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  • 251.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Role of birds in the biology of Lyme disease Borrelia2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lyme disease is a tick-transmitted illness caused by Borrelia burgdorferi sensu lato (s.l.), a group of spirochetes with at least three human pathogenic species, B. burgdorferi sensu stricto, B. afzelii and B. garinii. These spirochetes cycle between vertebrate reservoirs, mainly rodents, and ixodid ticks. Both terrestrial birds and seabirds can be infected with B. burgdorferi s.l. but the function of birds as reservoirs is largely unknown, even though they are potentially important epidemiologically due to their ability to carry ectoparasites and microorganisms over long distances. This thesis describes the role of birds in Lyme disease Borrelia biology in general and Borrelia ecology and epidemiology in particular.

    B. burgdorferi s.l. has previously been detected in the seabird tick Ixodes uriae and an enzootic Borrelia cycle distinct from terrestrial Borrelia cycles has been described. In this study B. garinii was isolated from the proposed seabird reservoirs and the tick I. uriae infesting them. The strains isolated did not show evident differences from human pathogenic B. garinii strains, indeed 7/8 strains had an ospC allele associated with Borrelia causing disseminated Lyme disease.

    Antibodies against B. burgdorferi s.l. were detected in people frequently bitten by I. uriae. Thus the marine enzootic Borrelia cycle may be a risk for humans, either by direct transfer of the spirochete from /. uriae or via introduction of Borrelia into a terrestrial enzootic Borrelia cycle.

    In order to investigate the role of passerine (Passeriformes) birds as amplification hosts in the terrestrial Borrelia cycle, experimental infections of canary finches (Serinus canaria) and redwing thrushes (Turdus iliacus) were carried out. The result showed that B. burgdorferi s.l. can persist for several months in passerine birds and the infection in redwing thrushes can be reactivated in response to migration. Thus, birds may be more infectious to ticks during their migration and therefore important long-range disseminators of B. burgdorferi s.l.

    Migration in birds is associated with elevated stress hormones that in turn can cause reactivation of latent infections. Lyme disease in humans could perhaps be activated when the immune response is modulated by stress. Herein I describe a patient with a stress activated latent Borrelia infection, which supports this hypothesis.

    The seabird tick I. uriae has a circumpolar distribution in both the northern and southern hemispheres and in this study identical B. garinii flagellin gene (flaB) sequences were detected in I. uriae from these hemispheres, indicating a transequatorial transport of B. garinii. Parsimony analysis of I. uriae ITS2 and 16S rDNA sequences suggested that northern and southern I. uriae might be reproductively separated. Therefore passive transport of infected ticks between the polar regions is unlikely and instead seabirds probably carry an active Borrelia infection during their migration.

    In conclusion, this work shows that migrating seabirds and passerine birds probably are important for the long-range dispersal of B. burgdorferi s.l., and that this mechanism of dispersal could be important for the distribution of human Lyme disease.

  • 252.
    Gylfe, Åsa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Strasevicius, Darius
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Marti Ras, Nuria
    Weihe, Pál
    Noppa, Laila
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Östberg, Yngve
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Baranton, Guy
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Isolation of Lyme disease Borrelia from puffins (Fratercula arctica) and seabird ticks (Ixodes uriae) on the Faeroe Islands1999In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 37, no 4, p. 890-896Article in journal (Refereed)
    Abstract [en]

    This is the first report on the isolation of Lyme disease Borrelia from seabirds on the Faeroe Islands and the characteristics of its enzootic cycle. The major components of the Borrelia cycle include the puffin (Fratercula arctica) as the reservoir and Ixodes uriae as the vector. The importance of this cycle and its impact on the spread of human Lyme borreliosis have not yet been established. Borrelia spirochetes isolated from 2 of 102 sampled puffins were compared to the borreliae previously obtained from seabird ticks, I. uriae. The rrf-rrl intergenic spacer and the rrs and the ospC genes were sequenced and a series of phylogenetic trees were constructed. Sequence data and restriction fragment length polymorphism analysis grouped the strains together with Borrelia garinii. In a seroepidemiological survey performed with residents involved in puffin hunting on the Faeroe Islands, 3 of 81 serum samples were found to be positive by two commonly used clinical tests: a flagellin-based enzyme-linked immunosorbent assay (ELISA) and Western blotting. These three positive serum samples also had high optical density values in a whole-cell ELISA. The finding of seropositive Faeroe Islanders who are regularly exposed to I. uriae indicate that there may be a transfer of B. garinii by this tick species to humans.

  • 253.
    Haapala, Jussi
    et al.
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Inkinen, Ritva
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Parkkinen, Jyrki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Ågren, Ulla
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Arokoski, Jari
    Department of Physical and Rehabilitation Medicine, Kuopio University Hospital, Kuopio, Finland.
    Kiviranta, Ilkka
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Coordinated regulation of hyaluronan and aggrecan content in the articular cartilage of immobilized and exercised dogs.1996In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 23, no 9, p. 1586-1593, article id 8877929Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the influence of joint loading and immobilization on articular cartilage hyaluronan concentration and histological distribution in the knee joints of young dogs subjected to 11 weeks' immobilization by splinting, and 15 weeks' running exercise at a rate of 40 km/day.

    METHODS: The amount of hyaluronan in articular cartilage was determined by a competitive binding assay using a biotinylated hyaluronan binding complex (HABC) of aggrecan and link protein. Histologic sections were stained for the localization of hyaluronan with the HABC probe. Extracted proteoglycans were characterized by sodium dodecyl sulfate agarose gel electrophoresis.

    RESULTS: Immobilization significantly reduced the concentration of hyaluronan in all sites studied (tibial and femoral condyles, patellar surface of femur). The proportion of hyaluronan to total uronic acid (mainly from aggrecan) remained unchanged because of a concurrent decrease in aggrecan. The ratio of hyaluronan and aggrecan remained constant also in runners. The staining pattern of free hyaluronan in the tissue sections and the electrophoretic mobility of the extracted proteoglycans were not affected by the different loading regimes.

    CONCLUSION: Reduced joint loading due to splint immobilization significantly decreases both hyaluronan and aggrecan in the articular cartilage. The remarkably parallel changes in aggrecan and hyaluronan content suggest that joint loading exerts a coordinated influence on their metabolism.

  • 254. Haddada, Meriem
    et al.
    Draoui, Hend
    Deschamps, Lydia
    Walker, Francine
    Delaunay, Tiphaine
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Magdolen, Viktor
    Darmoul, Dalila
    Kallikrein-related peptidase 7 overexpression in melanoma cells modulates cell adhesion leading to a malignant phenotype2018In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 399, no 9, p. 1099-1105Article in journal (Refereed)
    Abstract [en]

    We recently reported that human melanoma cells, but not benign melanocytes, aberrantly express kallikrein-related peptidase 7 (KLK7). Here, we show a KLK7 overexpression-mediated decrease of cell adhesion to extracellular matrix binding proteins, associated with downregulation of alpha 5/beta 1/alpha v/beta 3 integrin expression. We also report an up-regulation of MCAM/CD146 and an increase in spheroid formation of these cells. Our results demonstrate that aberrant KLK7 expression leads to a switch to a more malignant phenotype suggesting a potential role of KLK7 in melanoma invasion. Thus, KLK7 may represent a biomarker for melanoma progression and may be a potential therapeutic target for melanoma.

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

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

  • 256.
    Halin Bergström, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 31805Article in journal (Refereed)
    Abstract [en]

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer.

  • 257.
    Halin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Targeting the prostate tumor microenvironment and vasculature: the role of castration, tumor-associated macrophages and pigment epithelium-derived factor2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    BACKGROUND: Prostate cancer is the most common cancer among Swedish men. For patients with metastatic prostate cancer the standard therapy is castration, a treatment that initially provides symptomatic relief but unfortunately is not curative. New therapeutic targets for advanced prostate cancer are therefore needed.  Prostate cancers are composed of tumor epithelial cells as well as many non-epithelial cells such as cancer associated fibroblasts, blood vessels and inflammatory cells.  Many components of the tumor microenvironment such as tumor associated macrophages and angiogenesis have been shown to stimulate tumor progression. This thesis aims to explore mechanisms by which the local environment influences prostate tumor growth and how such mechanisms could be targeted for treatment.

    MATERIALS AND METHODS: We have used animal models of prostate cancer, in vitro cell culture systems and clinical materials from untreated prostate cancer patients with long follow up. Experiments were evaluated with stereological techniques, immunohistochemistry, western blotting, quantitative real-time PCR, PCR arrays and laser micro dissection.

    RESULTS: We found that the presence of a tumor induces adaptive changes in the surrounding non-malignant prostate tissue, and that androgen receptor negative prostate tumor cells respond to castration treatment with temporarily reduced growth when surrounded by normal castration-responsive prostate tissue. Further, we show that macrophages are important for prostate tumor growth and angiogenesis in the tumor and in the surrounding non-malignant tissue. In addition, the angiogenesis inhibitor Pigment epithelium-derived factor (PEDF) was found  to be down-regulated in metastatic rat and human prostate tumors. Over-expression of PEDF inhibited experimental prostate tumor growth, angiogenesis and metastatic growth and stimulated macrophage tumor infiltration and lymphangiogenesis. PEDF was found to be down-regulated by the prostate microenvironment and tumor necrosis factor (TNF) α.

    CONCLUSIONS: Our studies indicate that not only the nearby tumor microenvironment but also the surrounding non-malignant prostate tissue are important for prostate tumor growth. Both the tumor and the surrounding non-malignant prostate were characterized by increased angiogenesis and inflammatory cell infiltration. Targeting the surrounding prostate tissue with castration, targeting tumor associated macrophages, or targeting the vasculature directly using inhibitors like PEDF were all shown to repress prostate tumor growth and could prove beneficial for patients with advanced prostate cancer.

  • 258.
    Hallberg, Magnus
    et al.
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Hu, Guo-Zhen
    Tronnersjö, Susanna
    Shaikhibrahim, Zaki
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Balciunas, Darius
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Ronne, Hans
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Functional and physical interactions within the middle domain of the yeast mediator2006In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 276, no 2, p. 197-210Article in journal (Refereed)
    Abstract [en]

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

  • 259.
    Hallmans, Göran
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Vaught, Jimmie B
    Best practices for establishing a biobank2011In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 675, p. 241-260Article in journal (Refereed)
    Abstract [en]

    A biobank may be defined as the long-term storage of biological samples for research or clinical purposes. In addition to storage facilities, a biobank may comprise a complete organization with biological samples, data, personnel, policies, and procedures for handling specimens and performing other services, such as the management of the database and the planning of scientific studies. This combination of facilities, policies, and processes may also be called a biological resource center (BRC) ( www.iarc.fr ). Research using specimens from biobanks is regulated by European Union (EU) recommendations (Recommendations on Research on Human Biological Materials. The draft recommendation on research on human biological materials was approved by CDBI at its plenary meeting on 20 October 2005) and by voluntary best practices from the U.S. National Cancer Institute (NCI) ( http://biospecimens.cancer.gov ) and other organizations. Best practices for the management of research biobanks vary according to the institution and differing international regulations and standards. However, there are many areas of agreement that have resulted in best practices that should be followed in order to establish a biobank for the custodianship of high-quality specimens and data.

  • 260.
    Hamid, Nivia
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gustavsson, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Kerstin
    McGee, Karen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persson, Cathrine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rudd, Christopher E.
    Fällman, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    YopH dephosphorylates Cas and Fyn-binding protein in macrophages1999In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 27, no 4, p. 231-242Article in journal (Refereed)
    Abstract [en]

    The tyrosine phosphatase YopH is an essential virulence effector of pathogenic Yersinia spp. YopH, which is translocated from extracellularly located bacteria into interacting target cells, blocks phagocytosis by professional phagocytes. We show here that immunoprecipitation of YopH from lysates of J774 cells infected with Y. pseudotuberculosis expressing an inactive form of YopH resulted in co-precipitation of certain phosphotyrosine proteins. The association between the inactive YopH and phosphotyrosine proteins in the 120 kDa range was rapid and could be detected after 2 min of infection. The proteins were identified as the docking proteins Cas and Fyn-binding protein (FYB). Upon infection of J774 cells with Y. pseudotuberculosis lacking YopH expression both of these proteins became tyrosine phosphorylated. Moreover, this infection caused recruitment of Cas to peripheral focal complexes, and FYB was relocalized to areas surrounding these structures. Both Cas and FYB became dephosphorylated upon infection with Y. pseudotuberculosis expressing active YopH, and this was associated with disruption of focal complexes. With regard to the previous identification of Cas and focal complexes as targets of YopH in HeLa cells, the present study supports an important role for these targets in a general mechanism of bacterial uptake. 

  • 261. Hamidi, Anahita
    et al.
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thakur, Noopur
    Itoh, Susumu
    Marcusson, Anders
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Ludwig Institute for Cancer Research and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α2017In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 486, article id eaal4186Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor–β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-β are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3′-kinase (PI3K)–protein kinase B (AKT) pathway. We found that TGF-β activated PI3K in a manner dependent on the activity of the E3 ubiquitin ligase tumor necrosis factor receptor–associated factor 6 (TRAF6). TRAF6 polyubiquitylated the PI3K regulatory subunit p85α and promoted the formation of a complex between the TGF-β type I receptor (TβRI) and p85α, which led to the activation of PI3K and AKT. Lys63-linked polyubiquitylation of p85α on Lys513 and Lys519 in the iSH2 (inter–Src homology 2) domain was required for TGF-β–induced activation of PI3K-AKT signaling and cell motility in prostate cancer cells and activated macrophages. Unlike the activation of SMAD pathways, the TRAF6-mediated activation of PI3K and AKT was not dependent on the kinase activity of TβRI. In situ proximity ligation assays revealed that polyubiquitylation of p85α was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-β activates the PI3K-AKT pathway to drive cell migration.

  • 262.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Biomarker mRNAs as prognostic tools for lymph node analysis in colorectal cancer2019In: Biomarkers in Medicine, ISSN 1752-0363, E-ISSN 1752-0371, Vol. 13, no 10, p. 801-803Article in journal (Other academic)
  • 263.
    Han, Jing
    et al.
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Guo, Xiong
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Tan, Wuhong
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Zhang, Feng
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Liu, Jiangtao
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Wang, Weizhuo
    Department of Orthopedics Surgery, The Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China.
    Xu, Peng
    Department of Orthopaedics Surgery, The Xi’an Red Cross Hospital, Xi’an, China.
    Lammi, Mikko
    Department of Biosciences, Applied Biotechnology, University of Kuopio, Kuopio, Finland .
    The expression of p-ATF2 involved in the chondeocytes apoptosis of an endemic osteoarthritis, Kashin-Beck disease2013In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 14, article id 209Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The purpose of the study was to understand the function and expression of ATF2 by JNK and p38 signal pathways in the chondrocytes apoptosis of articular cartilage of the Kashin-Beck disease (KBD).

    METHODS: The changes of ATF2, JNK and p38 mRNAs and proteins were investigated between cartilage and chondrocyte as well as KBD and normal. JNK and p38 inhibitors were used as treatments to prevent apoptosis in chondrocytes from KBD patients.

    RESULTS: It was found that the protein levels of p-p38, p-JNK, ATF2 and p-ATF2 increased in KBD human cartilage which is in line with the higher mRNA levels of p38, JNK and ATF2 as compared both with normal cartilage and KBD chondrocytes. In addition, p-ATF2 was only detected in KBD cartilage. Furthermore, JNK inhibitor was more effective than p38 inhibitor in preventing chondrocyte apoptosis at equal concentrations of 10 μM.

    CONCLUSION: These findings indicated the expression of p-ATF2 by JNK and p38 signal pathways involved in the chondrocyte apoptosis in cartilage with KBD.

  • 264.
    Han, Jing
    et al.
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China; Biomat lab, Department of Mechanical Engineering, National University of Singapore, Singapore.
    Li, Danyang
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wang, Dong
    Biomat lab, Department of Mechanical Engineering, National University of Singapore, 117576, Singapore; Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
    Wang, Liyun
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR Chin.
    Guo, Xiong
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR Chin.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.
    Altered expression of chondroitin sulfate structure modifying sulfotransferases in the articular cartilage from adult osteoarthritis and Kashin-Beck disease2017In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 25, no 8, p. 1372-1375, article id 28274888Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the expression of enzymes involved in chondroitin sulfate (CS) sulfation in the articular cartilage isolated from adult patients with osteoarthritis (OA) and Kashin-Beck disease (KBD), using normal adults as controls.

    METHODS: Articular cartilage samples were collected from normal, OA and KBD adults aged 38-60 years old, and divided into three groups with six individual subjects in each group. The morphology and pathology grading of knee joint cartilage was examined by Safranin O staining. The localization and expression of enzymes involved in CS sulfation (CHST-3, CHST-11, CHST-12, CHST-13, CHST-15, and UST) were examined by immunohistochemical staining and semi-quantitative analysis.

    RESULTS: Positive staining rates for anabolic enzymes CHST-3, CHST-12, CHST-15, and UST were lower in the KBD and OA groups than those in the control group. Meanwhile, reduced levels of CHST-11, and CHST-13 in KBD group were observed, in contrast to those in OA and control groups. The expressions of all six CS sulfation enzymes were less detected in the superficial and deep zones of KBD cartilage compared with control and OA cartilage.

    CONCLUSION: The reduced expression of the CS structure modifying sulfotransferases in the chondrocytes of both KBD and OA adult patients may provide explanations for their cartilage damages, and therapeutic targets for their treatment.

  • 265.
    Hart, Andrew M
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Blond-McIndoe Research Laboratories, The University of Manchester, Stopford Building, Room 3.106, Oxford; Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK.
    Terenghi, Giorgio
    Frozen-section fluorescence microscopy and stereology in the quanti cation of neuronal death within dorsal root ganglia2004In: Journal of Molecular Histology, ISSN 1567-2379, E-ISSN 1567-2387, Vol. 35, no 6, p. 565-580Article in journal (Refereed)
    Abstract [en]

    Histochemical and morphological research increasingly relies upon quanti cation of complex biological systems. For such investigations to be meaningful, quanti cation techniques must meet the seemingly conflicting requirements of being theoretically robust, yet sufficiently practical to facilitate widespread applicability. Validity ought to be enhanced by theoretical simplicity, use of measured rather than assumed variables, and minimising observer interpretation. Practicality is facilitated by simplifying and reducing measurements, broadening applicability, and reducing costs and analysis time. As a result, quanti cation systems that rely upon sampling and estimation have been favoured over serial reconstruction techniques. To provide reliable estimates, sampling must be valid at all levels from tissue harvest, to the selection of microscope fields in which quanti cation is performed by techniques that account for the anisotropic distribution, and variable size of many elements in biological systems. These principles are embodied in the development of a stereological approach to the quanti cation of neuronal death within dorsal root ganglia after peripheral nerve injury. This frozen section technique is efficient and flexible, since it permits simultaneous morphological examination, TUNEL, or standard fluorescence immunohistochemistry, broadening its applicability. Section shrinkage is minimal, and counting by optical disection has proved to be time-efficient and sufficiently reproducible to reliably detect losses in the order of 5%, with minimal inter-observer variation. As is discussed, stereology has not yet met with universal acceptance, but by balancing theoretical validity with practical applicability, it has proved an excellent approach to the investigation of neuronal death within dorsal root ganglia.

  • 266.
    Hashemian, Sanaz
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    O'Rourke, Caitriona
    Phillips, James B.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Embryonic and mature astrocytes exert different effects on neuronal growth in rat ventral mesencephalic slice cultures2015In: SpringerPlus, E-ISSN 2193-1801, Vol. 4, article id 558Article in journal (Refereed)
    Abstract [en]

    One obstacle with grafting of dopamine neurons in Parkinson's disease is the insufficient ability of the transplant to reinnervate the host striatum. Another issue is the prospective interaction between the donor fetal tissue and the adult astrocytes of the host. To study nerve fiber growth and its interaction with immature/mature astrocytes, ventral mesencephalic (VM) organotypic rat tissue cultures from embryonic days (E) 12, E14, and E18 were studied up to 35 days in vitro (DIV), and co-cultures of E14 VM tissue and mature green fluorescent protein (GFP)-positive astrocytes were performed. Generally, nerve fibers grew from the tissue slice either in association with a monolayer of migrated astroglia surrounding the tissue (glial-associated), or distal to the astroglia as non-glial-associated outgrowth. The tyrosine hydroxylase (TH)-positive glial-associated nerve fiber outgrowth reached a plateau at 21 DIV in E12 and E14 cultures. In E18 cultures, TH-positive neurons displayed short processes and migrated onto the astrocytes. While the non-glial-associated nerve fiber outgrowth dominated the E14 cultures, it was found absent in E18 cultures. The GFP-positive cells in the VM and GFP-positive astrocyte co-cultures were generally located distal to the monolayer of migrated fetal astrocytes, a few GFP-positive cells were however observed within the astrocytic monolayer. In those cases TH-positive neurons migrated towards the GFP-positive cells. Both the non-glial-and glial-associated nerve fibers grew onto the GFP-positive cells. Taken together, the glial-associated growth has limited outgrowth compared to the non-glial-associated nerve fibers, while none of the outgrowth types were hampered by the mature astrocytes.

  • 267.
    Hauser, Jannek
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Christine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kumar, Ramesh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Regulated localization of an AID complex with E2A, PAX5 and IRF4 at the Igh locus2016In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 80, p. 78-90Article in journal (Refereed)
    Abstract [en]

    Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates somatic hypermutation (SH) and class switch recombination (CSR) by deaminating cytosine to uracil. The targeting of AID and therefore SH and CSR to Ig genes is a central process of the immune system, but the trans-acting factors mediating the specific targeting have remained elusive. Here we show that defective calmodulin inhibition of the transcription factor E2A after activation of the B cell receptor (BCR) leads to reduced BCR, IL4 plus CD40 ligand stimulated CSR to IgE and instead CSR to other Ig classes. AID that initiates CSR is shown to be in a complex with the transcription factors E2A, PAX5 and IRF4 on key sequences of the Igh locus. Calmodulin shows proximity with each of them after BCR stimulation. BCR signaling reduces binding of the proteins to some of the target sites on the Igh locus, and calmodulin resistance of E2A blocks these reductions. AID binds directly to the bHLH domain of E2A and to the PD domain of PAX5. E2A, AID, PAX5 and IRF4 are components of a CSR complex that is redistributed on the Igh locus by BCR signaling through calmodulin binding.

  • 268.
    Hauser, Jannek
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Saarikettu, Juha
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Calcium regulation of myogenesis by differential calmodulin inhibition of basic helix-loop-helix transcription factors2008In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 19, no 6, p. 2509-2519Article in journal (Refereed)
    Abstract [en]

    The members of the MyoD family of basic helix-loop-helix (bHLH) transcription factors are critical regulators of skeletal muscle differentiation that function as heterodimers with ubiquitously expressed E-protein bHLH transcription factors. These heterodimers must compete successfully with homodimers of E12 and other E-proteins to enable myogenesis. Here, we show that E12 mutants resistant to Ca(2+)-loaded calmodulin (CaM) inhibit MyoD-initiated myogenic conversion of transfected fibroblasts. Ca(2+) channel blockers reduce, and Ca(2+) stimulation increases, transcription by coexpressed MyoD and wild-type E12 but not CaM-resistant mutant E12. Furthermore, CaM-resistant E12 gives lower MyoD binding and higher E12 binding to a MyoD-responsive promoter in vivo and cannot rescue myogenic differentiation that has been inhibited by siRNA against E12 and E47. Our data support the concept that Ca(2+)-loaded CaM enables myogenesis by inhibiting DNA binding of E-protein homodimers, thereby promoting occupancy of myogenic bHLH protein/E-protein heterodimers on promoters of myogenic target genes.

  • 269.
    Hauser, Jannek
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Verma-Gaur, Jiyoti
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wallenius, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Initiation of antigen receptor-dependent differentiation into plasma cells by calmodulin inhibition of E2A2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 2, p. 1179-1187Article in journal (Refereed)
    Abstract [en]

    Differentiation of B lymphocytes into Ab-secreting plasmablasts and plasma cells is Ag driven. The interaction of Ag with the membrane-bound Ab of the BCR is critical in determining which clones enter the plasma cell response. However, not much is known about the coupling between BCR activation and the shift in transcription factor network from that of a B cell to that of ASC differentiation. Our genome-wide analysis shows that Ab-secreting cell differentiation of mouse B cells is induced by BCR activation through very fast regulatory events from the BCR. We identify activation of IFN regulatory factor-4 and down-regulation of Pax5, Bcl-6, MITF, Ets-1, Fli-1, and Spi-B gene expression as immediate early events. Furthermore, the transcription factor E2A is required for the rapid key down-regulations after BCR activation, and the Ca(2+) sensor protein calmodulin has the corresponding regulatory effect as BCR activation. Moreover, mutants in the calmodulin binding site of E2A show that Ca(2+) signaling through calmodulin inhibition of E2A is essential for the rapid down-regulation of immediate early genes after BCR activation in initiation of plasma cell differentiation.

  • 270.
    Hauser, Jannek
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wallenius, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sveshnikova, Natalia
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Saarikettu, Juha
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Calmodulin inhibition of E2A stops expression of surrogate light chains of the pre-B-cell receptor and CD192010In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 47, no 5, p. 1031-1038Article in journal (Refereed)
    Abstract [en]

    To create antibody diversity, B lymphocyte development is characterized by the ordered rearrangement of first immunoglobulin (Ig) heavy chain gene segments and then Ig light-chain gene segments. Early in B-cell development, expression of a pre-B-cell receptor (pre-BCR) composed of membrane-bound Ig heavy chain protein associated with surrogate light-chain (SLC) proteins serves as a critical checkpoint that monitors for functional heavy chain rearrangement. Signaling from the pre-BCR induces clonal expansion, but it also turns off transcription of the genes for the SLC proteins lambda5 and VpreB, which limits this proliferation. Here we show that signaling from the pre-BCR rapidly down-regulates lambda5 and VpreB and also the co-receptor CD19 in primary pre-B-cells. We show that calcium (Ca(2+)) signaling is essential for this silencing of the SLC and CD19 genes. The SLC genes are activated by the E2A transcription factor, and we show that E2A is required for pre-BCR-mediated regulation of the genes. E2A mutated in its binding site for the Ca(2+) sensor protein calmodulin, and thus with calmodulin-resistant DNA binding, makes lambda5, VpreB and CD19 expression resistant to the inhibition following pre-BCR activation. Thus, Ca(2+) down-regulates SLC and CD19 gene expression upon pre-BCR activation through inhibition of E2A by Ca(2+)/calmodulin.

  • 271. Hazlett, Karsten RO
    et al.
    Caldon, Seth D
    McArthur, Debbie G
    Cirillo, Kerry A
    Kirimanjeswara, Girish S
    Magguilli, Micheal L
    Malik, Meenakshi
    Shah, Aaloki
    Broderick, Scott
    Golovliov, Igor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Metzger, Dennis W
    Rajan, Krishna
    Sellati, Timothy J
    Loegering, Daniel J
    Adaptation of Francisella tularensis to the mammalian environment is governed by cues which can be mimicked in vitro2008In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 10, p. 4479-4488Article in journal (Refereed)
    Abstract [en]

    The intracellular bacterium Francisella tularensis survives in mammals, arthropods, and freshwater amoeba. It was previously established that the conventional media used for in vitro propagation of this microbe do not yield bacteria that mimic those harvested from infected mammals; whether these in vitro-cultivated bacteria resemble arthropod- or amoeba-adapted Francisella is unknown. As a foundation for our goal of identifying F. tularensis outer membrane proteins which are expressed during mammalian infection, we first sought to identify in vitro cultivation conditions that induce the bacterium's infection-derived phenotype. We compared Francisella LVS grown in brain heart infusion broth (BHI; a standard microbiological medium rarely used in Francisella research) to that grown in Mueller-Hinton broth (MHB; the most widely used F. tularensis medium, used here as a negative control) and macrophages (a natural host cell, used here as a positive control). BHI- and macrophage-grown F. tularensis cells showed similar expression of MglA-dependent and MglA-independent proteins; expression of the MglA-dependent proteins was repressed by the supraphysiological levels of free amino acids present in MHB. We observed that during macrophage infection, protein expression by intracellular bacteria differed from that by extracellular bacteria; BHI-grown bacteria mirrored the latter, while MHB-grown bacteria resembled neither. Naïve macrophages responding to BHI- and macrophage-grown bacteria produced markedly lower levels of proinflammatory mediators than those in cells exposed to MHB-grown bacteria. In contrast to MHB-grown bacteria, BHI-grown bacteria showed minimal delay during intracellular replication. Cumulatively, our findings provide compelling evidence that growth in BHI yields bacteria which recapitulate the phenotype of Francisella organisms that have emerged from macrophages.

  • 272.
    He, Shu-Lan
    et al.
    Key Laboratory of Environment and Gene Related Diseases, Xi'an Jiaotong University, Ministry Education, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, Xi'an Jiaotong University, Ministry of Health, Xi'an, China.
    Tan, Wu-Hong
    Key Laboratory of Environment and Gene Related Diseases, Xi'an Jiaotong University, Ministry Education, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, Xi'an Jiaotong University, Ministry of Health, Xi'an, China.
    Zhang, Zeng-Tie
    Key Laboratory of Environment and Gene Related Diseases, Xi'an Jiaotong University, Ministry Education, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, Xi'an Jiaotong University, Ministry of Health, Xi'an, China.
    Zhang, Feng
    Key Laboratory of Environment and Gene Related Diseases, Xi'an Jiaotong University, Ministry Education, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, Xi'an Jiaotong University, Ministry of Health, Xi'an, China.
    Qu, Cheng-Juan
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Lei, Yan-Xia
    Key Laboratory of Environment and Gene Related Diseases, Xi'an Jiaotong University, Ministry Education, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, Xi'an Jiaotong University, Ministry of Health, Xi'an, China.
    Zhu, Yan-He
    Key Laboratory of Environment and Gene Related Diseases, Xi'an Jiaotong University, Ministry Education, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, Xi'an Jiaotong University, Ministry of Health, Xi'an, China.
    Yu, Han-Jie
    Department of Biotechnology, Northwest University, Xi'an, China.
    Xiang, You-Zhang
    Shandong Institute for prevention & Treatment of Endemic Disease, Jinan, China.
    Guo, Xiong
    Key Laboratory of Environment and Gene Related Diseases, Xi'an Jiaotong University, Ministry Education, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, Xi'an Jiaotong University, Ministry of Health, Xi'an, China.
    Mitochondrial-related gene expression profiles suggest an important role of PGC-1alpha in the compensatory mechanism of endemic dilated cardiomyopathy.2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 17, p. 2604-2616, article id 23954821Article in journal (Refereed)
    Abstract [en]

    Keshan disease (KD) is an endemic dilated cardiomyopathy with unclear etiology. In this study, we compared mitochondrial-related gene expression profiles of peripheral blood mononuclear cells (PBMCs) derived from 16 KD patients and 16 normal controls in KD areas. Total RNA was isolated, amplified, labeled and hybridized to Agilent human 4 × 44k whole genome microarrays. Mitochondrial-related genes were screened out by the Third-Generation Human Mitochondria-Focused cDNA Microarray (hMitChip3). Quantitative real-time PCR, immunohistochemical and biochemical parameters related mitochondrial metabolism were conducted to validate our microarray results. In KD samples, 34 up-regulated genes (ratios ≥ 2.0) were detected by significance analysis of microarrays and ingenuity systems pathway analysis (IPA). The highest ranked molecular and cellular functions of the differentially regulated genes were closely related to amino acid metabolism, free radical scavenging, carbohydrate metabolism, and energy production. Using IPA, 40 significant pathways and four significant networks, involved mainly in apoptosis, mitochondrion dysfunction, and nuclear receptor signaling were identified. Based on our results, we suggest that PGC-1alpha regulated energy metabolism and anti-apoptosis might play an important role in the compensatory mechanism of KD. Our results may lead to the identification of potential diagnostic biomarkers for KD in PBMCs, and may help to understand the pathogenesis of KD.

  • 273.
    Hedblom, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Surgery, Cancer Research Institute and Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Translational Medicine, Lund University, Lund, Sweden.
    Hejazi, Seyed M.
    Canesin, Giacomo
    Choudhury, Reeham
    Hanafy, Khalid A.
    Csizmadia, Eva
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Translational Medicine, Lund University, Lund, Sweden.
    Wegiel, Barbara
    Heme detoxification by heme oxygenase-1 reinstates proliferative and immune balances upon genotoxic tissue injury2019In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 72Article in journal (Refereed)
    Abstract [en]

    Phenotypic changes of myeloid cells are critical to the regulation of premature aging, development of cancer, and responses to infection. Heme metabolism has a fundamental role in the regulation of myeloid cell function and activity. Here, we show that deletion of heme oxygenase-1 (HO-1), an enzyme that removes heme, results in an impaired DNA damage response (DDR), reduced cell proliferation, and increased cellular senescence. We detected increased levels of p16INK4a, H2AXγ, and senescence-associated-β-galactosidase (SA-β-Gal) in cells and tissues isolated from HO-1-deficient mice. Importantly, deficiency of HO-1 in residential macrophages in chimeric mice results in elevated DNA damage and senescence upon radiation-induced injury. Mechanistically, we found that mammalian target of rapamycin (mTOR)/S6 protein signaling is critical for heme and HO-1-regulated phenotype of macrophages. Collectively, our data indicate that HO-1, by detoxifying heme, blocks p16INK4a expression in macrophages, preventing DNA damage and cellular senescence.

  • 274.
    Hedman, H.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Alenius, Mattias
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lundgren, E.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Defective expression of beta 1-integrins in cells with constitutively active alpha L beta 2-integrins1997In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 232, no 2, p. 270-276Article in journal (Refereed)
    Abstract [en]

    We have investigated a potential relationship between expression of beta 1-integrins and adhesiveness of the beta 2-integrin LFA-1 (alpha L beta 2, CD11a/CD18). By an approach of random mutagenesis and selection we established clones from the human acute lymphatic leukemia cell line HPB-ALL with (i) constitutively active LFA-1 and (ii) with no apparent integrin-beta 1 cell surface expression. Thirty seven of 42 clones selected for activated LFA-1 were found to have lost apparent integrin-beta 1 expression. Conversely, 7 of 21 clones selected for lack of beta 1 expression were found to have activated LFA-1. Since this pointed toward a possible coupling between beta 1 expression and LFA-1 activity, we further analyzed at which level beta 1 expression was blocked. We focused on one clone, HAP4, with activated LFA-I and no detectable beta 1 cell surface expression and found, surprisingly, that it expressed wild-type levels of beta 1 mRNA and, in Western blots of whole cell lysates, apparently normal levels of beta 1 protein. However, in addition to beta 1 of the expected molecular weight, HAP4 expressed a unique 48-kDa band recognized by the polyclonal anti-beta 1 antiserum. Immunoprecipitation experiments revealed that the epitope recognized by the anti-beta 1 antibody 4B4 was hidden or lost. The alpha 4-chain was found in its precursor form but it did not associate with any beta-chain, and it was not processed to its mature form. Instead alpha 4-chains were eventually degraded. Taken together this showed that beta 1-chains were produced but not properly processed in HAP4. From this we propose that HAP4 is deficient in a gene product required both for proper beta 1 folding and for repression of LFA-1 adhesiveness.

  • 275.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Regulation of leukocyte integrin adhesiveness1995Doctoral thesis, comprehensive summary (Other academic)
  • 276. Heidler, Juliana
    et al.
    Al-Furoukh, Natalie
    Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
    Kukat, Christian
    Salwig, Isabelle
    Ingelmann, Marie-Elisabeth
    Seibel, Peter
    Krüger, Marcus
    Holtz, Jürgen
    Wittig, Ilka
    Braun, Thomas
    Szibor, Marten
    Nitric oxide-associated protein 1 (NOA1) is necessary for oxygen-dependent regulation of mitochondrial respiratory complexes.2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 37Article in journal (Refereed)
    Abstract [en]

    In eukaryotic cells, maintenance of cellular ATP stores depends mainly on mitochondrial oxidative phosphorylation (OXPHOS), which in turn requires sufficient cellular oxygenation. The crucial role of proper oxygenation for cellular viability is reflected by involvement of several mechanisms, which sense hypoxia and regulate activities of respiratory complexes according to available oxygen concentrations. Here, we focus on mouse nitric oxide-associated protein 1 (mNOA1), which has been identified as an important component of the machinery that adjusts OXPHOS activity to oxygen concentrations. mNOA1 is an evolutionary conserved GTP-binding protein that is involved in the regulation of mitochondrial protein translation and respiration. We found that mNOA1 is located mostly in the mitochondrial matrix from where it interacts with several high molecular mass complexes, most notably with the complex IV of the respiratory chain and the prohibitin complex. Knock-down of mNOA1 impaired enzyme activity I+III, resulting in oxidative stress and eventually cell death. mNOA1 is transcriptionally regulated in an oxygen-sensitive manner. We propose that oxygen-dependent regulation of mNOA1 is instrumental to adjusting OXPHOS activity to oxygen availability, thereby controlling mitochondrial metabolism.

  • 277.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ma, Li-Ping
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Fu, Michael
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hyaluronan is both a product and stimulator of cardiomyocytes: a study in cell cultures of cardiomyocytes and fibroblastsArticle in journal (Refereed)
  • 278.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ronquist, Gunnar
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Cardiomyocyte microvesicles convey bioinformatic messages to target cellsArticle in journal (Refereed)
  • 279.
    Helminen, Heikki
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hyttinen, Mika
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Arokoski, Jari
    Department of Physical and Rehabilitation Medicine, Kuopio University Hospital, Kuopio, Finland.
    Lapveteläinen, Tuomo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Jurvelin, Jukka
    Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
    Kiviranta, Ilkka
    Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Regular joint loading in youth assists in the establishment and strengthening of the collagen network of articular cartilage and contributes to the prevention of osteoarthrosis later in life. A hypothesis.2000In: Journal of Bone and Mineral Metabolism, ISSN 0914-8779, E-ISSN 1435-5604, Vol. 18, no 5, p. 245-257, article id 10959613Article, review/survey (Refereed)
    Abstract
  • 280.
    Henriksson, M L
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Telepnev, Maxim
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ras effector pathway activation by epidermal growth factor is inhibited in vivo by exoenzyme S ADP-ribosylation of Ras2000In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 347, no 1, p. 217-222Article in journal (Refereed)
  • 281.
    Henriksson, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cellular targets of Pseudomonas aeruginosa toxin Exoenzyme S2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pseudomonas aeruginosa is an opportunistic pathogen that can cause life-threatening infections in immunocompromised patients. It uses a type III secretion dependent mechanism to translocate toxic effector proteins directly into the eukaryotic cell. The enzymatic activity of two of these toxins, Exoenzyme S (ExoS) and Exoenzyme T (ExoT), have been studied in this thesis. ExoS is a bi-functional toxin known to contain a C-terminal ADP-ribosyltransferase activity, which has been shown to modify members of the Ras family in vitro. The N-terminal of ExoS contains a GTPase Activating Protein (GAP) domain, which shows specificity towards Rho proteins in vitro. ExoT shows high homology (76%) towards ExoS and has also been reported to contain ADP-ribosyltransferase activity in vitro. To study the biological effect of the two toxins, we inserted ExoS or ExoT into eukaryotic cells using the heterologous type III secretion system of Yersinia pseudotuberculosis. We found that Ras was ADP-ribosylated in vivo and this modification altered the ratio of GTP/GDP bound directly to Ras. We also found that ExoS could ADP-ribosylate several members of the Ras superfamily in vivo, modulating the activity of those proteins. In contrast, ExoT showed no ADP-ribosylation activity towards any of the GTPases tested. This suggests that ExoS is the major ADP-ribosyltransferase modulating small GTPase function encoded by P. aeruginosa. Furthermore, we have demonstrated that the GAP activity of ExoS abolishes the activation of RhoA, Cdc42 and Rap1 in vivo, and that ExoT shows GAP activity towards RhoA in vitro.

    The ADP-ribosyltransferase activity of ExoS is dependent on the eukaryotic protein 14-3-3. 14-3-3 proteins interact with ExoS in a phospho-independent manner. We identified the amino acids 424DALDL428 on ExoS to be necessary for the specific interaction between ExoS and 14-3-3. Deletion of these five amino acids abolishes the ADP-ribosylation of Ras and hence the cytotoxic effect of P. aeruginosa on cells. Thus the 14-3-3 binding motif on ExoS appears to be critical for both the ADP-ribosylation activity and the cytotoxic action of ExoS in vivo.

  • 282.
    Henriksson, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Trollér, Ulrika
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    14-3-3 proteins are required for the inhibition fo Ras by exoenzyme S2000In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 349, p. 697-701Article in journal (Refereed)
    Abstract [en]

    14-3-3 proteins play a regulatory role and participate in both signal transduction and checkpoint control pathways. 14-3-3 proteins bind phosphoserine ligands, such as Raf-l kinase and Bad, by recognizing the phosphorylated consensus motif, Arg-Ser-Xaa-pSer-Xaa-Pro (where 'Xaa' represents 'any residue', and 'pSer' is 'phosphoserine'). However, 14-3-3 proteins must bind unphosphorylated ligands, such as glycoprotein Ib alpha and Pseudomonas aeruginosa exoenzyme S (ExoS), since it has been suggested that specific residues of 14-3-3 proteins are required for activation of ExoS. Furthermore, an unphosphorylated peptide derived from a phage display library inhibited the binding of both ExoS and Raf-1 to 14-3-3, and bound within the same conserved amphipathic groove on the surface of 14-3-3 as the Raf-derived phosphopeptide (pS-Raf-259). In the present study we identify the interaction site on ExoS for 14-3-3, and show that ExoS and 14-3-3 do indeed interact in vivo. In addition, we show that this interaction is critical for the ADP-ribosylation of Ras by ExoS, both in vitro and in vivo. Loss of the 14-3-3 binding site on ExoS results in an ExoS molecule that is unable to efficiently inactivate Ras, and displays reduced killing activity.

  • 283. Herrmann, Bjorn
    et al.
    Isaksson, Jenny
    Ryberg, Martin
    Tångrot, Jeanette
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Saleh, Isam
    Versteeg, Bart
    Gravningen, Kirsten
    Bruisten, Sylvia
    Global Multilocus Sequence Type Analysis of Chlamydia trachomatis Strains from 16 Countries2015In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 53, no 7, p. 2172-2179Article in journal (Refereed)
    Abstract [en]

    The Uppsala University Chlamydia trachomatis multilocus sequence type (MLST) database (http://mlstdb.bmc.uu.se) is based on five target regions (non-housekeeping genes) and the ompA gene. Each target has various numbers of alleles-hctB, 89; CT058, 51; CT144, 30; CT172, 38; and pbpB, 35-derived from 13 studies. Our aims were to perform an overall analysis of all C. trachomatis MLST sequence types (STs) in the database, examine STs with global spread, and evaluate the phylogenetic capability by using the five targets. A total of 415 STs were recognized from 2,089 specimens. The addition of 49 ompA gene variants created 459 profiles. ST variation and their geographical distribution were characterized using eBURST and minimum spanning tree analyses. There were 609 samples from men having sex with men (MSM), with 4 predominating STs detected in this group, comprising 63% of MSM cases. Four other STs predominated among 1,383 heterosexual cases comprising, 31% of this group. The diversity index in ocular trachoma cases was significantly lower than in sexually transmitted chlamydia infections. Predominating STs were identified in 12 available C. trachomatis whole genomes which were compared to 22 C. trachomatis full genomes without predominating STs. No specific gene in the 12 genomes with predominating STs could be linked to successful spread of certain STs. Phylogenetic analysis showed that MLST targets provide a tree similar to trees based on whole-genome analysis. The presented MLST scheme identified C. trachomatis strains with global spread. It provides a tool for epidemiological investigations and is useful for phylogenetic analyses.

  • 284.
    Hessle, Pontus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Biomedicinprogrammet.
    Expression of genes involved in antigen presentation via MHC class I in bone metastases – Relations to androgen receptor activity2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 285. Heverin, Maura
    et al.
    Ali, Zeina
    Olin, Maria
    Tillander, Veronika
    Joibari, Masoumeh Motamedi
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Makoveichuk, Elena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Leitersdorf, Eran
    Warner, Margret
    Olivercrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Gustafsson, Jan-Åke
    Björkhem, Ingemar
    On the regulatory importance of 27-hydroxycholesterol in mouse liver2017In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 169, p. 10-21Article, review/survey (Refereed)
    Abstract [en]

    27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial. Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes. In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73-79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl). The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions. 

  • 286. Higelin, Julia
    et al.
    Catanese, Alberto
    Semelink-Sedlacek, Lena Luisa
    Oeztuerk, Sertap
    Lutz, Anne-Kathrin
    Bausinger, Julia
    Barbi, Gotthold
    Speit, Güenter
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ludolph, Albert C.
    Demestre, Maria
    Boeckers, Tobias M.
    NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons2018In: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 30, p. 150-162Article in journal (Refereed)
    Abstract [en]

    Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction. Motoneurons carrying a C9orf72 mutation exhibited cell specific signs of increased DNA damage. This phenotype was even more severe in NEK1c.2434A>T neurons that showed significantly increased DNA damage at basal level and impaired DDR after induction of DNA damage in an maturation-dependent manner. Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS. Therefore, our study contributes to the development of novel therapeutic strategies to reduce DNA damage accumulation in neurodegenerative diseases and ALS.

  • 287. Hille, Frank
    et al.
    Richter, Hagen
    Wong, Shi Pey
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany; Institute for Biology, Humboldt University, Germany.
    Bratovic, Majda
    Ressel, Sarah
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany; Institute for Biology, Humboldt University, Germany.
    The Biology of CRISPR-Cas: Backward and Forward2018In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 172, no 6, p. 1239-1259Article, review/survey (Refereed)
    Abstract [en]

    In bacteria and archaea, clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins constitute an adaptive immune system against phages and other foreign genetic elements. Here, we review the biology of the diverse CRISPR-Cas systems and the major progress achieved in recent years in understanding the underlying mechanisms of the three stages of CRISPR-Cas immunity: adaptation, crRNA biogenesis, and interference. The ecology and regulation of CRISPR-Cas in the context of phage infection, the roles of these systems beyond immunity, and the open questions that propel the field forward are also discussed.

  • 288. Hoernke, M
    et al.
    Mohan, Jagan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blomberg, J
    Kahra, Dana
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Daumke, O
    Westenhof, S
    Schweiger, C
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    TP driven stabilization of a membrane bound open confirmation of the ATPase EHD2 restrains caveolae dynamicsManuscript (preprint) (Other academic)
  • 289.
    Hogg, Matthew
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    DNA Polymerase ε2012In: The eukaryotic replisome: a guide to protein structure and function / [ed] MacNeill S, Springer Science+Business Media B.V., 2012, Vol. 62, p. 237-57Chapter in book (Refereed)
    Abstract [en]

    DNA polymerase ε (Pol ε) is one of three replicative DNA polymerases in eukaryotic cells. Pol ε is a multi-subunit DNA polymerase with many functions. For example, recent studies in yeast have suggested that Pol ε is essential during the initiation of DNA replication and also participates during leading strand synthesis. In this chapter, we will discuss the structure of Pol ε, the individual subunits and their function.

  • 290. Holland, Petter
    et al.
    Knaevelsrud, Helene
    Soreng, Kristiane
    Mathai, Benan J.
    Lystad, Alf Hakon
    Pankiv, Serhiy
    Bjorndal, Gunnveig T.
    Schultz, Sebastian W.
    Lobert, Viola H.
    Chan, Robin B.
    Zhou, Bowen
    Liestol, Knut
    Carlsson, Sven R.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Melia, Thomas J.
    Di Paolo, Gilbert
    Simonsen, Anne
    HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 13889Article in journal (Refereed)
    Abstract [en]

    A fundamental question is how autophagosome formation is regulated. Here we show that the PX domain protein HS1BP3 is a negative regulator of autophagosome formation. HS1BP3 depletion increased the formation of LC3-positive autophagosomes and degradation of cargo both in human cell culture and in zebrafish. HS1BP3 is localized to ATG16L1-and ATG9-positive autophagosome precursors and we show that HS1BP3 binds phosphatidic acid (PA) through its PX domain. Furthermore, we find the total PA content of cells to be significantly upregulated in the absence of HS1BP3, as a result of increased activity of the PA-producing enzyme phospholipase D (PLD) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 regulates autophagy by modulating the PA content of the ATG16L1-positive autophagosome precursor membranes through PLD1 activity and localization. Our findings provide key insights into how autophagosome formation is regulated by a novel negative-feedback mechanism on membrane lipids.

  • 291.
    Holst, Mikkel Roland
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Vidal-Quadras, Maite
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundborg, Magnus
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1893-1905Article in journal (Refereed)
    Abstract [en]

    Cellular blebbing, caused by local alterations in cellsurface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrinindependent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension- mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol- interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

  • 292. Hua, Dong
    et al.
    Liu, Meng-Yuan
    Cheng, Zhi-de
    Qin, Xiang-Jing
    Zhang, Hai-Mou
    Chen, Yong
    Qin, Gang-Jian
    Liang, Gang
    Li, Jinan
    Harvard Medical School, Boston, MA, USA.
    Han, Xiao-Feng
    Liu, Dong-Xu
    Small interfering RNA-directed targeting of toll-like receptor 4 inhibits human prostate cancer cell invasion, survival, and tumorigenicity2009In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, no 15, p. 2876-2884Article in journal (Refereed)
    Abstract [en]

    A major cause of tumor treatment failure is cancer cell metastasis. Toll-like receptor 4 (TLR4)-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. In this study, we investigated the biological roles of TLR4 in prostate metastatic cell invasion and survival, and the potential of gene silencing of TLR4 using small interfering RNA (siRNA) for treatment of cancer. In cultured human prostate cancer cell lines, TLR4 were higher PC3 and DU145 as compared with the poorly metastatic LNCaP indicating that up-regulation of TLR4 was positively correlated with metastasis of tumor cell. In the highly metastatic cancer cell PC3, gene silencing of TLR4 using siRNA significantly inhibited TLR4 mRNA expression and protein level. Knockdown of TLR4 in PC3 cells resulted in a dramatic reduction of tumor cell migration and invasion as indicated by a Matrigel invasion assay. Furthermore, TLR4 siRNA suppressed cell viability and ultimately caused the induction of apoptotic cell death. The effects were associated with abrogating TLR4-mediated signaling to downstream target molecules such as myeloid differentiation factor 88 (MyD88), adaptor-inducing IFN-beta (TRIF), and interferon regulatory factor-1 (IRF-1). In a mouse prostate cancer model, administration with the plasmid construct expressing siRNA for TLR4 obviously inhibited established tumor growth and survival. These studies revealed evidence of a multifaceted signaling network operating downstream of TLR4-mediated tumor cell invasion, proliferation, and survival. Thus, RNA interference-directed targeting of TLR4 may raise the potential of its application for cancer therapy.

  • 293. Huang, Hongyun
    et al.
    Young, Wise
    Chen, Lin
    Feng, Shiqing
    Al Zoubi, Ziad M.
    Sharma, Hari Shanker
    Saberi, Hooshang
    Moviglia, Gustavo A.
    He, Xijing
    Muresanu, Dafin F.
    Sharma, Alok
    Otom, Ali
    Andrews, Russell J.
    Al-Zoubi, Adeeb
    Bryukhovetskiy, Andrey S.
    Chernykh, Elena R.
    Domanska-Janik, Krystyna
    Jafar, Emad
    Johnson, W. Eustace
    Li, Ying
    Li, Daqing
    Luan, Zuo
    Mao, Gengsheng
    Shetty, Ashok K.
    Siniscalco, Dario
    Skaper, Stephen
    Sun, Tiansheng
    Wang, Yunliang
    Wiklund, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Xue, Qun
    You, Si-Wei
    Zheng, Zuncheng
    Dimitrijevic, Milan R.
    El Masri, W. S.
    Sanberg, Paul R.
    Xu, Qunyuan
    Luan, Guoming
    Chopp, Michael
    Cho, Kyoung-Suok
    Zhou, Xin-Fu
    Wu, Ping
    Liu, Kai
    Mobasheri, Hamid
    Ohtori, Seiji
    Tanaka, Hiroyuki
    Han, Fabin
    Feng, Yaping
    Zhang, Shaocheng
    Lu, Yingjie
    Zhang, Zhicheng
    Rao, Yaojian
    Tang, Zhouping
    Xi, Haitao
    Wu, Liang
    Shen, Shunji
    Xue, Mengzhou
    Xiang, Guanghong
    Guo, Xiaoling
    Yang, Xiaofeng
    Hao, Yujun
    Hu, Yong
    Li, Jinfeng
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Ao, Qiang
    Wang, Bin
    Zhang, Zhiwen
    Lu, Ming
    Li, Tong
    Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)2018In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 27, no 2, p. 310-324Article, review/survey (Refereed)
    Abstract [en]

    Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version "Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)". The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.

  • 294.
    Huch, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Interrelations between translation and general mRNA degradation in yeast2014In: Wiley Interdisciplinary Reviews: RNA, ISSN 1757-7012, Vol. 5, no 6, p. 747-763Article, review/survey (Refereed)
    Abstract [en]

    Messenger RNA (mRNA) degradation is an important element of gene expression that can be modulated by alterations in translation, such as reductions in initiation or elongation rates. Reducing translation initiation strongly affects mRNA degradation by driving mRNA toward the assembly of a decapping complex, leading to decapping. While mRNA stability decreases as a consequence of translational inhibition, in apparent contradiction several external stresses both inhibit translation initiation and stabilize mRNA. A key difference in these processes is that stresses induce multiple responses, one of which stabilizes mRNAs at the initial and rate-limiting step of general mRNA decay. Because this increase in mRNA stability is directly induced by stress, it is independent of the translational effects of stress, which provide the cell with an opportunity to assess its response to changing environmental conditions. After assessment, the cell can store mRNAs, reinitiate their translation or, alternatively, embark on a program of enhanced mRNA decay en masse. Finally, recent results suggest that mRNA decay is not limited to non-translating messages and can occur when ribosomes are not initiating but are still elongating on mRNA. This review will discuss the models for the mechanisms of these processes and recent developments in understanding the relationship between translation and general mRNA degradation, with a focus on yeast as a model system.

  • 295.
    Hughes, Kate
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Antonsson, Åsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Calmodulin-dependent Kinase II Mediates T Cell Receptor/CD3- and Phorbol Ester-induced Activation of IκB Kinase2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 38, p. 36008-36013Article in journal (Refereed)
  • 296.
    Hult, Andreas
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Towards a detailed understanding of the red blood cell storage lesion: and its consequences for in vivo survival following transfusion2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Red blood cells (RBCs) are vital for oxygen delivery to tissues and constitute the vast majority of all cells in blood. After leaving the red bone marrow as mature cells, RBCs have a lifespan of approximately 120 days before they are removed from the circulation by macrophages, mainly in the spleen and liver. RBC transfusion is a common therapy in modern healthcare. Major surgery, numerous cancer treatments and other, often lifesaving, interventions would be unthinkable without available blood supply. For this reason, hospitals store donated RBCs in blood banks.

    The metabolic and structural changes that occur during prolonged storage of RBCs (the storage lesion) have been studied in detail in vitro and include oxidative stress, a reduction in glycolysis, increased membrane rigidity and shedding of microparticles from the RBC membrane. Stored RBCs share several features of senescent RBCs, but also with RBCs undergoing an apoptotic-like process called eryptosis. A consequence of the storage lesion is the fact that as much as 25% of stored RBCs could be rapidly removed from the circulation within 24 hours after transfusion. The mechanisms behind this rapid macrophage-mediated recognition and removal of stored RBCs, and its immunological consequences, remain largely unknown. Therefore, the aims of this thesis were to investigate if cryopreserved human RBCs induced an inflammatory response following autologous transfusion into healthy volunteers, and to further understand the mechanisms behind macrophage recognition of stored RBCs in vitro and in vivo.

    Autologous transfusion of two units of cryopreserved RBCs into healthy human recipients was found to be associated with an increased extravascular RBC elimination already at 2 hours after transfusion. However, there were no signs of an increased production of any of the investigated pro-inflammatory cytokines, indicating that an increase in the destruction of RBCs per se did not induce an inflammatory response.

    Eryptosis is a form of induced RBC death associated with an increased cytoplasmic Ca2+ uptake. We found that a subset of human RBCs increased their Ca2+ permeability during prolonged storage at +4°C. Using a murine model, to further understand how RBCs with an increased Ca2+ permeability were eliminated by phagocytic cells in the spleen, it was found that such RBCs were taken up by marginal zone macrophages and dendritic cells (DCs) in a manner distinct from that of naturally senescent RBCs. The DC population particularly efficient in this process expressed CD207 and are known for their ability to promote immunological tolerance. Eryptotic cell uptake was not regulated by the phagocytosis-inhibitory protein CD47 on the RBCs.

    To investigate how RBCs damaged during liquid storage are recognized and taken up by macrophages, a model to store and transfuse murine RBCs was developed. This storage model generated murine RBCs with several characteristics similar to that of stored human RBCs (i.e. loss of ATP, formation of RBC microparticles and rapid clearance of up to 35% of the RBCs during the first 24 h after transfusion). In vitro phagocytosis of human as well as murine stored RBCs was serum dependent and could be inhibited by blocking class A scavenger receptors using fucoidan or dextran sulphate.

    In conclusion, the findings of this thesis contribute to further understanding how changes inflicted to RBCs during storage direct the fate of these cells in their interaction with cells of the immune system after transfusion. The observation of an increased Ca2+ permeability of stored RBCs, and the possible recognition of such cells by tolerance-promoting DCs, in combination with the findings that class A scavenger receptors and serum factors may mediate recognition of stored RBCs, may result in novel new directions of research within the field of transfusion medicine.

  • 297.
    Hult, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin.
    Toss, Fredrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Phagocytosis of liquid-stored red blood cells in vitro requires serum and macrophage scavenger receptorsManuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND: Red blood cells (RBCs) undergo structural and metabolic changes with prolonged storage, which ultimately may decrease their survival after transfusion. Although the storage-induced damage to RBCs has been rather well described biochemically, little is known about the mechanisms underlying the recognition and rapid clearance of the damaged cells by macrophages.STUDY DESIGN AND METHODS: We here used a murine model for cold (+4°C) RBC storage and transfusion. Phagocytosis of human or murine RBCs, liquid stored for 6-8 weeks or 10-14 days respectively, was investigated in murine peritoneal macrophages.RESULTS: The effects of storage on murine RBCs resembled that described for stored human RBCs with regard to decreased adenosine triphosphate (ATP) levels, accumulation of microparticles during storage, and RBC recovery kinetics after transfusion. Under serum-free conditions, phagocytosis of stored human or murine RBCs was reduced by 70-75%, as compared with that in the presence of heat-inactivated fetal calf serum (FCS). Human serum promoted phagocytosis of stored human RBCs similar to that seen with FCS. By blocking macrophage class A scavenger receptors with fucoidan or dextran sulphate, phagocytosis of human or murine RBCs was reduced by more than 90%. Phagocytosis of stored human RBCs was also sensitive to inhibition by the phosphatidylinositol 3 kinase-inhibitor LY294002, the ERK1/2-inhibitor PD98059, or the p38 MAPK-inhibitor SB203580.CONCLUSIONS: RBCs damaged during liquid storage may be recognized by macrophage class A scavenger receptors and serum-dependent mechanisms. This species-independent recognition mechanism may help to further understand the rapid clearance of stored RBCs shortly after transfusion.

  • 298. Hurwitz, Julia L.
    et al.
    Jones, Bart G.
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Max Planck Institute for Infection Biology, Berlin, Germany; Humboldt University, Berlin, Germany.
    Woodland, David L.
    Hypothesis: RNA and DNA Viral Sequence Integration into the Mammalian Host Genome Supports Long-Term B Cell and T Cell Adaptive Immunity2017In: Viral immunology, ISSN 0882-8245, E-ISSN 1557-8976, Vol. 30, no 9, p. 628-632Article in journal (Other academic)
    Abstract [en]

    Viral sequence integration into the mammalian genome has long been perceived as a health risk. In some cases, integration translates to chronic viral infection, and in other instances, oncogenic gene mutations occur. However, research also shows that animal cells can benefit from integrated viral sequences (e.g., to support host cell development or to silence foreign invaders). Here we propose that, comparable with the clustered regularly interspaced short palindromic repeats that provide bacteria with adaptive immunity against invasive bacteriophages, animal cells may co-opt integrated viral sequences to support immune memory. We hypothesize that host cells express viral peptides from open reading frames in integrated sequences to boost adaptive B cell and T cell responses long after replicating viruses are cleared. In support of this hypothesis, we examine previous literature describing (1) viruses that infect acutely (e.g., vaccinia viruses and orthomyxoviruses) followed by unexplained, long-term persistence of viral nucleotide sequences, viral peptides, and virus-specific adaptive immunity, (2) the high frequency of endogenous viral genetic elements found in animal genomes, and (3) mechanisms with which animal host machinery supports foreign sequence integration.

  • 299.
    Huttu, Mari
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Turunen, Siru
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Sokolinski, Viktoria
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Tiitu, Virpi
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; SIB-Labs, University of Eastern Finland, Kuopio, Finland.
    Lammi, Mikko
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
    Korhonen, Rami K
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Effects of medium and temperature on cellular responses in the superficial zone of hypo-osmotically challenged articular cartilage.2012In: Journal of Functional Biomaterials, ISSN 2079-4983, Vol. 3, no 3, p. 544-555, article id 23807905Article in journal (Refereed)
    Abstract [en]

    Osmotic loading of articular cartilage has been used to study cell-tissue interactions and mechanisms in chondrocyte volume regulation in situ. Since cell volume changes are likely to affect cell's mechanotransduction, it is important to understand how environmental factors, such as composition of the immersion medium and temperature affect cell volume changes in situ in osmotically challenged articular cartilage. In this study, chondrocytes were imaged in situ with a confocal laser scanning microscope (CLSM) through cartilage surface before and 3 min and 120 min after a hypo-osmotic challenge. Samples were measured either in phosphate buffered saline (PBS, without glucose and Ca(2+)) or in Dulbecco's modified Eagle's medium (DMEM, with glucose and Ca(2+)), and at 21 °C or at 37 °C. In all groups, cell volumes increased shortly after the hypotonic challenge and then recovered back to the original volumes. At both observation time points, cell volume changes as a result of the osmotic challenge were similar in PBS and DMEM in both temperatures. Our results indicate that the initial chondrocyte swelling and volume recovery as a result of the hypo-osmotic challenge of cartilage are not dependent on commonly used immersion media or temperature.

  • 300.
    Hyttinen, Mika
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Arokoski, Jari
    Department of Physical and Rehabilitation Medicine, Kuopio University Hospital, Kuopio, Finland.
    Parkkinen, Jyrki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lapveteläinen, Tuomo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Mauranen, Kari
    Department of Health Policy and Management, University of Kuopio, Kuopio, Finland.
    Király, Kari
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Age matters: collagen birefringence of superficial articular cartilage is increased in young guinea-pigs but decreased in older animals after identical physiological type of joint loading.2001In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 9, no 8, p. 694-701, article id 11795988Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To compare responses of the collagen network and glycosaminoglycans (GAGs) of articular cartilage to physiological type of joint loading in young growing and adult mature guinea-pigs.

    DESIGN: 10- and 44-week-old guinea-pigs were accustomed to treadmill running for 3 weeks. Thereafter the animals ran 2500 m/day, 5 days a week, for 15 weeks. Articular cartilage specimens from knee joints were collected at 28 and 62 weeks. Osteoarthritis (OA) prevalence and severity was evaluated by aid of light microscopy. The degree of collagen fibril network organization and content was analyzed with quantitative polarized light microscopy. The local concentration of GAGs was determined from cartilage sections with digital densitometry after safranin-O staining.

    RESULTS: In the young guinea-pigs, running increased up to 24% the optical retardation of polarized light by collagen in the superficial articular cartilage of femur, indicating either a higher degree of fibril assembly and organization or increased amount of collagen, or both. In contrast, in the adult mature animals the optical retardation decreased almost 50% after joint loading (P< 0.01-0.001). Running did not increase cartilage fibrillation. Significant changes in GAG content of cartilage were not found either in the young or adult mature runners.

    CONCLUSIONS: Increased birefringence of the superficial articular cartilage after joint loading in young guinea-pigs can be interpreted to be a sign of improved and decreased birefringence in older animals a sign of worsened property of the collagen network. It can be suggested therefore that joint loading strengthened the collagen network in the young runners. It can be hypothesized further that with time the inferior property of the collagen network predisposes the older runners to earlier OA than in controls.

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