrick
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nilsson, Anna Karin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lingner, Joachim
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rothstein, Rodney
    Chang, Michael
    Telomere Length Homeostasis Responds to Changes in Intracellular dNTP Pools2013In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 193, no 4, p. 1095-1105Article in journal (Refereed)
    Abstract [en]

    Telomeres, the ends of linear eukaryotic chromosomes, shorten due to incomplete DNA replication and nucleolytic degradation. Cells counteract this shortening by employing a specialized reverse transcriptase called telomerase, which uses deoxyribonucleoside triphosphates (dNTPs) to extend telomeres. Intracellular dNTP levels are tightly regulated and perturbation of these levels is known to affect DNA synthesis. We examined whether altering the levels of the dNTP pools or changing the relative ratios of the four dNTPs in Saccharomyces cerevisiae would affect the length of the telomeres. Lowering dNTP levels leads to a modest shortening of telomeres, while increasing dNTP pools has no significant effect on telomere length. Strikingly, altering the ratio of the four dNTPs dramatically affects telomere length homeostasis, both positively and negatively. Specifically, we find that intracellular dGTP levels positively correlate with both telomere length and telomerase nucleotide addition processivity in vivo. Our findings are consistent with in vitro data showing dGTP-dependent stimulation of telomerase activity in multiple organisms, and suggest that telomerase activity is modulated in vivo by dGTP levels.

  • 272.
    Gupta, Arun A.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Reinartz, Ines
    Karunanithy, Gogulan
    Spilotros, Alessandro
    Jonna, Venkateswara Rao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Svergun, Dmitri I.
    Baldwin, Andrew J.
    Schug, Alexander
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Formation of a Secretion-Competent Protein Complex by a Dynamic Wrap-around Binding Mechanism2018In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 18, Part B, p. 3157-3169Article in journal (Refereed)
    Abstract [en]

    Bacterial virulence is typically initiated by translocation of effector or toxic proteins across host cell membranes. A class of gram-negative pathogenic bacteria including Yersinia pseudotuberculosis and Yersinia pestis accomplishes this objective with a protein assembly called the type III secretion system. Yersinia effector proteins (Yop) are presented to the translocation apparatus through formation of specific complexes with their cognate chaperones (Syc). In the complexes where the structure is available, the Yops are extended and wrap around their cognate chaperone. This structural architecture enables secretion of the Yop from the bacterium in early stages of translocation. It has been shown previously that the chaperone-binding domain of YopE is disordered in its isolation but becomes substantially more ordered in its wrap-around complex with its chaperone SycE. Here, by means of NMR spectroscopy, small-angle X-ray scattering and molecular modeling, we demonstrate that while the free chaperone-binding domain of YopH (YopHCBD) adopts a fully ordered and globular fold, it populates an elongated, wrap-around conformation when it engages in a specific complex with its chaperone SycH2. Hence, in contrast to YopE that is unstructured in its free state, YopH transits from a globular free state to an elongated chaperone-bound state. We demonstrate that a sparsely populated YopHCBD state has an elevated affinity for SycH2 and represents an intermediate in the formation of the protein complex. Our results suggest that Yersinia has evolved a binding mechanism where SycH2 passively stimulates an elongated YopH conformation that is presented to the type III secretion system in a secretion-competent conformation.

  • 273. Gustafsson, A
    et al.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundgren, E
    Similar effects of treatment with alpha interferon on the protein synthesis of human large granular lymphocytes, T cells, and monocytes.1985In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 22, no 5, p. 519-28Article in journal (Refereed)
    Abstract [en]

    Preparations of human large granular lymphocytes (LGL), T cells, and monocytes (MC) were obtained through centrifugation on Percoll gradients and preparative E-rosetting. The different preparations contained more than 80% of the appropriate cell type, as judged by their ability to lyse 51Cr-labelled K562 cells, cell morphology, and the presence of cell surface structures recognized by the OKT3, OKT10, Leu 7 and OKM1 monoclonal antibodies. The protein synthesis is unstimulated and alpha interferon (IFN-alpha)-treated cells of the different types was studied by subjecting 35S-methionine-labelled cell extracts to two-dimensional gel electrophoresis. The general pattern of protein synthesis in LGL and T cells was virtually identical, whereas at least 7 major proteins were synthesized at a higher rate in monocytes. The effects of IFN-alpha on the protein synthesis of LGL and T cells were identical, IFN-alpha increasing the rate of synthesis of 9 proteins. These proteins were also expressed, but not always IFN-augmentable, in monocytes. No additional, cell-type associated, IFN-inducible proteins were found. This suggests that the augmenting effect of IFN-alpha on the cytotoxic capacity of LGL, T cells, and monocytes may be to affect common steps in their lytic machineries.

  • 274. Gustafsson, A
    et al.
    Sundström, S
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundgren, E
    Rapid induction of seven proteins in human lymphocytes by interferon; correlation to natural killer cell activity.1982In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 129, no 5, p. 1952-9Article in journal (Refereed)
    Abstract [en]

    The early effects of interferon (IFN) on the synthesis of protein in human nylon wool-nonadherent lymphocytes have been stimulated by use of two-dimensional electrophoresis. IFN-alpha or -beta as well as Escherichia coli-produced IFN-alpha 2 induced the rapid formation of seven proteins (Mr 80, 75, 62, 53, 38, 36, and 33 kD). At least five proteins were expressed within 2 hr of incubation with IFN. The synthesis of the seven proteins seemed to require rapid transcription of new RNA, because actinomycin D markedly inhibited their formation only when added less than 30 min after IFN. A good correlation was found between the ability of actinomycin D to inhibit both the formation of new proteins and the augmentation of natural killer (NK) cell activity. Screening of a panel of 10 hematopoietic and two anchorage-dependent cell lines revealed that p62 and p38 were induced in most cell lines, whereas p80 and p33 were preferentially induced in lymphoid cell lines. Three proteins could not be induced by IFN in any of the 12 cell lines, and thus could represent molecules mediating differentiated functions, possibly involved in NK cell function.

  • 275. Gustafsson, Anki
    et al.
    Hultberg, Anna
    Sjöström, Rolf
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kacskovics, Imre
    Breimer, Michael E
    Borén, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hammarström, Lennart
    Holgersson, Jan
    Carbohydrate-dependent inhibition of Helicobacter pylori colonization using porcine milk.2006In: Glycobiology, ISSN 0959-6658, Vol. 16, no 1, p. 1-10Article in journal (Refereed)
  • 276. Gustafsson, Robert
    et al.
    Berntsson, Ronnie P.-A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Martínez-Carranza, Markel
    El Tekle, Geniver
    Odegrip, Richard
    Johnson, Eric A.
    Stenmark, Pål
    Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster2017In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, no 22, p. 3781-3792Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins are highly toxic substances and are all encoded together with one of two alternative gene clusters, the HA or the OrfX gene cluster. Very little is known about the function and structure of the proteins encoded in the OrfX gene cluster, which in addition to the toxin contains five proteins (OrfX1, OrfX2, OrfX3, P47, and NTNH). We here present the structures of OrfX2 and P47, solved to 2.1 and 1.8 angstrom, respectively. We show that they belong to the TULIP protein superfamily, which are often involved in lipid binding. OrfX1 and OrfX2 were both found to bind phosphatidylinositol lipids.

  • 277.
    Haake, Ulrika
    et al.
    Umeå University, Faculty of Social Sciences, Department of Education.
    Fjellström, Mona
    Umeå University, Umeå University Library, Centre for teaching and learning (UPL).
    Wilhelmsson, Birgitta
    Umeå University, Faculty of Science and Technology, Department of Science and Mathematics Education.
    Arnqvist, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lindenius, Erik
    Umeå University, Faculty of Arts.
    Nilsson, Lennart
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Kvalitetssystem för utbildning på grund- och avancerad nivå vid Umeå universitet2015Other (Other (popular science, discussion, etc.))
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  • 278. Haas, Michael S
    et al.
    Alicot, Elisabeth M
    Schuerpf, Franziska
    Chiu, Isaac
    Li, Jinan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Moore, Francis D
    Carroll, Michael C
    Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction2010In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 87, no 4, p. 618-627Article in journal (Refereed)
    Abstract [en]

    The findings in this study identify potential therapeutics [i.e. N2 peptide or 21G6 F(ab')(2)] that prevent specific IgM binding to ischaemic antigens in the heart, resulting in a significant reduction in cardiac I/R injury.

  • 279.
    Hainzl, Tobias
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Huang, Shenghua
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Meriläinen, Gitte
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sauer-Eriksson, A Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Structural basis of signal-sequence recognition by the signal recognition particle 2011In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 18, no 3, p. 389-391Article in journal (Refereed)
    Abstract [en]

    The signal recognition particle (SRP) recognizes and binds the signal sequence of nascent proteins as they emerge from the ribosome. We present here the 3.0-Å structure of a signal sequence bound to the Methanococcus jannaschii SRP core. Structural comparison with the free SRP core shows that signal-sequence binding induces formation of the GM-linker helix and a 180° flip of the NG domain—structural changes that ensure a hierarchical succession of events during protein targeting.

  • 280. Hakobyan, Gohar
    et al.
    Davtyan, Hasmik
    Harutyunyan, Kristine
    Alexanyan, Knarik
    Amirkhanyan, Yelizaveta
    Gharibyan, Anna L.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Asatryan, Liana
    Tadevosyan, Yuri
    Similarities in Blood Mononuclear Cell Membrane Phospholipid Profiles During Malignancy2018In: Medical Sciences, ISSN 2076-3271, Vol. 6, no 4, article id 105Article in journal (Refereed)
    Abstract [en]

    Phospholipids (PLs), key elements of cellular membranes, are regulated reciprocally with membrane proteins and can act as sensors for alterations in physiological or pathological states of cells including initiation and development of cancer. On the other hand, peripheral blood mononuclear cells (MNCs) play an important role in antitumor immune response by reacting to cancerous modifications in distant organs. In the current study, we tested the hypothesis that tumor initiation and development are reflected in the alteration pattern of the MNC PL component. We analyzed MNC membrane PL fractions in samples from healthy individuals and from patients with diverse types of cancers to reveal possible alterations induced by malignancy. Compared to healthy controls, the cancer samples demonstrated shifts in several membrane PL profiles. In particular, when analyzing cancer data pooled together, there were significantly higher levels in lysophosphatidylcholine, phosphatidylcholine, and phosphatidylethanolamine fractions, and significantly lower quantities in phosphatidylinositol, phosphatidylserine, and phosphatidic acid fractions in cancer samples compared to controls. The levels of sphingomyelins and diphosphatidylglycerols were relatively unaffected. Most of the differences in PLs were sustained during the analysis of individual cancers such as breast cancer and chronic lymphocytic leukemia. Our findings suggest the presence of a common pattern of changes in MNC PLs during malignancy.

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  • 281.
    Hallberg, Magnus
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Studies of Functional Interactions within Yeast Mediator and a Proposed Novel Mechanism for Regulation of Gene Expression2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The yeast Mediator complex is required for transcriptional regulation both in vivo and in vitro and the identification of similar complexes from metazoans indicates that its function is conserved through evolution. Mediator subunit composition and structure is well characterized both by biochemical, genetic and biophysical methods. In contrast, little is known about the mechanisms by which Mediator operates and how the complex is regulated. The aim of my thesis was to elucidate how Mediator functions at the molecular level and to investigate functional interactions within Mediator.

    It is possible to recruit RNA polymerase II to a target promoter and thus to activate transcription by fusing Mediator subunits to a DNA binding domain. In order to investigate functional interactions within Mediator, we made such fusion proteins where different Mediator subunits were fused to the DNA binding domain of lexA. The expression of a reporter gene containing binding sites for lexA was subsequently measured in both a wild type strain and in strains where genes encoding specific Mediator subunits had been disrupted. We found that lexA-Med2 and lexA-Gal11 are strong activators that function independently of all Mediator subunits tested. On the other hand, lexA-Srb10 is a weak activator that depends on Srb8 and Srb11 and lexA-Med1 and lexA-Srb7 are both cryptic activators that become active in the absence of Srb8, Srb10, Srb11, or Sin4. Both lexA-Med1 and lexA-Srb7 proteins showed a stable association with the Mediator subunits Med4 and Med8 in wild type cells and in all deletion strains tested, indicating that they were functionally incorporated into the Mediator complex. We also showed that both Med4 and Med8 exist in two forms that differed in electrophoretic mobility and that these forms differed in their ability to associate with Mediator immuno-purified from the LEXA-SRB7 and LEXA-MED1 strains. Dephosphorylation assays of purified Mediator indicated that the two mobility forms of Med4 corresponded to the phosphorylated and unphosphorylated forms of the Med4 protein respectively.

    Some of the data presented in this study as well as previous genetic and biochemical data obtained in our lab suggested a functional link between the Med1, Med2, Srb10 and Srb11 proteins. We extended these findings by showing that the Srb10 kinase phosphorylates the Med2 protein at residue serine 208, both in vitro and in vivo. We also showed that a point mutation of the single phosphorylation site to an alanine or to an aspartic acid residue altered the gene expression of a specific set of genes. Taken together, these data indicate that posttranslational modification of Mediator subunits is a so far uncharacterized mechanism for regulation of gene expression.

    In order to study the function of the Srb7 subunit of Mediator, we isolated a temperature sensitive strain where the amino acids 2 to 8 of srb7 were deleted. The Mediator subunits Nut2 and Med7 were isolated as high copy suppressor of srb7-∆(2-8) and we were also able to show that Srb7 interacted with Nut2 and Med7 both in a 2-hybrid system and in co-immuno precipitation experiments using recombinantly expressed proteins. Interestingly, a deletion of amino acids 2 to 8 of Srb7 abolishes its interaction with both Med7 and Nut2 in vitro. Med4 also interacted with Srb7 in the 2-hybrid system and surprisingly, the first eight amino acids of Srb7 were shown to be sufficient for this interaction.

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  • 282.
    Hallberg, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hu, Guo-Zhen
    Balciunas, Darius
    Sheikhibrahim, Zaki
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Functional and physical interactions of the Mediator subunit Med21/Srb7Manuscript (Other academic)
  • 283.
    Hallberg, Magnus
    et al.
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Hu, Guo-Zhen
    Tronnersjö, Susanna
    Shaikhibrahim, Zaki
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Balciunas, Darius
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Ronne, Hans
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Functional and physical interactions within the middle domain of the yeast mediator2006In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 276, no 2, p. 197-210Article in journal (Refereed)
    Abstract [en]

    Med21 (Srb7) is a small essential subunit of the middle domain of the Mediator, which is conserved in all eukaryotes. It is thought to play an important role in both transcriptional activation and repression. In the yeast Saccharomyces cerevisiae, Med21 is known to interact both with the Mediator subunit Med6 and the global co-repressor Tup1. We have made a temperature-sensitive med21-ts mutant, which we used in a high copy number suppressor screen. We found ten yeast genes that can suppress the med21-ts mutation in high copy number. The three strongest suppressors were MED7 and MED10 (NUT2), which encode other Mediator subunits, and ASH1, which encodes a repressor of the HO gene. 2-Hybrid experiments confirmed multiple interactions between Med21, Med10, Med7 and Med4, and also revealed a Med21 self-interaction. The interactions of Med21 with Med7 and Med10 were verified by co-immunoprecipitation of tagged proteins produced in insect cells and E. coli, where both interactions were found to depend strongly on the amino acid residues 2-8 of Med21. These interactions, and the interactions of Med21 with Med6 and Tup1, suggest that Med21 may serve as a molecular switchboard that integrates different signals before they reach the core polymerase.

  • 284.
    Hallberg, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Polozkov, Gennady
    Deluen, Cécile
    Collart, Martine
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Phosphorylation of Serine 208 in Med2 is important for proper expression of genes required for anaerobic growth and purine and glykogen metabolismManuscript (Other academic)
  • 285.
    Hallberg, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Polozkov, Gennady
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hu, Guo-Zhen
    Beve, Jenny
    Gustafsson, Claes M.
    Ronne, Hans
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Site-specific Srb10-dependent phosphorylation of the yeast Mediator subunit Med2 regulates gene expression from the 2-microm plasmid2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 10, p. 3370-3375Article in journal (Refereed)
    Abstract [en]

    The yeast Mediator complex is required for transcriptional regulation both in vivo and in vitro, and its function is conserved in all eukaryotes. Mediator interacts with both transcriptional activators and RNA polymerase II, but little is known about the mechanisms by which it operates at the molecular level. Here, we show that the cyclin-dependent kinase Srb10 interacts with, and phosphorylates, the Med2 subunit of Mediator both in vivo and in vitro. A point mutation of the single phosphorylation site in Med2 results in a strongly reduced expression of the REP1, REP2, FLP1, and RAF1 genes, which are all located on the endogenous 2-microm plasmid. Combined with previous studies on the effects of SRB10/SRB11 deletions, our data suggest that posttranslational modifications of Mediator subunits are important for regulation of gene expression.

  • 286. Hamark, Christoffer
    et al.
    Berntsson, Ronnie Per-Arne
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Biochemistry and Biophysics, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Masuyer, Geoffrey
    Henriksson, Linda M.
    Gustafsson, Robert
    Stenmark, Pal
    Widmalm, Goran
    Glycans Confer Specificity to the Recognition of Ganglioside Receptors by Botulinum Neurotoxin A2017In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, no 1, p. 218-230Article in journal (Refereed)
    Abstract [en]

    The highly poisonous botulinum neurotoxins, produced by the bacterium Clostridium botulinum, act on their hosts by a high-affinity association to two receptors on neuronal cell surfaces as the first step of invasion. The glycan motifs of gangliosides serve as initial coreceptors for these protein complexes, whereby a membrane protein receptor is bound. Herein we set out to characterize the carbohydrate minimal binding epitope of the botulinum neurotoxin serotype A. By means of ligand-based NMR spectroscopy, X-ray crystallography, computer simulations, and isothermal titration calorimetry, a screening of ganglioside analogues together with a detailed characterization of various carbohydrate ligand complexes with the toxin were accomplished. We show that the representation of the glycan epitope to the protein affects the details of binding. Notably, both branches of the oligosaccharide GD la can associate to botulinum neurotoxin serotype A when expressed as individual trisaccharides. It is, however, the terminal branch of GD1a as well as this trisaccharide motif alone, corresponding to the sialyl-Thomsen-Friedenreich antigen, that represents the active ligand epitope, and these compounds bind to the neurotoxin with a high degree of predisposition but with low affinities. This finding does not correlate with the oligosaccharide moieties having a strong contribution to the total affinity, which was expected to be the case. We here propose that the glycan part of the ganglioside receptors mainly provides abundance and specificity, whereas the interaction with the membrane itself and protein receptor brings about the strong total binding of the toxin to the neuronal membrane.

  • 287. Hammer, Neal D
    et al.
    McGuffie, Bryan A
    Zhou, Yizhou
    Badtke, Matthew P
    Reineke, Ashley A
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gestwicki, Jason E
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chapman, Matthew R
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The C-terminal repeating units of CsgB direct bacterial functional amyloid nucleation2012In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 422, no 3, p. 376-389Article in journal (Refereed)
    Abstract [en]

    Curli are functional amyloids produced by enteric bacteria. The major curli fiber subunit, CsgA, self-assembles into an amyloid fiber in vitro. The minor curli subunit protein, CsgB, is required for CsgA polymerization on the cell surface. Both CsgA and CsgB are composed of five predicted β–strand-loop-β–strand-loop repeating units that feature conserved glutamine and asparagine residues. Because of this structural homology, we proposed that CsgB might form an amyloid template that initiates CsgA polymerization on the cell surface. To test this model, we purified wild-type CsgB, and found that it self-assembled into amyloid fibers in vitro. Preformed CsgB fibers seeded CsgA polymerization as did soluble CsgB added to the surface of cells secreting soluble CsgA. To define the molecular basis of CsgB nucleation, we generated a series of mutants that removed each of the five repeating units. Each of these CsgB deletion mutants was capable of self-assembly in vitro. In vivo, membrane-localized mutants lacking the 1st, 2nd or 3rd repeating units were able to convert CsgA into fibers. However, mutants missing either the 4th or 5th repeating units were unable to complement a csgB mutant. These mutant proteins were not localized to the outer membrane, but were instead secreted into the extracellular milieu. Synthetic CsgB peptides corresponding to repeating units 1, 2 and 4 self assembled into ordered amyloid polymers, while peptides corresponding to repeating units 3 and 5 did not, suggesting that there are redundant amyloidogenic domains in CsgB. Our results suggest a model where the rapid conversion of CsgB from unstructured protein to a β-sheet-rich amyloid template anchored to the cell surface is mediated by the C-terminal repeating units.

  • 288. Hansen, Lori M.
    et al.
    Gideonsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Canfield, Don R.
    Borén, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Solnick, Jay V.
    Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques2017In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 85, no 6, article id e00094Article in journal (Refereed)
    Abstract [en]

    Most Helicobacter pylori strains express the BabA adhesin, which binds to ABO/Leb blood group antigens on gastric mucin and epithelial cells and is found more commonly in strains that cause peptic ulcers or gastric cancer, rather than asymptomatic infection. We and others have previously reported that in mice, gerbils, and rhesus macaques, expression of babA is lost, either by phase variation or by gene conversion, in which the babB paralog recombines into the babA locus. The functional significance of loss of babA expression is unknown. Here we report that in rhesus monkeys, there is independent selective pressure for loss of babA and for overexpression of BabB, which confers a fitness advantage. Surprisingly, loss of babA by phase variation or gene conversion is not dependent on the capacity of BabA protein to bind Leb, which suggests that it may have other, unrecognized functions. These findings have implications for the role of outer membrane protein diversity in persistent H. pylori infection.

  • 289.
    Hansson, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Hellström, Sten
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Eriksson, Per-Olof
    Li, Jinan
    Berggren, Diana
    Plasminogen deficiency does not alter the healing of tympanic membrane perforations in vitroManuscript (Other academic)
  • 290.
    Hansson, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Li, Jinan
    Eriksson, Per-Olof
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Berggren, Diana
    Hellström, Sten
    The healing of tympanic membrane perforations is unaffected by urokinase-type plasminogen activator deficiencyManuscript (Other academic)
  • 291. Haracska, L
    et al.
    Unk, I
    Johnson, R E
    Johansson, Erik
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Burgers, P M
    Prakash, S
    Prakash, L
    Roles of yeast DNA polymerases delta and zeta and of Rev1 in the bypass of abasic sites.2001In: Genes & Development, ISSN 0890-9369, Vol. 15, no 8, p. 945-54Article in journal (Refereed)
  • 292. Harrysson Drotz, Stina
    et al.
    Tilston, Emma L
    Sparrman, Tobias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schleucher, Jürgen
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Contributions of matric and osmotic potentials to the unfrozen water content of frozen soils2009In: Geoderma, ISSN 0016-7061, E-ISSN 1872-6259, Vol. 148, no 3-4, p. 392-8Article in journal (Refereed)
    Abstract [en]

    Recent reports show that biogeochemical processes continue when the soil is frozen, but are limited by water availability. However, there is little knowledge about the interactive effects of soil and environmental variables on amounts of unfrozen water in frozen soils. The aims of this study were to determine the contributions of matric and osmotic potentials to the unfrozen water content of frozen soil. We determined the effects of matric and osmotic potential on unfrozen water contents of frozen mineral soil fractions (ranging from coarse sand to fine silt) at − 7 °C, and estimated the contributions of these potentials to liquid water contents in samples from organic surface layers of boreal soils frozen at − 4 °C. In the mineral soil fractions the unfrozen water contents appeared to be governed solely by the osmotic potential, but in the humus layers of the sampled boreal soils both the osmotic and matric potentials control unfrozen water content, with osmotic potential contributing 20 to 69% of the total water potential. We also determined pore size equivalents, where unfrozen water resides at − 4 °C, and found a strong correlation between these equivalents and microbial CO2 production. The larger the pores in which the unfrozen water is found the larger the microbial activity that can be sustained. The osmotic potential may therefore be a key determinant of unfrozen water and carbon dynamics in frozen soil.

  • 293. Hayakawa, H
    et al.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Thelander, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kitajima, S
    Cai, Y
    Oshiro, S
    Yakushiji, H
    Nakabeppu, Y
    Kuwano, M
    Sekiguchi, M
    Metabolic fate of oxidized guanine ribonucleotides in mammalian cells.1999In: Biochemistry, ISSN 0006-2960, Vol. 38, no 12, p. 3610-4Article in journal (Refereed)
  • 294.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ma, Li-Ping
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fu, Michael
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Growth factor PDGF-BB stimulates cultured cardiomyocytes to synthesize the extracellular matrix component hyaluronan2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 12, p. e14393-Article in journal (Refereed)
    Abstract [en]

    Co-cultivation of cardiomyocytes and fibroblasts (80%/20%) increased HA concentration far more that can be explained by HA synthesis by the two cell types separately, revealing a crosstalk between cardiomyocytes and fibroblasts that induces HA synthesis. We conclude that dynamic changes of the myocardium, such as in cardiac hypertrophy, do not depend on the cardiomyocyte alone, but are achieved when both cardiomyocytes and fibroblasts are present.

  • 295.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ma, Li-Ping
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Fu, Michael
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hyaluronan is both a product and stimulator of cardiomyocytes: a study in cell cultures of cardiomyocytes and fibroblastsArticle in journal (Refereed)
  • 296.
    Hellström, Sten
    et al.
    Department of CLINTEC/Otorhinolaryngology, Karolinska Medical University.
    Shen, Yue
    University of British Columbia.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    A reply to the commentary on "Animal models of chronic tympanic membrane perforation: in response to plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice" by Wang AY, Shen Y, Wang JT, Eikelboom RH and Dilley RJ; Clin Translat Med, 2014; 32015In: Clinical and translational medicine, ISSN 2001-1326, Vol. 4, no 8Article in journal (Refereed)
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  • 297.
    Henriksson, Sara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Helicobacter pylori: multitalented adaptation of binding properties2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Helicobacter pylori infects and persistently colonizes the stomach, which results in gastritis and in some individuals peptic ulcer disease or gastric cancer. Adherence of H. pylori to the epithelium is an important factor for development of disease. Attachment is mediated by the adhesins BabA and SabA that binds the ABO/Leb blood group antigens and sialylated glycoconjugates respectively.  High-affinity attachment could be anticipated to be of disadvantage for H. pylori because epithelial cells have a fast turnover rate and the dislocated and shed epithelial cells would carry attached bacteria to the acidic gastric juice in the lumen. However, here we describe that H. pylori manage to adapt to this innate clearance mechanism by unique acid regulatory binding properties of its adhesins. We propose that pH regulated binding properties enable bacteria to detachment from host cells for chemotactic guided motility and successful return to the more neutral epithelium for a fresh restart of the infectious cycle. By comparison of BabA from different stomach loci we identified amino acid key position for acid regulated binding activity.

    Previous studies found lower prevalence of Leb-binding among H. pylori isolates from southern Europe compared to Sweden. Here we tested if the reduced prevalence of Leb-binding could be explained by a novel binding mode; in among Spanish strains, we identified S812 that demonstrates preference for multivalent binding to ABO antigens in glycolipids; we found that 812 BabA had drifted in its preferred binding epitope away from the consensus a1,2fucosylation and towards the blood group A and B derivatives. Such epitope drift might in particular optimize binding to ABO antigens in densely packed lipid rafts.

    In parallel, we studied the influence of BabA for disease progression by an inventory of gastric biopsies. BabA correlated both with the oncoprotein CagA, the VacAs1 toxin and, in addition, to severe disease progression. We further correlate BabA expression with positive secretor phenotype and stronger adhesion of H. pylori in vitro.

    For functional adherence studies in vitro, we constructed a recombinant Leb-expressing cell lineage that supports BabA mediated H. pylori attachment.

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  • 298.
    Henriksson, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mendez, Melissa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bugaytsova, Jeanna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nordén, Jenny
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Berg, Douglas E
    Blixt, Ola
    Teneberg, Susann
    Borén, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Clinical isolates of Helicobacter pylori demonstrates alternative BabA-mediated adherence to human gastric mucosaManuscript (preprint) (Other academic)
    Abstract [en]

    Helicobacter pylori infection is life-long and can cause peptic ulcer disease and gastric cancer. The H. pylori BabA adhesin binds the ABO/Leb blood group (bg) antigens (Leb), which mediates attachment to the gastric epithelium. The prevalence of ABO binding is high worldwide and also in northern Europe. However, prevalence is reduced by 50% in Germany and is further reduced in Spain and Portugal. An inventory of strains from different European populations resulted in strains with high level of BabA expression but very little or no binding to Leb. The majority of such strains could not bind to human gastric mucosa in vitro. We further characterized a Spanish isolates, strain 812, that binds only weakly to soluble Leb-conjugate but still adheres firmly to gastric mucosa indicative of that it might bind to an alternative set of receptor. Receptor analysis by glycan arrays revealed higher binding of strain 812 to ALeb and Bleb glycans than to Leb, indicating that BabA from strain 812 has shifted its binding epitope somewhat away from the central Fuca1.2Gal bg domain and closer to the very terminal bg A and B determinants, i.e. GalNAca1.3Gal (bgA) or the Gala1.3Gal (bgB). By a colony screening approach we identified a subpopulation of 812 clones adapted for stronger Leb binding. Such affinity shifts comes from replacement of distinguishing amino acids by mechanisms of recombination with a BabA-related outer membrane protein.

  • 299. Hepburn, Lucy
    et al.
    Prajsnar, Tomasz K
    Klapholz, Catherine
    Moreno, Pablo
    Loynes, Catherine A
    Ogryzko, Nikolay V
    Brown, Karen
    Schiebler, Mark
    Hegyi, Krisztina
    Antrobus, Robin
    Hammond, Katherine L
    Connolly, John
    Ochoa, Bernardo
    Bryant, Clare
    Otto, Michael
    Surewaard, Bas
    Seneviratne, Suranjith L
    Grogono, Dorothy M
    Cachat, Julien
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kaser, Arthur
    Török, M Estée
    Peacock, Sharon J
    Holden, Matthew
    Blundell, Tom
    Wang, Lihui
    Ligoxygakis, Petros
    Minichiello, Liliana
    Woods, C Geoff
    Foster, Simon J
    Renshaw, Stephen A
    Floto, R Andres
    A Spaetzle-like role for nerve growth factor beta in vertebrate immunity to Staphylococcus aureus2014In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 346, no 6209, p. 641-646Article in journal (Refereed)
    Abstract [en]

    Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor β (NGFβ), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFβ or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFβ was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFβ-TRKA signaling in pathogen-specific host immunity.

  • 300.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Den humana mjölkens lipaser: egenskaper och fysiologiska aspekter1974Doctoral thesis, comprehensive summary (Other academic)
    Abstract [sv]

    I avhandlingen visas att:

    1.  Human mjölk innehåller två lipaser. Det ena är ett serum-stimulerat lipas (lipoprotein lipas). Lipoprotein lipaser är enzymer som har en central roll i den normala katabolismen av de triglyceridrika plasma- lipoproteinerna. Lipaset har sannolikt inte någon fysiologisk funktion i mjölken. En metod beskrivs med vilken lipaset har renats ca 9 500 gånger från mjölk.

    2.  Det serum-stimulerade lipaset från human mjölk har de klassiska egen­skaperna för ett serum-stimulerat lipas (lipoprotein lipas). Med en immunologisk metod visas att lipaset korsreagerar med motsvarande lipaser i bovin mjölk och human postheparin plasma. Slutsatsen är att det serum-stimulerade lipaset i human mjölk är väl värt att studera eftersom det mycket väl kan ha många egenskaper gemensamma med de fysiologiskt aktiva och viktiga humana serum-stimulerade lipaserna.

    3.  Det andra lipaset i human mjölk, det gallsalt-stimulerade lipaset, har en låg substratspecificitet. Gallsalter stimulerar enzymaktiviteten mot alla substrat som testats. Mot mjölkens egna triglycerider är lipaset helt inaktivt i frånvaro av gallsalter. I närvaro av gall- salter spjälkar lipaset alla tre esterbindningarna i triglycerid- molekylen så att slutprodukterna blir fria fettsyror och glycerol.

    4.  Gallsalter skyddar lipaset mot olika typer av inaktivering, t ex mot inaktivering av tarmens proteinnedbrytande enzymer. Det är sanno­likt att gallsalternas effekt beror på att de direkt interagerar med enzymproteinet. Lipaset visas ha sådana egenskaper att det väsentligt skulle kunna bidraga till den spjälkning av mjölktriglyceriderna som sker i tarmen hos den nyfödde.

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    Den humana mjölkens lipaser
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