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  • 51. Boudière, Laurence
    et al.
    Michaud, Morgane
    Petroutsos, Dimitris
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiology and Environmental Toxicology.
    Rébeillé, Fabrice
    Falconet, Denis
    Bastien, Olivier
    Roy, Sylvaine
    Finazzi, Giovanni
    Rolland, Norbert
    Jouhet, Juliette
    Block, Maryse A
    Maréchal, Eric
    Glycerolipids in photosynthesis: composition, synthesis and trafficking.2014In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1837, no 4, p. 470-80, article id S0005-2728(13)00163-1Article in journal (Refereed)
    Abstract [en]

    Glycerolipids constituting the matrix of photosynthetic membranes, from cyanobacteria to chloroplasts of eukaryotic cells, comprise monogalactosyldiacylglycerol, digalactosyldiacylglycerol, sulfoquinovosyldiacylglycerol and phosphatidylglycerol. This review covers our current knowledge on the structural and functional features of these lipids in various cellular models, from prokaryotes to eukaryotes. Their relative proportions in thylakoid membranes result from highly regulated and compartmentalized metabolic pathways, with a cooperation, in the case of eukaryotes, of non-plastidic compartments. This review also focuses on the role of each of these thylakoid glycerolipids in stabilizing protein complexes of the photosynthetic machinery, which might be one of the reasons for their fascinating conservation in the course of evolution. This article is part of a Special Issue entitled: Dynamic and ultrastructure of bioenergetic membranes and their components.

  • 52.
    Bozaykut, Perinur
    et al.
    Marmara Univ, Dept Biochem, Sch Med, TR-34854 Istanbul, Turkey.;Acibadem Mehmet Ali Aydinlar Univ, Dept Mol Biol & Genet, TR-34752 Istanbul, Turkey..
    Sozen, Erdi
    Marmara Univ, Dept Biochem, Sch Med, TR-34854 Istanbul, Turkey.;Marmara Univ, Genet & Metab Dis Res & Invest Ctr, TR-34854 Istanbul, Turkey..
    Kaga, Elif
    Marmara Univ, Dept Biochem, Sch Med, TR-34854 Istanbul, Turkey.;Univ Hlth Sci, Hlth Applicat & Res Ctr, Afyon, Turkey..
    Ece, Asli
    Marmara Univ, Dept Biochem, Sch Med, TR-34854 Istanbul, Turkey..
    Ozaltin, Esra
    Marmara Univ, Dept Biochem, Sch Med, TR-34854 Istanbul, Turkey..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala Univ, Dept Chem BMC, Analyt Chem, Uppsala, Sweden..
    Ozer, Nesrin Kartal
    Marmara Univ, Dept Biochem, Sch Med, TR-34854 Istanbul, Turkey.;Marmara Univ, Genet & Metab Dis Res & Invest Ctr, TR-34854 Istanbul, Turkey..
    Yilmaz, Betul Karademir
    Marmara Univ, Dept Biochem, Sch Med, TR-34854 Istanbul, Turkey.;Marmara Univ, Genet & Metab Dis Res & Invest Ctr, TR-34854 Istanbul, Turkey..
    HSP70 Inhibition Leads to the Activation of Proteasomal System under Mild Hyperthermia Conditions in Young and Senescent Fibroblasts2020In: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, Vol. 2020, article id 9369524Article in journal (Refereed)
    Abstract [en]

    Aging has been characterized with the accumulation of oxidized proteins, as a consequence of progressive decline in proteostasis capacity. Among others, proteasomal system is an efficient protein turnover complex to avoid aggregation of oxidized proteins. Heat shock protein 70 (HSP70) is another critical player that is involved in some key processes including the correct folding of misfolded proteins and targeting aggregated proteins to the proteasome for rapid degradation. The aim of this study was to determine the role of proteasomal system and heat shock proteins to maintain proteome balance during replicative senescence in mild hyperthermia conditions. Our results demonstrated that HSP40/70 machinery is induced by mild hyperthermia conditions independent from senescence conditions. Since HSP70 is largely responsible for the rapidly inducible cell protection following hyperthermia, the activation of "heat shock response" resulted in the elevation of HSP40/70 expressions as well as the proteasome activity. Interestingly, when HSP70 expression was inhibited, increased proteasomal activation was shown to be responsive to mild hyperthermia. Since HSP70 is involved in various stress-related pathways such as oxidative and endoplasmic reticulum stress, depletion of HSP70 expression may induce proteasomal degradation to maintain proteome balance of the cell. Thus, our data suggests that in mild heat stress conditions, molecular chaperone HSP70 plays an important role to avoid protein oxidation and aggregation; however, activities of proteasomal system are induced when HSP70 expression is depleted.

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  • 53.
    Braesch-Andersen, Ken
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Temperature dependence in human Rhinovirus infection of human MRC-52019Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Temperature has been known to be an important factor for in vitro studies where human cell cultures are infected with HRV (human Rhinovirus). The mechanisms behind the temperature effect on the struggle between virulence and cellular defense, are still largely unknown and may be a crucial part in finding a treatment to the common cold. In this study we focused on a few cellular key elements in this struggle and observed behavior changes in regards to the pre-infection growth temperature and the temperature during the viral infection.

    Past studies have focused mainly on the temperature post inoculation, but here we also wanted to correlate virulence to the growth temperatures preceding the viral infection. We found that the growth temperature of the cell did indeed affect its response to the HRV. If the cells had been growing in an optimal body temperature of 37°C before getting virally infected at 33°C, the viability of the cells did decrease in comparison to cells that had been growing in 33°C from before the viral infection.

    We could also observe a significant temperature dependence regarding IL-8 release upon HRV inoculation. HRV strive to block induction of inflammatory cytokines such as interferons and IL-1. It may be that impaired IL-8 release at lower temperatures will prevent important danger signals alerting the immune system when cytokine signaling is otherwise hampered by viral intervention.

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  • 54.
    Brandhorst, Daniel
    et al.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Parnaud, Geraldine
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Friberg, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lavallard, Vanessa
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Demuylder-Mischler, Sandrine
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Hughes, Stephen
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Saphoerster, Julia
    SERVA Electrophoresis GmbH, Uetersen, Germany..
    Kurfuerst, Manfred
    SERVA Electrophoresis GmbH, Uetersen, Germany..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berney, Thierry
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Johnson, Paul R. V.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Multicenter Assessment of Animal-free Collagenase AF-1 for Human Islet Isolation2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 10, p. 1688-1693Article in journal (Refereed)
    Abstract [en]

    Animal-free (AF) SERVA Collagenase AF-1 and Neutral Protease (NP) AF GMP Grade have recently become available for human islet isolation. This report describes the initial experiences of 3 different islet transplant centers. Thirty-four human pancreases were digested using 1 vial of the 6 different lots of Collagenase AF-1 (2,000-2,583 PZ-U/vial) supplemented with 4 different lots of NP AF in a range of 50 to 160 DMC-U per pancreas. Isolation, culture, and quality assessment were performed using standard techniques as previously described. All data are presented as mean +/- standard error of the mean (SEM). Variability of pancreas weight was associated with a wide range of collagenase and NP activities, ranging from 12.7 to 46.6 PZ-U/g (26.0 +/- 1.5 PZ-U/g) and 0.4 to 3.0 DMC-U/g (1.5 +/- 0.1 DMC-U/g), respectively. Postpurification islet yield was 296,494 +/- 33,620 islet equivalents (IEQ) equivalent to 3,274 +/- 450 IEQ/g with a purity of 55.9% +/- 3.2%. Quality assessment performed after 2 to 4 d of culture demonstrated a viability of 88.1% +/- 1.5% and a stimulation index of 3.7 +/- 0.7. Eighteen of the 34 preparations were transplanted into type 1 diabetic patients equivalent to a transplantation rate of 52.9%. Six preparations, which were infused into patients as first transplant, could be analyzed and increased the fasting C-peptide level from 0.11 +/- 0.08 pretransplant to 1.23 +/- 0.24 and 2.27 +/- 0.31 ng/mL 3 and 6 mo posttransplant (P < 0.05), respectively. Insulin requirements were simultaneously reduced at the same time from 39.2 +/- 3.8 IU/d before transplantation to 10.8 +/- 4.1 and 4.0 +/- 2.3 IU/d, after 3 and 6 mo posttransplant (P < 0.05), respectively. This study demonstrates the efficiency of AF SERVA Collagenase AF-1 and NP AF for clinical islet isolation and transplantation. The new plant-based production process makes these products a safe new option for the islet field.

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  • 55.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
    Johnson, Paul R.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England;Oxford NIHR Biomed Res Ctr, Oxford, England.
    Moench, Johanna
    Nordmark Arzneimittel, Uetersen, Germany.
    Kurfuerst, Manfred
    Nordmark Arzneimittel, Uetersen, Germany.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
    Comparison of Clostripain and Neutral Protease as Supplementary Enzymes for Human Islet Isolation2019In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 28, no 2, p. 176-184Article in journal (Refereed)
    Abstract [en]

    Although human islet transplantation has been established as valid and safe treatment for patients with type 1 diabetes, the utilization rates of human pancreases for clinical islet transplantation are still limited and substantially determined by the quality and composition of collagenase blends. While function and integrity of collagenase has been extensively investigated, information is still lacking about the most suitable supplementary neutral proteases. The present study compared islet isolation outcome after pancreas digestion by means of collagenase used alone or supplemented with either neutral protease (NP), clostripain (CP), or both proteases. Decent amounts of islet equivalents (IEQ) were isolated using collagenase alone (3090 +/- 550 IEQ/g), or in combination with NP (2340 +/- 450 IEQ/g) or CP (2740 +/- 280 IEQ/g). Nevertheless, the proportion of undigested tissue was higher after using collagenase alone (21.1 +/- 1.1%, P < 0.05) compared with addition of NP (13.3 +/- 2.2%) or CP plus NP (13.7 +/- 2.6%). Likewise, the percentage of embedded islets was highest using collagenase only (13 +/- 2%) and lowest adding NP plus CP (4 +/- 1%, P < 0.01). The latter combination resulted in lowest post-culture overall survival (42.7 +/- 3.9%), while highest survival was observed after supplementation with CP (74.5 +/- 4.8%, P < 0.01). An insulin response toward glucose challenge was present in all experimental groups, but the stimulation index was significantly decreased using collagenase plus NP (2.0 +/- 0.12) compared with supplementation with CP (3.16 +/- 0.4, P < 0.001). This study demonstrates for the first time that it is possible to isolate significant numbers of human islets combining collagenase only with CP. The supplementation with CP is an effective means to substantially reduce NP activity, which significantly decreases survival and viability after culture. This will facilitate the manufacturing of enzyme blends with less harmful characteristics.

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  • 56.
    Bryukhovetskiy, Igor
    et al.
    Far Eastern Fed Univ FEFU, Med Ctr, Sch Life Sci & Biomed, Vladivostok, Russia..
    Kosianova, Aleksandra
    Far Eastern Fed Univ FEFU, Med Ctr, Sch Life Sci & Biomed, Vladivostok, Russia..
    Zaitsev, Sergeis
    Far Eastern Fed Univ FEFU, Med Ctr, Sch Life Sci & Biomed, Vladivostok, Russia..
    Pak, Oleg
    Far Eastern Fed Univ FEFU, Med Ctr, Sch Life Sci & Biomed, Vladivostok, Russia..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glioblastoma: What can we do for these patients today and what will we be able to do in the future?2021In: NANOMEDICINE AND NEUROPROTECTION IN BRAIN DISEASES / [ed] Sharma, HS Sharma, A, ELSEVIER ACADEMIC PRESS INC , 2021, p. 99-118Chapter in book (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is an extremely aggressive primary human brain tumor. The median survival of GBM patients is 15 months in case of completing the modern complex treatment protocol. Chemotherapy can help to extend the life expectancy of patients. GBM treatment resistance is associated with cancer stem cells (CSCs). The present paper analyses the main reasons for ineffectiveness of the existing GBM treatment methods and suggests treating CSCs as a complex phenomenon, resulting from the coordinated interaction of normal stem cells and cancer cells (CCs) in immunosuppressive microsurroundings. The GBM treatment strategy is suggested not for only suppressing strategically important signaling pathways in CCs, but also for regulating interaction between normal stem cells and cancer cells. The paper considers the issue of controlling penetrability of the blood-brain barrier that is one of the main challenges in neuro-oncology. Also, the paper suggests the ways of extending life expectancy of GBM patients today and prospects for the near future.

  • 57.
    Bryukhovetskiy, Igor
    et al.
    Far Eastern Fed Univ, Sch Biomed, Dept Fundamental Med, Vladivostok, Russia.;Russian Acad Sci, Natl Sci Ctr Marine Biol, Far East Branch, Pharmacol Lab, Vladivostok, Russia..
    Pak, Oleg
    Far Eastern Fed Univ, Med Ctr, Vladivostok, Russia..
    Khotimchenko, Yuri
    Far Eastern Fed Univ, Sch Biomed, Dept Fundamental Med, Vladivostok, Russia.;Russian Acad Sci, Natl Sci Ctr Marine Biol, Far East Branch, Pharmacol Lab, Vladivostok, Russia..
    Bryukhovetskiy, Andrey
    NeuroVita Clin Intervent & Restorat Neurol & Ther, Moscow, Russia..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Personalized therapy and stem cell transplantation for pro-inflammatory modulation of cancer stem cells microenvironment in glioblastoma: Review2020In: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA / [ed] Bryukhovetskiy, I Sharma, A Zhang, Z Sharma, HS, LONDON ENGLAND: Elsevier, 2020, p. 67-98Chapter in book (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is one of the most aggressive types of brain tumor in humans. The prognosis for patients with GBM is unfavorable and treatment is largely ineffective, where modern treatment regimens typically increase survival by 15 months. GBM relapse and progression are associated with cancer stem cells (CSCs). The present review provides a critical analysis of the primary reasons underlying the lack of effectiveness of modern CSC management methods. An emphasis is placed on the role of the blood-brain barrier in the development of treatment resistance. The existing methods for increasing the efficiency of antitumor genotoxic therapy are also described, and a strategy for personalized regulation of CSC based on post-genome technologies is suggested. The hypothesis that GBM cells employ a special mechanism for DNA repair based on their interactions with normal stem cells, is presented and the function of the tumor microenvironment in fulfilling the antitumor potential of normal stem cells is explained. Additionally, the mechanisms by which cancer stem cells regulate glioblastoma progression and recurrence are described based on novel biomedical technologies.

  • 58.
    Bryukhovetskiy, Igor
    et al.
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Ponomarenko, Arina
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Lyakhova, Irina
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Zaitsev, Sergey
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Zayats, Yulia
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Korneyko, Maria
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Eliseikina, Marina
    Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Mischenko, Polina
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Shevchenko, Valerie
    Far Eastern Fed Univ, Vladivostok 690091, Russia;NN Blokhin Russian Canc Res Ctr, Moscow 115478, Russia.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Khotimchenko, Yuri
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Personalized regulation of glioblastoma cancer stem cells based on biomedical technologies: From theory to experiment (Review)2018In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 42, no 2, p. 691-702Article, review/survey (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. GBM represents >50% of primary tumors of the nervous system and similar to 20% of intracranial neoplasms. Standard treatment involves surgery, radiation and chemotherapy. However, the prognosis of GBM is usually poor, with a median survival of 15 months. Resistance of GBM to treatment can be explained by the presence of cancer stem cells (CSCs) among the GBM cell population. At present, there are no effective therapeutic strategies for the elimination of CSCs. The present review examined the nature of human GBM therapeutic resistance and attempted to systematize and put forward novel approaches for a personalized therapy of GBM that not only destroys tumor tissue, but also regulates cellular signaling and the morphogenetic properties of CSCs. The CSCs are considered to be an informationally accessible living system, and the CSC proteome should be used as a target for therapy directed at suppressing clonal selection mechanisms and CSC generation, destroying CSC hierarchy, and disrupting the interaction of CSCs with their microenvironment and extracellular matrix. These objectives can be achieved through the use of biomedical cellular products.

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  • 59.
    Bryukhovetskiy, Igor
    et al.
    Far Eastern Fed Univ, Sch Biomed, Dept Fundamental Med, Vladivostok, Russia.;Russian Acad Sci, Far East Branch, Natl Sci Ctr Marine Biol, Pharmacol Lab, Vladivostok, Russia.;Far Eastern Fed Univ, Med Ctr, Vladivostok, Russia..
    Shevchenko, Valeriy
    Far Eastern Fed Univ, Sch Biomed, Dept Fundamental Med, Vladivostok, Russia.;Minist Hlth Russia, NN Blokhin Natl Med Res Ctr Oncol, Inst Carcinogenesis, Lab Oncoprote, Moscow, Russia..
    Arnotskaya, Natalia
    Minist Hlth Russia, NN Blokhin Natl Med Res Ctr Oncol, Inst Carcinogenesis, Lab Oncoprote, Moscow, Russia..
    Kushnir, Tatyana
    Minist Hlth Russia, NN Blokhin Natl Med Res Ctr Oncol, Inst Carcinogenesis, Lab Oncoprote, Moscow, Russia..
    Pak, Oleg
    Far Eastern Fed Univ, Med Ctr, Vladivostok, Russia..
    Victor, Zgoda
    Inst Biomed Chem IBMC, Lab Syst Biol, Moscow, Russia..
    Zaitsev, Sergei
    Far Eastern Fed Univ, Sch Biomed, Dept Fundamental Med, Vladivostok, Russia..
    Khotimchenko, Yuri
    Far Eastern Fed Univ, Sch Biomed, Dept Fundamental Med, Vladivostok, Russia.;Russian Acad Sci, Far East Branch, Natl Sci Ctr Marine Biol, Pharmacol Lab, Vladivostok, Russia..
    Bryukhovetskiy, Andrey
    NeuroVita Clin Intervent & Restorat Neurol & Ther, Moscow, Russia..
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Transforming growth factor-beta mimics the key proteome properties of CD133- differentiated and CD133+ cancer stem cells in glioblastoma2020In: Novel therapeutic advances in glioblastoma / [ed] Bryukhovetskiy, I; Sharma, A; Zhang, Z; Sharma, HS, Elsevier BV , 2020, p. 219-242Chapter in book (Refereed)
    Abstract [en]

    Glioblastoma multiforme is the most aggressive type of primary brain tumor in humans. Its invasive growth is associated with cluster of differentiation (CD)133 cancer stem cells (CSCs) and CD133(-) differentiated glioblastoma cells (DGCs) with aggressive phenotype, which are developed under the influence of transforming growth factor (TGF)-beta. The present study aimed to compare the proteomes of CD133 CSCs and CD133(-) DGCs stimulated by TGF-beta, as well as the expression levels of the main proteins responsible for activating the signaling pathway of receptor interactions with the extracellular matrix (ECM). The U87MG GBM cell line was used in this study. CSCs were extracted from gliomaspheres through magnetic-activated cell sorting based on the expression of CD133 (CD133); CD133(-) DCGs served as a control. CD133(-) DGCs of the U87-MG cell line were treated with 10ng/mL TGF-beta 1, and cell proliferation and migration were analyzed via real-time quantitative microscopy. High-performance liquid chromatography mass spectrometry was used for proteome analysis. The results revealed 589 proteins with significantly changes in expression among CD133 CSCs compared with those in CD133(-) DGCs (P < 0.05). Bioinformatics analysis allowed to attribute 134 differentially expressed proteins to 15 signaling pathways; among these proteins, 14 were involved in signaling cascades associated with the interaction between CSCs and the ECM, and were upregulated > twofold, while four proteins activated this signaling cascade. TGF-beta-stimulation increased the mobility, suppressed the proliferation and transformed the proteome profile of CD133(-) DGCs. Were identified 13 key proteins that activate the signaling pathway of receptor interaction with the ECM and three proteins activating this signaling pathway in CD133(-) DGCs which had the same values as those of CD133 CSCs. In conclusion, TGF-beta increased the expression of proteins that activate the signaling pathway of receptor interaction with the ECM in CD133(-) DGCs to the level of those in CD133 CSCs.

  • 60.
    Buel, Gwen R.
    et al.
    Harvard Med Sch, Programs Biol & Biomed Sci, Boston, MA USA.;Weill Cornell Med Coll, Meyer Canc Ctr, Dept Pharmacol, New York, NY 10021 USA.;Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA..
    Dang, Huy Q.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Asara, John M.
    Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Boston, MA USA..
    Blenis, John
    Weill Cornell Med Coll, Meyer Canc Ctr, Dept Pharmacol, New York, NY 10021 USA.;Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA..
    Mutvei, Anders P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Prolonged deprivation of arginine or leucine induces PI3K/ Akt-dependent reactivation of mTORC12022In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 298, no 6, article id 102030Article in journal (Refereed)
    Abstract [en]

    The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids, which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Aktdependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach.

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  • 61.
    Busse, Niels
    et al.
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Paroni, Federico
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Richardson, Sarah J.
    Univ Exeter, Islet Biol Exeter, Med, Exeter EX4 4QJ, Devon, England..
    Laiho, Jutta E.
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland..
    Oikarinen, Maarit
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland..
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hyoty, Heikki
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland.;Pirkanmaa Hosp Dist, Fimlab Labs, Tampere, Finland..
    de Koning, Eelco
    Leiden Univ, Med Ctr, Dept Internal Med, Leiden, Netherlands.;Univ Med Ctr Utrecht, Hubrecht Inst, Utrecht, Netherlands..
    Morgan, Noel G.
    Univ Exeter, Islet Biol Exeter, Med, Exeter EX4 4QJ, Devon, England..
    Maedler, Kathrin
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Detection and localization of viral infection in the pancreas of patients with type 1 diabetes using short fluorescently-labelled oligonucleotide probes2017In: Oncotarget, E-ISSN 1949-2553, Vol. 8, no 8, p. 12620-12636Article in journal (Refereed)
    Abstract [en]

    Enteroviruses, specifically of the Coxsackie B virus family, have been implicated in triggering islet autoimmunity and type 1 diabetes, but their presence in pancreata of patients with diabetes has not been fully confirmed. To detect the presence of very low copies of the virus genome in tissue samples from T1D patients, we designed a panel of fluorescently labeled oligonucleotide probes, each of 17-22 nucleotides in length with a unique sequence to specifically bind to the enteroviral genome of the picornaviridae family. With these probes enteroviral RNA was detected with high sensitivity and specificity in infected cells and tissues, including in FFPE pancreas sections from patients with T1D. Detection was not impeded by variations in sample processing and storage thereby overcoming the potential limitations of fragmented RNA. Co-staining of small RNA probes in parallel with classical immunstaining enabled virus detection in a cell-specific manner and more sensitively than by viral protein.

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  • 62.
    Caja, Laia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dadras, Mahsa Shahidi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mezheyeuski, Artur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mendes Rodrigues-Junior, Dorival
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liu, Sijia
    Leiden Univ, Oncode Inst, Dept Cell & Chem Biol, Med Ctr, Leiden, Netherlands..
    Taylor Webb, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Gomez-Puerto, Maria Catalina
    Leiden Univ, Oncode Inst, Dept Cell & Chem Biol, Med Ctr, Leiden, Netherlands..
    ten Dijke, Peter
    Leiden Univ, Oncode Inst, Dept Cell & Chem Biol, Med Ctr, Leiden, Netherlands..
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The protein kinase LKB1 promotes self-renewal and blocks invasiveness in glioblastoma2022In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 237, no 1, p. 743-762Article in journal (Refereed)
    Abstract [en]

    The role of liver kinase B1 (LKB1) in glioblastoma (GBM) development remains poorly understood. LKB1 may regulate GBM cell metabolism and has been suggested to promote glioma invasiveness. After analyzing LKB1 expression in GBM patient mRNA databases and in tumor tissue via multiparametric immunohistochemistry, we observed that LKB1 was localized and enriched in GBM tumor cells that co-expressed SOX2 and NESTIN stemness markers. Thus, LKB1-specific immunohistochemistry can potentially reveal subpopulations of stem-like cells, advancing GBM patient molecular pathology. We further analyzed the functions of LKB1 in patient-derived GBM cultures under defined serum-free conditions. Silencing of endogenous LKB1 impaired 3D-gliomasphere frequency and promoted GBM cell invasion in vitro and in the zebrafish collagenous tail after extravasation of circulating GBM cells. Moreover, loss of LKB1 function revealed mitochondrial dysfunction resulting in decreased ATP levels. Treatment with the clinically used drug metformin impaired 3D-gliomasphere formation and enhanced cytotoxicity induced by temozolomide, the primary chemotherapeutic drug against GBM. The IC50 of temozolomide in the GBM cultures was significantly decreased in the presence of metformin. This combinatorial effect was further enhanced after LKB1 silencing, which at least partially, was due to increased apoptosis. The expression of genes involved in the maintenance of tumor stemness, such as growth factors and their receptors, including members of the platelet-derived growth factor (PDGF) family, was suppressed after LKB1 silencing. The defect in gliomasphere growth caused by LKB1 silencing was bypassed after supplementing the cells with exogenous PFDGF-BB. Our data support the parallel roles of LKB1 in maintaining mitochondrial homeostasis, 3D-gliomasphere survival, and hindering migration in GBM. Thus, the natural loss of, or pharmacological interference with LKB1 function, may be associated with benefits in patient survival but could result in tumor spread.

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  • 63.
    Caja, Laia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ortiz, Conrad
    Bertran, Esther
    Murillo, Miguel M
    Miró-Obradors, M Jesús
    Palacios, Evangelina
    Fabregat, Isabel
    Differential intracellular signalling induced by TGF-beta in rat adult hepatocytes and hepatoma cells: implications in liver carcinogenesis.2007In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 19, no 4, p. 683-94Article in journal (Refereed)
    Abstract [en]

    The transforming growth factor-beta (TGF-beta) regulates hepatocyte growth, inhibiting proliferation and inducing apoptosis. Indeed, escaping from the TGF-beta suppressor actions might be a prerequisite for liver tumour progression. In this work we show that TGF-beta plays a dual role in regulating apoptosis in FaO rat hepatoma cells, since, in addition to its pro-apoptotic effect, TGF-beta also activates survival signals, such as AKT, the epidermal growth factor receptor (EGFR) being required for its activation. TGF-beta induces the expression of the EGFR ligands transforming growth factor-alpha (TGF-alpha) and heparin-binding EGF-like growth factor (HB-EGF) and induces intracellular re-localization of the EGFR. Cells that overcome the apoptotic effects of TGF-beta undergo morphological changes reminiscent of an epithelial-mesenchymal transition (EMT) process. In contrast, TGF-beta does not activate AKT in adult hepatocytes, which correlates with lack of EGFR transactivation and no response to EGFR inhibitors. Although TGF-beta induces TGF-alpha and HB-EGF in adult hepatocytes, these cells show very low expression of TACE/ADAM 17 (TNF-alpha converting enzyme), which is required for EGFR ligand proteolysis and activation. Furthermore, adult hepatocytes do not undergo EMT processes in response to TGF-beta, which might be due, at least in part, to the fact that F-actin re-organization induced by TGF-beta in FaO cells require the EGFR pathway. Finally, results indicate that EGFR transactivation does not block TGF-beta-induced cell cycle arrest in FaO cells, but must be interfering with the pro-apoptotic signalling. In conclusion, TGF-beta is a suppressor factor for adult quiescent hepatocytes, but not for hepatoma cells, where it plays a dual role, both suppressing and promoting carcinogenesis.

  • 64. Caja, Laia
    et al.
    Shahidi Dadras, Mahsa
    Tzavlaki, Kalliopi
    Tan, E-Jean
    Hatem, Gad
    Maturi, Nagaprathyusha
    Moren, Anita
    Wik, Lotta
    Watanabe, Yukihide
    Savary, Katia
    Kamali-Moghaddam, Masood
    Uhrbom, Lene
    Heldin, Carl-Henrik
    Moustakas, Aristidis
    Snail regulates BMP and TGF-β pathways to control the differentiation status of glioma initiating cellsManuscript (preprint) (Other academic)
    Abstract
  • 65.
    Cancer, Matko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Drews, Lisa F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bolin, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Rosén, Gabriela
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nelander, Sven
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Forsberg Nilsson, Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weishaupt, Holger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Johansson, Fredrik K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells2019In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 881Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.

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  • 66. Carthy, Jonathon
    Bellomo, Claudia ()
    Vanlandewijck, Michael ()
    Heldin, Angelos ()
    Moren, Anita ()
    Kardassis, Dimitri ()
    Gahman, Timothy ()
    Shiau, Andrew ()
    Bickle, Marc ()
    Zerial, Marino ()
    Heldin, Carl-Henrik ()
    Moustakas, Aristidis ()
    Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myo broblast di erentiation2016In: Scientific Reports, E-ISSN 2045-2322Article in journal (Refereed)
  • 67.
    Ceder, Mikaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Characterization of Novel Solute Carriers in Humans, Mice and Flies: Solute Carriers in a Broad and Narrow Perspective2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The solute carrier family is the largest family of membrane-bound transporters in humans, with 430 members divided into 65 subfamilies. They transport various substrates across lipid barriers and are vital for absorption, distribution, metabolism and excretion in all cell types in the body. Despite being involved in vital functions, and their effect on both physiology and pathophysiology, many transporters are not characterized. The aim of this thesis was to study newly identified putative solute carriers of which little is known. In Paper I, the relationship of solute carriers in humans and fruit flies was studied. The study revealed that 54 of the 65 subfamilies in humans have one or more orthologues in fruit flies, and a total of 381 orthologues were identified in fruit flies. In Paper II, a comprehensive study of the putative solute carriers and their response to different sugar concentrations were performed. Several, but not all, putative solute carriers were altered in cell cultures maintained in media containing low or no glucose, and the expression normalized upon refeeding with glucose. Similar results were observed in fruit flies subjected to complete starvation or diets with varying sugar concentrations. Last, in Paper III and IV, characterization of one putative solute carrier, UNC93A, was performed. The studies revealed that UNC93A was a conserved protein with an abundant expression in the body of mice but with a restricted expression in fruit flies. The protein was found to possibly be expressed at, or close to, the plasma membrane of cells and to co-localize with Twik-Acid sensitive potassium channels. UNC93A was found to be important for the renal function in fruit flies and to affect survival and membrane potentials in cells. The findings of this thesis establish a high conservation of several putative solute carriers and that they have a highly dynamic regulation during fluctuating energy and glucose availability. Further, while several clear biological aspects of UNC93A was identified, the exact function of transporter proteins is cumbersome to find and more research about these transporters is needed to fully understand their mechanistic role and their association and/or involvement in health and sickness.

    List of papers
    1. Bridging the gap: The human and D. melanogaster repertoire of Solute Carriers
    Open this publication in new window or tab >>Bridging the gap: The human and D. melanogaster repertoire of Solute Carriers
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Basic Medicine Evolutionary Biology
    Identifiers
    urn:nbn:se:uu:diva-416367 (URN)
    Available from: 2020-07-16 Created: 2020-07-16 Last updated: 2020-07-27
    2. Glucose Availability Alters Gene and Protein Expression of Several Newly Classified and Putative Solute Carriers in Mice Cortex Cell Culture and D. melanogaster
    Open this publication in new window or tab >>Glucose Availability Alters Gene and Protein Expression of Several Newly Classified and Putative Solute Carriers in Mice Cortex Cell Culture and D. melanogaster
    Show others...
    2020 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 8, article id 579Article in journal (Refereed) Published
    Abstract [en]

    Many newly identified solute carriers (SLCs) and putative transporters have the possibility to be intricately involved in glucose metabolism. Here we show that many transporters of this type display a high degree of regulation at both mRNA and protein level following no or low glucose availability in mouse cortex cultures. We show that this is also the case in Drosophila melanogaster subjected to starvation or diets with different sugar content. Interestingly, re-introduction of glucose to media, or refeeding flies, normalized the gene expression of a number of the targets, indicating a fast and highly dynamic control. Our findings demonstrate high conservation of these transporters and how dependent both cell cultures and organisms are on gene and protein regulation during metabolic fluctuations. Several transporter genes were regulated simultaneously maybe to initiate alternative metabolic pathways as a response to low glucose levels, both in the cell cultures and in D. melanogaster. Our results display that newly identified SLCs of Major Facilitator Superfamily type, as well as the putative transporters included in our study, are regulated by glucose availability and could be involved in several cellular aspects dependent of glucose and/or its metabolites. Recently, a correlation between dysregulation of glucose in the central nervous system and numerous diseases such as obesity, type 2 diabetes mellitus as well as neurological disease such as Alzheimer’s and Parkinson’s diseases indicate a complex regulation and fine tuning of glucose levels in the brain. The fact that almost one third of transporters and transporter-related proteins remain orphans with unknown or contradictive substrate profile, location and function, pinpoint the need for further research about them to fully understand their mechanistic role and their impact on cellular metabolism.

    National Category
    Cell and Molecular Biology Neurosciences Biochemistry and Molecular Biology Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-416363 (URN)10.3389/fcell.2020.00579 (DOI)000553395800001 ()32733888 (PubMedID)
    Funder
    Swedish Research Council, 2016-01972The Swedish Brain Foundation, FO2018-0130Swedish Society for Medical Research (SSMF), 201507Novo Nordisk, 34224Stiftelsen Olle Engkvist Byggmästare, 20160614Magnus Bergvall Foundation, 201601754
    Available from: 2020-07-16 Created: 2020-07-16 Last updated: 2020-11-17Bibliographically approved
    3. The Neuronal and Peripheral Expressed Membrane-Bound UNC93A Respond to Nutrient Availability in Mice
    Open this publication in new window or tab >>The Neuronal and Peripheral Expressed Membrane-Bound UNC93A Respond to Nutrient Availability in Mice
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    2017 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 351Article in journal (Refereed) Published
    Abstract [en]

    Many transporters such as the solute carriers belonging to the Major facilitator superfamily Pfam clan are orphans in that their tissue and cellular localization as well as substrate profile and function are still unknown. Here we have characterized the putative solute carrier UNC93A. We aimed to investigate the expression profile on both protein and mRNA level of UNC93A in mouse since it has not been clarified. UNC93A staining was found in cortex, hippocampus and cerebellum. It was found to be expressed in many neurons, but not all, with staining located in close proximity to the plasma membrane. Furthermore, we aimed to extend the starvation data available for Unc93a in hypothalamic cell cultures from mouse. We investigated the Unc93a alterations with focus on amino acid deprivation in embryonic cortex cells from mice as well as 24 h starvation in adult male mice and compared it to recently studied putative and known solute carriers. Unc93a expression was found both in the brain and peripheral organs, in low to moderate levels in the adult mice and was affected by amino acid deprivation in embryonic cortex cultures and starvation in in vivo samples. In conclusion, the membrane-bound UNC93A is expressed in both the brain and peripheral tissues and responds to nutrient availability in mice.

    Place, publisher, year, edition, pages
    FRONTIERS MEDIA SA, 2017
    Keywords
    UNC93A, SLC, MFS, MFSD, transporter protein, starvation
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-340711 (URN)10.3389/fnmol.2017.00351 (DOI)000414018600001 ()29163028 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2021-01-27Bibliographically approved
    4. CG4928 is vital for renal function in fruit flies and membrane potential in cells: A first in-depth characterization of the putative Solute Carrier UNC93A
    Open this publication in new window or tab >>CG4928 is vital for renal function in fruit flies and membrane potential in cells: A first in-depth characterization of the putative Solute Carrier UNC93A
    Show others...
    2020 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 8, article id 580291Article in journal (Refereed) Published
    Abstract [en]

    The number of transporter proteins that are not fully characterized is immense. Here, we used Drosophila melanogaster and human cell lines to perform a first in-depth characterization of CG4928, an ortholog to the human UNC93A, of which little is known. Solute carriers regulate and maintain biochemical pathways important for the body, and malfunctioning transport is associated with multiple diseases. Based on phylogenetic analysis, CG4928 is closely related to human UNC93A and has a secondary and a tertiary protein structure and folding similar to major facilitator superfamily transporters. Ubiquitous knockdown of CG4928 causes flies to have a reduced secretion rate from the Malpighian tubules; altering potassium content in the body and in the Malpighian tubules, homologous to the renal system; and results in the development of edema. The edema could be rescued by using amiloride, a common diuretic, and by maintaining the flies on ion-free diets. CG4928-overexpressing cells did not facilitate the transport of sugars and amino acids; however, proximity ligation assay revealed that CG4928 co-localized with TASK(1) channels. Overexpression of CG4928 resulted in induced apoptosis and cytotoxicity, which could be restored when cells were kept in high-sodium media. Furthermore, the basal membrane potential was observed to be disrupted. Taken together, the results indicate that CG4928 is of importance for generating the cellular membrane potential by an unknown manner. However, we speculate that it most likely acts as a regulator or transporter of potassium flows over the membrane.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-416366 (URN)10.3389/fcell.2020.580291 (DOI)000582611200001 ()33163493 (PubMedID)
    Funder
    Swedish Research Council, 2016-01972The Swedish Brain Foundation, FO2018-0130Swedish Society for Medical Research (SSMF), 201507Novo Nordisk, 34224Stiftelsen Olle Engkvist Byggmästare, 20160614Magnus Bergvall Foundation, 201601754
    Available from: 2020-07-16 Created: 2020-07-16 Last updated: 2020-11-17Bibliographically approved
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  • 68.
    Ceder, Mikaela M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Klaesson, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tripathi, Rekha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schweizer, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Weldai, Lydia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Patil, Sourabh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Glucose Availability Alters Gene and Protein Expression of Several Newly Classified and Putative Solute Carriers in Mice Cortex Cell Culture and D. melanogaster2020In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 8, article id 579Article in journal (Refereed)
    Abstract [en]

    Many newly identified solute carriers (SLCs) and putative transporters have the possibility to be intricately involved in glucose metabolism. Here we show that many transporters of this type display a high degree of regulation at both mRNA and protein level following no or low glucose availability in mouse cortex cultures. We show that this is also the case in Drosophila melanogaster subjected to starvation or diets with different sugar content. Interestingly, re-introduction of glucose to media, or refeeding flies, normalized the gene expression of a number of the targets, indicating a fast and highly dynamic control. Our findings demonstrate high conservation of these transporters and how dependent both cell cultures and organisms are on gene and protein regulation during metabolic fluctuations. Several transporter genes were regulated simultaneously maybe to initiate alternative metabolic pathways as a response to low glucose levels, both in the cell cultures and in D. melanogaster. Our results display that newly identified SLCs of Major Facilitator Superfamily type, as well as the putative transporters included in our study, are regulated by glucose availability and could be involved in several cellular aspects dependent of glucose and/or its metabolites. Recently, a correlation between dysregulation of glucose in the central nervous system and numerous diseases such as obesity, type 2 diabetes mellitus as well as neurological disease such as Alzheimer’s and Parkinson’s diseases indicate a complex regulation and fine tuning of glucose levels in the brain. The fact that almost one third of transporters and transporter-related proteins remain orphans with unknown or contradictive substrate profile, location and function, pinpoint the need for further research about them to fully understand their mechanistic role and their impact on cellular metabolism.

    Download full text (pdf)
    fulltext
  • 69.
    Chacko, L. Johnson
    et al.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Blumer, M. J. F.
    Med Univ Innsbruck, Dept Anat Histol & Embryol, Div Clin & Funct Anat, Muellerstr 59, A-6020 Innsbruck, Austria..
    Pechriggl, E.
    Med Univ Innsbruck, Dept Anat Histol & Embryol, Div Clin & Funct Anat, Muellerstr 59, A-6020 Innsbruck, Austria..
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Dietl, W.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Haim, A.
    Med Univ Innsbruck, Dept Plast Reconstruct & Aesthet Surg, Innerkoflerstr 1, A-6020 Innsbruck, Austria..
    Fritsch, H.
    Med Univ Innsbruck, Dept Anat Histol & Embryol, Div Clin & Funct Anat, Muellerstr 59, A-6020 Innsbruck, Austria..
    Glueckert, R.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria.;Tirol Kliniken, Univ Clin Innsbruck, Anichstr 35, A-6020 Innsbruck, Austria..
    Dudas, J.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Schrott-Fischer, A.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Role of BDNF and neurotrophic receptors in human inner ear development2017In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, no 3, p. 347-363Article in journal (Refereed)
    Abstract [en]

    The expression patterns of the neurotrophin, brain-derived neurotrophic factor, BDNF, and the neurotrophic receptors-p75NTR and Trk receptors-in the developing human fetal inner ear between the gestational weeks (GW) 9 to 12 are examined via in situ hybridization and immunohistochemistry. BDNF mRNA expression was highest in the cochlea at GW 9 but declined in the course of development. In contrast to embryonic murine specimens, a decline in BDNF expression from the apical to the basal turn of the cochlea could not be observed. p75NTR immunostaining was most prominent in the nerve fibers that penetrate into the sensory epithelia of the cochlea, the urticule and the saccule as gestational age progresses. TrkB and TrkC expression intensified towards GW 12, at which point the BDNF mRNA localization was at its lowest. TrkA expression was limited to fiber subpopulations of the facial nerve at GW 10. In the adult human inner ear, we observed BDNF mRNA expression in the apical poles of the cochlear hair cells and supporting cells, while in the adult human utricle, the expression was localized in the vestibular hair cells. We demonstrate the highly specific staining patterns of BDNF mRNA and its putative receptors over a developmental period in which multiple hearing disorders are manifested. Our findings suggest that BDNF and neurotrophin receptors are important players during early human inner ear development. In particular, they seem to be important for the survival of the afferent sensory neurons.

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  • 70.
    Chacko, Lejo Johnson
    et al.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria.
    Sergi, Consolato
    Univ Alberta, Dept Lab Med & Pathol, 8440 112 St NW, Edmonton, AB T6G 2B7, Canada;Univ Alberta, Dept Pediat, 8440 112 St NW, Edmonton, AB T6G 2B7, Canada.
    Eberharter, Theresa
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria.
    Dudas, Jozsef
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala Univ Hosp, Uppsala, Sweden.
    Hoermann, Romed
    Med Univ Innsbruck, Dept Anat Histol & Embryol, Div Clin & Funct Anat, Muellerstr 59, A-6020 Innsbruck, Austria.
    Fritsch, Helga
    Med Univ Innsbruck, Dept Anat Histol & Embryol, Div Clin & Funct Anat, Muellerstr 59, A-6020 Innsbruck, Austria.
    Fischer, Natalie
    Tirol Kliniken, Univ Clin Innsbruck, Anichstr 35, A-6020 Innsbruck, Austria.
    Glueckert, Rudolf
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria;Tirol Kliniken, Univ Clin Innsbruck, Anichstr 35, A-6020 Innsbruck, Austria.
    Schrott-Fischer, Anneliese
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria.
    Early appearance of key transcription factors influence the spatiotemporal development of the human inner ear2020In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 379, no 3, p. 459-471Article in journal (Refereed)
    Abstract [en]

    Expression patterns of transcription factors leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), transforming growth factor-beta-activated kinase-1 (TAK1), SRY (sex-determining region Y)-box 2 (SOX2), and GATA binding protein 3 (GATA3) in the developing human fetal inner ear were studied between the gestation weeks 9 and 12. Further development of cochlear apex between gestational weeks 11 and 16 (GW11 and GW16) was examined using transmission electron microscopy. LGR5 was evident in the apical poles of the sensory epithelium of the cochlear duct and the vestibular end organs at GW11. Immunostaining was limited to hair cells of the organ of Corti by GW12. TAK1 was immune positive in inner hair cells of the organ of Corti by GW12 and colocalized with p75 neurotrophic receptor expression. Expression for SOX2 was confined primarily to the supporting cells of utricle at the earliest stage examined at GW9. Intense expression for GATA3 was presented in the cochlear sensory epithelium and spiral ganglia at GW9. Expression of GATA3 was present along the midline of both the utricle and saccule in the zone corresponding to the striolar reversal zone where the hair cell phenotype switches from type I to type II. The spatiotemporal gradient of the development of the organ of Corti was also evident with the apex of the cochlea forming by GW16. It seems that highly specific staining patterns of several transcriptions factors are critical in guiding the genesis of the inner ear over development. Our findings suggest that the spatiotemporal gradient in cochlear development extends at least until gestational week 16.

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  • 71.
    Chanzu, Harry
    et al.
    Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, B361 BBSRB,741 S Limestone, Lexington, KY 40536 USA.
    Lykins, Joshua
    Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, B361 BBSRB,741 S Limestone, Lexington, KY 40536 USA.
    Wigna-Kumar, Subershan
    Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, B361 BBSRB,741 S Limestone, Lexington, KY 40536 USA.
    Joshi, Smita
    Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, B361 BBSRB, 741 S Limestone, Lexington, KY 40536 USA; Lexington VA Med Ctr, Lexington, KY USA.
    Pokrovskaya, Irina
    Univ Arkansas Med Sci, Dept Physiol & Biophys, Little Rock, AR 72205 USA.
    Storrie, Brian
    Univ Arkansas Med Sci, Dept Physiol & Biophys, Little Rock, AR 72205 USA.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wood, Jeremy P.
    Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, B361 BBSRB, 741 S Limestone, Lexington, KY 40536 USA; Univ Kentucky, Gill Heart & Vasc Inst, Div Cardiovasc Med, Lexington, KY USA.
    Whiteheart, Sidney W.
    Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, B361 BBSRB, 741 S Limestone, Lexington, KY 40536 USA; Lexington VA Med Ctr, Lexington, KY USA.
    Platelet α-granule cargo packaging and release are affected by the luminal proteoglycan, serglycin2021In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 19, no 4, p. 1082-1095Article in journal (Refereed)
    Abstract [en]

    Background

    Serglycin (SRGN) is an intragranular, sulfated proteoglycan in hematopoietic cells that affects granule composition and function.

    Objective

    To understand how SRGN affects platelet granule packaging, cargo release, and extra-platelet microenvironments.

    Methods

    Platelets and megakaryocytes from SRGN−/− mice were assayed for secretion kinetics, cargo levels, granule morphology upon activation, and receptor shedding.

    Results

    Metabolic, 35SO4 labeling identified SRGN as a major sulfated macromolecule in megakaryocytes. SRGN colocalized with α-granule markers (platelet factor 4 [PF4], von Willebrand factor [VWF], and P-selectin), but its deletion did not affect α-granule morphology or number. Platelet α-granule composition was altered, with a reduction in basic proteins (pI ≥8; e.g., PF4, SDF-1, angiogenin) and constitutive release of PF4 from SRGN−/− megakaryocytes. P-Selectin, VWF, and fibrinogen were unaffected. Serotonin (5-HT) uptake and β-hexosaminidase (HEXB) were slightly elevated. Thrombin-induced exocytosis of PF4 from platelets was defective; however, release of RANTES/CCL5 was normal and osteopontin secretion was more rapid. Release of 5-HT and HEXB (from dense granules and lysosomes, respectively) were unaffected. Ultrastructural studies showed distinct morphologies in activated platelets. The α-granule lumen of SRGN−/− platelet had a grainy staining pattern, whereas that of wild-type granules had only fibrous material remaining. α-Granule swelling and decondensation were reduced in SRGN−/− platelets. Upon stimulation of platelets, a SRGN/PF4 complex was released in a time- and agonist-dependent manner. Shedding of GPVI from SRGN−/− platelets was modestly enhanced. Shedding of GP1b was unaffected.

    Conclusion

    The polyanionic proteoglycan SRGN influences α-granule packaging, cargo release, and shedding of platelet membrane proteins.

  • 72.
    Chen, Hongxin
    et al.
    Univ Helsinki, Dept Forest Sci, FIN-00014 Helsinki, Finland..
    Quintana, Julia
    Univ Helsinki, Dept Forest Sci, FIN-00014 Helsinki, Finland..
    Kovalchuk, Andriy
    Univ Helsinki, Dept Forest Sci, FIN-00014 Helsinki, Finland..
    Ubhayasekera, Wimal
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Asiegbu, Fred O.
    Univ Helsinki, Dept Forest Sci, FIN-00014 Helsinki, Finland..
    A cerato-platanin-like protein HaCPL2 from Heterobasidion annosum sensu stricto induces cell death in Nicotiana tabacum and Pinus sylvestris2015In: Fungal Genetics and Biology, ISSN 1087-1845, E-ISSN 1096-0937, Vol. 84, p. 41-51Article in journal (Refereed)
    Abstract [en]

    The cerato-platanin family is a group of small secreted cysteine-rich proteins exclusive for filamentous fungi. They have been shown to be involved in the interactions between fungi and plants. Functional characterization of members from this family has been performed mainly in Ascomycota, except Moniliophthora perniciosa. Our previous phylogenetic analysis revealed that recent gene duplication of cerato-platanins has occurred in Basidiomycota but not in Ascomycota, suggesting higher functional diversification of this protein family in Basidiomycota than in Ascomycota. In this study, we identified three cerato-platanin homologues from the basidiomycete conifer pathogen Heterobasidion annosum sensu stricto. Expression of the homologues under various conditions as well as their roles in the H. annosum s.s.-Pinus sylvestris (Scots pine) pathosystem was investigated. Results showed that HaCPL2 (ceratoplatanin-like protein 2) had the highest sequence similarity to cerato-platanin from Ceratocystis platani and hacpl2 was significantly induced during nutrient starvation and necrotrophic growth. The treatment with recombinant HaCPL2 induced cell death, phytoalexin production and defense gene expression in Nicotiana tabacum. Eliciting and cell death-inducing ability accompanied by retardation of apical root growth was also demonstrated in Scots pine seedlings. Our results suggest that HaCPL2 might contribute to the virulence of H. annosum s.s. by promoting plant cell death.

  • 73.
    Chen, Hwei-yen
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Jolly, Cecile
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Bublys, Kasparas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Marcu, Daniel
    Univ East Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England..
    Immler, Simone
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Univ East Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England.
    Trade-off between somatic and germline repair in a vertebrate supports the expensive germ line hypothesis2020In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, no 16, p. 8973-8979Article in journal (Refereed)
    Abstract [en]

    The disposable soma theory is a central tenet of the biology of aging where germline immortality comes at the cost of an aging soma [T. B. L. Kirkwood, Nature 270, 301–304 (1977); T. B. L. Kirkwood, Proc. R. Soc. Lond. B Biol. Sci. 205, 531–546 (1979); T. B. L. Kirkwood, S. N. Austad, Nature 408, 233–238 (2000)]. Limited resources and a possible trade-off between the repair and maintenance of the germ cells and growth and maintenance of the soma may explain the deterioration of the soma over time. Here we show that germline removal allows accelerated somatic healing under stress. We tested “the expensive germ line” hypothesis by generating germline-free zebrafish Danio rerio and testing the effect of the presence and absence of the germ line on somatic repair under benign and stressful conditions. We exposed male fish to sublethal low-dose ionizing radiation, a genotoxic stress affecting the soma and the germ line, and tested how fast the soma recovered following partial fin ablation. We found that somatic recovery from ablation occurred substantially faster in irradiated germline-free fish than in the control germline-carrying fish where somatic recovery was stunned. The germ line did show signs of postirradiation recovery in germline-carrying fish in several traits related to offspring number and fitness. These results support the theoretical conjecture that germline maintenance is costly and directly trades off with somatic maintenance.

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  • 74.
    Chen, Hwei-yen
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Maklakov, Alexei A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Condition dependence of male mortality drives the evolution of sex differences in longevity2014In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 24, no 20, p. 2423-2427Article in journal (Refereed)
    Abstract [en]

    Males and females age at different rates and have different life expectancies across the animal kingdom, but what causes the longevity "gender gaps" remains one of the most fiercely debated puzzles among biologists and demographers [1-7]. Classic theory predicts that the sex experiencing higher rate of extrinsic mortality evolves faster aging and reduced longevity [1]. However, condition dependence of mortality [8, 9] can counter this effect by selecting against senescence in whole-organism performance [5, 10]. Contrary to the prevailing view but in line with an emerging new theory [7-9, 11], we show that the evolution of sex difference in longevity depends on the factors that cause sex-specific mortality and cannot be predicted from the mortality rate alone. Experimental evolution in an obligately sexual roundworm, Caenorhabditis remanei, in which males live longer than females, reveals that sexual dimorphism in longevity erodes rapidly when the extrinsic mortality in males is increased at random. We thus experimentally demonstrate evolution of the sexual monomorphism in longevity in a sexually dimorphic organism. Strikingly, when extrinsic mortalityis increased in a way that favors survival of fast-moving individuals, males evolve increased longevities, thereby widening the gender gap. Thus,sex-specific selection on whole-organism performance in males renders them less prone to the ravages of old age than females, despite higher rates of extrinsic mortality. Our results reconcile previous research with recent theoretical breakthroughs [8, 9] by showing that sexual dimorphism inlongevity evolves rapidly and predictably as a result of the sex-specific interactions between environmental hazard and organism's condition.

  • 75.
    Chen, Song
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Mestres, Gemma
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Lan, Weihua
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Cytotoxicity of modified glass ionomer cement on odontoblast cells2016In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 27, no 7, article id 116Article in journal (Refereed)
    Abstract [en]

    Recently a modified glass ionomer cement (GIC) with enhanced bioactivity due to the incorporation of wollastonite or mineral trioxide aggregate (MTA) has been reported. The aim of this study was to evaluate the cytotoxic effect of the modified GIC on odontoblast-like cells. The cytotoxicity of a conventional GIC, wollastonite modified GIC (W-mGIC), MTA modified GIC (M-mGIC) and MTA cement has been evaluated using cement extracts, a culture media modified by the cement. Ion concentration and pH of each material in the culture media were measured and correlated to the results of the cytotoxicity study. Among the four groups, conventional GIC showed the most cytotoxicity effect, followed by W-mGIC and M-mGIC. MTA showed the least toxic effect. GIC showed the lowest pH (6.36) while MTA showed the highest (8.62). In terms of ion concentration, MTA showed the largest Ca2+ concentration (467.3 mg/L) while GIC showed the highest concentration of Si4+ (19.9 mg/L), Al3+ (7.2 mg/L) and Sr2+ (100.3 mg/L). Concentration of F- was under the detection limit (0.02 mg/L) for all samples. However the concentrations of these ions are considered too low to be toxic. Our study showed that the cytotoxicity of conventional GIC can be moderated by incorporating calcium silicate based ceramics. The modified GIC might be promising as novel dental restorative cements.

  • 76.
    Cheng, Shuzhen
    et al.
    Leiden Univ Med Ctr, Div Thrombosis & Hemostasis, Einthoven Lab Vasc & Regenerat Med, 2333 ZA Leiden, Netherlands.
    Wu, Di
    Dalian Polytech Univ, Natl Engn Res Ctr Seafood, Collaborat Innovat Ctr Seafood Deep Proc, Sch Food Sci & Technol, Dalian 116034, Peoples R China.
    Yuan, Lushun
    Leiden Univ Med Ctr, Dept Internal Med, Einthoven Lab Vasc & Regenerat Med, Nephrol, 2333 ZA Leiden, Netherlands.
    Liu, Hanxiong
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Du, Ming
    Dalian Polytech Univ, Natl Engn Res Ctr Seafood, Collaborat Innovat Ctr Seafood Deep Proc, Sch Food Sci & Technol, Dalian 116034, Peoples R China.
    Crassostrea gigas-Based Bioactive Peptide Protected Thrombin-Treated Endothelial Cells against Thrombosis and Cell Barrier Dysfunction2022In: Journal of Agricultural and Food Chemistry, ISSN 0021-8561, E-ISSN 1520-5118, Vol. 70, no 31, p. 9664-9673Article in journal (Refereed)
    Abstract [en]

    The activation of thrombin-treated endothelial cells resulted in disruption of the vascular tissues. A novel oyster-derived bioactive dodecapeptide (IEELEELEAER, P-2-CG) was reported to protect the human umbilical vein endothelial cells and their barrier function via the decrease of VE-cadherin disruption and the restoration of the F-actin arrangement. The promotion of the extrinsic pathway in this case triggers the release of tissue factors that occurs on the surface of the endothelial cells, thus changing the antithrombotic to prothrombotic. P-2-CG induced accordingly a prolongation of plasma clotting time and thrombin generation time, following the alteration of the antithrombotic phenotype. Furthermore, the antithrombotic activity of P-2-CG was also supported by the reduction of FXa and the inhibition of other factors release, for instance, inflammation factors, ROS, etc. In addition to its antithrombogenic role, P-2-CG displayed anti-inflammatory and antioxidant properties via the mitogen-activated protein kinase cascades and central signaling pathways as shown in an in vitro model of endothelial dysfunction.

  • 77.
    Chisari, Andrea
    et al.
    Natl Univ Mar del Plata, Dept Chem, Sch Sci, Mar Del Plata, Argentina..
    Golan, Irene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Campisano, Sabrina
    Natl Univ Mar del Plata, Dept Chem, Sch Sci, Mar Del Plata, Argentina..
    Gélabert, Caroline
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sancho, Patricia
    IIS Aragon, Translat Res Unit, Hosp Univ Miguel Servet, Zaragoza, Spain..
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types2021In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, article id 723798Article, review/survey (Refereed)
    Abstract [en]

    Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.

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  • 78.
    Cho, S. Ei
    et al.
    Stanford Univ, Biol, Stanford, CA USA.
    Roy, J.
    Stanford Univ, Biol, Stanford, CA USA.
    Ivarsson, Ylva
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Cyert, M. S.
    Stanford Univ, Biol, Stanford, CA USA.
    Investigating the phospho-regulation of ER shaping protein RTN1A (Reticulon-1A) by the Calcineurin phosphatase.2017In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 28, no 26, p. 3727-3727Article in journal (Other academic)
  • 79.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The neutrophil: one cell on many missions or many cells with different agendas?2018In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 371, no 3, p. 415-423Article, review/survey (Refereed)
    Abstract [en]

    The unique role of neutrophils in host defense is not only based on their abilities to kill bacteria but is also due to their abundance in circulation and their ability to quickly migrate and accumulate in great numbers at afflicted sites. The high number of circulating neutrophils is the result of regulated release of new neutrophils from bone marrow as well as from marginated pools to balance their recruitment to tissue. Marginated pools, such as the spleen and lung, have previously been attributed to passively delay neutrophil transit time due to their large capillary network, but recent reports demonstrate that they are comprised of neutrophils with specific functions. The spleen, for instance, holds neutrophil subpopulations at different anatomical locations with distinct functions important for, e.g., bacterial eradication, and the lung was recently shown to re-educate neutrophils that had trafficked from a site of sterile injury to home back to bone marrow for elimination. Further, recent reports demonstrate subpopulations of neutrophils with different actions during homeostasis, infection, tissue restitution and cancer. It is becoming increasingly clear that this cannot be due to different stages of neutrophil activation during their life span but instead points towards distinct subpopulations of neutrophils with different effector functions. Whether these cellular distinctions are due to different education or origin is, however, not yet known. Together, the accumulating information about the heterogeneous neutrophils presents important insights into their role in development of pathologies, as well as revealing novel targets in the form of certain subpopulations to treat disease.

  • 80.
    Coschiera, Andrea
    et al.
    Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Yoshihara, Masahito
    Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden.;Grad Sch Med, Dept Artificial Intelligence Med, Chiba, Japan.;Chiba Univ, Chiba, Japan..
    Lauter, Gilbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden.
    Ezer, Sini
    Univ Helsinki, Stem Cells & Metab Res Program, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Pucci, Mariangela
    Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden.;Dept Biosci & Technol Food Agr & Environm, Teramo, Italy.;Univ Teramo, Teramo, Italy..
    Li, Haonan
    Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Kavsek, Alan
    Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Riedel, Christian G.
    Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Kere, Juha
    Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden.;Univ Helsinki, Stem Cells & Metab Res Program, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Swoboda, Peter
    Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Primary cilia promote the differentiation of human neurons through the WNT signaling pathway2024In: BMC Biology, E-ISSN 1741-7007, Vol. 22, no 1, article id 48Article in journal (Refereed)
    Abstract [en]

    Background

    Primary cilia emanate from most human cell types, including neurons. Cilia are important for communicating with the cell’s immediate environment: signal reception and transduction to/from the ciliated cell. Deregulation of ciliary signaling can lead to ciliopathies and certain neurodevelopmental disorders. In the developing brain cilia play well-documented roles for the expansion of the neural progenitor cell pool, while information about the roles of cilia during post-mitotic neuron differentiation and maturation is scarce.

    Results

    We employed ciliated Lund Human Mesencephalic (LUHMES) cells in time course experiments to assess the impact of ciliary signaling on neuron differentiation. By comparing ciliated and non-ciliated neuronal precursor cells and neurons in wild type and in RFX2 -/- mutant neurons with altered cilia, we discovered an early-differentiation “ciliary time window” during which transient cilia promote axon outgrowth, branching and arborization. Experiments in neurons with IFT88 and IFT172 ciliary gene knockdowns, leading to shorter cilia, confirm these results. Cilia promote neuron differentiation by tipping WNT signaling toward the non-canonical pathway, in turn activating WNT pathway output genes implicated in cyto-architectural changes.

    Conclusions

    We provide a mechanistic entry point into when and how ciliary signaling coordinates, promotes and translates into anatomical changes. We hypothesize that ciliary alterations causing neuron differentiation defects may result in “mild” impairments of brain development, possibly underpinning certain aspects of neurodevelopmental disorders.

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  • 81.
    Cracknell, Tobias
    et al.
    Univ York, Dept Biol, York YO32 5UQ, N Yorkshire, England..
    Mannsverk, Steinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nichols, Angus
    Univ York, Dept Biol, York YO32 5UQ, N Yorkshire, England..
    Dowle, Adam
    Univ York, Dept Biol, Technol Facil, York YO32 5UQ, N Yorkshire, England..
    Blanco, Gonzalo
    Univ York, Dept Biol, York YO32 5UQ, N Yorkshire, England..
    Proteomic resolution of IGFN1 complexes reveals a functional interaction with the actin nucleating protein COBL2020In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 395, no 2, article id 112179Article in journal (Refereed)
    Abstract [en]

    The Igfn1 gene produces multiple proteins by alternative splicing predominantly expressed in skeletal muscle. Igfn1 deficient clones derived from C2C12 myoblasts show reduced fusion index and morphological differences compared to control myotubes. Here, we first show that G:F actin ratios are significantly higher in differentiating IGFN1-deficient C2C12 myoblasts, suggesting that fusion and differentiation defects are underpinned by deficient actin remodelling. We obtained pull-downs from skeletal muscle with IGFN1 fragments and applied a proteomics approach. The proteomic composition of IGFN1 complexes identified the cytoskeleton and an association with the proteasome as the main networks. The actin nucleating protein COBL was selected for further validation. COBL is expressed in C2C12 myoblasts from the first stages of myoblast fusion but not in proliferating cells. COBL is also expressed in adult muscle and, as IGFN1, localizes to the Z-disc. We show that IGFN1 interacts, stabilizes and colocalizes with COBL and prevents the ability of COBL to form actin ruffles in COS7 cells. COBL loss of function C2C12-derived clones are able to fuse, therefore indicating that COBL or the IGFN1/COBL interaction are not essential for myoblast fusion.

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  • 82. Crona, Mikael
    et al.
    Avesson, Lotta
    Sahlin, Margareta
    Lundin, Daniel
    Hinas, Andrea
    Klose, Ralph
    Söderbom, Fredrik
    Department of Molecular Biology, Swedish University of Agricultural Sciences, Uppsala Biomedical Center, SE-75124 Uppsala, Sweden .
    Sjöberg, Britt-Marie
    A Rare Combination of Ribonucleotide Reductases in the Social Amoeba Dictyostelium discoideum2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 12, p. 8198-208Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductases (RNRs) catalyze the only pathway for de novo synthesis of deoxyribonucleotides needed for DNA replication and repair. The vast majority of eukaryotes encodes only a class I RNR, but interestingly some eukaryotes, including the social amoeba Dictyostelium discoideum, encode both a class I and a class II RNR. The amino acid sequence of the D. discoideum class I RNR is similar to other eukaryotic RNRs, whereas that of its class II RNR is most similar to the monomeric class II RNRs found in Lactobacillus spp. and a few other bacteria. Here we report the first study of RNRs in a eukaryotic organism that encodes class I and class II RNRs. Both classes of RNR genes were expressed in D. discoideum cells, although the class I transcripts were more abundant and strongly enriched during mid-development compared with the class II transcript. The quaternary structure, allosteric regulation, and properties of the diiron-oxo/radical cofactor of D. discoideum class I RNR are similar to those of the mammalian RNRs. Inhibition of D. discoideum class I RNR by hydroxyurea resulted in a 90% reduction in spore formation and decreased the germination viability of the surviving spores by 75%. Class II RNR could not compensate for class I inhibition during development, and an excess of vitamin B12 coenzyme, which is essential for class II activity, did not improve spore formation. We suggest that class I is the principal RNR during D. discoideum development and growth and is important for spore formation, possibly by providing dNTPs for mitochondrial replication.

  • 83.
    da Bandeira, Diana Sa
    et al.
    Univ Edinburgh, Ctr Cardiovasc Sci, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland.;Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Kilpatrick, Alastair Morris
    Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Marques, Madalena
    Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Gomez-Salazar, Mario
    Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Ventura, Telma
    Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Gonzalez, Zaniah Nashira
    Univ Edinburgh, Ctr Cardiovasc Sci, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland.;Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Stefancova, Dorota
    Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Rossi, Fiona
    Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Vermeren, Matthieu
    Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Vink, Chris Sebastiaan
    Univ Edinburgh, Ctr Inflammat Res, Inst Regenerat & Repair, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland..
    Beltran, Mariana
    Univ Edinburgh, Ctr Inflammat Res, Inst Regenerat & Repair, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland..
    Henderson, Neil Cowan
    Univ Edinburgh, Ctr Inflammat Res, Inst Regenerat & Repair, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Jung, Bongnam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Harvard Med Sch, Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA..
    van der Linden, Reinier
    Hubrecht Inst, Dept van Oudenaarden Quantitat Biol, NL-3584 Utrecht, Netherlands..
    van de Werken, Harmen Jan George
    Univ Med Ctr, Canc Computat Biol Ctr, Erasmus MC Canc Inst, NL-3000 Rotterdam, Netherlands.;Dept Urol, NL-3000 Rotterdam, Netherlands.;Dept Immunol, NL-3000 Rotterdam, Netherlands..
    van Ijcken, Wilfred F. J.
    Erasmus MC Univ Med Ctr, Ctr Biom, Dept Cell Biol, NL-3015 Rotterdam, Netherlands..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, S-14157 Huddinge, Sweden..
    Forbes, Stuart John
    Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    Cuervo, Henar
    Univ Illinois, Coll Med, Dept Physiol & Biophys, Chicago, IL 60612 USA..
    Crisan, Mihaela
    Univ Edinburgh, Ctr Cardiovasc Sci, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland.;Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland..
    PDGFR beta(+) cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny2022In: Cell Reports, E-ISSN 2211-1247, Vol. 40, no 3, article id 111114Article in journal (Refereed)
    Abstract [en]

    Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFR beta signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFR beta is involved. Here, we show that PDGFR beta is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFR beta(+) cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFR beta(+) embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of HSPCs in vitro.

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  • 84.
    Dahl, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Mechanisms for Quantitative Regulation of TGF-ß Signaling2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancer is a widely spread disease, and many cancer variants are today still difficult to treat. Efforts are being made to understand the complexity of cancer, both at a clinical level but also at a pre-clinical level. The aim is of course to merge the research from both disciplines, as an example, find out how to treat a tumour in a patient and what molecular mechanisms are behind the origin of the tumour. Basic research provides a platform that in the long run will help to create treatments for many cancer variants that exist today. Transforming Growth Factor Beta (TGF-ß) is a cytokine that regulates many cellular events such as cell differentiation, cell proliferation and migration. TGF-ß signaling is important to study since many studies show that patients with cancer actually have accumulated mutations in proteins connected to the pathway. In this thesis I try to enhance the knowledge of the TGF-ß signaling pathway, looking in more detail how the signaling output is regulated by the response to the ligand, explained in paper four. Furthermore I try to reveal the protein network that control transmission of the signal from the cell surface to the nucleus. We found that PARP-1 (paper one and two) and PARP-2 (paper three) associates with the signaling pathway to regulate the Smad proteins and to negatively regulate the transcription of Smad target genes.

    List of papers
    1. PARP-1 attenuates Smad-mediated transcription
    Open this publication in new window or tab >>PARP-1 attenuates Smad-mediated transcription
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    2010 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 40, no 4, p. 521-532Article in journal (Refereed) Published
    Abstract [en]

    The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and orchestrate transcription. Termination of Smad-activated transcription involves Smad dephosphorylation, nuclear export, or ubiquitin-mediated degradation. In an unbiased proteomic screen, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a Smad-interacting partner. PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-β-induced epithelial-mesenchymal transition. Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-128847 (URN)10.1016/j.molcel.2010.10.029 (DOI)000284988400006 ()21095583 (PubMedID)
    Available from: 2010-07-28 Created: 2010-07-27 Last updated: 2022-01-28Bibliographically approved
    2. Regulation of novel gene targets of TGFβ signaling by PARP-1
    Open this publication in new window or tab >>Regulation of novel gene targets of TGFβ signaling by PARP-1
    (English)Manuscript (preprint) (Other academic)
    National Category
    Natural Sciences Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-172851 (URN)
    Available from: 2012-04-16 Created: 2012-04-16 Last updated: 2012-08-01
    3. PARP-2 activation and association with Smads during regulation of TGFβ signaling
    Open this publication in new window or tab >>PARP-2 activation and association with Smads during regulation of TGFβ signaling
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Natural Sciences Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-172853 (URN)
    Available from: 2012-04-16 Created: 2012-04-16 Last updated: 2012-08-01
    4. Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics
    Open this publication in new window or tab >>Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics
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    2011 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 7, no 492Article in journal (Refereed) Published
    Abstract [en]

    Mammalian cells can decode the concentration of extracellular transforming growth factor-beta (TGF-beta) and transduce this cue into appropriate cell fate decisions. How variable TGF-beta ligand doses quantitatively control intracellular signaling dynamics and how continuous ligand doses are translated into discontinuous cellular fate decisions remain poorly understood. Using a combined experimental and mathematical modeling approach, we discovered that cells respond differently to continuous and pulsating TGF-beta stimulation. The TGF-beta pathway elicits a transient signaling response to a single pulse of TGF-beta stimulation, whereas it is capable of integrating repeated pulses of ligand stimulation at short time interval, resulting in sustained phospho-Smad2 and transcriptional responses. Additionally, the TGF-beta pathway displays different sensitivities to ligand doses at different time scales. While ligand-induced short-term Smad2 phosphorylation is graded, long-term Smad2 phosphorylation is switch-like to a small change in TGF-beta levels. Correspondingly, the short-term Smad7 gene expression is graded, while long-term PAI-1 gene expression is switch-like, as is the long-term growth inhibitory response. Our results suggest that long-term switch-like signaling responses in the TGF-beta pathway might be critical for cell fate determination.

    Place, publisher, year, edition, pages
    EMBO and Macmillan Publishers Limited, 2011
    Keywords
    mathematical model, Smad, TGF-beta, ultrasensitivity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-155228 (URN)10.1038/msb.2011.22 (DOI)000291351000003 ()
    Available from: 2011-06-21 Created: 2011-06-20 Last updated: 2022-01-28Bibliographically approved
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  • 85. Dahl, Markus
    et al.
    Lönn, Peter
    Heldin, Carl-Henrik
    Moustakas, Aristidis
    Regulation of novel gene targets of TGFβ signaling by PARP-1Manuscript (preprint) (Other academic)
  • 86. Dahl, Markus
    et al.
    Lönn, Peter
    Vanlandewijck, Michael
    Zieba, Agata
    O. Hottiger, Michael
    Söderberg, Ola
    Heldin, Carl-Henrik
    Moustakas, Aristidis
    PARP-2 activation and association with Smads during regulation of TGFβ signalingManuscript (preprint) (Other academic)
  • 87. Daly, Craig J
    et al.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    McGrath, John C
    Visualization and analysis of vascular receptors using confocal laser scanning microscopy and fluorescent ligands2012In: Receptor Binding Techniques / [ed] Anthony P. Davenport, New York: Humana Press, 2012, Vol. 897, p. 95-107Chapter in book (Refereed)
    Abstract [en]

    The use of fluorescent ligands to analyze receptor distribution is increasing in popularity. This is due to the ever growing number of fluorescent ligands and the increased sensitivity of microscope-based technologies. Image-analysis methods have advanced to a stage where quantification of fluorescent signals is relatively simple (if used appropriately). In this chapter we describe a method of analyzing the 2D and 3D distribution of fluorescent ligands in segments of blood vessels. In addition, we introduce the issues surrounding the accurate analysis of colocalization of two different fluorescent ligands.

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  • 88.
    Davidsson, Anton
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Challenging specificity of chemicalcompounds targeting GPCRs with cellprofiling2020Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    Screening compounds with image-based analysis is an important part in the processof drug discovery. It is an efficient way to screen compounds as it gives moreinformation than for example HTS. High-content screening as it is also called, hasreally progressed in recent years, as the field of data science evolves, and with it sodoes the efficiency of how images can be processed into information. Anotherimportant part of the drug discovery field is the family of receptors GPCRs, a largefamily of over 800 different receptors in humans. The reason GPCRs are importantin drug discovery is because of the large number of drugs targeting them. In thisexperiment we wanted to use image-based analysis to challenge drugs orcompounds that were said to be specific and see if they actually are that specific, orif we can see indications of the drug also working somewhere else. While the drugswe tested did not appear to cause any morphological perturbations large enough todistinguish them from the control, some drugs appear to cluster differently. Thismight suggest that they affect multiple targets, but it needs to be followed up upon inorder to draw any substantial conclusions.

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  • 89.
    Deng, Pan
    et al.
    Huazhong Univ Sci & Technol, State Key Lab Digital Mfg Equipment & Technol, Wuhan, Hubei, Peoples R China.
    Fu, Cheng-Jie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Wu, Zhigang
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology. Huazhong Univ Sci & Technol, State Key Lab Digital Mfg Equipment & Technol, Wuhan, Hubei, Peoples R China.
    High purity and viability cell separation of a bacterivorous jakobid flagellate based on a steep velocity gradient induced soft inertial force2018In: RSC Advances, E-ISSN 2046-2069, Vol. 8, no 62, p. 35512-35520Article in journal (Refereed)
    Abstract [en]

    Cell separation is one of the key limiting factors for precise analysis of non-axenic microbial lab cultures or environmental samples, and it remains a challenge to isolate target cells with high purity and viability via high-throughput cell sorting. During the past decade, hydrodynamic microfluidic platforms have attracted great attention in cell preparation for their high efficiency, robust performance and low cost. Here, we employ the use of a low-velocity sheath flow with high viscosity near the wall and a high-velocity sheath flow with low viscosity on the other side of the sample flow in a soft inertial separation chip. This not only prevents hard interactions between cells and chip walls but, in comparison to previous inertial separation methods, generates a significant increase in deflection of large cells while keeping the small ones in the original flow. We first conducted experiments on a mixture of small and large fluorescent particles (1.0 and 9.9 m, respectively) and removed over 99% of the small particles. The separation efficiency was then tested on a culture of a bacterivorous jakobid flagellate, Seculamonas ecuadoriensis fed on the live bacterium, Klebsiella sp. Using our microfluidic chip, over 94% of live bacteria were removed while maintaining high jakobid cell viability. For comparison, we also conducted size-based cell sorting of the same culture using flow cytometry, which is widely used as a rapid and automated separation tool. Compared with the latter, our chip showed more than 40% higher separation efficiency. Thus, our device provides high purity and viability for cell separation of a sensitive cell sample (jakobid cells). Potentially, the method can be further used for applications in diagnostics, biological analyses and environmental assessment of mixed microbial samples.

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  • 90.
    Dinic, Jelena
    Stockholms universitet, Wenner-Grens institut.
    Plasma membrane order; the role of cholesterol and links to actin filaments2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The connection between T cell activation, plasma membrane order and actin filament dynamics was the main focus of this study. Laurdan and di-4-ANEPPDHQ, membrane order sensing probes, were shown to report only on lipid packing rather than being influenced by the presence of membrane-inserted peptides justifying their use in membrane order studies. These dyes were used to follow plasma membrane order in live cells at 37°C. Disrupting actin filaments had a disordering effect while stabilizing actin filaments had an ordering effect on the plasma membrane, indicating there is a basal level of ordered domains in resting cells. Lowering PI(4,5)P2 levels decreased the proportion of ordered domains strongly suggesting that the connection of actin filaments to the plasma membrane is responsible for the maintaining the level of ordered membrane domains. Membrane blebs, which are detached from the underlying actin filaments, contained a low fraction of ordered domains. Aggregation of membrane components resulted in a higher proportion of ordered plasma membrane domains and an increase in cell peripheral actin polymerization. This strongly suggests that the attachment of actin filaments to the plasma membrane induces the formation of ordered domains. Limited cholesterol depletion with methyl-beta-cyclodextrin triggered peripheral actin polymerization. Cholesterol depleted cells showed an increase in plasma membrane order as a result of actin filament accumulation underneath the membrane. Moderate cholesterol depletion also induced membrane domain aggregation and activation of T cell signaling events. The T cell receptor (TCR) aggregation caused redistribution of domains resulting in TCR patches of higher order and the bulk membrane correspondingly depleted of ordered domains. This suggests the preexistence of small ordered membrane domains in resting T cells that aggregate upon cell activation. Increased actin polymerization at the TCR aggregation sites showed that actin polymerization is strongly correlated with the changes in the distribution of ordered domains. The distribution of the TCR in resting cells and its colocalization with actin filaments is cell cycle dependent. We conclude that actin filament attachment to the plasma membrane, which is regulated via PI(4,5)P2, plays a crucial role in the formation of ordered domains.

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  • 91.
    Dinic, Jelena
    et al.
    Stockholms universitet, Wenner-Grens institut.
    Biverståhl, Henrik
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Mäler, Lena
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Parmryd, Ingela
    Stockholms universitet, Wenner-Grens institut.
    Laurdan and di-4-ANEPPDHQ do not respond to membrane-inserted peptides and are good probes for lipid packing2011In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1808, no 1, p. 298-306Article in journal (Refereed)
    Abstract [en]

    Laurdan and di-4-ANEPPDHQ are used as probes for membrane order, with a blue shift in emission for membranes in liquid-ordered (lo) phase relative to membranes in liquid-disordered (ld) phase. Their use as membrane order probes requires that their spectral shifts are unaffected by membrane proteins, which we have examined by using membrane inserting peptides and large unilamellar vesicles (LUVs). The transmembrane polypeptides, mastoparan and bovine prion protein-derived peptide (bPrPp), were added to LUVs of either lo or ld phase, up to 1:10 peptide/total lipid ratio. The excitation and emission spectra of laurdan and di-4-ANEPPDHQ in both lipid phases were unaltered by peptide addition. The integrity and size distribution of the LUVs upon addition of the polypeptides were determined by dynamic light scattering. The insertion efficiency of the polypeptides into LUVs was determined by measuring their secondary structure by circular dichroism. Mastoparan had an α-helical and bPrPp a β-strand conformation compatible with insertion into the lipid bilayer. Our results suggest that the presence of proteins in biological membranes does not influence the spectra of laurdan and di-4-ANEPPDHQ, supporting that the dyes are appropriate probes for assessing lipid order in cells.

  • 92.
    Dmytriyeva, Oksana
    et al.
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci, Lab Neural Plast, DK-2200 Copenhagen, Denmark.;Univ Copenhagen, Dept Biomed Sci, Fac Hlth & Med Sci, Lab Mol Pharmacol, DK-2200 Copenhagen, Denmark.;Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark..
    Ajenjo, Amaia de Diego
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci, Lab Neural Plast, DK-2200 Copenhagen, Denmark..
    Lundo, Kathrine
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci, Lab Neural Plast, DK-2200 Copenhagen, Denmark.;Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark..
    Hertz, Henrik
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci, Lab Neuropsychiat, DK-2200 Copenhagen, Denmark..
    Rasmussen, Kim K.
    Univ Hosp Copenhagen, Bispebjerg Frederiksberg Hosp, Res Lab Stereol & Neurosci, DK-2200 Copenhagen, Denmark..
    Christiansen, Anders T.
    Univ Hosp Copenhagen, Bispebjerg Frederiksberg Hosp, Res Lab Stereol & Neurosci, DK-2200 Copenhagen, Denmark..
    Klingelhofer, Jorg
    Univ Hosp Copenhagen, Bispebjerg Frederiksberg Hosp, Res Lab Stereol & Neurosci, DK-2200 Copenhagen, Denmark..
    Nielsen, Alexander L.
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Hoeber, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Kozlova: Regenerative neurobiology.
    Woldbye, David P. D.
    Univ Hosp Copenhagen, Bispebjerg Frederiksberg Hosp, Res Lab Stereol & Neurosci, DK-2200 Copenhagen, Denmark..
    Pankratova, Stanislava
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci, Lab Neural Plast, DK-2200 Copenhagen, Denmark.;Univ Hosp Copenhagen, Bispebjerg Frederiksberg Hosp, Res Lab Stereol & Neurosci, DK-2200 Copenhagen, Denmark..
    Neurotrophic Effects of Vascular Endothelial Growth Factor B and Novel Mimetic Peptides on Neurons from the Central Nervous System2020In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 11, no 9, p. 1270-1282Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor B (VEGFB) is a pleiotropic trophic factor, which in contrast to the closely related VEGFA is known to have a limited effect on angiogenesis. VEGFB improves survival in various tissues including the nervous system, where the effect was observed mainly for peripheral neurons. The neurotrophic effect of VEGFB on central nervous system neurons has been less investigated. Here we demonstrated that VEGFB promotes neurite outgrowth from primary cerebellar granule, hippocampal, and retinal neurons in vitro. VEGFB protected hippocampal and retinal neurons from both oxidative stress and glutamate-induced neuronal death. The VEGF receptor 1 (VEGFR1) is required for VEGFB-induced neurotrophic and neuroprotective effects. Using a structure-based approach, we designed short peptides, termed Vefin1-7, mimicking the binding interface of VEGFB to VEGFR1. Vefins were analyzed for their secondary structure and binding to VEGF receptors and compared with previously described peptides derived from VEGFA, another ligand of VEGFR1. We show that Vefins have neurotrophic and neuroprotective effects on primary hippocampal, cerebellar granule, and retinal neurons in vitro with potencies comparable to VEGFB. Similar to VEGFB, Vefins were not mitogenic for MCF-7 cancer cells. Furthermore, one of the peptides, Vefin7, even dose-dependently inhibited the proliferation of MCF-7 cells in vitro. Unraveling the neurotrophic and neuroprotective potentials of VEGFB, the only nonangiogenic factor of the VEGF family, is promising for the development of neuroprotective peptide-based therapies.

  • 93.
    Doszyn, Olga
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Sex differences in neuronal differentiation of human stem cells2019Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    Sexual dimorphism has been long noted in human neurobiology, apparent most notably in sex-biased distribution of multiple neurological disorders or diseases, from autism spectrum disorder to Parkinson's disease. With the advances in molecular biology, genetics and epigenetics have come into focus as key players in sexually dimorphic neural development; and yet, many studies in the field of neuroscience overlook the importance of sex for the human brain.

    For this project, human embryonic and neural stem cells were chosen for three main reasons. Firstly, they provide an easily obtainable, scalable and physiologically native model for the early stages of development. Secondly, neural stem cells populations are retained within the adult human brain, and are implicated to play a role in cognition and mental illness, and as such are of interest in themselves. Thirdly, stem cell lines are widely used in research, including clinical trials of transplantation treatments, and for this reason should be meticulously examined and characterized.

    Here, the morphology, behaviour, and expression of selected genes in four stem cell lines, two of female and two of male origin, was examined in side-by-side comparisons prior to and during neuronal differentiation using a variety of methods including light microscopy, time-lapse two-photon microscopy, quantitative real-time PCR and immunocytochemistry. The obtained results have shown previously uncharacterised differences between those cell lines, such as a higher rate of proliferation but a slower rate of neuronal differentiation in male cell cultures compared to female cells cultivated in the same conditions, and a sex-biased expression of several markers of neuronal maturation at late stages of differentiation, as well as diverse patterns of expression of X- and Y-linked genes involved in stem cell proliferation and neural development.

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  • 94.
    Doudna, Jennifer
    et al.
    Univ Calif Berkeley, Berkeley, CA 94720 USA..
    Bar-Ziv, Roy
    Weizmann Inst Sci, IL-76100 Rehovot, Israel..
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Noireaux, Vincent
    Univ Minnesota, Minneapolis, MN 55455 USA..
    Berro, Julien
    Yale Univ, New Haven, CT 06520 USA..
    Saiz, Leonor
    Univ Calif Davis, Davis, CA 95616 USA..
    Vavylonis, Dimitrios
    Lehigh Univ, Bethlehem, PA 18015 USA..
    Faulon, Jean-Loup
    INRA, Jouy En Josas, France..
    Fordyce, Polly
    Stanford Univ, Stanford, CA 94305 USA..
    How Will Kinetics and Thermodynamics Inform Our Future Efforts to Understand and Build Biological Systems?2017In: CELL SYSTEMS, ISSN 2405-4712, Vol. 4, no 2, p. 144-146Article in journal (Refereed)
  • 95.
    Einarsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Troell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Vet Inst, Dept Microbiol, S-75007 Uppsala, Sweden.
    Höppner, Marc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Kiel, Inst Clin Mol Biol, Kiel, Germany.
    Grabherr, Mannfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ribacke, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Coordinated Changes in Gene Expression Throughout Encystation of Giardia intestinalis2016In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 3, article id e0004571Article in journal (Refereed)
    Abstract [en]

    Differentiation into infectious cysts through the process of encystation is crucial for transmission and survival of the intestinal protozoan parasite Giardia intestinalis. Hitherto the majority of studies have focused on the early events, leaving late encystation poorly defined. In order to further study encystation, focusing on the later events, we developed a new encystation protocol that generates a higher yield of mature cysts compared to standard methods. Transcriptome changes during the entire differentiation from trophozoites to cysts were thereafter studied using RNA sequencing (RNA-seq). A high level of periodicity was observed for up-and down-regulated genes, both at the level of the entire transcriptome and putative regulators. This suggests the trajectory of differentiation to be coordinated through developmentally linked gene regulatory activities. Our study identifies a core of 13 genes that are consistently up-regulated during initial encystation. Of these, two constitute previously uncharacterized proteins that we were able to localize to a new type of encystation-specific vesicles. Interestingly, the largest transcriptional changes were seen in the late phase of encystation with the majority of the highly up-regulated genes encoding hypothetical proteins. Several of these were epitope-tagged and localized to further characterize these previously unknown genetic components of encystation and possibly excystation. Finally, we also detected a switch of variant specific surface proteins (VSPs) in the late phase of encystation. This occurred at the same time as nuclear division and DNA replication, suggesting a potential link between the processes.

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  • 96.
    Einarsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Ástvaldsson, Ásgeir
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Hultenby, Kjell
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Jerlstrom-Hultqvist, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Comparative cell biology and evolution of Annexins in Diplomonads2016In: mSphere, E-ISSN 2379-5042, Vol. 1, no 2, article id e00032-15Article in journal (Refereed)
    Abstract [en]

    Annexins are multifunctional, calcium-binding proteins found in organisms across all kingdoms. Most studies of annexins from single-celled eukaryotes have focused on the alpha-giardins, proteins assigned to the group E annexins, expressed by the diplomonad Giardia intestinalis. We have characterized the annexin gene family in another diplomonad parasite, Spironucleus salmonicida, by phylogenetic and experimental approaches. We constructed a comprehensive phylogeny of the diplomonad group E annexins and found that they are abundant across the group with frequent gene duplications and losses. The annexins of S. salmonicida were found to be related to alpha-giardins but with better-preserved type II Ca2+ coordination sites. Two annexins were confirmed to bind phospholipids in a Ca2+-dependent fashion but with different specificities. Superresolution and confocal microscopy of epitope-tagged S. salmonicida annexins revealed localization to distinct parts of the cytoskeleton and membrane. The ultrastructural details of the localization of several annexins were determined by proximity labeling and transmission electron microscopy. Two annexins localize to a novel cytoskeletal structure in the anterior of the cell. Our results show that the annexin gene family is expanded in diplomonads and that these group E annexins are associated mostly with cytoskeletal and membrane structures. IMPORTANCE Annexins are proteins that associate with phospholipids in a Ca2+-dependent fashion. These proteins have been intensely studied in animals and plants because of their importance in diverse cellular processes, yet very little is known about annexins in single-celled eukaryotes, which represent the largest diversity of organisms. The human intestinal parasite Giardia intestinalis is known to have more annexins than humans, and they contribute to its pathogenic potential. In this study, we investigated the annexin complement in the salmon pathogen Spironucleus salmonicida, a relative of G. intestinalis. We found that S. salmonicida has a large repertoire of annexins and that the gene family has expanded separately across diplomonads, with members showing sequence diversity similar to that seen across kingdom-level groups such as plants and animals. S. salmonicida annexins are prominent components of the cytoskeleton and membrane. Two annexins are associated with a previously unrecognized structure in the anterior of the cell.

  • 97.
    Ekbom, Lisa H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evaluation of the ADVIA®60 on highvalue platelets2005Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Platelets are the smallest cells in the blood. They are formed in the bone-marrow and are important for the blood coagulation. Platelet tranfusions are given to patients propyhlactically before an operation but also in therapeutical purpose in connection with bleeding. It’s importent that the quality controls of the platelet concentrates are reliable.

    ADVIA®60 (Bayer HealthCare) is a fully automated cell counter which uses impedance principle to count platelets in blood samples. The purpose of the study was to evaluate this new instrument for use in the blood bank of Akademiska Sjukhuset in Uppsala. The instrument was bought to be used for quality control of platelet concentrates. 30 samples from platelet concentrates, from both apheresis and from buffy coats, were analyzed 10 times each on ADVIA®60 and the coefficient of variation (CV) was calculated for each sample. CV variated from 0,8 % to 2,9 % which is good considering that according to Bayer HealthCare the CV should be < 5 % for thrombocytes on ADVIA®60. The instrument was newly calibrated when the study was performed. Platelet count can also be performed by immunological or optical principles.

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  • 98.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Staying Clear of the Dragons2016In: CELL SYSTEMS, ISSN 2405-4712, Vol. 2, no 4, p. 219-220Article in journal (Refereed)
  • 99.
    Engblom, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Stochastic simulation of pattern formation in growing tissue: A multilevel approach2019In: Bulletin of Mathematical Biology, ISSN 0092-8240, E-ISSN 1522-9602, Vol. 81, p. 3010-3023Article in journal (Refereed)
  • 100. Engel, Stephanie
    et al.
    Scolari, Silvia
    Thaa, Bastian
    Krebs, Nils
    Korte, Thomas
    Herrmann, Andreas
    Veit, Michael
    FLIM-FRET and FRAP reveal association of influenza virus haemagglutinin with membrane rafts.2010In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 425, no 3, p. 567-73Article in journal (Refereed)
    Abstract [en]

    It has been supposed that the HA (haemagglutinin) of influenza virus must be recruited to membrane rafts to perform its function in membrane fusion and virus budding. In the present study, we aimed at substantiating this association in living cells by biophysical methods. To this end, we fused the cyan fluorescent protein Cer (Cerulean) to the cytoplasmic tail of HA. Upon expression in CHO (Chinese-hamster ovary) cells HA-Cer was glycosylated and transported to the plasma membrane in a similar manner to authentic HA. We measured FLIM-FRET (Förster resonance energy transfer by fluorescence lifetime imaging microscopy) and showed strong association of HA-Cer with Myr-Pal-YFP (myristoylated and palmitoylated peptide fused to yellow fluorescent protein), an established marker for rafts of the inner leaflet of the plasma membrane. Clustering was significantly reduced when rafts were disintegrated by cholesterol extraction and when the known raft-targeting signals of HA, the palmitoylation sites and amino acids in its transmembrane region, were removed. FRAP (fluorescence recovery after photobleaching) showed that removal of raft-targeting signals moderately increased the mobility of HA in the plasma membrane, indicating that the signals influence access of HA to slowly diffusing rafts. However, Myr-Pal-YFP exhibited a much faster mobility compared with HA-Cer, demonstrating that HA and the raft marker do not diffuse together in a stable raft complex for long periods of time.

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