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  • 251.
    Medini, Paolo
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Experience-dependent plasticity of visual cortical microcircuits2014Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 278, s. 367-384Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The recent decade testified a tremendous increase in our knowledge on how cell-type-specific microcircuits process sensory information in the neocortex and on how such circuitry reacts to manipulations of the sensory environment. Experience-dependent plasticity has now been investigated with techniques endowed with cell resolution during both postnatal development and in adult animals. This review recapitulates the main recent findings in the field using mainly the primary visual cortex as a model system to highlight the more important questions and physiological principles (such as the role of non-competitive mechanisms, the role of inhibition in excitatory cell plasticity, the functional importance of spine and axonal plasticity on a microscale level). I will also discuss on which scientific problems the debate and controversies are more pronounced. New technologies that allow to perturbate cell-type-specific subcircuits will certainly shine new light in the years to come at least on some of the still open questions. (C) 2014 The Author. Published by Elsevier Ltd. on behalf of IBRO.

  • 252.
    Mei, Ya-Fang
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Silver, Jim
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Completely replication-competent adenovirus 11p GFP (RCAd11pGFP) vector with an insertion upstream of the full-length E1 regionArtikel i tidskrift (Övrigt vetenskapligt)
  • 253. Melo, Arthur Alves
    et al.
    Hegde, Balachandra G.
    Shah, Claudio
    Larsson, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Isas, J. Mario
    Kunz, Severine
    Lundmark, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Langen, Ralf
    Daumke, Oliver
    Structural insights into the activation mechanism of dynamin-like EHD ATPases2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 22, s. 5629-5634Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Eps15 (epidermal growth factor receptor pathway substrate 15)homology domain containing proteins (EHDs) comprise a family of dynamin-related mechano-chemical ATPases involved in cellular membrane trafficking. Previous studies have revealed the structure of the EHD2 dimer, but the molecular mechanisms of membrane recruitment and assembly have remained obscure. Here, we determined the crystal structure of an amino-terminally truncated EHD4 dimer. Compared with the EHD2 structure, the helical domains are 50 degrees rotated relative to the GTPase domain. Using electron paramagnetic spin resonance (EPR), we show that this rotation aligns the two membrane-binding regions in the helical domain toward the lipid bilayer, allowing membrane interaction. A loop rearrangement in GTPase domain creates a new interface for oligomer formation. Our results suggest that the EHD4 structure represents the active EHD conformation, whereas the EHD2 structure is autoinhibited, and reveal a complex series of domain rearrangements accompanying activation. A comparison with other peripheral membrane proteins elucidates common and specific features of this activation mechanism.

  • 254. Messing, Jutta
    et al.
    Niehues, Michael
    Shevtsova, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Boren, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hensel, Andreas
    Antiadhesive Properties of Arabinogalactan Protein from Ribes nigrum Seeds against Bacterial Adhesion of Helicobacter pylori2014Ingår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, nr 3, s. 3696-3717Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fruit extracts from black currants (Ribes nigrum L.) are traditionally used for treatment of gastritis based on seed polysaccharides that inhibit the adhesion of Helicobacter pylori to stomach cells. For detailed investigations an arabinogalactan protein (F2) was isolated from seeds and characterized concerning molecular weight, carbohydrate, amino acid composition, linkage, configuration and reaction with beta-glucosyl Yariv. Functional testing of F2 was performed by semiquantitative in situ adhesion assay on sections of human gastric mucosa and by quantitative in vitro adhesion assay with FITC-labled H. pylori strain J99 and human stomach AGS cells. Bacterial adhesins affected were identified by overlay assay with immobilized ligands. I-125-radiolabeled F2 served for binding studies to H. pylori and interaction experiments with BabA and SabA. F2 had no cytotoxic effects against H. pylori and AGS cells; but inhibited bacterial binding to human gastric cells. F2 inhibited the binding of BabA and fibronectin-binding adhesin to its specific ligands. Radiolabeled F2 bound non-specifically to different strains of H. pylori; and to BabA deficient mutant. F2 did not lead to subsequent feedback regulation or increased expression of adhesins or virulence factors. From these data the non-specific interactions between F2 and the H. pylori lead to moderate antiadhesive effects.

  • 255. Metzler, Veronika M.
    et al.
    de Brot, Simone
    Robinson, Robert S.
    Jeyapalan, Jennie N.
    Rakha, Emad
    Walton, Thomas
    Gardner, David S.
    Lund, Emma F.
    Whitchurch, Jonathan
    Haigh, Daisy
    Lochray, Jack M.
    Robinson, Brian D.
    Allegrucci, Cinzia
    Fray, Rupert G.
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Translational Medicine, Lund University, Malmo, Sweden.
    Odum, Niels
    Miftakhova, Regina R.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation.
    Rizvanov, Albert A.
    Hughes, Ieuan A.
    Tadokoro-Cuccaro, Rieko
    Heery, David M.
    Rutland, Catrin S.
    Mongan, Nigel P.
    Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development2017Ingår i: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 56, s. 79-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models.

  • 256. Meyer, Barbara J.
    et al.
    Stewart, Frances M.
    Brown, Elizabeth A.
    Cooney, Josephine
    Nilsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Ramsay, Jane E.
    Griffin, Bruce A.
    Caslake, Muriel J.
    Freeman, Dilys J.
    Maternal Obesity Is Associated With the Formation of Small Dense LDL and Hypoadiponectinemia in the Third Trimester2013Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, nr 2, s. 643-652Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Maternal obesity is associated with high plasma triglyceride, poor vascular function, and an increased risk for pregnancy complications. In normal-weight pregnant women, higher triglyceride is associated with increased small, dense low-density lipoprotein (LDL). Hypothesis: In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of very low-density lipoprotein-1 particles and formation of small dense LDL via lipoprotein lipase. Design: Women (n = 55) of body mass index of 18-46 kg/m(2) were sampled longitudinally at 12, 26, and 35 weeks' gestation and 4 months postnatally. Setting: Women were recruited at hospital antenatal appointments, and study visits were in a clinical research suite. Outcome Measures: Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin, and adiponectin were determined. Results: Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum, and then returned to higher postnatal levels than normal-weight women. Estradiol response to pregnancy (trimester 1-3 incremental area under the curve) was positively associated with plasma triglyceride response (r(2) adjusted 25%, P < .001). In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal-weight women[mean (SD) 40.7 (18.8) vs 21.9 (10.9)%, P = .014], and 35% of obese, 14% of overweight, and none of the normal-weight women displayed an atherogenic LDL subfraction phenotype. The small, dense LDL mass response to pregnancy was inversely associated with adiponectin response (17%, P = .013). Conclusions: Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome.

  • 257. Meyers, Nathan L
    et al.
    Larsson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi. Department of Medicine, UCLA, Los Angeles, California.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Small, Donald M
    A Pressure-dependent Model for the Regulation of Lipoprotein Lipase by Apolipoprotein C-II2015Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, nr 29, s. 18029-18044Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Apolipoprotein C-II (apoC-II) is the co-factor for lipoprotein lipase (LPL) at the surface of triacylglycerol-rich lipoproteins. LPL hydrolyzes triacylglycerol, which increases local surface pressure as surface area decreases and amphipathic products transiently accumulate at the lipoprotein surface. To understand how apoC-II adapts to these pressure changes, we characterized the behavior of apoC-II at multiple lipid/water interfaces. ApoC-II adsorption to a triacylglycerol/water interface resulted in large increases in surface pressure. ApoC-II was exchangeable at this interface and desorbed on interfacial compressions. These compressions increase surface pressure and mimic the action of LPL. Analysis of gradual compressions showed that apoC-II undergoes a two-step desorption, which indicates that lipid-bound apoC-II can exhibit at least two conformations. We characterized apoC-II at phospholipid/triacylglycerol/water interfaces, which more closely mimic lipoprotein surfaces. ApoC-II had a large exclusion pressure, similar to that of apoC-I and apoC-III. However, apoC-II desorbed at retention pressures higher than those seen with the other apoCs. This suggests that it is unlikely that apoC-I and apoC-III inhibit LPL via displacement of apoC-II from the lipoprotein surface. Upon rapid compressions and re-expansions, re-adsorption of apoC-II increased pressure by lower amounts than its initial adsorption. This indicates that apoC-II removed phospholipid from the interface upon desorption. These results suggest that apoC-II regulates the activity of LPL in a pressure-dependent manner. ApoC-II is provided as a component of triacylglycerol-rich lipoproteins and is the co-factor for LPL as pressure increases. Above its retention pressure, apoC-II desorbs and removes phospholipid. This triggers release of LPL from lipoproteins.

  • 258. Minkevich, N. I.
    et al.
    Rakitina, T. V.
    Bogachuk, A. P.
    Radchenko, V. V.
    Surina, E. A.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Yanamandra, Kiran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iomdina, E. N.
    Babichenko, I. I.
    Kostanyan, I. A.
    Lipkin, V. M.
    Formation of amyloid-like fibrillar structures and destruction of fibroblasts of the Tenon's capsule in progressive myopia due to resistance of the pigment epithelium-derived factor to restricted proteolysis2012Ingår i: Russian journal of bioorganic chemistry, ISSN 1068-1620, E-ISSN 1608-330X, Vol. 38, nr 6, s. 605-612Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously shown that, normally, two forms of the pigment epithelium-derived factor (PEDF) with molecular weights of 50 and 45 kDa are present in the Tenon's capsule in equal amounts. These forms represent the full-length protein and a product of restricted proteolysis of PEDF. In persons with myopia, the full-length uncleaved factor was predominantly detected, which correlated with the disturbance of collagen fiber formation. An immunohistochemical study of the Tenon's capsule using polyclonal antibodies to PEDF showed that, in the control group, the factor is localized solely inside fibroblasts, whereas in patients with myopia, PEDF is distributed outside the cell as a halo around destroyed fibroblasts. It was shown in the present work using atomic force microscopy and immunodot assay with antibodies specific to amyloid fibrils that only the full-length PEDF is capable of forming amyloid-like fibrillar structures. The accumulation of fibrils leads to the destruction of fibroblasts and is a cause of changes in the biochemical composition and morphological structure of the Tenon's capsule in myopia.

  • 259.
    Mondol, Tanumoy
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    Biology and Biological Engineering Department, Chalmers University of Technology, Gothenburg, Sweden.
    Copper binding triggers compaction in N-terminal tail of human copper pump ATP7B2016Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 470, nr 3, s. 663-669Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein conformational changes are fundamental to biological reactions. For copper ion transport, the multi-domain protein ATP7B in the Golgi network receives copper from the cytoplasmic copper chaperone Atox1 and, with energy from ATP hydrolysis, moves the metal to the lumen for loading of copper dependent enzymes. Although anticipated, conformational changes involved in ATP7B's functional cycle remain elusive. Using spectroscopic methods we here demonstrate that the four most N-terminal metal binding domains in ATP7B, upon stoichiometric copper addition, adopt a more compact arrangement which has a higher thermal stability than in the absence of copper. In contrast to previous reports, no stable complex was found in solution between the metal-binding domains and the nucleotide-binding domain of ATP7B. Metal-dependent movement of the first four metal-binding domains in ATP7B may be a trigger that initiates the overall catalytic cycle.

  • 260.
    Monsen, Tor
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Flow Cytometry Analysis Using Sysmex UF-1000i Classifies Uropathogens Based on Bacterial, Leukocyte, and Erythrocyte Counts in Urine Specimens among Patients with Urinary Tract Infections2015Ingår i: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 53, nr 2, s. 539-545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Urinary tract infections (UTIs) are the second most common bacterial infection. Urine culture is the gold standard for diagnosis, but new techniques, such as flow cytometry analysis (FCA), have been introduced. The aim of the present study was to evaluate FCA characteristics regarding bacteriuria, leukocyturia, and erythrocyturia in relation to cultured uropathogens in specimens from patients with a suspected UTI. We also wanted to evaluate whether the FCA characteristics can identify uropathogens prior to culture. From a prospective study, 1,587 consecutive urine specimens underwent FCA prior to culture during January and February 2012. Outpatients and inpatients (79.6% and 19.4%, respectively) were included, of whom women represented 67.5%. In total, 620 specimens yielded growth, of which Escherichia coli represented 65%, Enterococcus spp.8%, Klebsiella spp. 7%, and Staphylococcus spp. 5%. For the uropathogens, the outcome of FCA was compared against the results for specimens with E. coli and those with a negative culture. E. coli had high bacterial (median, 17,914/mu l), leukocyte (median, 348/mu l), and erythrocyte (median, 23/mu l) counts. With the exception of Klebsiella spp., the majority of the uropathogens had considerable or significantly lower bacterial counts than that of E. coli. High leukocyte counts were found in specimens with Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, and group C streptococci. Elevated erythrocyte counts were found for P. vulgaris, P. aeruginosa, and group C streptococci, as well as for Staphylococcus saprophyticus. In essence, FCA adds new information about the bacterial, leukocyte, and erythrocyte counts in urine specimens for different uropathogens. Based on FCA characteristics, uropathogens can be classified and identified prior to culture. E. coli and Klebsiella spp. have similar FCA characteristics.

  • 261. Moreno, Renata
    et al.
    Hernandez-Arranz, Sofia
    La Rosa, Ruggero
    Yuste, Luis
    Madhushani, Anjana
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Shingler, Victoria
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Rojo, Fernando
    The Crc and Hfq proteins of Pseudomonas putida cooperate in catabolite repression and formation of ribonucleic acid complexes with specific target motifs2015Ingår i: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920, Vol. 17, nr 1, s. 105-118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Crc protein is a global regulator that has a key role in catabolite repression and optimization of metabolism in Pseudomonads. Crc inhibits gene expression post-transcriptionally, preventing translation of mRNAs bearing an AAnAAnAA motif [the catabolite activity (CA) motif] close to the translation start site. Although Crc was initially believed to bind RNA by itself, this idea was recently challenged by results suggesting that a protein co-purifying with Crc, presumably the Hfq protein, could account for the detected RNA-binding activity. Hfq is an abundant protein that has a central role in post-transcriptional gene regulation. Herein, we show that the Pseudomonas putidaHfq protein can recognize the CA motifs of RNAs through its distal face and that Crc facilitates formation of a more stable complex at these targets. Crc was unable to bind RNA in the absence of Hfq. However, pull-down assays showed that Crc and Hfq can form a co-complex with RNA containing a CA motif in vitro. Inactivation of the hfq or the crc gene impaired catabolite repression to a similar extent. We propose that Crc and Hfq cooperate in catabolite repression, probably through forming a stable co-complex with RNAs containing CA motifs to result in inhibition of translation initiation.

  • 262. Morin, Eric
    et al.
    Sjöberg, Elin
    Tjomsland, Vegard
    Testini, Chiara
    Lindskog, Cecilia
    Franklin, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Sund, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå University, Wallenberg Centre for Molecular Medicine, Umeå, Sweden.
    Kiflemariam, Sara
    Sjöblom, Tobias
    Claesson-Welsh, Lena
    VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival2018Ingår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, nr 3, s. 311-322Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. 

  • 263.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Proinflammatory S100A8/A9 in amyloid formation in the aging prostate: risk factor for cancer2016Ingår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 38, s. S28-S28Artikel i tidskrift (Övrigt vetenskapligt)
  • 264. Movérare-Skrtic, Sofia
    et al.
    Henning, Petra
    Liu, Xianwen
    Nagano, Kenichi
    Saito, Hiroaki
    Börjesson, Anna E.
    Sjögren, Klara
    Windahl, Sara H.
    Farman, Helen
    Kindlund, Bert
    Engdahl, Cecilia
    Koskela, Antti
    Zhang, Fu-Ping
    Eriksson, Emma E.
    Zaman, Farasat
    Hammarstedt, Ann
    Isaksson, Hanna
    Bally, Marta
    Kassem, Ali
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Lindholm, Catharina
    Sandberg, Olof
    Aspenberg, Per
    Sävendahl, Lars
    Feng, Jian Q.
    Tuckermann, Jan
    Tuukkanen, Juha
    Poutanen, Matti
    Baron, Roland
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Gori, Francesca
    Ohlsson, Claes
    Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures2014Ingår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 20, nr 11, s. 1279-1288Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.

  • 265.
    Mu, Yabing
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Gudey, Shyam Kumar
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Landström, Marene
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Non-Smad signaling pathways2012Ingår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 347, nr 1, s. 11-20Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Transforming growth factor-beta (TGF beta) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGF beta signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (T beta RI and T beta RII, respectively). The activated T beta R complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGF beta also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGF beta-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGF beta-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGF beta are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGF beta-induced responses by non-Smad signaling pathways.

  • 266. Mudway, I S
    et al.
    Stenfors, Nikolai
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Department of Respiratory Medicine and Allergy, University Hospital, Umeå.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Department of Respiratory Medicine and Allergy, University Hospital, Umeå.
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Department of Respiratory Medicine and Allergy, University Hospital, Umeå.
    Dunster, C
    Marklund, S L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Frew, A J
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Department of Respiratory Medicine and Allergy, University Hospital, Umeå.
    Kelly, F J
    Differences in basal airway antioxidant concentrations are not predictive of individual responsiveness to ozone: a comparison of healthy and mild asthmatic subjects2001Ingår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 31, nr 8, s. 962-974Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The air pollutant ozone induces both airway inflammation and restrictions in lung function. These responses have been proposed to arise as a consequence of the oxidizing nature of ozone, depleting endogenous antioxidant defenses with ensuing tissue injury. In this study we examined the impact of an environmentally relevant ozone challenge on the antioxidant defenses present at the surface of the lung in two groups known to have profound differences in their antioxidant defense network: healthy control (HC) and mild asthmatic (MA) subjects. We hypothesized that baseline differences in antioxidant concentrations within the respiratory tract lining fluid (RTLF), as well as induced responses, would predict the magnitude of individual responsiveness. We observed a significant loss of ascorbate (ASC) from proximal (-45.1%, p <.01) and distal RTLFs (-11.7%, p <.05) in healthy subjects 6 h after the end of the ozone challenge. This was associated (Rs, -0.71, p <.01) with increased glutathione disulphide (GSSG) in these compartments (p =.01 and p <.05). Corresponding responses were not seen in asthmatics, where basal ASC concentrations were significantly lower (p <.01) and associated with elevated concentrations of GSSG (p <.05). In neither group was any evidence of lipid oxidation seen following ozone. Despite differences in antioxidant levels and response, the magnitude of ozone-induced neutrophilia (+20.6%, p <.01 [HC] vs. +15.2%, p =.01 [MA]) and decrements in FEV(1) (-8.0%, p <.01 [HC] vs. -3.2%, p <.05 [MA]) did not differ between the two groups. These data demonstrate significant differences between the interaction of ozone with RTLF antioxidants in MA and HC subjects. These responses and variations in basal antioxidant defense were not, however, useful predictive markers of group or individual responsiveness to ozone.

  • 267. Mysling, Simon
    et al.
    Kolby Kristensen, Kristian
    Larsson, Mikael
    Kovrov, Oleg
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Bensadouen, André
    Jorgensen, Thomas J. D.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Young, Stephen G.
    Ploug, Michael
    The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding2016Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 5, artikel-id e20958Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lipoprotein lipase (LPL) undergoes spontaneous inactivation via global unfolding and this unfolding is prevented by GPIHBP1 (Mysling et al., 2016). We now show: (1) that ANGPTL4 inactivates LPL by catalyzing the unfolding of its hydrolase domain; (2) that binding to GPIHBP1 renders LPL largely refractory to this inhibition; and (3) that both the LU domain and the intrinsically disordered acidic domain of GPIHBP1 are required for this protective effect. Genetic studies have found that a common polymorphic variant in ANGPTL4 results in lower plasma triglyceride levels. We now report: (1) that this ANGPTL4 variant is less efficient in catalyzing the unfolding of LPL; and (2) that its Glu-to-Lys substitution destabilizes its N-terminal alpha-helix. Our work elucidates the molecular basis for regulation of LPL activity by ANGPTL4, highlights the physiological relevance of the inherent instability of LPL, and sheds light on the molecular defects in a clinically relevant variant of ANGPTL4.

  • 268.
    Myte, Robin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sundkvist, Anneli
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Harlid, Sophia
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort2019Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, nr 7, s. 649-659Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Vasterbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.

  • 269.
    Méndez, Melissa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Diversity and adaptation in the adherence properties of Helicobacter pylori2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 270.
    Méndez, Melissa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kersulyte, Dangeruta
    Sjöström, Rolf
    Balqui, Jacqueline
    Velapatiño, Billie
    Cabrera, Lilia
    Herrera, Phabiola
    Kalia, Awdhesh
    Gilman, Robert
    Berg, Douglas
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Functional polymorphism and blood group tropism in Helicobacter pylori BabA from remote Amazon diasporasManuskript (preprint) (Övrigt vetenskapligt)
  • 271. Nettleton, Jennifer A
    et al.
    Follis, Jack L
    Ngwa, Julius S
    Smith, Caren E
    Ahmad, Shafqat
    Tanaka, Toshiko
    Wojczynski, Mary K
    Voortman, Trudy
    Lemaitre, Rozenn N
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Houston, Denise K
    Perälä, Mia-Maria
    Qi, Qibin
    Sonestedt, Emily
    Manichaikul, Ani
    Kanoni, Stavroula
    Ganna, Andrea
    Mikkilä, Vera
    North, Kari E
    Siscovick, David S
    Harald, Kennet
    Mckeown, Nicola M
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Rissanen, Harri
    Liu, Yongmei
    Lahti, Jari
    Hu, Frank B
    Bandinelli, Stefania
    Rukh, Gull
    Rich, Stephen
    Booij, Lisanne
    Dmitriou, Maria
    Ax, Erika
    Raitakari, Olli
    Mukamal, Kenneth
    Männistö, Satu
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Jula, Antti
    Ericson, Ulrika
    Jacobs, David R, Jr
    Van Rooij, Frank J A
    Deloukas, Panos
    Sjögren, Per
    Kähönen, Mika
    Djousse, Luc
    Perola, Markus
    Barroso, Inês
    Hofman, Albert
    Stirrups, Kathleen
    Viikari, Jorma
    Uitterlinden, André G
    Kalafati, Ioanna P
    Franco, Oscar H.
    Mozaffarian, Dariush
    Salomaa, Veikko
    Borecki, Ingrid B
    Knekt, Paul
    Kritchevsky, Stephen B
    Eriksson, Johan G
    Dedoussis, George V
    Qi, Lu
    Ferrucci, Luigi
    Orho-Melander, Marju
    Zillikens, M Carola
    Ingelsson, Erik
    Lehtimäki, Terho
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden.
    Cupples, L Adrienne
    Loos, Ruth J F
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden; Department of Nutrition, Harvard Chan School of Public Health, Boston, MA, USA.
    Gene x dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry2015Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, nr 16, s. 4728-4738Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

  • 272.
    Nicoll, Rachel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Howard, John McLaren
    Henein, Michael Y.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    A Review of the Effect of Diet on Cardiovascular Calcification2015Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, nr 4, s. 8861-8883Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Cardiovascular (CV) calcification is known as sub-clinical atherosclerosis and is recognised as a predictor of CV events and mortality. As yet there is no treatment for CV calcification and conventional CV risk factors are not consistently correlated, leaving clinicians uncertain as to optimum management for these patients. For this reason, a review of studies investigating diet and serum levels of macro- and micronutrients was carried out. Although there were few human studies of macronutrients, nevertheless transfats and simple sugars should be avoided, while long chain -3 fats from oily fish may be protective. Among the micronutrients, an intake of 800 g/day calcium was beneficial in those without renal disease or hyperparathyroidism, while inorganic phosphorus from food preservatives and colas may induce calcification. A high intake of magnesium (380 mg/day) and phylloquinone (500 g/day) proved protective, as did a serum 25(OH)D concentration of 75 nmol/L. Although oxidative damage appears to be a cause of CV calcification, the antioxidant vitamins proved to be largely ineffective, while supplementation of -tocopherol may induce calcification. Nevertheless other antioxidant compounds (epigallocatechin gallate from green tea and resveratrol from red wine) were protective. Finally, a homocysteine concentration >12 mu mol/L was predictive of CV calcification, although a plasma folate concentration of >39.4 nmol/L could both lower homocysteine and protect against calcification. In terms of a dietary programme, these recommendations indicate avoiding sugar and the transfats and preservatives found in processed foods and drinks and adopting a diet high in oily fish and vegetables. The micronutrients magnesium and vitamin K may be worthy of further investigation as a treatment option for CV calcification.

  • 273.
    Nicoll, Rachel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Zhao, Ying
    Ibrahimi, Pranvera
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Henein, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Diabetes and Hypertension Consistently Predict the Presence and Extent of Coronary Artery Calcification in Symptomatic Patients: A Systematic Review and Meta-Analysis2016Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 17, nr 9, artikel-id 1481Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Background: The relationship of conventional cardiovascular risk factors (age, gender, ethnicity, diabetes, dyslipidaemia, hypertension, obesity, exercise, and the number of risk factors) to coronary artery calcification (CAC) presence and extent has never before been assessed in a systematic review and meta-analysis.

    Methods: We included only English language studies that assessed at least three conventional risk factors apart from age, gender, and ethnicity, but excluded studies in which all patients had another confirmed condition such as renal disease.

    Results: In total, 10 studies, comprising 15,769 patients, were investigated in the systematic review and seven studies, comprising 12,682 patients, were included in the meta-analysis, which demonstrated the importance of diabetes and hypertension as predictors of CAC presence and extent, with age also predicting CAC presence. Male gender, dyslipidaemia, family history of coronary artery disease, obesity, and smoking were overall not predictive of either CAC presence or extent, despite dyslipidaemia being a key risk factor for coronary artery disease (CAD).

    Conclusion: Diabetes and hypertension consistently predict the presence and extent of CAC in symptomatic patients.

     

  • 274.
    Nielsen, Søren B
    et al.
    Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
    Wilhelm, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Vad, Brian
    Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Otzen, Daniel
    Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
    The interaction of equine lysozyme: oleic acid complexes with lipid membranes suggests a cargo off-loading mechanism2010Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 398, nr 2, s. 351-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The normal function of equine lysozyme (EL) is the hydrolysis of peptidoglycan residues of bacterial cell walls. EL is closely related to alpha-lactalbumins with respect to sequence and structure and further possesses the calcium binding site of alpha-lactalbumins. Recently, EL multimeric complexes with oleic acids (ELOA) were shown to possess tinctorial and morphological properties, similar to amyloidal aggregates, and to be cytotoxic. ELOA's interactions with phospholipid membranes appears to be central to its biological action, similar to human alpha-lactalbumin made lethal to tumor cells (HAMLET). Here, we describe the interaction of ELOA with phospholipid membranes. Confocal scanning laser microscopy shows that ELOA, but not native EL, accumulates on the surface of giant unilamellar vesicles, without inducing significant membrane permeability. Quartz crystal microbalance with dissipation (QCM-D) data indicated an essentially non-disruptive binding of ELOA to supported lipid bilayers, leading to formation of highly dissipative and "soft" lipid membrane; at higher concentrations of ELOA, the lipid membrane desorbs from the surface probably as bilayer sheets of vesicles. This membrane rearrangement occurred to a similar extent when free oleic acid (OA) was added, but not when free OA was removed from ELOA by prior incubation with BSA, emphasizing the role of OA in this process. NMR data indicated an equilibrium between free and bound OA which shifts towards free OA as ELOA is progressively diluted indicating that OA is relatively loosely bound. Activity measurements together with fluorescence spectroscopy and circular dichroism suggested a conversion of ELOA toward a more native-like state on interaction with lipid membranes, although complete refolding was not observed. Altogether, these results suggest that ELOA may act as an OA carrier and facilitate OA transfer to the membrane. ELOA's properties illustrate that protein folding variants may possess specific functional properties distinct from the native protein. Abbreviations QCM-D, Quartz crystal microbalance with dissipation; CD, Circular dichroism; EL, equine lysozyme; ELOA, EL complex with oleic acid; OA, oleic acid, CSLM, Confocal scanning laser microscopy, Df, dissipation-frequency.

  • 275.
    Nilsson, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Vesterlund, Liselotte
    Karolinska Institute.
    Oldenborg, Per-Arne
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Macrophage expression of LRP1, a receptor for apoptotic cells and unopsonized erythrocytes, can be regulated by glucocorticoids2012Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 417, nr 4, s. 1304-1309Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macrophage phagocytosis of apoptotic cells, or unopsonized viable CD47(-/-) red blood cells, can be mediated by the interaction between calreticulin (CRT) on the target cell and LDL receptor-related protein-1 (LRP1/CD91/alpha 2-macroglobulin receptor) on the macrophage. Glucocorticoids (GC) are powerful in treatment of a range of inflammatory conditions, and were shown to enhance macrophage uptake of apoptotic cells. Here we investigated if the ability of GC to promote macrophage uptake of apoptotic cells could in part be mediated by an upregulation of macrophage LRP1 expression. Using both resident peritoneal and bone marrow-derived macrophages, we found that the GC dexamethasone could dose- and time-dependently increase macrophage LRP1 expression. The GC receptor-inhibitor RU486 could dose-dependently prevent LRP1 upregulation. Dexamethasone-treated macrophages did also show enhanced phagocytosis of apoptotic thymocytes as well as unopsonized viable CD47(-/-) red blood cells, which was sensitive to inhibition by the LRP1-agonist RAP. In conclusion, these data suggest that GC-stimulated macrophage uptake of apoptotic cells may involve an upregulation of macrophage LRP1 expression and enhanced LRP1-mediated phagocytosis. (C) 2012 Elsevier Inc. All rights reserved.

  • 276.
    Nilsson, Stefan K
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Christensen, Stine
    Raarup, Merete K
    Ryan, Robert O
    Nielsen, Morten S
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Endocytosis of apolipoprotein A-V by members of the low density lipoprotein receptor and the VPS10p domain receptor families.2008Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, nr 38, s. 25920-25927Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Apolipoprotein A-V (apoA-V) is present in low amounts in plasma and has been found to modulate triacylglycerol levels in humans and in animal models. ApoA-V displays affinity for members of the low density lipoprotein receptor (LDL-R) gene family, known as the classical lipoprotein receptors, including LRP1 and SorLA/LR11. In addition to LDL-A binding repeats, the mosaic receptor SorLA/LR11 also possesses a Vps10p domain. Here we show that apoA-V also binds to sortilin, a receptor from the Vsp10p domain gene family that lacks LDL-A repeats. Binding of apoA-V to sortilin was competed by neurotensin, a ligand that binds specifically to the Vps10p domain. To investigate the biological fate of receptor-bound apoA-V, binding experiments were conducted with cultured human embryonic kidney cells transfected with either SorLA/LR11 or sortilin. Compared with nontransfected cells, apoA-V binding to SorLA/LR11- and sortilin-expressing cells was markedly enhanced. Internalization experiments, live imaging studies, and fluorescence resonance energy transfer analyses demonstrated that labeled apoA-V was rapidly internalized, co-localized with receptors in early endosomes, and followed the receptors through endosomes to the trans-Golgi network. The observed decrease of fluorescence signal intensity as a function of time during live imaging experiments suggested ligand uncoupling in endosomes with subsequent delivery to lysosomes for degradation. This interpretation was supported by experiments with (125)I-labeled apoA-V, demonstrating clear differences in degradation between transfected and nontransfected cells. We conclude that apoA-V binds to receptors possessing LDL-A repeats and Vsp10p domains and that apoA-V is internalized into cells via these receptors. This could be a mechanism by which apoA-V modulates lipoprotein metabolism in vivo.

  • 277.
    Nilsson, Torbjörn K
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Hurtig-Wennlöf, Anita
    Sjostrom, Michael
    Herrmann, Wolfgang
    Obeid, Rima
    Owen, Jennifer R
    Zeisel, Steven
    Plasma 1-carbon metabolites and academic achievement in 15-yr-old adolescents2016Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 30, nr 4, s. 1683-1688Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Academic achievement in adolescents is correlated with 1-carbon metabolism (1-CM), as folate intake is positively related and total plasma homocysteine (tHcy) negatively related to academic success. Because another 1-CM nutrient, choline is essential for fetal neurocognitive development, we hypothesized that choline and betaine could also be positively related to academic achievement in adolescents. In a sample of 15-yr-old children (n = 324), we measured plasma concentrations of homocysteine, choline, and betaine and genotyped them for 2 polymorphisms with effects on 1-CM, methylenetetrahydrofolate reductase (MTHFR) 677C>T, rs1801133, and phosphatidylethanolamine N-methyltransferase (PEMT), rs12325817 (G>C). The sum of school grades in 17 major subjects was used as an outcome measure for academic achievement. Lifestyle and family socioeconomic status (SES) data were obtained from questionnaires. Plasma choline was significantly and positively associated with academic achievement independent of SES factors (paternal education and income, maternal education and income, smoking, school) and of folate intake (P = 0.009, R-2 = 0.285). With the addition of the PEMT rs12325817 polymorphism, the association value was only marginally changed. Plasma betaine concentration, tHcy, and the MTHFR 677C>T polymorphism did not affect academic achievement in any tested model involving choline. Dietary intake of choline is marginal in many adolescents and may be a public health concern.

  • 278.
    Nilsson, Torbjörn K
    et al.
    Department of Laboratory Medicine, Clinical Chemistry, Örebro University Hospital, and School of Health and Medical Sciences, Örebro University.
    Laanpere, Margit
    Altmäe, Signe
    Serra-Majem, Lluís
    Salumets, Andres
    A folate receptor alpha double-mutated haplotype 1816delC-1841A is distributed throughout Eurasia and associated with lower erythrocyte folate levels2012Ingår i: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 39, nr 4, s. 4471-4478Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Folate is crucial for various cellular functions. Several transport mechanisms allow folate to enter the intracellular compartment with folate receptor-α being the major high-affinity receptor. Rare genetic variations in exons of the FR-α gene, FOLR1, were recently shown to cause severe folate deficiency accompanied by neurological and other disturbances. So far, similar effects by genetic variation in noncoding parts of the FOLR1 gene have not been identified. The aim of our study was to determine biochemically the haplotype structure of two linked polymorphisms in the FOLR1 gene, 1816delC and 1841G>A, the prevalences of the mutated alleles across Eurasia, and their possible effects on physiological folate levels in vivo. For this purpose we employed allele-specific PCR and Pyrosequencing technology and performed genotyping in 738 subjects from Spain, 387 from Sweden, 952 from Estonia, and 47 from Korea. We demonstrate the presence of an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, with the prevalence of the mutated allele being highest among Koreans (q = 0.074), lower in Estonians (q = 0.017), Spaniards (q = 0.0061), and the lowest among Swedes (q = 0.0026). Erythrocyte folate levels were studied in the Spanish population sample, where subjects carrying the double-mutated FOLR1 haplotype had significantly reduced levels by 27% (P = 0.039), adjusted for serum vitamin B(12) levels and MTHFR 677C>T genotype, while the mean serum folate levels were only 20% lower among the carriers (P = 0.11). Plasma homocysteine and cobalamin levels did not differ. Thus, we have demonstrated by molecular haplotyping an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, spread over the whole Eurasian continent, which may be of functional importance for uptake of folate in red blood cells.

  • 279.
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    The Colours of Diabetes: advances and novel applications of molecular optical techniques for studies of the pancreas2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Diabetes is a rapidly increasing health problem. In a global perspective,approximately 415 million people suffered from diabetes in 2015 and this number ispredicted to increase to 640 million by 2040. To tackle this pandemic there is a needfor better analytical tools by which we can increase our understanding of the disease.One discipline that has already provided much needed insight to diabetes etiology isoptical molecular imaging. Using various forms of light it is possible to create animage of the analysed sample that can provide information about molecularmechanistic aspects of the disease and to follow spatial and temporal dynamics.

    The overall aim of this thesis is to improve and adapt existing andnovel optical imaging approaches for their specific use in diabetes research. Hereby,we have focused on three techniques: (I) Optical projection tomography (OPT),which can be described as the optical equivalent of x-ray computed tomography(CT), and two vibrational microspectroscopic (VMS) techniques, which records theunique vibrational signatures of molecules building up the sample: (II) Fouriertransforminfrared vibrational microspectroscopy (FT-IR) and (III) Ramanvibrational microspectroscopy (Raman).

    The computational tools and hardware applications presented here generallyimprove OPT data quality, processing speed, sample size and channel capacity.Jointly, these developments enable OPT as a routine tool in diabetes research,facilitating aspects of e.g. pancreatic β-cell generation, proliferation,reprogramming, destruction and preservation to be studied throughout the pancreaticvolume and in large cohorts of experimental animals. Further, a novel application ofmultivariate analysis of VMS data derived from pancreatic tissues is introduced.This approach enables detection of novel biochemical alterations in the pancreasduring diabetes disease progression and can be used to confirm previously reportedbiochemical alterations, but at an earlier stage. Finally, our studies indicate thatRaman imaging is applicable to in vivo studies of grafted islets of Langerhans,allowing for longitudinal studies of pancreatic islet biochemistry.viIn summary, presented here are new and improved methods by which opticalimaging techniques can be utilised to study 3D-spatial, quantitative andmolecular/biochemical alterations of the normal and diseased pancreas.

  • 280.
    Nord, Christoffer
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Dicker, Andrea
    Eriksson, Anna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Grong, Eivind
    Ilegems, Erwin
    Marvik, Ronald
    Kulseng, Bard
    Berggren, Per-Olof
    Gorzsas, Andras
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Biochemical profiling of diabetes disease progression by multivariate vibrational microspectroscopy of the pancreas2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 6646Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite the dramatic increase in the prevalence of diabetes, techniques for in situ studies of the underlying pancreatic biochemistry are lacking. Such methods would facilitate obtaining mechanistic understanding of diabetes pathophysiology and aid in prognostic and/or diagnostic assessments. In this report we demonstrate how a multivariate imaging approach (orthogonal projections to latent structures - discriminant analysis) can be applied to generate full vibrational microspectroscopic profiles of pancreatic tissues. These profiles enable extraction of known and previously unrecorded biochemical alterations in models of diabetes, and allow for classification of the investigated tissue with regards to tissue type, strain and stage of disease progression. Most significantly, the approach provided evidence for dramatic alterations of the pancreatic biochemistry at the initial onset of immune-infiltration in the Non Obese Diabetic model for type 1 diabetes. Further, it enabled detection of a previously undocumented accumulation of collagen fibrils in the leptin deficient ob/ob mouse islets. By generating high quality spectral profiles through the tissue capsule of hydrated human pancreata and by in vivo Raman imaging of pancreatic islets transplanted to the anterior chamber of the eye, we provide critical feasibility studies for the translation of this technique to diagnostic assessments of pancreatic biochemistry in vivo.

  • 281.
    Nord, Christoffer
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Dicker, Andrea
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Sweden.
    Eriksson, Anna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Grong, Eivind
    Dept. of Gastrointestinal Surgery, St. Olavs Hospital, Trondheim University Hospital, Norway; Dept. of Cancer Research and Molecular Medicine, NTNU, Norway.
    Ilegems, Erwin
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Sweden.
    Mårvik, Ronald
    Dept. of Gastrointestinal Surgery, St. Olavs Hospital, Trondheim University Hospital, Norway; Dept. of Cancer Research and Molecular Medicine, NTNU, Norway.
    Kulseng, Bård
    Dept. of Cancer Research and Molecular Medicine, NTNU, Norway.
    Berggren, Per‐Olof
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Sweden.
    Gorzsás, András
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Multivariate image analysis facilitates label‐free, biochemicalprofiling of the diabetic pancreasManuskript (preprint) (Övrigt vetenskapligt)
  • 282. Nordin, Joel Z.
    et al.
    Lee, Yi
    Vader, Pieter
    Maeger, Imre
    Johansson, Henrik J.
    Heusermann, Wolf
    Wiklander, Oscar P. B.
    Hallbrink, Mattias
    Seow, Yiqi
    Bultema, Jarred J.
    Gilthorpe, Jonathan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Davies, Tim
    Fairchild, Paul J.
    Gabrielsson, Susanne
    Meisner-Kober, Nicole C.
    Lehtio, Janne
    Smith, C. I. Edvard
    Wood, Matthew J. A.
    Andaloussi, Samir E. L.
    Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties2015Ingår i: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 11, nr 4, s. 879-883Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Extracellular vesicles (EVs) are natural nanoparticles that mediate intercellular transfer of RNA and proteins and are of great medical interest; serving as novel biomarkers and potential therapeutic agents. However, there is little consensus on the most appropriate method to isolate high-yield and high-purity EVs from various biological fluids. Here, we describe a systematic comparison between two protocols for EV purification: ultrafiltration with subsequent liquid chromatography (UF-LC) and differential ultracentrifugation (UC). A significantly higher EV yield resulted from UF-LC as compared to UC, without affecting vesicle protein composition. Importantly, we provide novel evidence that, in contrast to UC-purified EVs, the biophysical properties of UF-LC-purified EVs are preserved, leading toadifferent in vivo biodistribution, with less accumulation in lungs. Finally, we show that UF-LC is scalable and adaptable for EV isolation from complex media types such as stem cell media, which is of huge significance for future clinical applications involving EVs. 

  • 283.
    Nordlund, Anna
    et al.
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Leinartaitė, Lina
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Saraboji, Kadhirvel
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Aisenbrey, Christopher
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gröbner, Gerhard
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Danielsson, Jens
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Logan, Derek T
    Department of Molecular Biophysics, Lund University, S-221 00 Lund, Sweden.
    Oliveberg, Mikael
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Functional features cause misfolding of the ALS-provoking enzyme SOD12009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 24, s. 9667-9672Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically on the correct coordination of Cu and Zn. Loss of these cofactors not only promotes SOD1 aggregation in vitro but also seems to be a key prerequisite for pathogenic misfolding in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We examine here the consequences of Zn2+ loss by selectively removing the Zn site, which has been implicated as the main modulator of SOD1 stability and disease competence. After Zn-site removal, the remaining Cu ligands can coordinate a nonnative Zn2+ ion with μM affinity in the denatured state, and then retain this ion throughout the folding reaction. Without the restriction of a metallated Zn site, however, the Cu ligands fail to correctly coordinate the nonnative Zn2+ ion: Trapping of a water molecule causes H48 to change rotamer and swing outwards. The misligation is sterically incompatible with the native structure. As a consequence, SOD1 unfolds locally and interacts with neighboring molecules in the crystal lattice. The findings point to a critical role for the native Zn site in controlling SOD1 misfolding, and show that even subtle changes of the metal-loading sequence can render the wild-type protein the same structural properties as ALS-provoking mutations. This frustrated character of the SOD1 molecule seems to arise from a compromise between optimization of functional and structural features.

  • 284.
    Nordén, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Multifaceted adhesion properties of Helicobacter pylori in promotion of gastric disease2011Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Helicobacter pylori is a Gram-negative spiral-shaped bacteria that resides in the gastric mucosa and adheres to the epithelial lining of the human stomach. H. pylori adhesion mediates inflammation of the epithelium, which can lead to more severe diseases such as chronic active gastritis and gastric carcinoma. In order to adhere tightly to the mucosal lining, H. pylori expresses adhesion proteins called adhesins. The best-charachterized adhesins are blood group antigen binding adhesin, BabA, and sialic acid binding adhesin, SabA. During chronic infection there is an adhesion/inflammation-associated balance between BabA- and SabA-mediated binding modes. BabA is the major mediator of binding when the stomach is in good health and the corresponding binding receptors are ABO blood group antigens such as the difucosylated Lewis b antigen that is expressed on MUC5AC mucins by the surface epithelium. However, in chronic inflammation of the gastric mucosa there are dynamic shifts in the glycosylation patterns; in inflamed gastric tissue, SabA is an important mediator of bacterial binding and adherence. The corresponding binding receptors for the SabA adhesin are complex sialylated antigens such as sLewis x (sLex) and sLewis a (sLea). In this thesis, I describe our findings that SabA also promotes H. pylori binding to red blood cells in the gastric mucosal small blood vessels. The minimal binding epitope on the erythrocyte surfaces is the sialylated NeuAcα2-3Gal-disaccharide and this bacterial adherence promotes hemagglutination, i.e. the rapid aggregation of the erythrocytes.

    Another important finding is that the binding properties of SabA are of polymorphic nature. In particular, clinical isolates demonstrate variant types of relative binding affinity for the series of sialyl-di Lewis x (sdiLex), sialyl-Lewis a (sLea) and sialyl-lactosamine (sLn). The relative binding to sialylated glycans is strain dependent and H. pylori strains J99 and SMI9 display different SabA-mediated binding modes for sialylated glycans. By introduction of the sabA gene from strain J99 into strain SMI9, the detailed binding mode of SMI9sabAJ99 was altered and preferably displayed the original binding mode of strain J99. Thus, the polymorphism of SabA-mediated binding is an inherent property of the adhesion protein itself, i.e. the polypeptide itself and is not encoded or influenced by the strain genome background. The individualized binding properties or polymorphism in binding modes provides SabA with the opportunity to adapt to individual hosts and to the inflammatory changes in glycosylation. SabA expression makes use of slipped-strand mispairing for H. pylori to swiftly attach and detach from the epithelium. Furthermore, the ability to fluently attach and detach from the epithelial surfaces is an important feature of H. pylori and its ability to evade the mucosal inflammatory responses, as well as from the rapid turnover and shedding of gastric mucosa. Here, I describe a novel blood group antigen binding outer membrane protein, FecA3. This is an adhesin candidate, which independently of BabA, binds the series of fucosylated blood group antigens. The similar binding modes of BabA and FecA3 for ABO blood group antigens is not fully understood but the expression of FecA3 is regulated by the nickel-responsive regulator NikR, which acts as a sensor regulated by the availability of free nickel ions. Ni2+increases when pH is lowered, thus regulation of FecA3 is suggested to be governed by local pH. Taken together, the high-affinity binding by BabA, and continuous biopanning for the fittest, in particular for the low-affinity binding of FecA3, might be contrasting but complementary properties and features of the different adhesins that are of importance during different stages of mucosal inflammation and disease development.

  • 285.
    Nordén, Jenny
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Westermark, M
    Bugaytsova, J
    Mendez, AM
    Henriksson, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Characterization of BabA independent binding activity for ABO blood group antigens by Helicobacter pyloriManuskript (preprint) (Övrigt vetenskapligt)
  • 286.
    Nygård Skalman, Lars
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Holst, Mikkel Roland
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Lundmark, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Endocytic response to the pore-forming toxin listeriolysin OManuskript (preprint) (Övrigt vetenskapligt)
  • 287. Nystrom, K.
    et al.
    Pettersson, G.
    Wanrooij, Paulina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Brunet, S.
    Said, J.
    Ortolani, G.
    Waldenstrom, J.
    Adamek, L.
    Tang, K. -W
    Norberg, P.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hellstrand, K.
    Norder, H.
    Lagging, M.
    Inosine triphosphate pyrophosphatase enhances the effect of ribavirin on hepatitis C virus cell culture infection2017Ingår i: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 66, nr 1, s. S321-S321Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genetic variants of the inosine triphosphate pyrophosphatase gene (ITPA), resulting in decreased enzymatic activity of the corresponding enzyme, ITPase, are known to correlate with a decreased risk of ribavirin-induced anemia, but are also associated with an increased SVR in patients treated with peginterferon-alpha and ribavirin. As both ITPase and ribavirin are involved in the nucleotide salvage pathway and reduced risk of relapse after treatment of hepatitis C, we have investigated the effect of ITPase activity and ribavirin treatment of HCVcc infection of hepatocytes

  • 288. Nystrom, Kristina
    et al.
    Wanrooij, Paulina H.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Waldenstrom, Jesper
    Adamek, Ludmila
    Brunet, Sofia
    Said, Joanna
    Nilsson, Staffan
    Wind-Rotolo, Megan
    Hellstrand, Kristoffer
    Norder, Helene
    Tang, Ka-Wei
    Lagging, Martin
    Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus2018Ingår i: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, nr 19, artikel-id e01087-18Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A third of humans carry genetic variants of the ITP pyrophosphatase (ITPase) gene (ITPA) that lead to reduced enzyme activity. Reduced ITPase activity was earlier reported to protect against ribavirin-induced hemolytic anemia and to diminish relapse following ribavirin and interferon therapy for hepatitis C virus (HCV) genotype 2 or 3 infections. While several hypotheses have been put forward to explain the antiviral actions of ribavirin, details regarding the mechanisms of interaction between reduced ITPase activity and ribavirin remain unclear. The in vitro effect of reduced ITPase activity was assessed by means of transfection of hepatocytes (Huh7.5 cells) with a small interfering RNA (siRNA) directed against ITPA or a negative-control siRNA in the presence or absence of ribavirin in an HCV culture system. Low ribavirin concentrations strikingly depleted intracellular GTP levels in HCV-infected hepatocytes whereas higher ribavirin concentrations induced G-to-A and C-to-U single nucleotide substitutions in the HCV genome, with an ensuing reduction of HCV RNA expression and HCV core antigen production. Ribavirin triphosphate (RTP) was dephosphorylated in vitro by recombinant ITPase to a similar extent as ITP, a naturally occurring substrate of ITPase, and reducing ITPA expression in Huh 7.5 cells by siRNA increased intracellular levels of RTP in addition to increasing HCV mutagenesis and reducing progeny virus production. Our results extend the understanding of the biological impact of reduced ITPase activity, demonstrate that RTP is a substrate of ITPase, and may point to personalized ribavirin dosage according to ITPA genotype in addition to novel antiviral strategies. IMPORTANCE This study highlights the multiple modes of action of ribavirin, including depletion of intracellular GTP and increased hepatitis C virus mutagenesis. In cell culture, reduced ITP pyrophosphatase (ITPase) enzyme activity affected the intracellular concentrations of ribavirin triphosphate (RTP) and augmented the impact of ribavirin on the mutation rate and virus production. Additionally, our results imply that RTP, similar to ITP, a naturally occurring substrate of ITPase, is dephosphorylated in vitro by ITPase.

  • 289.
    Näsström, Elin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Dongol, Sabina
    Karkey, Abhilasha
    Basnyat, Buddha
    Thieu, Nga Tran Vu
    Van, Tan Trinh
    Thwaites, Guy E.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Baker, Stephen
    Diagnostic metabolite biomarkers of chronic typhoid carriage2018Ingår i: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 12, nr 1, artikel-id e0006215Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Salmonella Typhi and Salmonella Paratyphi A are the agents of enteric (typhoid) fever; both can establish chronic carriage in the gallbladder. Chronic Salmonella carriers are typically asymptomatic, intermittently shedding bacteria in the feces, and contributing to disease transmission. Detecting chronic carriers is of public health relevance in areas where enteric fever is endemic, but there are no routinely used methods for prospectively identifying those carrying Salmonella in their gallbladder.

    Methodology/Principal findings: Here we aimed to identify biomarkers of Salmonella carriage using metabolite profiling. We performed metabolite profiling on plasma from Nepali patients undergoing cholecystectomy with confirmed S. Typhi or S. Paratyphi A gallbladder carriage (and non-carriage controls) using two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) and supervised pattern recognition modeling. We were able to significantly discriminate Salmonella carriage samples from non-carriage control samples. We were also able to detect differential signatures between S. Typhi and S. Paratyphi A carriers. We additionally compared carriage metabolite profiles with profiles generated during acute infection; these data revealed substantial heterogeneity between metabolites associated with acute enteric fever and chronic carriage. Lastly, we found that Salmonella carriers could be significantly distinguished from non-carriage controls using only five metabolites, indicating the potential of these metabolites as diagnostic markers for detecting chronic Salmonella carriers.

    Conclusions/Significance: Our novel approach has highlighted the potential of using metabolomics to search for diagnostic markers of chronic Salmonella carriage. We suggest further epidemiological investigations of these potential biomarkers in alternative endemic enteric fever settings.

  • 290.
    Näsström, Elin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Parry, Christopher M.
    Thieu, Nga Tran Vu
    Maude, Rapeephan R.
    de Jong, Hanna K.
    Fukushima, Masako
    Rzhepishevska, Olena
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Marks, Florian
    Panzner, Ursula
    Im, Justin
    Jeon, Hyonjin
    Park, Seeun
    Chaudhury, Zabeen
    Ghose, Aniruddha
    Samad, Rasheda
    Van, Tan Trinh
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Dondorp, Arjen M.
    Thwaites, Guy E.
    Faiz, Abul
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Baker, Stephen
    Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa2017Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 6, artikel-id e15651Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Salmonella Typhi is the causative agent of typhoid. Typhoid is diagnosed by blood culture, a method that lacks sensitivity, portability and speed. We have previously shown that specific metabolomic profiles can be detected in the blood of typhoid patients from Nepal (Nasstrom et al., 2014). Here, we performed mass spectrometry on plasma from Bangladeshi and Senegalese patients with culture confirmed typhoid fever, clinically suspected typhoid, and other febrile diseases including malaria. After applying supervised pattern recognition modelling, we could significantly distinguish metabolite profiles in plasma from the culture confirmed typhoid patients. After comparing the direction of change and degree of multivariate significance, we identified 24 metabolites that were consistently up- or down regulated in a further Bangladeshi/Senegalese validation cohort, and the Nepali cohort from our previous work. We have identified and validated a metabolite panel that can distinguish typhoid from other febrile diseases, providing a new approach for typhoid diagnostics.

  • 291.
    Näsström, Elin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Thieu, Nga Tran Vu
    Dongol, Sabina
    Karkey, Abhilasha
    Vinh, Phat Voong
    Thanh, Tuyen Ha
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Arjyal, Amit
    Thwaites, Guy
    Dolecek, Christiane
    Basnyat, Buddha
    Baker, Stephen
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Salmonella Typhi and Salmonella Paratyphi A elaborate distinct systemic metabolite signatures during enteric fever2014Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 3, artikel-id e03100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The host-pathogen interactions induced by Salmonella Typhi and Salmonella Paratyphi A during enteric fever are poorly understood. This knowledge gap, and the human restricted nature of these bacteria, limit our understanding of the disease and impede the development of new diagnostic approaches. To investigate metabolite signals associated with enteric fever we performed two-dimensional gas chromatography with time-of-flight mass spectrometry (GCxGC/TOFMS) on plasma from patients with S. Typhi and S. Paratyphi A infections and asymptomatic controls, identifying 695 individual metabolite peaks. Applying supervised pattern recognition, we found highly significant and reproducible metabolite profiles separating S. Typhi cases, S. Paratyphi A cases, and controls, calculating that a combination of six metabolites could accurately define the etiological agent. For the first time we show that reproducible and serovar specific systemic biomarkers can be detected during enteric fever. Our work defines several biologically plausible metabolites that can be used to detect enteric fever, and unlocks the potential of this method in diagnosing other systemic bacterial infections.

  • 292.
    Olivecrona, Thomas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Liu, Guoqing
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Hultin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Bengtsson-Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Regulation of lipoprotein lipase1993Ingår i: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 21, nr 2, s. 509-513Artikel i tidskrift (Refereegranskat)
  • 293.
    Olofsson, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Helicobacter pylori outer membrane vesicles and the host-pathogen interaction2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 294.
    Olofsson, Annelie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nygård Skalman, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Petzold, Katja
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jurgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gröbner, Gerhard
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lundmark, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Endocytosis of Helicobacter pylori vesiclesManuskript (preprint) (Övrigt vetenskapligt)
  • 295.
    Olofsson, Annelie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Vallström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Petzold, Katja
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Carlsson, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Haas, Rainer
    Max-von-Pettenkofer-Institute of Hygiene and Medical Microbiology, Dept of Bacteriology, Munich, Germany.
    Backert, Steffen
    School of Biomolecular and Biomedical Sciences, University College Dublin, Ireland.
    Nyunt Wai, Sun
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Gröbner, Gerhard
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Characterization of Helicobacter pylori vesicles and their cognate properties for intimate host interactionsManuskript (preprint) (Övrigt vetenskapligt)
  • 296.
    Olofsson, Annelie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Vikström, Elena
    Linköpings Universitet.
    Tegtmeyer, Nicole
    Friedrich Alexander University Erlangen/Nuremberg.
    Westermark, Marie
    Magnusson, Karl-Eric
    Linköpings Universitet.
    Backert, Steffen
    Friedrich Alexander University Erlangen/Nuremberg.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Helicobacter pylori vesicles and host cell responsesManuskript (preprint) (Övrigt vetenskapligt)
  • 297. Oteng, Antwi-Boasiako
    et al.
    Ruppert, Philip M. M.
    Boutens, Lily
    Dijk, Wieneke
    van Dierendonck, Xanthe A. M. H.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Stienstra, Rinke
    Kersten, Sander
    Characterization of ANGPTL4 function in macrophages and adipocytes using Angptl4-knockout and Angptl4-hypomorphic mice[S]2019Ingår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 60, nr 10, s. 1741-1754Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Angiopoietin-like protein (ANGPTL)4 regulates plasma lipids, making it an attractive target for correcting dyslipidemia. However, ANGPTL4 inactivation in mice fed a high fat diet causes chylous ascites, an acute-phase response, and mesenteric lymphadenopathy. Here, we studied the role of ANGPTL4 in lipid uptake in macrophages and in the above-mentioned pathologies using Angptl4-hypomorphic and Angptl4(-/-) mice. Angptl4 expression in peritoneal and bone marrow-derived macrophages was highly induced by lipids. Recombinant ANGPTL4 decreased lipid uptake in macrophages, whereas deficiency of ANGPTL4 increased lipid uptake, upregulated lipid-induced genes, and increased respiration. ANGPTL4 deficiency did not alter LPL protein levels in macrophages. Angptl4-hypomorphic mice with partial expression of a truncated N-terminal ANGPTL4 exhibited reduced fasting plasma triglyceride, cholesterol, and NEFAs, strongly resembling Angptl4(-/-) mice. However, during high fat feeding, Angptl4-hypomorphic mice showed markedly delayed and attenuated elevation in plasma serum amyloid A and much milder chylous ascites than Angptl4(-/-) mice, despite similar abundance of lipid-laden giant cells in mesenteric lymph nodes. In conclusion, ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. Compared with the absence of ANGPTL4, low levels of N-terminal ANGPTL4 mitigate the development of chylous ascites and an acute-phase response in mice.

  • 298. Ouberai, Myriam
    et al.
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Vestling, Monika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Dumy, Pascal
    Chierici, Sabine
    Garcia, Julian
    Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds2011Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, nr 4, s. 1140-1147Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The multifaceted nature of Alzheimer's disease (AD) has led to the development of multi-targeted compounds based on the classical AD drug, tacrine, first known to inhibit the acetylcholine-degrading enzyme acetylcholinesterase (AChE). In the present work, we explore the potentiality of multimers of tacrine in this field. The synthesis using the so-called "click chemistry" and the in vitro study of the conjugates are described. Two or four copies of the tacrine molecule are "clicked" on a constrained cyclopeptide template proven to be a convenient tool for multimeric presentation. The multimers significantly inhibit self-induced amyloid fibril formation from Aβ(40) at low inhibitor to Aβ molar ratios at which the tacrine monomer is fully inactive (Thioflavin T assays and AFM observation). Moreover, they have the capacity to bind to Aβ(40) fibrils (SPR assays) while retaining the AChE inhibitory activity of the parent tacrine.

  • 299. Ovchinnikov, Victor
    et al.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Karplus, Martin
    A Simple and Accurate Method To Calculate Free Energy Profiles and Reaction Rates from Restrained Molecular Simulations of Diffusive Processes2016Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, nr 33, s. 8457-8472Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A method is developed to obtain simultaneously free energy profiles and diffusion constants from restrained molecular simulations in diffusive systems. The method is based on low-order expansions of the free energy and diffusivity as functions of the reaction coordinate. These expansions lead to simple analytical relationships between simulation statistics and model parameters. The method is tested on 1D and 2D model systems; its accuracy is found to be comparable to or better than that of the existing alternatives, which are briefly discussed. An important aspect of the method is that the free energy is constructed by integrating its derivatives, which can be computed without need for overlapping sampling windows. The implementation of the method in any molecular simulation program that supports external umbrella potentials (e.g., CHARMM) requires modification of only a few lines of code. As a demonstration of its applicability to realistic biomolecular systems, the method is applied to model the alpha-helix <-> beta-sheet transition in a 16-residue peptide in implicit solvent, with the reaction coordinate provided by the string method. Possible modifications of the method are briefly discussed; they include generalization to multidimensional reaction coordinates [in the spirit of the model of Ermak and McCammon (Ermak, D. L.; McCammon, J. A. J. Chem. Phys. 1978, 69, 1352-1360)], a higher-order expansion of the free energy surface, applicability in nonequilibrium systems, and a simple test for Markovianity. In view of the small overhead of the method relative to standard umbrella sampling, we suggest its routine application in the cases where umbrella potential simulations are appropriate.

  • 300. Pang, M-F
    et al.
    Georgoudaki, A-M
    Lambut, L.
    Johansson, J.
    Tabor, V.
    Hagikura, K.
    Jin, Y.
    Jansson, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Alexander, J. S.
    Nelson, C. M.
    Jakobsson, L.
    Betsholtz, C.
    Sund, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Karlsson, M. C. I.
    Fuxe, J.
    TGF-beta 1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis2016Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, nr 6, s. 748-760Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-beta (TGF-beta 1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-beta 1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-beta 1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-beta 1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-beta 1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.

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