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  • 851. Wolfstetter, Georg
    et al.
    Shirinian, Margret
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Stute, Christiana
    Grabbe, Caroline
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hummel, Thomas
    Baumgartner, Stefan
    Palmer, Ruth H
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holz, Anne
    Fusion of circular and longitudinal muscles in Drosophila is independent of the endoderm but further visceral muscle differentiation requires a close contact between mesoderm and endoderm.2009In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 126, no 8-9, p. 721-736Article in journal (Refereed)
    Abstract [en]

    In this study we describe the morphological and genetic analysis of the Drosophila mutant gürtelchen (gurt). gurt was identified by screening an EMS collection for novel mutations affecting visceral mesoderm development and was named after the distinct belt shaped visceral phenotype. Interestingly, determination of visceral cell identities and subsequent visceral myoblast fusion is not affected in mutant embryos indicating a later defect in visceral development. gurt is in fact a new huckebein (hkb) allele and as such exhibits nearly complete loss of endodermal derived structures. Targeted ablation of the endodermal primordia produces a phenotype that resembles the visceral defects observed in huckebein(gürtelchen) (hkb(gurt)) mutant embryos. It was shown previously that visceral mesoderm development requires complex interactions between visceral myoblasts and adjacent tissues. Signals from the neighbouring somatic myoblasts play an important role in cell type determination and are a prerequisite for visceral muscle fusion. Furthermore, the visceral mesoderm is known to influence endodermal migration and midgut epithelium formation. Our analyses of the visceral phenotype of hkb(gurt) mutant embryos reveal that the adjacent endoderm plays a critical role in the later stages of visceral muscle development, and is required for visceral muscle elongation and outgrowth after proper myoblast fusion.

  • 852.
    Wu, Cuiyan
    et al.
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Liu, Huan
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Zhang, Feng'e
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Shao, Wanzhen
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Yang, Lei
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Ning, Yujie
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Wang, Sen
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Zhao, Guanghui
    Department of Knee Joint, Xi'an Hong Hui Hospital, Xi'an, P.R. China.
    Lee, Byeong Jae
    Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, Korea.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Guo, Xiong
    Long noncoding RNA expression profile reveals lncRNAs signature associated with extracellular matrix degradation in kashin-beck disease2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17553Article in journal (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD) is a deformative, endemic osteochondropathy involving degeneration and necrosis of growth plates and articular cartilage. The pathogenesis of KBD is related to gene expression and regulation mechanisms, but long noncoding RNAs (lncRNAs) in KBD have not been investigated. In this study, we identified 316 up-regulated and 631 down-regulated lncRNAs (≥ 2-fold change) in KBD chondrocytes using microarray analysis, of which more than three-quarters were intergenic lncRNAs and antisense lncRNAs. We also identified 232 up-regulated and 427 down-regulated mRNAs (≥ 2-fold change). A lncRNA-mRNA correlation analysis combined 343 lncRNAs and 292 mRNAs to form 509 coding-noncoding gene co-expression networks (CNC networks). Eleven lncRNAs were predicted to have cis-regulated target genes, including NAV2 (neuron navigator 2), TOX (thymocyte selection-associated high mobility group box), LAMA4 (laminin, alpha 4), and DEPTOR (DEP domain containing mTOR-interacting protein). The differentially expressed mRNAs in KBD significantly contribute to biological events associated with the extracellular matrix. Meanwhile, 34 mRNAs and 55 co-expressed lncRNAs constituted a network that influences the extracellular matrix. In the network, FBLN1 and LAMA 4 were the core genes with the highest significance. These novel findings indicate that lncRNAs may play a role in extracellular matrix destruction in KBD.

  • 853.
    Wu, Shi-Xun
    et al.
    College of Medicine of Xi'an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases, Ministry of Health, Xi'an, China; Department of Orthopedics Surgery, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, China.
    Wang, Wei-Zhuo
    Department of Orthopedics Surgery, The Second Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China.
    Zhang, Feng
    aculty of Public Health, College of Medicine of Xi'an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases, Ministry of Health, Xi'an, China.
    Wu, Cui-Yan
    aculty of Public Health, College of Medicine of Xi'an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases, Ministry of Health, Xi'an, China.
    Dennis, Bannel
    aculty of Public Health, College of Medicine of Xi'an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases, Ministry of Health, Xi'an, China.
    Qu, Cheng-Juan
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
    Bai, Yi-Dong
    Department of Cellular and Structural Biology, University of Texas Health Sciences Center at San Antonio, San Antonio, USA.
    Guo, Xiong
    College of Medicine of Xi'an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases, Ministry of Health, Xi'an, China.
    Expression profiles of genes involved in apoptosis and selenium metabolism in articular cartilage of patients with Kashin-Beck osteoarthritis.2014In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 535, no 2, p. 124-130, article id 24316489Article in journal (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD) is a special type of endemic osteoarthritis. It has been suggested that alterations in selenium metabolism and apoptosis play a role in KBD. However, the underlying molecular mechanism remains largely unclear. We performed a microarray analysis using RNA isolated from cartilages of KBD patients and healthy controls, through Significance Analysis of Microarray (SAM) software. Functional gene networks and crucial molecules associated with differentially expressed genes were investigated via Ingenuity Pathway Analysis (IPA) and hub gene analysis. Quantitative real-time PCR was used to check the validation of chip test. We identified 52 up-regulated apoptosis-related genes and 26 down-regulated selenium-related genes between KBD and controls, and these genes associated with the "MYC-mediated apoptosis signaling pathway". We confirmed the results from array studies with quantitative real-time PCR analysis. Our results suggest that abnormal regulation of selenium metabolism and apoptosis through the MYC mediated signaling pathway contributes to the pathogenesis of KBD, but the relationship between apoptosis gene and selenium gene was not found.

  • 854.
    Wuolikainen, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Acimovic, Jure
    Loevgren-Sandblom, Anita
    Parini, Paolo
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bjoerkhem, Ingemar
    Cholesterol, Oxysterol, Triglyceride, and Coenzyme Q Homeostasis in ALS. Evidence against the Hypothesis That Elevated 27-Hydroxycholesterol Is a Pathogenic Factor2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e113619-Article in journal (Refereed)
    Abstract [en]

    High plasma levels of cholesterol have been suggested to be neuroprotective for the degenerative disease amyotrophic lateral sclerosis (ALS) and to be associated with increased survival time. The gene encoding cholesterol 27-hydroxylase, CYP27A1, was recently identified as a susceptibility gene for sporadic ALS. A product of this enzyme is 27-hydroxycholesterol. We investigated plasma samples from 52 ALS patients and 40 control subjects (spouses) regarding cholesterol homeostasis, lipid profiles, and coenzyme Q. Eleven of the patients carried mutations in C9orf72 and seven in SOD1. Plasma levels of 27-hydroxycholesterol were significantly lower in male patients with ALS than in controls. It was not possible to link the reduced levels to any specific mutation, and there was no significant correlation between 27-hydroxycholesterol and survival. With normalization for diet using the spouses, a correlation was found between survival and total cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, and coenzyme Q. We conclude that cholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol and lipid profiles in plasma are of limited prognostic value in individual ALS patients.

  • 855. Xing, Xuanxuan
    et al.
    Kane, Daniel P.
    Bulock, Chelsea R.
    Moore, Elizabeth A.
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Shcherbakova, Polina V.
    A recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 374Article in journal (Refereed)
    Abstract [en]

    Alterations in the exonuclease domain of DNA polymerase ε (Polε) cause ultramutated tumors. Severe mutator effects of the most common variant, Polε-P286R, modeled in yeast suggested that its pathogenicity involves yet unknown mechanisms beyond simple proofreading deficiency. We show that, despite producing a catastrophic amount of replication errors in vivo, the yeast Polε-P286R analog retains partial exonuclease activity and is more accurate than exonuclease-dead Polε. The major consequence of the arginine substitution is a dramatically increased DNA polymerase activity. This is manifested as a superior ability to copy synthetic and natural templates, extend mismatched primer termini, and bypass secondary DNA structures. We discuss a model wherein the cancer-associated substitution limits access of the 3'-terminus to the exonuclease site and promotes binding at the polymerase site, thus stimulating polymerization. We propose that the ultramutator effect results from increased polymerase activity amplifying the contribution of Polε errors to the genomic mutation rate.

  • 856.
    Yamazaki, Yasuo
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schönherr, Christina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Varshney, Gaurav K.
    Dogru, Murat
    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).
    Palmer, Ruth H.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation2013In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 32, no 4, p. 524-537Article in journal (Refereed)
    Abstract [en]

    Diverse cellular processes depend on endocytosis, intracellular vesicle trafficking, sorting and exocytosis, processes regulated post-transcriptionally by modifications such as phosphorylation and ubiquitylation. In addition to sorting to the lysosome, cargo is recycled to the plasma membrane via recycling endosomes. Here, we describe a role of the goliath gene family of protease-associated (PA) domain E3 ligases in regulating recycling endosome trafficking. The two Drosophila members of this family-Goliath and Godzilla(CG10277) - are located on endosomes, and both ectopic expression and loss-of-function lead to the accumulation of Rab5-positive giant endosomes. Furthermore, the human homologue RNF167 exhibits similar behaviour. We show that the soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) protein VAMP3 is a target of these ubiquitin ligases, and that recycling endosome trafficking is abrogated in response to their activity. Furthermore, mutation of the Godzilla ubiquitylation target lysines on VAMP3 abrogates the formation of enlarged endosomes induced by either Godzilla or RNF167. Thus, Goliath ubiquitin ligases play a novel role in regulating recycling endosome trafficking via ubiquitylation of the VAMP3 SNARE protein.

  • 857.
    Yang, Hai-Ling
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eriksson, Therese
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Vernersson, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Vigny, Marc
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmer, Ruth
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    The ligand Jelly Belly (Jeb) activates the Drosophila Alk RTK to drive PC12 cell differentiation, but is unable to activate the mouse ALK RTK2007In: Journal of experimental zoology, part B Molecular and developmental evolution, ISSN 1552-5007, Vol. 308, no 3, p. 269-282Article in journal (Refereed)
    Abstract [en]

    The Drosophila Alk receptor tyrosine kinase (RTK) drives founder cell specification in the developing visceral mesoderm and is crucial for the formation of the fly gut. Activation of Alk occurs in response to the secreted ligand Jelly Belly. No homologues of Jelly Belly are described in vertebrates, therefore we have approached the question of the evolutionary conservation of the Jeb-Alk interaction by asking whether vertebrate ALK is able to function in Drosophila. Here we show that the mouse ALK RTK is unable to rescue a Drosophila Alk mutant, indicating that mouse ALK is unable to recognise and respond to the Drosophila Jeb molecule. Furthermore, the overexpression of a dominant-negative Drosophila Alk transgene is able to block the visceral muscle fusion event, which an identically designed dominant-negative construct for the mouse ALK is not. Using PC12 cells as a model for neurite outgrowth, we show here for the first time that activation of dAlk by Jeb results in neurite extension. However, the mouse Alk receptor is unable to respond in any way to the Drosophila Jeb protein in the PC12 system. In conclusion, we find that the mammalian ALK receptor is unable to respond to the Jeb ligand in vivo or in vitro. These results suggest that either (i) mouse ALK and mouse Jeb have co-evolved to the extent that mALK can no longer recognise the Drosophila Jeb ligand or (ii) that the mALK RTK has evolved such that it is no longer activated by a Jeb-like molecule in vertebrates.

  • 858.
    Yang, Hairu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Drosophila skeletal muscles regulate the cellular immune response against wasp infection2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Drosophila melanogaster is widely used as a model organism to study the innate immune system because it lacks an adaptive immune response that could mask its innate immune response. The innate immune response of Drosophila primarily consists of humoral and cellular immune responses. The humoral immune response ismediated by antimicrobial peptides, and is induced by bacterial and fungal infections. The cellular immune response is mediated by blood cells (hemocytes), and is induced by bacterial and wasp infection. While the humoral immune response of Drosophila has been studied extensively, the cellular immune response is less well understood.

    In this work, I investigated the communication between different signaling pathways and tissues in Drosophila during infection by the parasitic wasp Leptopilina boulardi. I find that JAK/STAT signaling is strongly activated by wasp infection, in both hemocytes and (unexpectedly) larval skeletal muscles. This activation is mediated by the cytokines Upd2 and Upd3, which are secreted from circulating hemocytes. Deletion of upd2 or/and upd3 weakens the wasp-induced activation of JAK/STAT signaling in skeletal muscles and the cellular immune response to wasp infection, leading to reduced encapsulation of wasp eggs and a decrease in the number of circulating lamelloyctes. The suppression of JAK/STAT signaling also significantly weakens the cellular immune response in skeletal muscles, but not in fat bodies and hemocytes. However, the activation of this signaling in skeletal muscles has no obvious effect on the cellular immune response. Together, these results suggest that rather than being uninvolved bystanders, Drosophila skeletal musclesactively participate in cellular immune responses against wasp infection.

    To answer how Drosophila larval muscles participate cellular immune response, I min-screened the effects of several immune related signaling pathways in the muscles and the fat body on the cellular immune response. Interestingly, the cellular immune response was only significantly compromised by the suppression ofinsulin signaling in skeletal muscles, in a way that was veryreminiscent of the phenotypes induced by suppressing JAK/STAT signaling in muscles. While wasp infection activates JAK/STAT signaling in muscles, it has the opposite effect on insulin signaling. In addition, I find that insulin signaling in skeletal muscles can positively regulate JAK/STAT signaling. On the other hand, suppression of JAK/STAT signaling in muscles reduces insulin signaling locally in muscles and systemically in the fat body. Suppression of either insulin or JAK/STAT signaling in muscles leads to reductions in glycogen storage in muscles, the trehalose concentration in the hemolymph, and the frequency of feeding behavior. All these results indicate that JAK/STAT and insulin signaling in Drosophila skeletal muscles regulate cellular immune responses via their effects on carbohydrate metabolism. Our findings shed new light on the interactions between diabetes, metabolism, the immune system, and tissue communication.

  • 859.
    Yang, Hairu
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
    Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15713Article in journal (Refereed)
    Abstract [en]

    We recently found that JAK/STAT signaling in skeletal muscles is important for the immune response of Drosophila larvae against wasp infection, but it was not clear how muscles could affect the immune response. Here we show that insulin signaling is required in muscles, but not in fat body or hemocytes, during larval development for an efficient encapsulation response and for the formation of lamellocytes. This effect requires TOR signaling. We show that muscle tissue affects the immune response by acting as a master regulator of carbohydrate metabolism in the infected animal, via JAK/STAT and insulin signaling in the muscles, and that there is indirect positive feedback between JAK/STAT and insulin signaling in the muscles. Specifically, stimulation of JAK/STAT signaling in the muscles can rescue the deficient immune response when insulin signaling is suppressed. Our results shed new light on the interaction between metabolism, immunity, and tissue communication.

  • 860.
    Yang, Lei
    et al.
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, PR China.
    Zhang, Jianping
    School of Clinical Medicine, Hainan Medical University, Haikou, PR China.
    Zhao, Guanghui
    Hong Hui Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, PR China.
    Wu, Cuiyan
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, PR China.
    Ning, Yujie
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, PR China.
    Wang, Xi
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, PR China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, PR China.
    Guo, Xiong
    School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi'an, PR China.
    Gene expression profiles and molecular mechanism of cultured human chondrocytes' exposure to T-2 toxin and deoxynivalenol2017In: Toxicon, ISSN 0041-0101, E-ISSN 1879-3150, Vol. 140, p. 38-44Article in journal (Refereed)
    Abstract [en]

    T-2 toxin and deoxynivalenol (DON) are secondary metabolites produced by Fusarium fungi and are commonly found on food and feed. Although T-2 toxin and DON have been suggested as the etiology of Kashin-Beck disease (KBD), an endemic osteochondropathy, little is known about the mechanism when human chondrocytes are exposed to T-2 toxin and DON. The purpose of this study is to identify the gene expression differences and underlying molecular changes modulated by T-2 toxin and DON in vitro in human chondrocytes. After the experiments of cell viability, the gene expression profiles were analyzed in cells that were treated with 0.01 μg/ml T-2 toxin and 1.0 μg/ml DON for 72 h by Affymetrix Human Gene Chip. The array results showed that 882 and 2118 genes were differentially expressed for T-2 toxin and DON exposure, respectively. Enrichment analysis revealed that diverse cellular processes including DNA damage, cell cycle regulation and metabolism of extracellular matrix were affected when human chondrocytes were exposed to T-2 toxin and DON. These results demonstrate the gene expression differences and molecular mechanism of cultured human chondrocytes exposure to T-2 toxin and DON, and provide a new insight into future research in the etiology of KBD.

  • 861.
    Yasmin, Lubna
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Exoenzyme S of Pseudomonas aeruginosa: cellular targets and interaction with 14-3-32007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pseudomonas aeruginosa is an opportunistic pathogen that is a serious problem for immuno-compromised patients. Toxins such as exoenzyme (Exo) S, ExoT, ExoY and ExoU are secreted and translocated from the bacteria into the eukaryotic cell via the bacterial encoded type III secretion system. Our research focuses on ExoS, a bifunctional toxin comprising a Rho-GTPase-activating protein domain (RhoGAP) and a 14-3-3 dependent ADP-ribosyltransferase domain. In addition, ExoS contains a membrane localization domain termed MLD. In this study, cell lines expressing activated forms of various components of the Ras signaling pathway have been used to understand the functional and mechanical activation of ExoS-ADP-ribosyltransferase activity and to reveal its cellular targets in the cell. Our observations suggested that Ras GTPase is the dominant target by which ExoS mediates cell death and activated Ras is able to protect cells against cell death, regardless of whether it has been ADP-ribosylated by ExoS.

    It has been reported that the 14-3-3 cofactor protein is required for ADP-ribosyltransferase activity of ExoS and a phosphorylation-independent interaction occurs between 14-3-3 and the C-terminal part of ExoS. We have undertaken a deeper analysis including structural and biological investigation of this interaction. Our results suggested that leucine-428 of ExoS is the most critical residue for ExoS enzymatic activity. Structural analysis showed that ExoS binds to 14-3-3 in a novel binding mode mostly relying on hydrophobic contacts. Our structure was supported by biochemical and cytotoxicity analyses, which revealed that the substitution of important residues of ExoS significantly weakens the ability of ExoS to modify endogenous targets such as RAS/RAP1 and to induce cell death. Further, mutation of key residues within the ExoS binding site for 14-3-3 impairs virulence in a mouse pneumonia model. Leucine residues-422, 423, 426, and 428 of ExoS are important for the interaction with the ″roof″ of the amphiphatic groove of 14-3-3.

    In conclusion, we show the mechanism of cell signal transduction pathways affected upon ExoS infection and also demonstrate that the hydrophobic residues of ExoS in 14-3-3 interaction motif have a significant role for ExoS enzymatic activity.

  • 862.
    Ylärinne, Janne
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, P. R. China.
    Scaffold-free approach produces neocartilage tissue of similar quality as the use of HyStem™ and Hydromatrix™ scaffolds2017In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 28, no 4, article id 59Article in journal (Refereed)
    Abstract [en]

    Numerous biomaterials are being considered for cartilage tissue engineering, while scaffold-free systems have also been introduced. Thus, it is important to know do the scaffolds improve the formation of manufactured neocartilages. This study compares scaffold-free cultures to two scaffold-containing ones. Six million bovine primary chondrocytes were embedded in HyStem™ or HydroMatrix™ scaffolds, or suspended in scaffold-free chondrocyte culture medium, and then loaded into agarose gel supported culture well pockets. Neocartilages were grown in the presence of hypertonic high glucose DMEM medium for up to 6 weeks. By the end of culture periods, the formed tissues were analyzed by histological staining for proteoglycans (PGs) and type II collagen, gene expression measurements of aggrecan, Sox9, procollagen α1(II), and procollagen α2(I) were performed using quantitative RT-PCR, and analyses of PG contents and structure were conducted by spectrophotometric and agarose gel electrophoretic methods. Histological stainings showed that the PGs and type II collagen were abundantly present in both the scaffold-free and the scaffold-containing tissues. The PG content gradually increased following the culture period. However, the mRNA expression levels of the cartilage-specific genes of aggrecan, procollagen α1(II) and Sox9 gradually decreased following culture period, while procollagen α2(I) levels increased. After 6-week-cultivations, the PG concentrations in neocartilage tissues manufactured with HyStem™ or HydroMatrix™ scaffolds, and in scaffold-free agarose gel-supported cell cultures, were similar to native cartilage. No obvious benefits could be seen on the extracellular matrix assembly in HyStem™ or HydroMatrix™ scaffolds cultures.

  • 863. Yu, Chuanhe
    et al.
    Gan, Haiyun
    Serra-Cardona, Albert
    Zhang, Lin
    Gan, Songlin
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Xu, Rui-Ming
    Zhang, Zhiguo
    A mechanism for preventing asymmetric histone segregation onto replicating DNA strands2018In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 361, no 6409, p. 1386-+-, article id eaat8849Article in journal (Refereed)
    Abstract [en]

    How parental histone (H3-H4)2 tetramers, the primary carriers of epigenetic modifications, are transferred onto leading and lagging strands of DNA replication forks for epigenetic inheritance remains elusive. Here we show that parental (H3-H4)2 tetramers are assembled into nucleosomes onto both leading and lagging strands, with a slight preference for lagging strands. The lagging strand preference increases markedly in cells lacking Dpb3 and Dpb4, two subunits of the leading strand DNA polymerase, Pol ε, due to the impairment of parental (H3-H4)2 transfer to leading strands. Dpb3-Dpb4 binds H3-H4 in vitro and participates in the inheritance of heterochromatin. These results indicate that different proteins facilitate the transfer of parental (H3-H4)2 onto leading vs lagging strands, and that Dbp3-Dpb4 plays a significant role in this poorly understood process.

  • 864.
    Yu, F
    et al.
    Pennsylvania State University.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Larsson, L
    Human single masseter muscle fibers contain unique combinations of myosin and myosin binding protein C isoforms2002In: Journal of Muscle Research and Cell Motility, ISSN 0142-4319, E-ISSN 1573-2657, Vol. 23, no 4, p. 317-326Article in journal (Refereed)
    Abstract [en]

    Striated craniofacial and limb muscles differ in their embryological origin, regulatory program during myogenesis, and innervation. In an attempt to explore the effects of these differences on the striated muscle phenotype in humans, the expression of myosin and myosin-associated thick filament proteins were studied at the single fiber level both in the human jaw-closing masseter muscle and in two limb muscles (biceps brachii and quadriceps femoris muscles). In the masseter, unique combinations of myosin heavy chain (MyHC) and myosin binding protein C (MyBP-C) isoforms were observed at the single fiber level. Compared to the limb muscles, the MyHC isoform expression was more complex in the masseter while the opposite was observed for MyBP-C. In limb muscles, a coordinated expression of three MyHC and three MyBP-C isoforms were observed, i.e., single fibers contained one or two MyHC isoforms, and up to three MyBP-C isoforms. Also, the relative content of the different MyBP-C isoforms correlated with the MyHC isoform expression. In the masseter, on the other hand, up to five different MyHC isoforms could be observed in the same fiber, but only one MyBP-C isoform was identified irrespective MyHC isoform expression. This MyBP-C isoform had a migration rate similar to the slow MyBP-C isoform in limb muscle fibers. In conclusion, a unique myofibrillar protein isoform expression was observed in the human masseter muscle fibers, suggesting significant differences in structural and functional properties between muscle fibers from human masseter and limb muscles.

  • 865.
    Yu, Fang-Fang
    et al.
    Institute of Endemic Diseases, School of Public Health of Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Lin, Xia-Lu
    Institute of Endemic Diseases, School of Public Health of Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Wang, Xi
    Institute of Endemic Diseases, School of Public Health of Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Liu, Huan
    Institute of Endemic Diseases, School of Public Health of Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Yang, Lei
    Institute of Endemic Diseases, School of Public Health of Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Goldring, Mary B.
    Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA.
    Lammi, Mikko J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Institute of Endemic Diseases, School of Public Health of Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Guo, Xiong
    Institute of Endemic Diseases, School of Public Health of Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Selenium promotes metabolic conversion of T-2 toxin to HT-2 toxin in cultured human chondrocytes2017In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 44, p. 218-224Article in journal (Refereed)
    Abstract [en]

    To explore the metabolism of T-2 toxin in human chondrocytes (HCs) and determine the impact of selenium supplementation. For determination of cytotoxicity using the MTT assay, optical density values were read with an automatic enzyme-linked immunosorbent assay reader at 510nm. Cell survival was calculated and the cytotoxicity estimated. To identify the metabolites of T-2 toxin, the medium supernatants and C28/I2 cells were analyzed by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) separately. For HPLC-MS/MS, the mobile phase A was water and phase B was 98% methanol. The gradient for the elution was: 0-0.5min, 50% of B; 0.5-2.0min, 100% of B; 2.0-3.5min, 100% of B; 3.6-6min, 50% of B. T-2 toxin increased the toxicity to C28/I2 cells significantly in a dose- and time-dependent manner (viability range 91.5-22.0%). Supplementation with selenium (100ng/mL) could increase the cell viability after the 24h incubation. The concentration of T-2 toxin in the cell medium decreased from 20 to 6.67±1.02ng/mL, and the concentration of HT-2 toxin increased from 0 to 6.88±1.23ng/mL during the 48h incubation, whereas the relative concentration of T-2 toxin in cells increased from 0 to 12.80±1.84ng/g. Supplementary selenium in the HCs cultures reduced the cytotoxicity induced by T-2 toxin significantly, and was associated with rapid conversion of T-2 toxin in the culture medium to HT-2 toxin. T-2 toxin was more toxic to HCs than HT-2 toxin at equivalent concentrations. HT-2 toxin was a detectable metabolite of T-2 toxin in cultured HCs, and selenium enhanced the metabolic conversion of T-2 toxin, reducing its cytotoxicity to HCs.

  • 866.
    Yu, Ji-Guo
    Umeå University, Faculty of Medicine, Integrative Medical Biology.
    Re-evaluation of exercise-induced muscle soreness: an immunohistochemical and ultrastructural study2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Delayed onset muscle soreness (DOMS) is a familiar experience for the elite and novice athletes. Symptoms can range from muscle tenderness to severe deliberating pain. It is generally believed that eccentric contractions produce higher tension on muscle fibres and connective tissues than concentric and isometric contractions. This higher mechanical stress induces initial injury, and subsequent damage is linked to inflammatory process and to changes in the excitation-contraction coupling within the muscles. Classically myofibrillar ultrastrctural changes in DOMS muscles are mainly related with myofibrillar Z-disc. Z-disc streaming and broadening have long been deemed as the hallmarks of DOMS muscles. Recent studies on rabbit models have shown a rapid loss of the intermediate filament protein desmin after eccentric contractions and this was believed to be the initial event which triggers a subsequent muscle fibre necrosis. Even though numerous studies have been conducted on both human muscles and animal models following eccentric exercise, the mechanisms responsible for the perception of DOMS have not been clearly identified.

    To re-evaluate the exercise-induced muscle soreness with respect to the muscle fibre structural changes, in the present study three different modes of eccentric exercise were used as a model to introduce DOMS in healthy young subjects. Biopsies from the soleus muscle and vastus lateralis muscle were taken from control subjects and those who had taken part in the exercise, at different time intervals after exercise. The biopsies were analyzed with general histology, enzymehistochemistry, immunohistochemistry and electronmicroscopy.

    All the three exercise protocols induced DOMS, which reached its peak value at 24-48 hour post exercise. Examination of the biopsies taken after the three exercise modes showed no loss of desmin or fibre necrosis of any biopsy. However, in biopsies taken 1 hour post exercise, some influx of fibrinogen into muscle fibres was observed. Despite that, the sarcolemma integrity revealed by stainings with dystrophin and laminin was seemingly not destroyed. Further analysis of the biopsies taken after the downstairs running with high-resolution immunohistochemistry revealed the following alterations: 1) F-actin and desmin were in much greater amounts and distributed differently from normal muscle; 2) alpha-actinin, nebulin and titin were initially lacking in focal areas and were subsequently reappearing. These changes were mainly observed in the 2-3 days and 7-8 days post exercise biopsies. The staining patterns were proposed to represent different stages of sarcomere formation. These findings therefore support the suggestion that myofibrils in muscles subjected to eccentric contractions adapt to unaccustomed activity by the addition of new sarcomeres. Electronmicroscopy showed ultrastructural changes also mainly in biopsies taken 2-3 days and 7-8 days post exercise. These changes were classified into four types on bases of their different staining patterns. For each of the four types of changes, there was a corresponding type of changes revealed by the immunohistochemical method. It was concluded that alterations revealed by electronmicroscopy were suggestive of myofibrillar remodeling rather than the conventionally suggested injury.

    The present study will change the dogma that myofibrillar disruption/damage is a hallmark of DOMS. The findings of this study is of clinical importance as the myofibrils contrary to becoming weakened, are reinforced by cytoskeletal elements during the addition of new sarcomeres. The latter gives for the first time a mechanistic explanation for the lack of further damage upon additional exercise (second bout effect). Furthermore, the current methods of analysis of biopsies from eccentric exercised subjects can be used as an in situ model to analyze the molecular changes taking place in the muscle fibres affected by DOMS.

  • 867.
    Yuan, Ming
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Antiphagocytosis by Yersinia pseudotuberculosis: role of the YopH target proteins2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The enteropathogenic bacterium Yersinia pseudotuberculosis binds to β1 integrins on a host cell via its surface protein invasin. This event stimulates signal transduction to the actin cytoskeleton of the eukaryotic cell, which allows the cell to engulf the bacterium that is attached to its surface. However, the pathogen Y. pseudotuberculosis can evade such phagocytosis by injecting virulence effectors that interfere with the antipathogenic machinery of the host cells. One of these virulence effectors is the tyrosine phosphatase YopH. Through its enzymatic activity, YopH blocks phagocytosis by affecting the signalling that is associated with cytoskeletal rearrangements.

    Cas is a substrate of YopH in both professional and non-professional phagocytes. We showed that YopH binds to the central substrate domain of Cas and that this interaction is required for YopH to target focal adhesion structures in host cells. We also demonstrated that YopH binds another substrate, FAK, through Cas. Moreover, we suggested that targeting of Cas is necessary for the cytotoxic effects mediated by YopH.

    The protein Fyb is specific to immune cells, and it has been identified as a substrate of YopH in macrophages. We discovered that both the N-terminal substrate-binding domain and the C-terminal catalytic region of YopH bind Fyb in a phosphotyrosine-dependent manner. Moreover, we observed that both the substrate-binding domain and the phosphatase activity of YopH are essential for the effects of this protein on macrophages, which include dephosphorylation of Fyb, blocking of phagocytosis, and cytotoxicity.

    The role of Fyb in macrophages is largely unknown, although there is evidence that this protein is involved in integrin-linked actin organization. We identified a novel interaction partner of Fyb, mAbp1, which is a protein that binds to F-actin. Studies in vitro indicated that mAbp1 binds to the N terminus of Fyb via a C-terminal SH3 domain. We also found that both Fyb and mAbp1 co-localize with F-actin at the leading edges of macrophages. Further studies suggested that mAbp1 influences the spreading of macrophages and the antiphagocytosis mediated by pathogenic Yersinia. These results support a role for Fyb in signalling that affects F-actin dynamics, and they also provide additional insight into the mechanisms involved. Fyb has been shown to form a complex with SKAP-HOM, another substrate of YopH in macrophages. Our data implied that the level of SKAP-HOM protein depends on the presence of Fyb, but the function of the Fyb/SKAP-HOM complex in macrophages has not been determined. However, since Fyb is the only known haematopoietic-specific substrate of YopH, it is possible that Fyb is involved in other antimicrobial functions.

  • 868. Zegenhagen, Loreen
    et al.
    Kurhade, Chaitanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Koniszewski, Nikolaus
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kroeger, Andrea
    Brain heterogeneity leads to differential innate immune responses and modulates pathogenesis of viral infections2016In: Cytokine & growth factor reviews, ISSN 1359-6101, E-ISSN 1879-0305, Vol. 30, p. 95-101Article, review/survey (Refereed)
    Abstract [en]

    The central nervous system (CNS) is a highly complex organ with highly specialized cell subtypes. Viral infections often target specific structures of the brain and replicate in certain regions. Studies in mice deficient in type I Interferon (IFN) receptor or IFN-I3 have highlighted the importance of the type I IFN system against viral infections and non-viral autoimmune disorders in the CNS. Direct antiviral effects of type I IFNs appear to be crucial in limiting early spread of a number of viruses in CNS tissues. Increased efforts have been made to characterize IFN expression and responses in the brain. In this context, it is important to identify cells that produce IFN, decipher pathways leading to type I IFN expression and to characterize responding cells. In this review we give an overview about region specific aspects that influence local innate immune responses. The route of entry is critical, but also the susceptibility of different cell types, heterogeneity in subpopulations and micro-environmental cues play an important role in antiviral responses. Recent work has outlined the tremendous importance of type I IFNs, particularly in the limitation of viral spread within the CNS. This review will address recent advances in understanding the mechanisms of local type I IFN production and response, in the particular context of the CNS. 

  • 869. Zhang, Cheng-Gang
    et al.
    Welin, Dag
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kellerth, Jan-Olof
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Hart, Andrew McKay
    Motorneuron protection by N-acetyl-cysteine after ventral root avulsion and ventral rhizotomy2005In: British Journal of Plastic Surgery, ISSN 0007-1226, E-ISSN 1465-3087, Vol. 58, no 6, p. 765-773Article in journal (Refereed)
    Abstract [en]

    Motor recovery after proximal nerve injury remains extremely poor, despite advances in surgical care. Several neurobiological hurdles are implicated, the most fundamental being extensive cell death within the motorneuron pool. N-acetyl-cysteine almost completely protects sensory neurons after peripheral axotomy, hence its efficacy in protecting motorneurons after ventral root avulsion/rhizotomy was investigated. In adult rats, the motorneurons supplying medial gastrocnemius were unilaterally pre-labelled with retrograde tracer (true-blue/fluoro-gold), prior to L5 and 6 ventral root avulsion, or rhizotomy. Groups received either intraperitoneal N-acetyl-cysteine (ip, 150 or 750 mg/kg/day), immediate or delayed intrathecal N-acetyl-cysteine treatment (it, 2.4 mg/day), or saline; untreated animals served as controls. Either 4 (avulsion model) or 8 (rhizotomy model) weeks later, the pre-labelled motorneurons' mean soma area and survival were quantified. Untreated controls possessed markedly fewer motorneurons than normal due to cell death (avulsion 53% death; rhizotomy 26% death, P<0.01 vs. normal). Motorneurons were significantly protected by N-acetyl-cysteine after avulsion (ip 150 mg/kg/day 40% death; it 30% death, P<0.01 vs. no treatment), but particularly after rhizotomy (ip 150 mg/kg/day 17% death; ip 750 mg/kg/day 7% death; it 5% death, P<0.05 vs. no treatment). Delaying intrathecal treatment for 1 week after avulsion did not impair neuroprotection, but a 2-week delay was deleterious (42% death, P<0.05 vs. 1-week delay, 32% death). Treatment prevented the decrease in soma area usually found after both types of injury. N-acetyl-cysteine has considerable clinical potential for adjuvant treatment of major proximal nerve injuries, including brachial plexus injury, in order that motorneurons may survive until surgical repair facilitates regeneration.

  • 870.
    Zhang, Feng
    et al.
    Key Laboratory of Environment and Gene Related Diseases, Ministry of Education, Faculty of Public Health, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China.
    Guo, Xiong
    Key Laboratory of Environment and Gene Related Diseases, Ministry of Education, Faculty of Public Health, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China.
    Duan, Chen
    Key Laboratory of Environment and Gene Related Diseases, Ministry of Education, Faculty of Public Health, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China.
    Wu, Shixun
    Key Laboratory of Environment and Gene Related Diseases, Ministry of Education, Faculty of Public Health, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China.
    Yu, Hanjie
    Northwest University, Xi’an, Shaanxi, China.
    Lammi, Mikko
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Identification of differentially expressed genes and pathways between primary osteoarthritis and endemic osteoarthritis (Kashin–Beck disease)2013In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 42, no 1, p. 71-79, article id 23157206Article in journal (Refereed)
    Abstract [en]

    Objectives: Primary osteoarthritis (OA) and Kashin–Beck disease (KBD) exhibit similar clinical manifestations and common articular cartilage lesions. Revealing the pathogenetic differences between OA and KBD is helpful for differential diagnosis and may provide new insights into the pathogenesis of OA and KBD. In this study, we compared the genome-wide gene ontology (GO) and pathway expression patterns of articular cartilage derived from both OA and KBD patients.

    Methods: Total RNA was isolated, amplified, labelled, and hybridized using Agilent whole genome microarray analysis. Gene set enrichment analysis (GSEA) was used to identify differentially expressed genes and pathways between OA and KBD. Nine differentially expressed GO categories and 85 differentially expressed pathways were identified by this study.

    Results: The reactive oxygen species (ROS)-related HOUSTIS_ROS pathway and the vascular endothelial growth factor (VEGF)-related ABE_VEGFA_TARGETS_2HR pathway were significantly up-regulated in OA compared to KBD. Higher expression levels of the collagen-related COLLAGEN GO, EXTRACELLULAR_MATRIX_PART GO, and nitric oxide (NO)-related BIOCARTA_NO1_PATHWAY pathways were detected in KBD than in OA.

    Conclusions: ROS-induced cartilage lesions seem to be more involved in the pathogenesis of OA whereas NO-mediated chondrocyte apoptosis contributes more to the development of KBD.

  • 871. Zhang, L
    et al.
    Pennington, M.W
    Baur, P
    Byrnes, M.E
    deChastonay, J
    Wilson, Sara I
    Kay, J
    Dunn, B.M
    Bindings of mutant HIV-I proteases with junction B peptides containing methyleneamino isostere replacements1997In: Protein and Peptide Letters, ISSN 0929-8665, Vol. 4, p. 225-235Article in journal (Refereed)
  • 872.
    Zhao, Guang-Hui
    et al.
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
    Yang, Lei
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China; School of Nursing, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China; School of Nursing, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
    Guo, Xiong
    Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
    A preliminary analysis of microRNA profiles in the subchondral bone between Kashin-Beck disease and primary knee osteoarthritis2019In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 38, no 9, p. 2637-2645, article id 31062252Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Kashin-Beck disease (KBD) is a chronic osteochondral disorder primarily associated with cartilage degeneration. The bone texture structure in KBD was also changed but it was not identical to primary knee osteoarthritis (OA). This study investigates the differences in microRNA (miRNA) profiles of subchondral bone collected from patients suffering from KBD in comparison with those with primary knee osteoarthritis (OA).

    METHODS: Subchondral bone tissues were taken from four patients with KBD and four patients with primary knee OA undergoing total knee replacement. The miRNA array profiling was performed using an Affymetrix miRNA 4.0 Array, and then the target gene predictions and function annotations of the predicted targets were performed.

    RESULTS: Our results showed that 124 miRNAs had lower expression levels in the subchondral bone sampled from KBD patients in comparison with OA patients. Gene ontology (GO) and KEGG pathway analyses of the predicted targets demonstrated numerous significantly enriched GO terms and signal pathways essential for bone development and integrity, such as metabolic processes, PI3K-Akt, and MAPK signaling pathways.

    CONCLUSIONS: Our study confirms that a large set of miRNAs are differentially expressed in the subchondral bone of patients with KBD and OA and contributes new insights into potential pathological changes in the subchondral bone of KBD patients.

  • 873.
    Zhou, Yang
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Chen, Changchun
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Marcus J. O.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The pre-mRNA retention and splicing complex controls tRNA maturation by promoting TAN1 expression2013In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 41, no 11, p. 5669-5678Article in journal (Refereed)
    Abstract [en]

    The conserved pre-mRNA retention and splicing (RES) complex, which in yeast consists of Bud13p, Snu17p and Pml1p, is thought to promote nuclear retention of unspliced pre-mRNAs and enhance splicing of a subset of transcripts. Here, we find that the absence of Bud13p or Snu17p causes greatly reduced levels of the modified nucleoside N-4-acetylcytidine (ac(4)C) in tRNA and that a lack of Pml1p reduces ac(4)C levels at elevated temperatures. The ac(4)C nucleoside is normally found at position 12 in the tRNA species specific for serine and leucine. We show that the tRNA modification defect in RES-deficient cells is attributable to inefficient splicing of TAN1 pre-mRNA and the effects of reduced Tan1p levels on formation of ac(4)C. Analyses of cis-acting elements in TAN1 pre-mRNA showed that the intron sequence between the 5' splice site and branchpoint is necessary and sufficient to mediate RES dependency. We also show that in RES-deficient cells, the TAN1 pre-mRNA is targeted for degradation by the cytoplasmic nonsense-mediated mRNA decay pathway, indicating that poor nuclear retention may contribute to the tRNA modification defect. Our results demonstrate that TAN1 pre-mRNA processing has an unprecedented requirement for RES factors and that the complex controls the formation of ac(4)C in tRNA.

  • 874.
    Zhu, Yan-He
    et al.
    Institute of Endemic Diseases, Health Science Center, School of Public Health, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, China.
    Wang, Xin-Feng
    Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
    Yang, Guang
    Second Department of Cardiology, Shaanxi Province People's Hospital, Xi'an, China.
    Wei, Jin
    Department of Cardiology, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China..
    Tan, Wu-Hong
    Institute of Endemic Diseases, Health Science Center, School of Public Health, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, China.
    Wang, Li-Xin
    Institute of Endemic Diseases, Health Science Center, School of Public Health, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, China.
    Guo, Xiong
    Institute of Endemic Diseases, Health Science Center, School of Public Health, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Institute of Endemic Diseases, Health Science Center, School of Public Health, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, China.
    Xu, Jie-Hua
    Department of Human Anatomy and Histo-Embryology, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
    Efficacy of long-term selenium supplementation in the treatment of chronic Keshan disease with congestive heart failure2019In: Current medical science, ISSN 2096-5230, Vol. 39, no 2, p. 237-242Article in journal (Refereed)
    Abstract [en]

    Few effective treatments for chronic Keshan disease have been available till now. The efficacy of long-term selenium supplementation in the treatment of chronic Keshan disease with congestive heart failure is inconclusive. This study aimed to determine whether selenium supplementation is associated with a decreased risk of cardiac death in chronic Keshan disease with congestive heart failure by ten years of follow-up. A retrospective long-term follow-up analysis was performed on a monitored cohort consisting of 302 chronic Keshan disease patients with a mean age of 40.8±11.4 years. Of the 302 chronic Keshan disease patients, 170 (56.3%) were given selenium supplementation until the end point of follow-up. Cox proportional hazards regression models were used to identify the independent predictors of cardiac events. Our results showed that during the follow-up, there were 101 deaths of patients with chronic Keshan disease in the selenium supplementation group (101/170, 59.4%) and 98 in non-selenium supplementation group (98/132, 74.2%). Multivariate analyses suggested that selenium supplementation was associated with a decreased risk of cardiac death (HR 0.39, 95% CI 0.28-0.53) after adjustment for baseline age, sex, cigarette smoking, family history of Keshan disease, body mass index (BMI), heart rate, electrocardiogram (ECG) abnormalities, blood pressure, initial cardiothoracic ratio, left ventricular ejection fractions (LVEF) and whole-blood selenium concentration. Our ten-year follow-up analysis indicated that selenium supplementation, specifically combined with the use of angiotensin-converting enzyme inhibitor and beta blocker therapy, improved the survival of patients with chronic Keshan disease with congestive heart failure. BMI, selenium deficiency, male, combined ECG abnormalities, LVEF, and fast heart rate increased the risk of cardiac events.

  • 875.
    Zlatkov, Nikola
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Regulatory mechanisms involved in pathoadaptation of extraintestinal pathogenic Escherichia coli2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Establishment of commensal bacteria within a new niche of their host usually promotes the transition from commensalism to pathogenicity. Extraintestinal Pathogenic Escherichia coli (ExPEC) represent different pathovars with biphasic lifestyle – they can reside in the gut as commensals or they can escape and cause diseases elsewhere in the human body. Depending on the disease they are linked to, ExPEC can be divided into Uropathogenic E. coli (UPEC), Newborn Meningitis-causing E. coli (NMEC) and Sepsis-associated E. coli (SEPEC).

    Pathoadaptive mutations linked to c-di-GMP signaling were investigated in the NMEC strain IHE3034 which lacks the main global stress regulator RpoS. We investigated the role of ycgG2 in the lifestyle of NMEC. Deletion of ycgG2, shown by us to encode an YcgG allozyme with c-di-GMP phosphodiesterase (PDE) activity, and the restored RpoS led to a decrease in the S-fimbriae, otherwise robustly produced in artificial urine, hinting that the urinary tract could serve as a habitat for NMEC. We showed that NMEC were capable of aerobic citrate utilization in the presence of a co-substrate - a property that normally does not exist in E. coli. Our data hint that this metabolic upgrade is enhanced by the lack, or reduced activity, of c-di-GMP PDEs. We also found that citrate utilization is a property of ExPEC, since we reconstituted it in E. coli UTI89 (a cystitis isolate) via inactivation of its RpoS, and since a set of pyelonephritis E. coli isolates use citrate aerobically in the presence of glucose. The main reason for this metabolic capability is the absence of RpoS which leads to the production of the citrate transporter CitT. Furthermore, we highlighted the deletion of the fec operon (required for the ferric citrate uptake) in a large group of different ExPEC strains and we showed that NMEC can use CitT for in vitro ferric citrate uptake dependent on YcgG2 as an alternative system.

    Another pathoadaptive mutation which influences the fitness of ExPEC is the clyA (cytolysin A) gene inactivation, resulting from different deletions in different ExPEC genomes. When we restored the clyA+ locus, the UPEC strain 536 displayed increased susceptibility to antimicrobial peptides and urea. We also showed that the ClyA expression in 536 was increased by the presence of the DNA-binding regulator SfaX and another stand-alone PDE similar to YcgG2, called SfaY. The results were further confirmed by ClyA downregulation in NMEC deficient in SfaY and SfaX.

    We also studied the role of sfaY - a gene coding for another stand-alone c-di-GMP PDE. The expression of sfaY is under the regulation of the main promoter of the horizontally acquired sfa gene cluster. The latter is responsible for the regulation and assembly of the virulence-associated S-fimbriae, via which ExPEC bacteria bind to sialylated receptors. We found that NMEC are competent for filamentation because of a c-di-GMP-dependent program under the control of a phase-variation event which selectively turns ‘ON’ the sfa promoter in a subpopulation of bacteria. When SfaY is present, c-di-GMP levels are reduced, thus inducing the SOS stress response via the canonical LexA-RecA pathway. The signaling resulted in an internal differentiation of the bacterial population into a subpopulation exhibiting a filamentous morphotype (bacteria with induced SOS stress response) and a subpopulation of small motile and non-motile bacteria. Hence, this molecular program could serve as a clue to explain the formation of the intracellular bacterial communities observed during urinary tract infection by UPEC.

  • 876.
    Åström, S U
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordlund, M E
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Erickson, F L
    Hannig, E M
    Byström, Anders S
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Genetic interactions between a null allele of the RIT1 gene encoding an initiator tRNA-specific modification enzyme and genes encoding translation factors in Saccharomyces cerevisiae1999In: Molecular General Genetics, ISSN 0026-8925, E-ISSN 1432-1874, Vol. 261, no 6, p. 967-976Article in journal (Refereed)
    Abstract [en]

    The Saccharomyces cerevisiae gene RIT1 encodes a phospho-ribosyl transferase that exclusively modifies the initiator tRNA (tRNAMet(i)) by the addition of a 2'-O-ribosyl phosphate group to Adenosine 64. As a result, tRNAMet(i) is prevented from participating in the elongation steps of protein synthesis. We previously showed that the modification is not essential for the function of tRNAMet(i) in the initiation of translation, since rit1 null strains are viable and show no obvious growth defects. Here, we demonstrate that yeast strains in which a rit1 null allele is combined with mutations in any of the genes for the three subunits of eukaryotic initiation factor-2 (eIF-2), or with disruption alleles of two of the four initiator methionine tRNA (IMT) genes, show synergistic growth defects. A multicopy plasmid carrying an IMT gene can alleviate these defects. On the other hand, introduction of a high-copy-number plasmid carrying the TEF2 gene, which encodes the eukaryotic elongation factor 1alpha (eEF-1alpha), into rit1 null strains with two intact IMT genes had the opposite effect, indicating that increased levels of eEF-1alpha are deleterious to these strains, presumably due to sequestration of the unmodified met-tRNAMet(i) for elongation. Thus, under conditions in which the components of the ternary met-tRNAMet(i):GTP:eIF-2 complex become limiting or are functionally impaired, the presence of the 2'-O-ribosyl phosphate modification in tRNAMet(i) is important for the provision of adequate amounts of tRNAMet(i) for formation of this ternary complex.

  • 877.
    Östberg, Yngve
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berg, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Comstedt, Pär
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wieslander, Åke
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Functional analysis of a lipid galactosyltransferase synthesizing the major envelope lipid in the Lyme disease spirochete Borrelia burgdorferi2007In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 272, no 1, p. 22-29Article in journal (Refereed)
    Abstract [en]

    One of the major lipids in the membranes of Borrelia burgdorferi is monogalactosyl diacylglycerol (MGalDAG), a glycolipid recently shown to carry antigenic potency. Herein, it is shown that the gene mgs (TIGR designation bb0454) of B. burgdorferi encodes for the protein bbMGS that, when expressed in Escherichia coli, catalyzes the glycosylation of 1,2-diacylglycerol with specificity for the donor substrate UDP-Gal yielding MGalDAG. Related lipid enzymes were found in many Gram-positive bacteria. The presence of this galactosyltransferase activity and synthesis of a cholesteryl galactoside by another enzyme were verified in B. burgdorferi cell extract. Besides MGalDAG, phosphatidylcholine, phosphatidylglycerol, and cholesterol were also found as major lipids in the cell envelope. The high isoelectric point of bbMGS and clustered basic residues in its amino acid sequence suggest that the enzyme interacts with acidic lipids in the plasma membrane, in agreement with strong enzymatic activation of bbMGS by phosphatidylglycerol. The membrane packing and immunological properties of MGalDAG are likely to be of great importance in vivo.

  • 878.
    Östberg, Yngve
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bunikis, Ignas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The etiological agent of Lyme disease, Borrelia burgdorferi, appears to contain2004In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 186, no 24, p. 8472-8477Article in journal (Refereed)
    Abstract [en]

    Small regulatory RNAs (sRNAs) have recently been shown to be the main controllers of several regulatory pathways. The function of sRNAs depends in many cases on the RNA-binding protein Hfq, especially for sRNAs with an antisense function. In this study, the genome of Borrelia burgdorferi was subjected to different searches for sRNAs, including direct homology and comparative genomics searches and ortholog- and annotation-based search strategies. Two new sRNAs were found, one of which showed complementarity to the rpoS region, which it possibly controls by an antisense mechanism. The role of the other sRNA is unknown, although observed complementarities against particular mRNA sequences suggest an antisense mechanism. We suggest that the low level of sRNAs observed in B. burgdorferi is at least partly due to the presumed lack of both functional Hfq protein and RNase E activity.

  • 879.
    Östberg, Yngve
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Carroll, James A
    Pinne, Marija
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Krum, Jonathan G
    Rosa, Patricia
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pleiotropic effects of inactivating a carboxyl-terminal protease, CtpA, in Borrelia burgdorferi2004In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 186, no 7, p. 2074-2084Article in journal (Refereed)
    Abstract [en]

    The aetiological agent of Lyme disease, Borrelia burgdorferi cycles between its tick vector and mammalian hosts, implying that it can sense different environments and consequently change the expression of genes encoding several surface-associated proteins. The genome of the type strain B. burgdorferi B31 has revealed 175 different gene families. The p13 gene, situated on the chromosome, encodes a channel-forming protein that belongs to the gene family 48 consisting of eight additional paralogous genes. The heterogeneity of the P13 protein from different Lyme disease Borrelia strains was investigated. The predicted surface-exposed domains are the most heterogeneous regions and contain probable epitopes of P13. The membrane-spanning architecture of P13 was determined and a model for the location of this protein in the outer membrane is presented. The transcription of the paralogues of gene family 48 during in vitro culturing and in a mouse infection model was also analysed. The bba01 gene is the only p13 paralogue present in all three Lyme-disease-causing genospecies; it is stable during cultivation in vitro and the BBA01 protein was expressed in all Borrelia strains investigated. Conversely, paralogues bbi31, bbq06 and bbh41 were only detected in B. burgdorferi and the corresponding plasmids harbouring bbi31 and bbh41 were lost during in vitro passage. Finally, p13 and bbi31 are the only members of gene family 48 that are transcribed in mice, suggesting their importance during mammalian infection.

  • 880.
    Östberg, Yngve
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Pinne, Marija
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Benz, Roland
    Rosa, Patricia
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Elimination of channel-forming activity by insertional inactivation of the p13 gene in Borrelia burgdorferi2002In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 184, no 24, p. 6811-6819Article in journal (Refereed)
    Abstract [en]

    P13 is a chromosomally encoded 13-kDa integral outer membrane protein of the Lyme disease agent, Borrelia burgdorferi. The aim of this study was to investigate the function of the P13 protein. Here, we inactivated the p13 gene by targeted mutagenesis and investigated the porin activities of outer membrane proteins by using lipid bilayer experiments. Channel-forming activity was lost in the p13 mutant compared to wild-type B. burgdorferi, indicating that P13 may function as a porin. We purified native P13 to homogeneity by fast performance liquid chromatography and demonstrated that pure P13 has channel-forming activity with a single-channel conductance in 1 M KCl of 3.5 nS, the same as the porin activity that was lost in the p13 mutant. Further characterization of the channel formed by P13 suggested that it is cation selective and voltage independent. In addition, no major physiological effects of the inactivated p13 gene could be detected under normal growth conditions. The inactivation of p13 is the first reported inactivation of a gene encoding an integral outer membrane protein in B. burgdorferi. Here, we describe both genetic and biophysical experiments indicating that P13 in B. burgdorferi is an outer membrane protein with porin activity.

  • 881.
    Österlund, Camilla
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Activation of lung epithelial cells by group 2 mite allergens2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Throughout many parts of the world house dust mites (HDM) are considered as a major source of indoor aeroallergens and they are powerful inducers of allergic diseases. Proteolytic HDM allergens are recognised as being able to directly activate respiratory epithelial cells and thereby actively participate in innate immune responses. Although several major HDM allergens lack proteolytic activity, their possible ability to similarly interact with epithelial cells is not known.

    The overall aim of this thesis was therefore to elucidate if and how major non-proteolytic group 2 allergens from different mite species interact with respiratory epithelial cells. The effects of the structurally related Der p 2, Der f 2 and Eur m 2 from different HDM species as well as the storage mite allergen Lep d 2 were studied in vitro using human respiratory epithelial cells. Also the non-proteolytic, but structurally dissimilar, Fel d 1 from cat, Can f 2 from dog, Bet v 1 from birch and Phl p 5a from timothy were studied.

    In this thesis evidence that major group 2 mite allergens activate bronchial epithelial cells is presented. Following allergen exposure the secreted amount of the inflammatory mediators G-CSF, GM-CSF, IL-6, IL-8, MCP-1, MIP-3α and sICAM-1 was increased. Surface expression of ICAM-1 was also increased following allergen exposure. Moreover, Fel d 1 and Can f 2 induced secretion of the same mediators from bronchial epithelial cells, representing two additional protein structures being able to directly induce cell activation. In experiments using specific inhibitors and siRNA transfection, it was shown that the mite allergens engage TLR4 and activation through MyD88, MAPK and NF-κB signal transduction pathways.

    In conclusion, the novel findings in this thesis provide knowledge on how major aeroallergens, in addition to their ability to provoke specific adaptive immune responses, may aggravate a respiratory airway disease by adjuvant-like activation of inflammatory responses in bronchial epithelial cells. This differs from previously reported allergen-induction of epithelial cells by the clear independency of proteolytic activation.

  • 882.
    Östman, J.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, E.
    Caspase independent cytotoxicity induced by oligomeric TTR- mutants in neuroblastoma cellsManuscript (Other academic)
  • 883.
    Öztokatli, Hande
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hörnberg, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berghard, Anna
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Retinoic acid receptor and CNGA2 channel signaling are part of a regulatory feedback loop controlling axonal convergence and survival of olfactory sensory neurons2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 2, p. 617-627Article in journal (Refereed)
    Abstract [en]

    Little is known about the identities and functions of extracellular signaling molecules that work in concert with neuronal activity to regulate refinement and maintenance of the mouse olfactory sensory map. We show that expression of a dominant negative retinoic acid receptor (RAR) in olfactory sensory neurons (OSNs) increased the number of glomeruli that incorrectly contained OSN axons expressing different odorant receptors. This phenotype became apparent postnatally, coincided with increased cell death, and was preceded by increased Neuropilin-1 and reduced Kirrel-2 expressions. Kirrel-2-mediated cell adhesion influences odorant receptor-specific axonal convergence and is regulated by odorant receptor signaling via the olfactory cyclic nucleotide-gated (CNG) ion channel. Accordingly, we found that inhibited RAR function correlated with reduced CNG channel expression. Naris occlusion experiments and analysis of CNG channel-deficient mice further indicated that RAR-regulated CNG channel levels influenced the intrinsic neuronal activity required for cell survival in the absence of odor stimulation. Finally, we showed that CNG channel activity regulated expression of the retinoic acid-degrading enzyme Cyp26B1. Combined, these results identify a novel homeostatic feedback mechanism involving retinoic acid metabolism and CNG channel activity, which influences glomerular homogeneity and maintenance of precisely connected OSNs.

15161718 851 - 883 of 883
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