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  • 246751.
    Yttergren, Åsa
    et al.
    Umea Univ, Umea Forum Studies Law & Soc, Umea, Sweden..
    Westerstrand, Jenny
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Centre for Gender Research.
    The Swedish Legal Approach to Prostitution. Trends and Tendencies in the Prostitution Debate2016In: NORA: Nordic Journal of Feminist and Gender Research, ISSN 0803-8740, E-ISSN 1502-394X, Vol. 24, no 1, p. 45-55Article in journal (Refereed)
  • 246752.
    Ytterman, Caroline
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Archaeology and Ancient History, Archaeology.
    Grundämnes-distribuering och bendensitet: En XRF-undersökning av vikingatida och medeltida lårben från fyra arkeologiska lokaler2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    This essay focuses on developing non-destructive methods to investigate the relationship between elemental distribution and bone porosity in archaeological bone. The skeletal material, which was analyzed, came from the archaeological sites of Skara (county of Västergötland), Varnhem (county of Västergötland), Sigtuna (county of Uppland) and Kopparsvik (county of Gotland). The essay is based on the results of a previous project, Osteoporosis och osteoarthritis, då och nu (Sten 2012). That project aimed at establishing whether medieval people, buried on the above mentioned archaeological sites, were suffersing from osteoporosis and/or osteoarthritis. This knowledge might help the medical research of today to solve the problem of possibly preventing those bone diseases. The method used was DXA-scanning, which was developed for examine osteoporosis in bone from living people. The result showed that the skeletons from the Skara site had an increased bone mineral density (BMD) compared to the skeletons from the other three sites.

    This essay investigates why these skeletal remains have a higher BMD and how this affects the results of methods like DXA. In this bachelor project various X-ray instruments were used to analyze the BMD of the skeletal remains. The X-ray pictures were then modified to exhibit high and low density areas in the bone. The elemental distribution of the surface area of the neck of the femur was examined with a μXRF-spectrometer. As a complement to the μXRF-spectrometer a SEM (scanning electron microscope) was used to analyze the elemental distribution of a cross section of the femur neck. Soil samples were collected from Skara and Varnhem and analyzed by using μXRF-spectrometry to find out if there was a correlation between the elemental content of the bone and surrounding soil. The skeletal remains from Skara exhibited increased values of iron and manganese combined with higher bone density. The soil from Skara showed a high level of particularly iron. This could be the reason for the increased BMD of the individuals from Skara when using the DXA-analysis. It is likely that, in each archaeological site, iron and manganese ions have diffused from both ground water and soil into the bones and thus increased the BMD. This is especially notified of the skeletal remains of Skara.

  • 246753.
    Yttermyr, Cecilia
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Social and Economic Geography.
    Privatoffentligt partnerskap i Sandviken: En studie av nyliberala trender mellan Sandvikens kommun och Sandvik2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 246754.
    Yttréus, Anna
    Uppsala University, Faculty of Educational Sciences, Department of Studies in Education, Culture and Media. Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Education.
    Lärares planeringsarbete inom svenska och matematik på grundskolan2010Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Syftet med denna studie är att få kännedom om hur lärare arbetar med planering utifrån kursplaner och mål samt hur planeringen kan genomföras i ämnena svenska och matematik på grundskolan. Utifrån studiens syfte ställs dessa frågeställningar: Hur använder lärare skolverkets kursplaner och mål i planeringen? Hur genomför lärare sitt planeringsarbete i ämnet svenska på grundskolan? Hur genomför lärare sitt planeringsarbete i matematik på grundskolan? Vilken betydelse har den lokala pedagogiska planeringen? Kvalitativa intervjuer användes som metod med utgångspunkt i Jan Trosts bok om detsamma. I studien genomfördes fem informella intervjuer med lärare som arbetar med svenska och matematik på grundskolan. I resultatet tydliggörs att lärares planeringsarbete kan genomföras på många olika sätt och att de intervjuade lärarna ger en tydlig bild om hur denna process implementeras i grundskolan. Relevant litteratur bearbetas och jämförs med resultatet i diskussionsdelen där även skillnader och olikheter i planeringsmodellerna behandlas.

  • 246755. Yu, Bao-Zhu
    et al.
    Apitz-Castro, Rafael J.
    Jain, Mahendra K.
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Role of 57-72 loop in the allosteric action of bile salts on pancreatic IB phospholipase A(2): Regulation of fat and cholesterol homeostasis2007In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1768, no 10, p. 2478-2490Article in journal (Refereed)
    Abstract [en]

    Mono- and biphasic kinetic effects of bile salts on the pancreatic IB phospholipase A2 (PLA2) catalyzed interfacial hydrolysis are characterized. This novel phenomenon is modeled as allosteric action of bile salts with PLA2 at the interface. The results and controls also show that these kinetic effects are not due to surface dilution or solubilization or disruption of the bilayer interface where in the mixed-micelles substrate replenishment becomes the rate-limiting step. The PLA2-catalyzed rate of hydrolysis of zwitterionic dimyristoylphosphatidylcholine (DMPC) vesicles depends on the concentration and structure of the bile salt. The sigmoidal rate increase with cholate saturates at 0.06 mole fraction and changes little at the higher mole fractions. Also, with the rate-lowering bile salts (B), such as taurochenodeoxycholate (TCDOC), the initial sigmoidal rate increase at lower mole fraction is followed by nearly complete reversal to the rate at the pre-activation level at higher mole fractions. The rate-lowering effect of TCDOC is not observed with the (62–66)-loop deleted ΔPLA2, or with the Naja venom PLA2 that is evolutionarily devoid of the loop. The rate increase is modeled with the assumption that the binding of PLA2 to DMPC interface is cooperatively promoted by bile salt followed by allosteric kcat-activation of the bound enzyme by the anionic interface. The rate-lowering effect of bile salts is attributed to the formation of a specific catalytically inert EB complex in the interface, which is noticeably different than the 1:1 EB complex in the aqueous phase. The cholate-activated rate of hydrolysis is lowered by hypolidemic ezetimibe and guggul extract which are not interfacial competitive inhibitors of PLA2. We propose that the biphasic modulation of the pancreatic PLA2 activity by bile salts regulates gastrointestinal fat metabolism and cholesterol homeostasis.

  • 246756. Yu, Bao-Zhu
    et al.
    Bai, Shi
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Jain, Mahendra K.
    Allosteric Effect of Amphiphile Binding to Phospholipase A22009In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 14, p. 3219-3229Article in journal (Refereed)
    Abstract [en]

    In the preceding paper, we showed that the formation of the second premicellar complex of pig pancreatic IB phospholipase A2 (PLA2) can be considered a proxy for interface-activated substrate binding. Here we show that this conclusion is supported by results from premicellar;E-i(#) (i = 1, 2, or 3) complexes with a wide range of mutants of PLA2. Results also show a structural bass-for the correlated functional changes during the formation of E-2(#), and this is interpreted as an allosteric T (inactive) to R (active) transition. For example, the dissociation constant K-2(#) for decylsulfate bound to E-2(#) is lower at lower pH, at higher calcium concentrations, or with an inhibitor bound to the active site. Also, the lower limits of the K-2(#) values are comparable under these conditions. The pH-dependent increase in K-2(#) with a pK(a) of 6.5 is attributed to E71 which participates in the binding of the second calcium which in turn influences the enzyme binding to phosphatidylcholine interface. Most mutants exhibited kinetic and spectroscopic behavior that is comparable to that of native PLA2 and Delta PLA2 with a deleted 62-66 loop. However, the Delta Y52L substitution mutant cannot undergo the calcium-, pH-, or interface-dependent changes. We suggest that the Y52L substitution impairs the R to T transition and also hinders the approach of the Michaelis complex to the transition state. This allosteric change may be mediated by the structural motifs that connect the D48-D99 catalytic diad, the substrate-binding slot, and the residues of the i-face. Our interpretation is that the 57-72 loop and the H48DNCY52 segment of PLA2 are involved in transmitting the effect of the cooperative amphiphile binding to the i-face as a structural change in the active site.

  • 246757. Yu, Bao-Zhu
    et al.
    Kaimal, Rajani
    Bai, Shi
    El Sayed, Khalid A.
    Tatulian, Suren A.
    Apitz, Rafael J.
    Jain, Mahendra K.
    Deng, Ruitang
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Effect of Guggulsterone and Cembranoids of Commiphora mukul on Pancreatic Phospholipase A(2): Role in Hypocholesterolemia2009In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 72, no 1, p. 24-28Article in journal (Refereed)
    Abstract [en]

    Guggulsterone (7) and cembranoids (8-12) from Commiphora mukul stem bark resin guggul were shown to be specific modulators of two independent sites that are also modulated by bile salts (1-6) to control cholesterol absorption and catabolism. Guggulsterone (7) antagonized the chenodeoxycholic acid (3)-activated nuclear farnesoid X receptor (FXR), which regulates cholesterol metabolism in the liver. The cembranoids did not show a noticeable effect on FXR, but lowered the cholate (I)-activated rate of human pancreatic 113 phospholipase A2 (hPLA2), which controls gastrointestinal absorption of fat and cholesterol. Analysis of the data using a kinetic model has suggested an allosteric mechanism for the rate increase of hPLA2 by cholate and also for the rate-lowering effect by certain bile salts or cembranoids on the cholate-activated hPLA2 hydrolysis of phosphatidylcholine vesicles. The allosteric inhibition of PLA2 by certain bile salts and cembranoids showed some structural specificity. Biophysical studies also showed specific interaction of the bile salts with the interface-bound cholate-activated PLA2. Since cholesterol homeostasis in mammals is regulated by FXR in the liver for metabolism and by PLA2 in the intestine for absorption, modulation of PLA2 and FXR by bile acids and selected guggul components suggests novel possibilities for hypolipidemic and hypocholesterolemic therapies.

  • 246758. Yu, Bao-Zhu
    et al.
    Polenova, Tatyana
    Jain, Mahendra Kumar
    Berg, Otto
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Premicellar complexes of sphingomyelinase mediate enzyme exchange for the stationary phase turnover2005In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1712, no 2, p. 137-151Article in journal (Refereed)
    Abstract [en]

    During the steady state reaction progress in the scooting mode with highly processive turnover, Bacillus cereus sphingomyelinase (SMase) remains tightly bound to sphingomyelin (SM) vesicles (Yu et al., Biochim. Biophys. Acta 1583, 121–131, 2002). In this paper, we analyze the kinetics of SMase-catalyzed hydrolysis of SM dispersed in diheptanoylphosphatidyl-choline (DC7PC) micelles. Results show that the resulting decrease in the turnover processivity induces the stationary phase in the reaction progress. The exchange of the bound enzyme (E*) between the vesicle during such reaction progress is mediated via the premicellar complexes (Ei#) of SMase with DC7PC. Biophysical studies indicate that in Ei# monodisperse DC7PC is bound to the interface binding surface (i-face) of SMase that is also involved in its binding to micelles or vesicles. In the presence of magnesium, required for the catalytic turnover, three different complexes of SMase with monodisperse DC7PC (Ei# with i = 1, 2, 3) are sequentially formed with Hill coefficients of 3, 4 and 8, respectively. As a result, during the stationary phase reaction progress, the initial rate is linear for an extended period and all the substrate in the reaction mixture is hydrolyzed at the end of the reaction progress. At low mole fraction (X) of total added SM, exchange is rapid and the processive turnover is limited by the steps of the interfacial turnover cycle without becoming microscopically limited by local substrate depletion or enzyme exchange. At high X, less DC7PC will be monodisperse, Ei# does not form and the turnover becomes limited by slow enzyme exchange. Transferred NOESY enhancement results show that monomeric DC7PC in solution is in a rapid exchange with that bound to Ei# at a rate comparable to that in micelles. Significance of the exchange and equilibrium properties of the Ei# complexes for the interpretation of the stationary phase reaction progress is discussed.

  • 246759.
    Yu, BZ
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology. MOLECULAR EVOLUTION.
    Poi, MJ
    Ramagopal, UA
    Jain, R
    Ramakumar, S
    Berg, OG
    Tsai, MD
    Sekar, K
    Jain, MK
    Structural basis of the anionic interface preference and kcat*-activation of pancreatic phospholipase A22000In: Biochemistry, Vol. 39, p. 12312-12323Article in journal (Refereed)
  • 246760.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Adenovirus for Cancer Therapy: With a Focus on its Surface Modification2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surface of tumor cells. We engineered Ad5 virus with the protein transduction domain (PTD) from the HIV-1 Tat protein (Tat-PTD) inserted in the hypervariable region 5 (HVR5) of the hexon protein in the virus capsid. Tat-PTD-modified Ad5 shows a dramatically increased transduction level of CAR-negative cells and bypassed fiber-mediated transduction. It also overcomes the fiber-masking problem, which is caused by release of excess fiber proteins from infected cells. To achieve specific viral replication in neuroblastoma and neuroendocrine tumor cells, we identified the secretogranin III (SCG3) promoter and constructed an adenovirus Ad5PTD(ASH1-SCG3-E1A) wherein E1A gene expression is controlled by the SCG3 promoter and the achaete-scute complex homolog 1 (ASH1) enhancer. This virus shows selective and efficient killing of neuroblastoma cell lines in vitro, and delays human neuroblastoma xenograft tumor growth on nude mice. To further enhance the viral oncolytic efficacy, we also switched the fiber 5 to fiber 35 to generate Ad5PTDf35. This vector shows dramatically increased transduction capacity of primary human cell cultures including hematopoietic cells and their derivatives, pancreatic islets and exocrine cells, mesenchymal stem cells and primary tumor cells including primary cancer initiating cells. Ad5PTDf35-based adenovirus could be a useful platform for gene delivery and oncolytic virus development. Viral oncolysis alone cannot completely eradicate tumors. Therefore, we further armed the Ad5PTDf35-D24 virus with a secreted form of Helicobacter pylori Neutrophil Activating Protein (HP-NAP). Expression of HP-NAP recruits neutrophils to the site of infection, activates an innate immune response against tumor cells and provokes a Th1-type adaptive immune response. Established tumor on nude mice could be completely eradicated in some cases after treatment with this virus and the survival of mice was significantly prolonged.

    List of papers
    1. Adenovirus with Hexon Tat-Protein Transduction Domain Modification Exhibits Increased Therapeutic Effect in Experimental Neuroblastoma and Neuroendocrine Tumors
    Open this publication in new window or tab >>Adenovirus with Hexon Tat-Protein Transduction Domain Modification Exhibits Increased Therapeutic Effect in Experimental Neuroblastoma and Neuroendocrine Tumors
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    2011 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 85, no 24, p. 13114-13123Article in journal (Refereed) Published
    Abstract [en]

    Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surfaces of tumor cells. Furthermore, infected cells overproduce adenovirus fiber proteins, which are released prior to cell lysis. The released fibers block CAR on noninfected neighboring cells, thereby preventing progeny virus entry. Our aim was to add a CAR-independent infection route to Ad5 to increase the infectivity of tumor cells with low CAR expression and prevent the fiber-masking problem. We constructed Ad5 viruses that encode the protein transduction domain (PTD) of the HIV-1 Tat protein (Tat-PTD) in hypervariable region 5 (HVR5) of the hexon protein. Tat-PTD functions as a cell-penetrating peptide, and Tat-PTD-modified Ad5 showed a dramatic increased transduction of CAR-negative cell lines compared to unmodified vector. Moreover, while tumor cell infectivity was severely reduced for Ad5 in the presence of fiber proteins, it was only marginally reduced for Tat-PTD-modified Ad5. Furthermore, because of the sequence alteration in the hexon HVR, coagulation factor X-mediated virus uptake was significantly reduced. Mice harboring human neuroblastoma and neuroendocrine tumors show suppressed tumor growths and prolonged survival when treated with Tat-PTD-modified oncolytic viruses. Our data suggest that modification of Ad5 with Tat-PTD in HVR5 expands its utility as an oncolytic agent.

    Keywords
    adenovirus, cell penetrating peptide, Tat-PTD, neuroblastoma, neuroendocrine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-165614 (URN)10.1128/JVI.05759-11 (DOI)000297642000029 ()
    Funder
    Swedish Research Council, K2008-68X-15270-04-3
    Available from: 2012-01-16 Created: 2012-01-09 Last updated: 2018-06-04Bibliographically approved
    2. Tat‐PTD‐modified Oncolytic Adenovirus Driven by the SCG3 Promoter and ASH1 Enhancer for Neuroblastoma Therapy
    Open this publication in new window or tab >>Tat‐PTD‐modified Oncolytic Adenovirus Driven by the SCG3 Promoter and ASH1 Enhancer for Neuroblastoma Therapy
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    2013 (English)In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 24, no 8, p. 766-775Article in journal (Refereed) Published
    Abstract [en]

    Secretogranin III (SGC3) belongs to the granin family and is highly expressed in endocrine and neural tissues. The human SCG3 promoterhas not yet been characterized. We identified that a 0.5 kb DNA fragment upstream of the SCG3 gene can selectively drivetransgene expression in neuroblastoma cell lines. The strength of transgene expression was further increased and specificity maintained,by addition of the human achaete‐scute complex homolog 1 (ASH1) enhancer. We developed an oncolytic serotype 5‐basedadenovirus, where the SCG3 promoter and ASH1 enhancer drive E1A gene expression. The virus was further modified with a cellpenetratingpeptide (Tat‐PTD) in the virus capsid, which we have previously shown results in increased adenovirus transductionefficiency of many neuroblastoma cell lines. The virus, Ad5PTD(ASH1‐SCG3‐E1A), shows selective and efficient killing of neuroblastomacell lines in vitro, including cisplatin‐, etoposide‐ and doxorubicin‐insensitive neuroblastoma cells. Furthermore, it delays tumorgrowth and thereby prolonged survival for nude mice harboring subcutaneous human neuroblastoma xenograft. In conclusion, wereport a novel oncolytic adenovirus with potential use for neuroblastoma therapy.

    Keywords
    Tat-PTD, neuroblastoma, cancer therapy, adenovirus
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Clinical Virology; Medical Virology; Molecular Biotechnology; Molecular Medicine
    Identifiers
    urn:nbn:se:uu:diva-203651 (URN)10.1089/hum.2012.132 (DOI)000323181200007 ()
    Funder
    Swedish Cancer Society, 10‐0105Swedish Cancer Society, 10‐0552Swedish Research Council, K2013‐55X‐22191‐01‐3
    Note

    De två (2) första författarna delar förstaförfattarskapet.

    Other funds:

    TheSwedish Cancer Society (10‐0105 and 10‐0552), the Swedish ChildrenCancer Foundation (PROJ10/027, NBCNSPDHEL10/013,JIN C. ET AL. 20138PROJ11/062), Gunnar Nilsson’s Cancer Foundation, the SwedishResearch Council (K2013‐55X‐22191‐01‐3) and the Marcus andMarianne Wallenberg’s Foundation.

    Available from: 2013-07-16 Created: 2013-07-16 Last updated: 2017-12-06Bibliographically approved
    3. Adenovirus Serotype 5 Vectors with Tat-PTD Modified Hexon and Serotype 35 Fiber Show Greatly Enhanced Transduction Capacity of Primary Cell Cultures
    Open this publication in new window or tab >>Adenovirus Serotype 5 Vectors with Tat-PTD Modified Hexon and Serotype 35 Fiber Show Greatly Enhanced Transduction Capacity of Primary Cell Cultures
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e54952-Article in journal (Refereed) Published
    Abstract [en]

    Recombinant adenovirus serotype 5 (Ad5) vectors represent one of the most efficient gene delivery vectors in life sciences. However, Ad5 is dependent on expression of the coxsackievirus-adenovirus- receptor (CAR) on the surface of target cell for efficient transduction, which limits it's utility for certain cell types. Herein we present a new vector, Ad5PTDf35, which is an Ad5 vector having serotype 35 fiber-specificity and Tat-PTD hexon-modification. This vector shows dramatically increased transduction capacity of primary human cell cultures including T cells, monocytes, macrophages, dendritic cells, pancreatic islets and exocrine cells, mesenchymal stem cells and tumor initiating cells. Biodistribution in mice following systemic administration (tail-vein injection) show significantly reduced uptake in the liver and spleen of Ad5PTDf35 compared to unmodified Ad5. Therefore, replication-competent viruses with these modifications may be further developed as oncolytic agents for cancer therapy. User-friendly backbone plasmids containing these modifications were developed for compatibility to the AdEasy-system to facilitate the development of surface-modified adenoviruses for gene delivery to difficult-to-transduce cells in basic, pre-clinical and clinical research.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-197480 (URN)10.1371/journal.pone.0054952 (DOI)000315210400045 ()
    Available from: 2013-03-26 Created: 2013-03-26 Last updated: 2017-12-06Bibliographically approved
    4. An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors
    Open this publication in new window or tab >>An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors
    Show others...
    2013 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, no 11, p. 2008-2018Article in journal (Refereed) Published
    Abstract [en]

    Helicobacter pylori Neutrophil Activating Protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate anti-tumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Δ24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as TNF-α and MIP2-α in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours post-virus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting anti-tumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus.

    Keywords
    Helicobacter pylori, Neutrophil Activating Protein, adenovirus, cancer therapy
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Molecular Medicine; Clinical Virology; Medical Virology; Clinical Immunology
    Identifiers
    urn:nbn:se:uu:diva-203649 (URN)10.1038/mt.2013.153 (DOI)000326937000007 ()23817216 (PubMedID)
    Funder
    Swedish Cancer Society, 10‐0105Swedish Cancer Society, 10‐0552Swedish Research Council, K2013‐55X‐22191‐01‐3
    Note

    De två (2) sista författarna delar sistaförfattarskapet.

    Open access under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License (CC BY-NC-ND). 2013.

    Supported funds:

    The Swedish Children Cancer Foundation(PROJ10/027), Gunnar Nilsson’s Cancer Foundation, Marcus and Marianne Wallenberg’sFoundation

    Available from: 2013-07-16 Created: 2013-07-16 Last updated: 2017-12-06Bibliographically approved
  • 246761.
    Yu, Di
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leja, Justyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Majdalani, Nadim
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Adenovirus with Hexon Tat-Protein Transduction Domain Modification Exhibits Increased Therapeutic Effect in Experimental Neuroblastoma and Neuroendocrine Tumors2011In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 85, no 24, p. 13114-13123Article in journal (Refereed)
    Abstract [en]

    Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surfaces of tumor cells. Furthermore, infected cells overproduce adenovirus fiber proteins, which are released prior to cell lysis. The released fibers block CAR on noninfected neighboring cells, thereby preventing progeny virus entry. Our aim was to add a CAR-independent infection route to Ad5 to increase the infectivity of tumor cells with low CAR expression and prevent the fiber-masking problem. We constructed Ad5 viruses that encode the protein transduction domain (PTD) of the HIV-1 Tat protein (Tat-PTD) in hypervariable region 5 (HVR5) of the hexon protein. Tat-PTD functions as a cell-penetrating peptide, and Tat-PTD-modified Ad5 showed a dramatic increased transduction of CAR-negative cell lines compared to unmodified vector. Moreover, while tumor cell infectivity was severely reduced for Ad5 in the presence of fiber proteins, it was only marginally reduced for Tat-PTD-modified Ad5. Furthermore, because of the sequence alteration in the hexon HVR, coagulation factor X-mediated virus uptake was significantly reduced. Mice harboring human neuroblastoma and neuroendocrine tumors show suppressed tumor growths and prolonged survival when treated with Tat-PTD-modified oncolytic viruses. Our data suggest that modification of Ad5 with Tat-PTD in HVR5 expands its utility as an oncolytic agent.

  • 246762.
    Yu, Di
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Xu, Jing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Adamson, Rachel
    Maitland, Norman
    Fan, Xiaolong
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Adenovirus Serotype 5 Vectors with Tat-PTD Modified Hexon and Serotype 35 Fiber Show Greatly Enhanced Transduction Capacity of Primary Cell Cultures2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e54952-Article in journal (Refereed)
    Abstract [en]

    Recombinant adenovirus serotype 5 (Ad5) vectors represent one of the most efficient gene delivery vectors in life sciences. However, Ad5 is dependent on expression of the coxsackievirus-adenovirus- receptor (CAR) on the surface of target cell for efficient transduction, which limits it's utility for certain cell types. Herein we present a new vector, Ad5PTDf35, which is an Ad5 vector having serotype 35 fiber-specificity and Tat-PTD hexon-modification. This vector shows dramatically increased transduction capacity of primary human cell cultures including T cells, monocytes, macrophages, dendritic cells, pancreatic islets and exocrine cells, mesenchymal stem cells and tumor initiating cells. Biodistribution in mice following systemic administration (tail-vein injection) show significantly reduced uptake in the liver and spleen of Ad5PTDf35 compared to unmodified Ad5. Therefore, replication-competent viruses with these modifications may be further developed as oncolytic agents for cancer therapy. User-friendly backbone plasmids containing these modifications were developed for compatibility to the AdEasy-system to facilitate the development of surface-modified adenoviruses for gene delivery to difficult-to-transduce cells in basic, pre-clinical and clinical research.

  • 246763.
    Yu, Di
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Leja, Justyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for Treatment of Liver Metastases from Neuroendocrine Cancer2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 1, p. 54-66Article in journal (Refereed)
    Abstract [en]

    Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET). AdVince includes the gene promoter from human chromogranin A for selective replication in neuroendocrine cells, miR122 target sequences for reduced liver toxicity, and a cell-penetrating peptide in the capsid for increased infectivity of tumor cells and optimized spread within tumors. This paper describes the preclinical evaluation of AdVince on freshly isolated human gastrointestinal NET cells resected from liver metastases and freshly isolated human hepatocytes as well as in fresh human blood. AdVince selectively replicates in and kills NET cells. Approximately, 73-fold higher concentration of AdVince is needed to induce similar level of cytotoxicity in NET cells as in hepatocytes. AdVince did not activate complement or induce considerable amount of proinflammatory cytokines or chemokines in human blood. The data presented herein indicate that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET.

  • 246764.
    Yu, DY
    et al.
    Uppsala University.
    Kotilainen, M
    Uppsala University.
    Pollanen, E
    Uppsala University.
    Mehto, M
    Uppsala University.
    Elomaa, P
    Uppsala University.
    Helariutta, Y
    Uppsala University.
    Albert, VA
    Uppsala University.
    Teeri, TH
    Uppsala University.
    Organ identity genes and modified patterns of flower development in Gerbera hybrida (Asteraceae)1999In: PLANT JOURNAL, ISSN 0960-7412, Vol. 17, no 1, p. 51-62Article in journal (Other scientific)
    Abstract [en]

    We have used Gerbera hybrida (the cultivated ornamental, gerbera) to investigate the molecular basis of flower development in Asteraceae, a family of flowering plants that have heteromorphic flowers and specialized floral organs. Flowers of the same genot

  • 246765.
    Yu, F
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Stål, P
    Thornell, L-E
    Larsson, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Human single masseter muscle fibers contain unique combinations of myosin and myosin binding protein C isoforms2002In: Journal of Muscle Research and Cell Motility, Vol. 23, p. 317-Article in journal (Refereed)
  • 246766. Yu, Feifan
    et al.
    Gudmundsdotter, Lindvi
    Akal, Anastassja
    Gunneriusson, Elin
    Frejd, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Nygren, Per-Ake
    An affibody-adalimumab hybrid blocks combined IL-6 and TNF-triggered serum amyloid A secretion in vivo2014In: MABS, ISSN 1942-0862, Vol. 6, no 6, p. 1598-1607Article in journal (Refereed)
    Abstract [en]

    In inflammatory disease conditions, the regulation of the cytokine system is impaired, leading to tissue damages. Here, we used protein engineering to develop biologicals suitable for blocking a combination of inflammation driving cytokines by a single construct. From a set of interleukin (IL)-6-binding affibody molecules selected by phage display, five variants with a capability of blocking the interaction between complexes of soluble IL-6 receptor a (sIL-6R alpha) and IL6 and the co-receptor gp130 were identified. In cell assays designed to analyze any blocking capacity of the classical or the alternative (trans) signaling IL-6 pathways, one variant, Z(IL-6_13) with an affinity (K-D) for IL-6 of similar to 500 pM, showed the best performance. To construct fusion proteins ("AffiMabs") with dual cytokine specificities, Z(IL-6_13) was fused to either the N-or C-terminus of both the heavy and light chains of the anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab (Humira (R)). One AffiMab construct with Z(IL-6_13) positioned at the N-terminus of the heavy chain, denoted Z(IL-6_13)-HCAda, was determined to be the most optimal, and it was subsequently evaluated in an acute Serum Amyloid A (SAA) model in mice. Administration of the AffiMab or adalimumab prior to challenge with a mix of IL-6 and TNF reduced the levels of serum SAA in a dose-dependent manner. Interestingly, the highest dose (70 mg/kg body weight) of adalimumab only resulted in a 50% reduction of SAA-levels, whereas the corresponding dose of the Z(IL-6_13)-HCAda AffiMab with combined IL-6/TNF specificity, resulted in SAA levels below the detection limit.

  • 246767.
    Yu, Fusheng
    et al.
    China Univ Petr, State Key Lab Petr Resources & Prospecting, Beijing 102249, Peoples R China.;China Univ Petr, Dept Earth Sci, Fuxue Rd, Beijing 102249, Peoples R China..
    Koyi, Hemin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Cenozoic tectonic model of the Bohai Bay Basin in China2016In: Geological Magazine, ISSN 0016-7568, E-ISSN 1469-5081, Vol. 153, no 5-6, p. 866-886Article in journal (Refereed)
    Abstract [en]

    Modelling results and seismic interpretation illustrate that the Cenozoic evolution of the Bohai Bay Basin (BBB) can be divided into different stages. A transtensional phase during Paleocene - early Oligocene time created NE-trending strike-slip faults and E-W-trending normal faults which were driven roughly by N-S-extension, making an angle of 25 degrees with the strike-slip faults. Seismic data interpretation yields evidence that inversion phases occurred within the NE Xialiaohe Depression of the greater Bohai Bay Basin. This inversion phase is attributed to rotation and partial inversion that occurred during late Oligocene time, leading to formation of inversion structures along the NE part of Tanlu Fault. This episode is attributed to an anticlockwise rotation of the eastern part of the BBB driven by the convergence between the Pacific and Eurasian plates. The tectonic scenario described was simulated in scaled analogue models, which were extended by pulling two basement plates away from each other. Partial inversion was simulated by rotation of one of the plates relative to the other. Model results show many of the features observed in the BBB. Our model results are used to argue that, unlike the two-episode extension and whole-basin inversion models previously proposed for the BBB, a single N-S-aligned extension followed by anticlockwise rotation accounts for the Cenozoic evolution of the BBB and produces some of the structural complexities observed in the basin.

  • 246768.
    Yu, Fusheng
    et al.
    China Univ Petr, State Key Lab Petr Resources & Prospecting, Fuxue Rd, Beijing, Peoples R China.;China Univ Petr, Dept Earth Sci, Fuxue Rd, Beijing, Peoples R China..
    Koyi, Hemin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Theoretical and experimental estimation of geometric relationship of non-parallel conjugate normal faults2017In: Tectonophysics, ISSN 0040-1951, E-ISSN 1879-3266, Vol. 703 - 704, p. 85-97Article in journal (Refereed)
    Abstract [en]

    Intersecting and crossing conjugate normal faults develop at different scales. Equations of geometric parameters of non-parallel conjugate normal faults can be deduced from their trigonometric relations. Physical models can also be used to verify the theoretical calculations and compared with natural examples. In this study, we have used a theoretical approach to outline some key geometric parameters of conjugate normal faults (intersection angles, plunge of intersection line, and vertical and horizontal distances of the intersection point, etc.) and compared them to equivalent geometric values in scaled analogue models. The comparison shows that theoretical plots used for geometric estimation of conjugate normal faults constrain reasonably the geometric parameters in natural cases. Data from the Lufeng Sag of Pearl River Mouth Basin in the northern part of South China Sea, where conjugate non-parallel basement faults propagate and intersect in cover units are compatible with the theoretical geometric estimation. (C) 2017 Elsevier B.V. All rights reserved.

  • 246769.
    Yu, Fusheng
    et al.
    China Univ Petr, State Key Lab Petr Resources & Prospecting, Fuxue Rd, Beijing, Peoples R China.;China Univ Petr, Dept Earth Sci, Fuxue Rd, Beijing, Peoples R China..
    Koyi, Hemin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Zhang, Xiangtao
    CNOOC China Ltd, Shenzhen Co, Guangzhou, Guangdong, Peoples R China..
    Intersection patterns of normal faults in the Lufeng Sag of Pearl River Mouth Basin, China: Insights from 4D physical simulations2016In: Journal of Structural Geology, ISSN 0191-8141, E-ISSN 1873-1201, Vol. 93, p. 67-90Article in journal (Refereed)
    Abstract [en]

    Interpretation of seismic data from the Lufeng Sag of the Pearl River Mouth Basin (PRMB) in the northern part of South China Sea shows that different intersection patterns developed in the cover units above basement normal faults. A series of analogue models are used to investigate the intersection patterns and deformation in the sedimentary cover sequences above a basement horst bounded by two non-parallel faults. Modelling results show that during their upward propagation, the basement faults may intersect within the cover sequences and form a graben above the basement horst. Length and width of the graben increase with cover thickness. The strike and dip intersection points are controlled directly by the thickness of the cover sequences, dip and strike of the basement faults, and width of the basement horst. The intersection point migrates along the axis of the graben toward the wide end of the basement horst, when the cover sequence thickens. In contrast, it migrates toward the narrow end of the basement horst, where both fault dip and angle of strike difference increase. The intersection point moves upward with increasing width of the basement horst crest. Model profiles also indicate that in the presence of a ductile layer between the cover and basement such intersection patterns do not form. Interpretation of seismic data and model results show that the intersection pattern developed in the Lufeng Sag is a result of propagation of basement faults into cover units during different extension stages of the basin. Results of this study can be applied to many other sedimentary basins where such fault intersection patterns are likely to form when non-parallel conjugate basement faults are active during sedimentation.

  • 246770. Yu, Fushun
    et al.
    Hedström, Margaretha
    Cristea, Alexander
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Dalén, Nils
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Effects of ageing and gender on contractile properties in human skeletal muscle and single fibres2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 190, no 3, p. 229-241Article in journal (Refereed)
    Abstract [en]

    Aim: The objective of this study is to improve our understanding of the mechanisms underlying the ageing- and gender-related muscle weakness.

    Methods: Ageing- and gender-related differences in regulation of muscle contraction have been studied in knee-extensor muscles at the whole muscle and single muscle fibre levels in young and old sedentary men and women. In vivo knee-extensor muscle function was measured at slow (30° s−1) and faster (180 ° s−1) speeds of movement. Maximum velocity of unloaded shortening (V0) and maximum force normalized to cross-sectional area (CSA) [specific tension (ST)] were measured in single 'skinned' skeletal muscle fibre segments.

    Results: Significant ageing- and gender-related differences were observed in muscle torque. A 33–55% ageing-related decline (P < 0.001) in maximum torque was observed irrespective of gender. At the single muscle fibre level, the ageing-related decline in knee-extensor muscle function was accompanied by a 20–28% decline in ST in muscle fibres expressing the type I MyHC isoform in both men and women, and a 29% decline in type IIa muscle fibre CSA, but the decreased fast-twitch fibre size was restricted to the men. Furthermore, in both men and women, V0 decreased in muscle cells expressing the type I and IIa MyHC isoforms.

    Conclusion: The present results provide evidence of specific ageing- and gender-related differences in regulation of muscle contraction at the cellular level. It is suggested that these cellular changes have a significant impact on muscle function and the ageing-related motor handicap.

  • 246771.
    Yu, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Pharmacological evaluation of novel 5-HT1A receptor ligands1996In: Uppsala Dissertations from the Faculty of Medicine, Vol. 619Other (Other scientific)
  • 246772.
    Yu, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Lewander, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Pharmacokinetic and pharmacodynamic studies of (R)-8-hydroxy-2-(di-n-propylamino)tetralin in the rat1997In: European Neuropsychopharmacology, Vol. 7, p. 165-Article in journal (Refereed)
  • 246773.
    Yu, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Liu, Y
    Hacksell, U
    Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lewander, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Oral cavity absorption of (R)-8-hydroxy-2-(di-n-propylamino)tetralin and (S)-8-Acetyl-2-(di-n-propylamino)tetralin in the rat1996In: Journal Pharm Pharmacol, Vol. 48, p. 41-Article in journal (Refereed)
  • 246774.
    Yu, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Liu, Y
    Li, H.B.
    Martin, A.R.
    Hacksell, U
    Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lewander, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Pharmacodynamic and pharmacokinetic studies in rats of S-8-(2-Furyl)- and R-8-phenyl-2-(di-n-propylamino) tetralin. two novel 5-HT1A receptor agonists in-vitro with different properties in-vivo1997In: Journal of Pharmacological Pharmacology, Vol. 49, p. 169-Article in journal (Refereed)
  • 246775.
    Yu, H
    et al.
    Uppsala University.
    Liu, Y
    Uppsala University.
    Li, HB
    Uppsala University.
    Martin, AR
    Uppsala University.
    Hacksell, U
    Uppsala University.
    Lewander, T
    Uppsala University.
    Pharmacodynamic and pharmacokinetic studies in rats of S-8-(2-furyl)- and R-8-phenyl-2-(di-n-propylamino)tetralin, two novel 5-HT1A receptor agonists in-vitro with different properties in-vivo1997In: JOURNAL OF PHARMACY AND PHARMACOLOGY, Vol. 49, no 2, p. 169-177Other (Other scientific)
    Abstract [en]

    R- and S-8-(2-Furyl)- and R- and S-8-phenyl-2-(di-n-propylamino)tetralins (R- and S-LY-55 and R- and S-LY-49, respectively), novel enantiopure dipropylaminotetralins, have been screened as 5-HT1A receptor ligands. All had nanomolar affinities for 5-HT1A

  • 246776.
    Yu, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Liu, Y
    Malmberg, A
    Mohell, N
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Hacksell, U
    Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lewander, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Differential serotoinergic and dopaminergic activities of the (R)- and the (S)-enantiomers of 2-(di-n-propylamino)tetralin1996In: European Journal of Pharmacology, Vol. 303, p. 151-Article in journal (Refereed)
  • 246777.
    Yu, Haisan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    The EU ETS and Firm Profits: An Ex-post Analysis for Swedish Energy Firms2011Report (Other academic)
  • 246778.
    Yu, Haishan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Economic growth and social welfare with global regime-switching environmental thresholdsManuscript (preprint) (Other academic)
    Abstract [en]

    Scientific evidence indicates that human development faces multiple and interacting regime-switching environmental thresholds such as climate change, ocean acidification and biodiversity loss. And crossing one or more such thresholds would trigger rapid and large changes in our life-support system with widespread consequences. This paper attempts to study the effects of such thresholds on human well-being in a growth theoretical framework. We derive the accounting prices of pollution stocks such as the concentration of greenhouse gases for the risk of triggering catastrophic events, which are needed for conducting a dynamic cost-benefit analysis. We first analyze a simple model with a single threshold and then extend it to a planar system with correlated double thresholds with a joint probability distribution. the results can be applied for analyzing global climate change and ocean acidification risks, which are highlighted in a Nature article by Rockström et al. (2009).

  • 246779.
    Yu, Haishan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Essays on Environmental and Energy Economics2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Essay I: In January, 2005, the EU launched the first international emissions trading system (EU ETS), aimed at reducing carbon emissions in a cost-effective way by means of a market-based instrument. In this paper, we use the treatment/control, before/after design of the natural experiment approach to investigate the treatment effect of the EU ETS on the profitability of a sample of Swedish energy firms in 2005 and 2006. We also investigate whether under-cap and over-cap firms respond differently to the EU ETS. The estimation results in general suggest no significant impact in 2005 and a negative significant impact in 2006. The sub-sample analysis suggests that profitability of under-cap and over-cap firms were affected differently by the EU ETS in 2005, but not in 2006.

    Essay II: The paper empirically explores the possible causes behind electricity price jumps in the Nordic electricity market, Nord Pool. A time-series model (a mixed GARCH-EARJI jump model) capturing the common statistical features of electricity prices is used to identify price jumps. By the model, a categorical variable is defined distinguishing no, positive and negative jumps. The causes for the jumps are then explored through the use of ordered probit models in a second stage. The empirical results indicate that the structure of the market plays an important role in whether shocks in the demand and supply for electricity translate into price jumps.

    Essay III: Scientific evidence indicates that human development faces multiple and interacting regime-switching environmental thresholds such as climate change, ocean acidification and biodiversity loss. And crossing one or more such thresholds would trigger rapid and large changes in our life-support system with widespread consequences. This paper attempts to study the effects of such thresholds on human well-being in a growth theoretical framework. We derive the accounting prices of pollution stocks such as the concentration of greenhouse gases for the risk of triggering catastrophic events, which are needed for conducting a dynamic cost-benefit analysis. We first analyze a simple model with a single threshold and then extend it to a planar system with correlated double thresholds with a joint probability distribution. the results can be applied for analyzing global climate change and ocean acidification risks, which are highlighted in a Nature article by Rockström et al. (2009).

    Essay IV: Lump-sum transfers as a means of tackling climate change are mainly perceived as a theoretical construct to achieve the first best Pareto optimum. The previous literature on lump-sum transfers normally focuses on the two polar cases: the absence of lump-sum transfers and perfect or unconstrained lump-sum transfers, leaving the middle way aside. In this paper, we attempt to explore the unmarked part by developing a model where transfer costs are explicitly taken into account. We show that whether the Pareto optimum characterized by the equalization of marginal abatement costs is attainable depends on the formation of transfer costs. When the marginal transfer cost is zero, the separability of equity and efficiency under perfect lump-sum transfers is kept. However, when the marginal transfer cost is positive, the optimum with equalization of marginal abatement costs is neither attainable, nor desirable. We also simulate a policy experiment in China to review the optimal abatement and transfer patterns between China's provinces within a framework of imperfect lump-sum transfers. The highlighted welfare gains is supportive of considering lump-sum transfers as a national climate change policy.

    List of papers
    1. The EU ETS and firm profits: an ex-post analysis for Swedish energy firms
    Open this publication in new window or tab >>The EU ETS and firm profits: an ex-post analysis for Swedish energy firms
    2013 (English)In: Environmental Economics, ISSN 1998-6041, Vol. 4, no 3, p. 59-71Article in journal (Refereed) Published
    Abstract [en]

    In January, 2005, the EU launched the first international emissions trading system (EU ETS), aimed at reducing carbon emissions in a cost-effective way by means of a market-based instrument. In this paper, we use the treatment/control, before/after design of the natural experiment approach to investigate the treatment effect of the EU ETS on the profitability of a sample of Swedish energy firms in 2005 and 2006. We also investigate whether under-cap and over-cap firms respond differently to the EU ETS. The estimation results in general suggest no significant impact in 2005 and a negative significant impact in 2006. The sub-sample analysis suggests that profitability of under-cap and over-cap firms were affected differently by the EU ETS in 2005, but not in 2006.

    National Category
    Economics
    Identifiers
    urn:nbn:se:uu:diva-222281 (URN)
    Available from: 2014-04-09 Created: 2014-04-09 Last updated: 2014-05-13Bibliographically approved
    2. Why do electricity prices jump? Empirical Evidence from the Nordic electricity market
    Open this publication in new window or tab >>Why do electricity prices jump? Empirical Evidence from the Nordic electricity market
    2012 (English)In: Energy Economics, ISSN 0140-9883, E-ISSN 1873-6181, Vol. 34, no 6, p. 1774-1781Article in journal (Refereed) Published
    Abstract [en]

    The paper empirically explores the possible causes behind electricity price jumps in the Nordic electricity market, Nord Pool. A time-series model (a mixed GARCH-EARJI jump model) capturing the common statistical features of electricity prices is used to identify price jumps. By the model, a categorical variable is defined distinguishing no, positive and negative jumps. The causes for the jumps are then explored through the use of ordered probit models in a second stage. The empirical results indicate that the structure of the market plays an important role in whether shocks in the demand and supply for electricity translate into price jumps.

    National Category
    Economics
    Identifiers
    urn:nbn:se:uu:diva-222280 (URN)10.1016/j.eneco.2012.07.006 (DOI)000310943800004 ()
    Available from: 2014-04-09 Created: 2014-04-09 Last updated: 2017-12-05Bibliographically approved
    3. Economic growth and social welfare with global regime-switching environmental thresholds
    Open this publication in new window or tab >>Economic growth and social welfare with global regime-switching environmental thresholds
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Scientific evidence indicates that human development faces multiple and interacting regime-switching environmental thresholds such as climate change, ocean acidification and biodiversity loss. And crossing one or more such thresholds would trigger rapid and large changes in our life-support system with widespread consequences. This paper attempts to study the effects of such thresholds on human well-being in a growth theoretical framework. We derive the accounting prices of pollution stocks such as the concentration of greenhouse gases for the risk of triggering catastrophic events, which are needed for conducting a dynamic cost-benefit analysis. We first analyze a simple model with a single threshold and then extend it to a planar system with correlated double thresholds with a joint probability distribution. the results can be applied for analyzing global climate change and ocean acidification risks, which are highlighted in a Nature article by Rockström et al. (2009).

    National Category
    Economics
    Identifiers
    urn:nbn:se:uu:diva-222692 (URN)
    Available from: 2014-04-13 Created: 2014-04-13 Last updated: 2014-05-13
    4. Optimal carbon abatement in the presence of lump-sum transfer costs
    Open this publication in new window or tab >>Optimal carbon abatement in the presence of lump-sum transfer costs
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Lump-sum transfers as a means of tackling climate change are mainly perceived as a theoretical construct to achieve the first best Pareto optimum. The previous literature on lump-sum transfers normally focuses on the two polar cases: the absence of lump-sum transfers and perfect or unconstrained lump-sum transfers, leaving the middle way aside. In this paper, we attempt to explore the unmarked part by developing a model where transfer costs are explicitly taken into account. We show that whether the Pareto optimum characterized by the equalization of marginal abatement costs is attainable depends on the formation of transfer costs. When the marginal transfer cost is zero, the separability of equity and efficiency under perfect lump-sum transfers is kept. However, when the marginal transfer cost is positive, the optimum with equalization of marginal abatement costs is neither attainable, nor desirable. We also simulate a policy experiment in China to review the optimal abatement and transfer patterns between China's provinces within a framework of imperfect lump-sum transfers. The highlighted welfare gains is supportive of considering lump-sum transfers as a national climate change policy.

    National Category
    Economics
    Identifiers
    urn:nbn:se:uu:diva-222693 (URN)
    Available from: 2014-04-13 Created: 2014-04-13 Last updated: 2014-05-13
  • 246780.
    Yu, Haishan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Optimal carbon abatement in the presence of lump-sum transfer costsManuscript (preprint) (Other academic)
    Abstract [en]

    Lump-sum transfers as a means of tackling climate change are mainly perceived as a theoretical construct to achieve the first best Pareto optimum. The previous literature on lump-sum transfers normally focuses on the two polar cases: the absence of lump-sum transfers and perfect or unconstrained lump-sum transfers, leaving the middle way aside. In this paper, we attempt to explore the unmarked part by developing a model where transfer costs are explicitly taken into account. We show that whether the Pareto optimum characterized by the equalization of marginal abatement costs is attainable depends on the formation of transfer costs. When the marginal transfer cost is zero, the separability of equity and efficiency under perfect lump-sum transfers is kept. However, when the marginal transfer cost is positive, the optimum with equalization of marginal abatement costs is neither attainable, nor desirable. We also simulate a policy experiment in China to review the optimal abatement and transfer patterns between China's provinces within a framework of imperfect lump-sum transfers. The highlighted welfare gains is supportive of considering lump-sum transfers as a national climate change policy.

  • 246781.
    Yu, Haishan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    The EU ETS and firm profits: an ex-post analysis for Swedish energy firms2013In: Environmental Economics, ISSN 1998-6041, Vol. 4, no 3, p. 59-71Article in journal (Refereed)
    Abstract [en]

    In January, 2005, the EU launched the first international emissions trading system (EU ETS), aimed at reducing carbon emissions in a cost-effective way by means of a market-based instrument. In this paper, we use the treatment/control, before/after design of the natural experiment approach to investigate the treatment effect of the EU ETS on the profitability of a sample of Swedish energy firms in 2005 and 2006. We also investigate whether under-cap and over-cap firms respond differently to the EU ETS. The estimation results in general suggest no significant impact in 2005 and a negative significant impact in 2006. The sub-sample analysis suggests that profitability of under-cap and over-cap firms were affected differently by the EU ETS in 2005, but not in 2006.

  • 246782.
    Yu, Han
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    THE PROTECTION SCOPE OF EU TRADE MARK LAW IN RELATION TO TRADE MARK FUNCTIONS2019Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The function of a trade mark plays an essential role in the proper interpretation and enforcement of trade mark law. In the case of double identity, whether a trade mark can fulfill its function, traditionally the function of guaranteeing the origin of products or services, is the benchmark of the scope of protection for a trade mark proprietor. Since the functions of guaranteeing the quality, communication, advertising, and investment have been identified and developed by the CJEU, it becomes controversial that whether the function of a trade mark can still be the benchmark of the scope of protection in the case of infringement. The purpose of the thesis is to analyze the reason of recognizing the functions other than that of guaranteeing the origin and examine the justification of such recognition. It is analyzed that the origin function of a trade mark could provide enough protection for the trade mark proprietor through the national cases and the comparison with similar cases in China. The recognition of the contemporary functions would potentially expand the scope of protection for trade mark proprietors and thus distort the integrity of Article 9 of the EUTMR and the fair competition that the EU trade mark law intends to promote. It is proposed that the CJEU should clarify the definition and scope of the contemporary functions and the protection gaps that could be created by confining the function of a trade mark in the case of double identity to the origin function. In addition, the balance among trade mark proprietors, their competitors, and consumers should be taken into consideration in order to justify the contemporary functions of a trade mark.

  • 246783.
    Yu, Hans
    et al.
    Univ Bodenkultur Wien, Interuniv Dept Agrobiotechnol IFA Tulln, Inst Biotechnol Anim Prod, Tulln, Austria.;Univ Vet Med Vienna, Dept Biomed Sci, Inst Anim Breeding & Genet, Vienna, Austria..
    Reiser, Judith
    Ludwig Maximilians Univ Munchen, Inst Mol Anim Breeding & Biotechnol, Munich, Germany..
    Besenfelder, Urban
    Univ Bodenkultur Wien, Interuniv Dept Agrobiotechnol IFA Tulln, Inst Biotechnol Anim Prod, Tulln, Austria.;Univ Vet Med Vienna, Reprod Ctr Wieselburg, Vienna, Austria..
    Razzazi-Fazeli, Ebrahim
    Univ Vet Med Vienna, VetCore Facil Res, Vienna, Austria..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brem, Gottfried
    Univ Bodenkultur Wien, Interuniv Dept Agrobiotechnol IFA Tulln, Inst Biotechnol Anim Prod, Tulln, Austria.;Univ Vet Med Vienna, Dept Biomed Sci, Inst Anim Breeding & Genet, Vienna, Austria..
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mayrhofer, Corina
    Univ Bodenkultur Wien, Interuniv Dept Agrobiotechnol IFA Tulln, Inst Biotechnol Anim Prod, Tulln, Austria.;Univ Vet Med Vienna, Dept Biomed Sci, Inst Anim Breeding & Genet, Vienna, Austria..
    Exploring the oviductal fluid proteome by a lectin-based affinity approach2016In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 16, no 23, p. 2962-2966Article in journal (Refereed)
    Abstract [en]

    The analysis of glycoproteins in body fluids represents a central task in the study of vital processes. Herein, we assessed the combined use of Concanavalin A and Wheat Germ Agglutinin as ligands to fractionate and enrich glycoproteins from oviductal fluid (OF), which is a source of molecules involved in fertilization. First, the selectivity was corroborated by a gel-based approach using glycoprotein staining and enzymatic deglycosylation. Nanoliquid chromatography-tandem mass spectrometry (nLC-ESI-MS/MS) further allowed the reliable identification of 134 nonbound as well as 130 lectin-bound OF proteins. Enrichment analysis revealed that 77% of the annotated proteins in the lectin-bound fraction were known glycoproteins (p-value [FDR] = 1.45E-31). The low variance of the number of peptide spectrum matches for each protein within replicates indicated a consistent reproducibility of the whole workflow (median CV 17.3% for technical replicates and 20.7% for biological replicates). Taken together, this study highlights the applicability of a lectin-based workflow for the comprehensive analysis of OF proteins and gives for the first time an insight into the broad glycoprotein content of OF.

  • 246784.
    Yu, Hong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Pharmacological evaluation of novel 5-HT1A receptor ligands: pharmacodynamic and pharmacokinetic studies of 2-(di- -propylamino)tetralin derivatives1996Doctoral thesis, comprehensive summary (Other academic)
  • 246785.
    Yu, J
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Coirini, H
    Kallstrom, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Wiesel, F-A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Johnson, AE
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Differential modulaton of Dopamine D1 receptor binding and mRNA expression in the basal ganglia by the dopamine D1-receptor antagonist SCH-233901998In: Synapse, Vol. 30, p. 38-Article in journal (Refereed)
  • 246786.
    Yu, J
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Kallstrom, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Wiesel, F-A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Johnson, A.E.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Neurochemical changes in the entopeduncular nucleus and increased oral behavior in rats treated subchronically with clozapine or haloperidol1999In: Synapse, Vol. 34, p. 192-Article in journal (Refereed)
  • 246787.
    Yu, Jiang
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Effects of antipsychotics on GABA neurons in the basal ganglia of the rat2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antipsychotics are used in the treatment of psychosis and, based on their propensities to induce extrapyramidal side effects (EPS), are divided into typical (haloperidol) and atypical (clozapine) subtypes. The incidence of EPS, arises from an imbalance in the neurotransmission between two majorGABAergic pathways of the basal ganglia that connect the striatum directly to the entopeduncular nucleus (EP) and the substantia nigra reticulata or indirectly via the globus pallidus and the subthalamic nucleus. The striatonigral/EP neurons express dopamine D1-receptors and preprodynorphin (PPD) while striatopallidal neurons contain D2-receptors and preproenkephalin (PPE).

    The GABA neurons contain glutamic acid decarboxylase (GAD, the rate limiting enzyme of GABA synthesis), which exists in two isoforms-- GAD65 and GAD67. In situ hybridization and receptor autoradiographic methods were used in rats. It was shown that the modulation of basal ganglia D1-receptor binding by a typical antipsychotic (fluphenazine) was primarily due to the blockade of D1-receptors. In the EP, GAD65 and GAD67 mRNAs were most abundant in the rostra1 limbic and the caudal motor subregions, respectively. Subchronic administration of clozapine increased D1-receptor binding and GAD65 mRNA levels; haloperidol enhanced both GAD65 and GAD67 mRNA expression in the rostra1 and caudal EP. Both drugs induced vacuous chewing movements (VCMs). The glutamate receptor (NMDA) antagonist, MK-801, which excerted a week effect on VCMs, increased GAD67 mRNA in both EP subregions. Whereas haloperidol only increased PPE mRNA expression, MK-801 enhanced both PPE and PPD mRNA levels in the striatum.

    The biochemical differences between haloperidol and clozapine in the EP may be linked to their different clinical profiles of the two antipsychotics. The modulation of GAD65 mRNA expression in the EP may play a role in the display of VCMs. Whereas haloperidol primarily influenced the indirect pathway, MK-801 activated both thedirect and indirect pathways.

  • 246788. Yu, J-L
    et al.
    Johansson, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ljungh, Å
    Fibronectin exposes different domains after adsorption to a heparinized and an unheparinized poly(vinyl chloride) surface.1997In: Biomaterials, Vol. 18, p. 1-Article in journal (Refereed)
  • 246789. Yu, K-H
    et al.
    Hong, K-S
    Lee, B-C
    Oh, M-S
    Cho, Y-J
    Koo, J-S
    Park, J-M
    Bae, H-J
    Han, M-K
    Ju, Y-S
    Kang, D-W
    Appelros, P.
    Norrving, B.
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Comparison of 90-day case-fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis2011In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 123, no 5, p. 325-331Article in journal (Refereed)
    Abstract [en]

    Background - It has not been clarified whether the disparity in ischemic stroke outcome between populations is caused by ethnic and geographic differences or by variations in case mix. Propensity score matching (PSM) analysis can overcome some analytical problems but is rarely used in stroke outcome research. This study was to compare the ischemic stroke case-fatality between two PSM cohorts of Sweden and Korea. Methods - Prognostic variables related to baseline characteristics and stroke care were included in our PSM model. Then, we selected 7675 Swedish and 1220 Korean patients with ischemic stroke from each stroke registers and performed one-to-one matching based on propensity scores of each patient. Results - After PSM, all measured variables were well balanced in 1163 matched subjects, and the 90-day case-fatality was identical 6.2% (HR 0.997, 95%CI 0.905-1.099) in Sweden and Korea. Conclusions - No difference is found in the 90-day case-fatality in propensity score-matched Swedish and Korean patients with ischemic stroke.

  • 246790. Yu, Li-Ying
    et al.
    Jokitalo, Eija
    Sun, Yun-Fu
    Mehlen, Patrick
    Lindholm, Dan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Saarma, Mart
    Arumäe, Urmas
    GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway2003In: J of Cell Biology, Vol. 163, p. 987-Article in journal (Refereed)
  • 246791. Yu, Li-Ying
    et al.
    Korhonen, Laura
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Martinez, Rodrigo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Jokitalo, Eija
    Chen, Yuming
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Arumäe, Urmas
    Lindholm, Dan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Regulation of sympathetic neuron and neuroblastoma cell death by XIAP and its association with proteasomes in neural cells2003In: Molecular and Cellular Neuroscience, Vol. 22, p. 308-Article in journal (Refereed)
  • 246792.
    Yu, N
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology.
    Fu, YX
    Sambuughin, N
    Ramsay, M
    Jenkins, T
    Leskinen, E
    Patthy, L
    Jorde, LB
    Kuromori, T
    Li, WH
    Global patterns of human DNA sequence variation in a 10-kb region on chromosome 12001In: MOLECULAR BIOLOGY AND EVOLUTION, Vol. 18, no 2, p. 214-222Article in journal (Refereed)
  • 246793.
    Yu, Nancy Yiu-Lin
    et al.
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.;Karolinska Inst, Sci Life Lab, S-17121 Solna, Sweden..
    Hallstrom, Bjorn M.
    KTH Royal Inst Technol, Sci Life Lab, S-17121 Solna, Sweden..
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, S-17121 Solna, Sweden..
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kawaji, Hideya
    RIKEN, Prevent Med & Diag Innovat Program, Wako, Saitama 3510198, Japan.;RIKEN, Yokohama Inst, Div Genom Technol, Ctr Life Sci Technol,Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan.;RIKEN, Omics Sci Ctr, Yokohama, Kanagawa 2300045, Japan..
    Carninci, Piero
    RIKEN, Yokohama Inst, Div Genom Technol, Ctr Life Sci Technol,Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan.;RIKEN, Omics Sci Ctr, Yokohama, Kanagawa 2300045, Japan..
    Forrest, Alistair R. R.
    RIKEN, Yokohama Inst, Div Genom Technol, Ctr Life Sci Technol,Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan.;RIKEN, Omics Sci Ctr, Yokohama, Kanagawa 2300045, Japan..
    Hayashizaki, Yoshihide
    RIKEN, Prevent Med & Diag Innovat Program, Wako, Saitama 3510198, Japan.;RIKEN, Omics Sci Ctr, Yokohama, Kanagawa 2300045, Japan..
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, S-17121 Solna, Sweden..
    Daub, Carsten O.
    Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.;Karolinska Inst, Sci Life Lab, S-17121 Solna, Sweden.;RIKEN, Yokohama Inst, Div Genom Technol, Ctr Life Sci Technol,Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan.;RIKEN, Omics Sci Ctr, Yokohama, Kanagawa 2300045, Japan..
    Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium2015In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, no 14, p. 6787-6798Article in journal (Refereed)
    Abstract [en]

    Understanding the normal state of human tissue transcriptome profiles is essential for recognizing tissue disease states and identifying disease markers. Recently, the Human Protein Atlas and the FANTOM5 consortium have each published extensive transcriptome data for human samples using Illumina-sequenced RNA-Seq and Heliscope-sequenced CAGE. Here, we report on the first large-scale complex tissue transcriptome comparison between full-length versus 5'-capped mRNA sequencing data. Overall gene expression correlation was high between the 22 corresponding tissues analyzed (R > 0.8). For genes ubiquitously expressed across all tissues, the two data sets showed high genome-wide correlation (91% agreement), with differences observed for a small number of individual genes indicating the need to update their gene models. Among the identified single-tissue enriched genes, up to 75% showed consensus of 7-fold enrichment in the same tissue in both methods, while another 17% exhibited multiple tissue enrichment and/or high expression variety in the other data set, likely dependent on the cell type proportions included in each tissue sample. Our results show that RNA-Seq and CAGE tissue transcriptome data sets are highly complementary for improving gene model annotations and highlight biological complexities within tissue transcriptomes. Furthermore, integration with image-based protein expression data is highly advantageous for understanding expression specificities for many genes.

  • 246794.
    Yu, Ou
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology.
    Research and optimization of a H.264AVC motion estimation algorithm based on a 3G network2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The new video codec standard H.264/AVC is jointly developed by ISO/IEC Moving Picture Expert Group MPEG and ITU-T Video Coding Experts Group [1] [2], VCEG. It has higher coding efficiency than the MPEG-4, thus could be applied to high definition application in low bit-rate wireless environment.[3] However H.264/AVC has harsh requirement on the hardware, basically due to the complexity of the algorithms it used. And end devices, e.g. smart phones usually do not have sufficient computing capability, also it is restricted by limited battery power. As a result, it is crucial to reduce the computing complexity of H.264/AVC codec, and in the same time, keep the video quality unharmed.

    After the analysis of the H.264/AVC coding algorithm, it can be found that ME (motion estimation) consumes the biggest part of the computing power. So in order to adopt H.264/AVC to real-time, low bit-rate video application, it is very important to optimize ME algorithm. In this thesis, basic knowledge and key technology of H.264/AVC is introduced  in the  first  place. Then it systematically illustrate the existing block-matching ME algorithms, both the algorithm flow and different technology involved, also the pros and cons of each. In the next part, a very famous algorithm UMHexagonS, now accepted by ITU-T, is introduced in detail, and the author explain in different aspects why this algorithm could gain more efficiency over others. And on the base of the analysis, the author proposes some improvement to the UMHexagonS, taking thoughts of some classic ME algorithms into it. In the last phase of the thesis, both Subjective quality assessment experiment and objective quality assessment experiment are used to examine the performance of the improved algorithm. It has been shown by experiments that the improved ME algorithm requires less computing power than UMHexagonS, while keeping video quality at the same level. The improved algorithm could be used in a wireless environment such as a 3G network.

  • 246795.
    Yu, Qian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    α-Cell signalling in glucose-regulated glucagon secretion2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glucagon is a blood glucose-elevating hormone released from α-cells in the islets of Langerhans during hypoglycaemia. Glucagon is critical for glucose homeostasis and inappropriate regulation of its secretion underlies both impaired counter-regulation of hypoglycaemia and chronic hyperglycaemia in diabetes patients. The mechanisms by which glucose controls glucagon secretion are poorly understood, but have been suggested to involve both direct effects of the sugar on α-cells and indirect effects mediated by paracrine factors released within the islet, including insulin and gamma-hydroxybutyrate (GHB) from β-cells, and somatostatin from δ-cells. This thesis addresses the role of the intracellular messengers ATP, Ca2+ and cAMP in glucose-regulated glucagon secretion. Various fluorescence microscopy techniques were used to monitor changes of these messengers in single, dispersed α-cells and those in situ within intact islets, and glucagon secretion from islets was measured with an immunoassay. Glucose induced elevations of α-cell ATP, which were smaller and showed a left-shifted concentration-dependence compared to those in β-cells, consistent with α-cells being less dependent on oxidative metabolism and optimized for sensing hypoglycaemia. α-Cells showed Ca2+ oscillations with little glucose dependence. Surprisingly, these oscillations became synchronized in phase with Ca2+ oscillations in β-cells at high glucose. Since Ca2+ is a main trigger of exocytosis in both cell types, and since insulin and glucagon secretion is pulsatile in opposite phase, the results indicate that factors other than Ca2+ are more important for shaping glucagon secretion. Consistent with a key role of cAMP for the regulation of glucagon release, the concentration of the messenger was relatively high in α-cells at low glucose concentrations, and elevations of glucose suppressed cAMP in parallel with glucagon secretion. This effect was independent of paracrine signalling from insulin and somatostatin. The glucose-induced suppression of glucagon secretion was prevented by cAMP-elevating agents and mimicked by inhibitors of protein kinase A. GHB lacked effects both on Ca2+, cAMP and glucagon secretion from mouse islets, but tended to stimulate glucagon secretion by a somatostatin-receptor-dependent mechanism in human islets. The data indicate that GHB is not an inhibitor of glucagon secretion and that α-cell-intrinsic glucose sensing involves signalling via cAMP and protein kinase A.

    List of papers
    1. Submembrane ATP and Ca2+ kinetics in alpha-cells: unexpected signaling for glucagon secretion
    Open this publication in new window or tab >>Submembrane ATP and Ca2+ kinetics in alpha-cells: unexpected signaling for glucagon secretion
    Show others...
    2015 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 8, p. 3379-3388Article in journal (Refereed) Published
    Abstract [en]

    Cytoplasmic ATP and Ca2+ are implicated in current models of glucose's control of glucagon and insulin secretion from pancreatic alpha- and beta-cells, respectively, but little is known about ATP and its relation to Ca2+ in alpha-cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca2+ indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca2+ and ATP ([Ca2+](pm); [ATP](pm)) in superficial alpha- and beta-cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP's controlling glucagon and insulin secretion during hypo- and hyperglycemia, respectively, the dose-response relationship for glucoseinduced [ATP](pm) generation was left shifted in alpha-cells compared to beta-cells. Both cell types showed [Ca2+](pm) and [ATP](pm) oscillations in opposite phase, probably reflecting energy-consuming Ca2+ transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca2+](pm) synchronized in the same phase between alpha- and beta-cells. This paradox can be explained by the overriding of Ca2+ stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca2+. The data indicate that an alpha-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia.

    Keywords
    oscillations, islet of Langerhans, signal transduction, paracrine
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-261252 (URN)10.1096/fj.14-265918 (DOI)000358796900025 ()25911612 (PubMedID)
    Funder
    Swedish Diabetes AssociationSwedish Research CouncilNovo Nordisk
    Available from: 2015-09-01 Created: 2015-08-31 Last updated: 2018-07-31Bibliographically approved
    2. Glucose controls glucagon secretion by directly modulating cAMP in α‑cells
    Open this publication in new window or tab >>Glucose controls glucagon secretion by directly modulating cAMP in α‑cells
    Show others...
    (English)In: Article in journal (Other (popular science, discussion, etc.)) Submitted
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-356473 (URN)
    Available from: 2018-07-29 Created: 2018-07-29 Last updated: 2018-07-31
    3. Quantitative assessment of glucose-regulated cAMP signalling and protein kinase A-mediated glucagon secretion.
    Open this publication in new window or tab >>Quantitative assessment of glucose-regulated cAMP signalling and protein kinase A-mediated glucagon secretion.
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-356474 (URN)
    Available from: 2018-07-29 Created: 2018-07-29 Last updated: 2018-08-03
    4. γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion
    Open this publication in new window or tab >>γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion
    Show others...
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-356475 (URN)
    Available from: 2018-07-29 Created: 2018-07-29 Last updated: 2018-07-31
  • 246796.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quantitative assessment of glucose-regulated cAMP signalling and protein kinase A-mediated glucagon secretion.Manuscript (preprint) (Other (popular science, discussion, etc.))
  • 246797.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lai, Bao Khanh
    Université Catholique de Louvain, Brussels, Belgium.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Helander, Anders
    Karolinska Institutet.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gilon, Patrick
    Université Catholique de Louvain, Brussels, Belgium.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretionManuscript (preprint) (Other (popular science, discussion, etc.))
  • 246798.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Jia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Paradoxical Ca2+ kinetics in islet-located glucagon-releasing alpha cells2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S268-S269Article in journal (Other academic)
  • 246799.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Jia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Paradoxical synchronisation of Ca2+ oscillations between alpha and beta cells within intact pancreatic islets2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S252-S252Article in journal (Other academic)
  • 246800.
    Yu, Qian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shuai, Hongyan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ahooghalandari, Parvin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose controls glucagon secretion by directly modulating cAMP in alpha cells2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 7, p. 1212-1224Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis

    Glucagon is critical for normal glucose homeostasis and aberrant secretion of the hormone aggravates dysregulated glucose control in diabetes. However, the mechanisms by which glucose controls glucagon secretion from pancreatic alpha cells remain elusive. The aim of this study was to investigate the role of the intracellular messenger cAMP in alpha-cell-intrinsic glucose regulation of glucagon release.

    Methods

    Subplasmalemmal cAMP and Ca2+ concentrations were recorded in isolated and islet-located alpha cells using fluorescent reporters and total internal reflection microscopy. Glucagon secretion from mouse islets was measured using ELISA.

    Results

    Glucose induced Ca2+-independent alterations of the subplasmalemmal cAMP concentration in alpha cells that correlated with changes in glucagon release. Glucose-lowering-induced stimulation of glucagon secretion thus corresponded to an elevation in cAMP that was independent of paracrine signalling from insulin or somatostatin. Imposed cAMP elevations stimulated glucagon secretion and abolished inhibition by glucose elevation, while protein kinase A inhibition mimicked glucose suppression of glucagon release.

    Conclusions/interpretation

    Glucose concentrations in the hypoglycaemic range control glucagon secretion by directly modulating the cAMP concentration in alpha cells independently of paracrine influences. These findings define a novel mechanism for glucose regulation of glucagon release that underlies recovery from hypoglycaemia and may be disturbed in diabetes.

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