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  • 1.
    Abdulamir, Dalia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Evaluation of the Role of Histidines Regarding the Self-assembly and Fibrillar Stability of Amyloid βeta2015Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
  • 2.
    Adhikari, Deepak
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Signaling pathways in the development of female germ cells2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Primordial follicles are the first small follicles to appear in the mammalian ovary. Women are born with a fixed number of primordial follicles in the ovaries. Once formed, the pool of primordial follicles serves as a source of developing follicles and oocytes. The first aim of this thesis was to investigate the functional role of the intra-oocyte signaling pathways, especially the phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin complex 1 (mTORC1) pathways in the regulation of primordial follicle activation and survival. We found that a primordial follicle remains dormant when the PI3K and mTORC1 signaling in its oocyte is activated to an appropriate level, which is just sufficient to maintain its survival, but not sufficient for its growth initiation. Hyperactivation of either of these signaling pathways causes global activation of the entire pool of primordial follicles leading to the exhaustion of all the follicles in young adulthood in mice. Mammalian oocytes, while growing within the follicles, remain arrested at prophase I of meiosis. Oocytes within the fully-grown antral follicles resume meiosis upon a preovulatory surge of leutinizing hormone (LH), which indicates that LH mediates the resumption of meiosis. The prophase I arrest in the follicle-enclosed oocyte is the result of low maturation promoting factor (MPF) activity, and resumption of meiosis upon the arrival of hormonal signals is mediated by activation of MPF. MPF is a complex of cyclin dependent kinase 1 (Cdk1) and cyclin B1, which is essential and sufficient for entry into mitosis. Although much of the mitotic cell cycle machinery is shared during meiosis, lack of Cdk2  in mice leads to a postnatal loss of all oocytes, indicating that Cdk2 is important for oocyte survival, and probably oocyte meiosis also. There have been conflicting results earlier about the role of Cdk2 in metaphase II arrest of Xenopus  oocytes. Thus the second aim of the thesis was to identify the specific Cdk that is essential for mouse oocyte meiotic maturation. We generated mouse models with oocytespecific deletion of Cdk1  or Cdk2  and studied the specific requirements of Cdk1 and Cdk2 during resumption of oocyte meiosis. We found that only Cdk1 is essential and sufficient for the oocyte meiotic maturation. Cdk1 does not only phosphorylate the meiotic phosphoproteins during meiosis resumption but also phosphorylates and suppresses the downstream protein phosphatase 1, which is essential for protecting the Cdk1 substrates from dephosphorylation.

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    Thesis-Deepak Adhikari
  • 3.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Flohr, Gilian
    Hogeschool Leiden, Zernikedreef 11,2333 CK Leiden, The Netherlands.
    Gorre, Nagaraju
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shen, Yan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Yang, Hairu
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lan, Zijian
    University of Louisville Health Sciences Center, Louisville, Kentucky, USA.
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles2009Ingår i: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 15, nr 12, s. 765-770Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To maintain the length of reproductive life in a woman, it is essential that most of her ovarian primordial follicles are maintained in a quiescent state to provide a continuous supply of oocytes. However, our understanding of the molecular mechanisms that control the quiescence and activation of primordial follicles is still in its infancy. In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles. In mutant mice lacking the Tsc2 gene in oocytes, the pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in oocytes. This results in depletion of follicles in early adulthood, causing premature ovarian failure (POF). Our results suggest that the Tsc1-Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation. Our results also indicate that deregulation of Tsc/mTOR signaling in oocytes may cause pathological conditions of the ovary such as infertility and POF.

  • 4.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Molecular mechanisms underlying the activation of mammalian primordial follicles2009Ingår i: Endocrine reviews, ISSN 0163-769X, E-ISSN 1945-7189, Vol. 30, nr 5, s. 438-464Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In humans and other mammalian species, the pool of resting primordial follicles serves as the source of developing follicles and fertilizable ova for the entire length of female reproductive life. One question that has intrigued biologists is: what are the mechanisms controlling the activation of dormant primordial follicles. Studies from previous decades have laid a solid, but yet incomplete, foundation. In recent years, molecular mechanisms underlying follicular activation have become more evident, mainly through the use of genetically modified mouse models. As hypothesized in the 1990s, the pool of primordial follicles is now known to be maintained in a dormant state by various forms of inhibitory machinery, which are provided by several inhibitory signals and molecules. Several recently reported mutant mouse models have shown that a synergistic and coordinated suppression of follicular activation provided by multiple inhibitory molecules is necessary to preserve the dormant follicular pool. Loss of function of any of the inhibitory molecules for follicular activation, including PTEN (phosphatase and tensin homolog deleted on chromosome 10), Foxo3a, p27, and Foxl2, leads to premature and irreversible activation of the primordial follicle pool. Such global activation of the primordial follicle pool leads to the exhaustion of the resting follicle reserve, resulting in premature ovarian failure in mice. In this review, we summarize both historical and recent results on mammalian primordial follicular activation and focus on the up-to-date knowledge of molecular networks controlling this important physiological event. We believe that information obtained from mutant mouse models may also reflect the molecular machinery responsible for follicular activation in humans. These advances may provide a better understanding of human ovarian physiology and pathophysiology for future clinical applications.

  • 5.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    mTOR signaling in the control of activation of primordial follicles2010Ingår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 9, nr 9, s. 1673-1674Artikel i tidskrift (Refereegranskat)
  • 6.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Liu, Kui
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Regulation of quiescence and activation of oocyte growth in primordial follicles2013Ingår i: Oogenesis / [ed] Giovanni Coticchio; David F. Albertini; Lucia De Santis, London: Springer, 2013, 1, s. 49-62Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Once formed, the pool of dormant primordial follicles serves as the source of developing follicles and fertilizable ova for the duration of a female’s reproductive life. Depending upon the species, primordial follicles can remain quiescent for months, years, or even decades, and the highly regulated process of primordial follicle activation ensures the availability of growing follicles throughout the reproductive period. We have recently begun to elucidate the molecular mechanisms underlying the maintenance of follicular quiescence and the activation of primordial follicles, mainly through the use of genetically modified mouse models. Both overactivation as well as the failure of activation of primordial follicles can lead to pathological conditions such as premature ovarian failure (POF) in the experimental models. A thorough understanding of the underlying mechanisms that regulate quiescence and activation of oocyte growth in primordial follicles will have important biological and clinical implications.

  • 7.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zheng, Wenjing
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shen, Yan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gorre, Nagaraju
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hämäläinen, Tuula
    Cooney, Austin J
    Huhtaniemi, Ilpo
    Lan, Zi-Jian
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles2010Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, nr 3, s. 397-410Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.

  • 8.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zheng, Wenjing
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Shen, Yan
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Gorre, Nagaraju
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ning, Yao
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Halet, Guillaume
    Univ Rennes 1, CNRS, UMR 6061, Inst Genet & Dev Rennes, F-35043 Rennes, France .
    Kaldis, Philipp
    NUS, A STAR, IMCB, Singapore 138673, Singapore.
    Liu, Kui
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes2012Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, nr 11, s. 2476-2484Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Previous studies have shown that deletions of Cdk3, Cdk4 or Cdk6 in mice result in viable animals with normal oocyte maturation, indicating that these Cdks are not essential for the meiotic maturation of oocytes. In addition, conventional knockout of Cdk1 and Cdk2 leads to embryonic lethality and postnatal follicular depletion, respectively, making it impossible to study the functions of Cdk1 and Cdk2 in oocyte meiosis. In this study, we generated conditional knockout mice with oocyte-specific deletions of Cdk1 and Cdk2. We showed that the lack of Cdk1, but not of Cdk2, leads to female infertility due to a failure of the resumption of meiosis in the oocyte. Re-introduction of Cdk1 mRNA into Cdk1-null oocytes largely resumed meiosis. Thus, Cdk1 is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. We also found that Cdk1 maintains the phosphorylation status of protein phosphatase 1 and lamin A/C in oocytes in order for meiosis resumption to occur.

  • 9.
    Adolfsson, Dan E.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tyagi, Mohit
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Singh, Pardeep
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Deuschmann, Adrian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gharibyan, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Jayaweera, Sanduni Wasana
    Lindgren, Anders E. G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils2020Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 85, nr 21, s. 14174-14189Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.

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    fulltext
  • 10.
    Aguilar, Ximena
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Blomberg, Jeanette
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jurgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Björklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Interaction Studies of the Human and Arabidopsis thaliana Med25-ACID Proteins with the Herpes Simplex Virus VP16-and Plant-Specific Dreb2a Transcription Factors2014Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 9, nr 5, s. e98575-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mediator is an evolutionary conserved multi-protein complex present in all eukaryotes. It functions as a transcriptional coregulator by conveying signals from activators and repressors to the RNA polymerase II transcription machinery. The Arabidopsis thaliana Med25 (aMed25) ACtivation Interaction Domain (ACID) interacts with the Dreb2a activator which is involved in plant stress response pathways, while Human Med25-ACID (hMed25) interacts with the herpes simplex virus VP16 activator. Despite low sequence similarity, hMed25-ACID also interacts with the plant-specific Dreb2a transcriptional activator protein. We have used GST pull-down-, surface plasmon resonance-, isothermal titration calorimetry and NMR chemical shift experiments to characterize interactions between Dreb2a and VP16, with the hMed25 and aMed25-ACIDs. We found that VP16 interacts with aMed25-ACID with similar affinity as with hMed25-ACID and that the binding surface on aMed25-ACID overlaps with the binding site for Dreb2a. We also show that the Dreb2a interaction region in hMed25-ACID overlaps with the earlier reported VP16 binding site. In addition, we show that hMed25-ACID/Dreb2a and aMed25-ACID/Dreb2a display similar binding affinities but different binding energetics. Our results therefore indicate that interaction between transcriptional regulators and their target proteins in Mediator are less dependent on the primary sequences in the interaction domains but that these domains fold into similar structures upon interaction.

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    fulltext
  • 11.
    Akhunzianov, Almaz A.
    et al.
    Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation.
    Nesterova, Alfiya I.
    Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation; Republican Clinical Oncology Dispensary Named after Prof. M.Z. Sigal, Kazan, Russian Federation.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Filina, Yulia V.
    Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation.
    Rizvanov, Albert A.
    Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation.
    Miftakhova, Regina R.
    Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation.
    Unravelling the Therapeutic Potential of Antibiotics in Hypoxia in a Breast Cancer MCF-7 Cell Line Model2023Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, nr 14, artikel-id 11540Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antibiotics inhibit breast cancer stem cells (CSCs) by suppressing mitochondrial biogenesis. However, the effectiveness of antibiotics in clinical settings is inconsistent. This inconsistency raises the question of whether the tumor microenvironment, particularly hypoxia, plays a role in the response to antibiotics. Therefore, the goal of this study was to evaluate the effectiveness of five commonly used antibiotics for inhibiting CSCs under hypoxia using an MCF-7 cell line model. We assessed the number of CSCs through the mammosphere formation assay and aldehyde dehydrogenase (ALDH)-bright cell count. Additionally, we examined the impact of antibiotics on the mitochondrial stress response and membrane potential. Furthermore, we analyzed the levels of proteins associated with therapeutic resistance. There was no significant difference in the number of CSCs between cells cultured under normoxic and hypoxic conditions. However, hypoxia did affect the rate of CSC inhibition by antibiotics. Specifically, azithromycin was unable to inhibit sphere formation in hypoxia. Erythromycin and doxycycline did not reduce the ratio of ALDH-bright cells, despite decreasing the number of mammospheres. Furthermore, treatment with chloramphenicol, doxycycline, and tetracycline led to the overexpression of the breast cancer resistance protein. Our findings suggest that hypoxia may weaken the inhibitory effects of antibiotics on the breast cancer model.

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  • 12.
    Aksenova, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Muñoz, Iván
    Volkov, Kirill
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ariño, Joaquín
    Mironova, Ludmila
    The HAL3-PPZ1 dependent regulation of nonsense suppression efficiency in yeast and its influence on manifestation of the yeast prion-like determinant [ISP(+)].2007Ingår i: Genes to Cells, ISSN 1356-9597, E-ISSN 1365-2443, Vol. 12, nr 4, s. 435-546Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The efficiency of stop codons read-through in yeast is controlled by multiple interactions of genetic and epigenetic factors. In this study, we demonstrate the participation of the Hal3-Ppz1 protein complex in regulation of read-through efficiency and manifestation of non-Mendelian anti-suppressor determinant [ISP(+)]. Over-expression of HAL3 in [ISP(+)] strain causes nonsense suppression, whereas its inactivation displays as anti-suppression of sup35 mutation in [isp(-)] strain. [ISP(+)] strains carrying hal3Delta deletion cannot be cured from [ISP(+)] in the presence of GuHCl. Since Hal3p is a negative regulatory subunit of Ppz1 protein phosphatase, consequences of PPZ1 over-expression and deletion are opposite to those of HAL3. The observed effects are mediated by the catalytic function of Ppz1 and are probably related to the participation of Ppz1 in regulation of eEF1Balpha elongation factor activity. Importantly, [ISP(+)] status of yeast strains is determined by fluctuation in Hal3p level, since [ISP(+)] strains have less Hal3p than their [isp(-)] derivatives obtained by GuHCl treatment. A model considering epigenetic (possibly prion) regulation of Hal3p amount as a mechanism underlying [ISP(+)] status of yeast cell is suggested.

  • 13.
    Aksenova, Anna
    et al.
    Department of Biology, Tufts University, Medford, Massachusetts, United States of America.
    Volkov, Kirill
    School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
    Maceluch, Jaroslaw
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pursell, Zachary F
    Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
    Rogozin, Igor B
    National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.
    Kunkel, Thomas A
    Laboratory of Molecular Genetics and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Heath, Department of Health and Human Services, Research Triangle Park, North Carolina, United States of America.
    Pavlov, Youri I
    Eppley Institute for Research in Cancer, Department of Biochemistry and Molecular Biology, and Department of Microbiology and Pathology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mismatch repair-independent increase in spontaneous mutagenesis in yeast lacking non-essential subunits of DNA polymerase ε2010Ingår i: PLoS genetics, ISSN 1553-7404, Vol. 6, nr 11, s. e1001209-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Yeast DNA polymerase ε (Pol ε) is a highly accurate and processive enzyme that participates in nuclear DNA replication of the leading strand template. In addition to a large subunit (Pol2) harboring the polymerase and proofreading exonuclease active sites, Pol ε also has one essential subunit (Dpb2) and two smaller, non-essential subunits (Dpb3 and Dpb4) whose functions are not fully understood. To probe the functions of Dpb3 and Dpb4, here we investigate the consequences of their absence on the biochemical properties of Pol ε in vitro and on genome stability in vivo. The fidelity of DNA synthesis in vitro by purified Pol2/Dpb2, i.e. lacking Dpb3 and Dpb4, is comparable to the four-subunit Pol ε holoenzyme. Nonetheless, deletion of DPB3 and DPB4 elevates spontaneous frameshift and base substitution rates in vivo, to the same extent as the loss of Pol ε proofreading activity in a pol2-4 strain. In contrast to pol2-4, however, the dpb3Δdpb4Δ does not lead to a synergistic increase of mutation rates with defects in DNA mismatch repair. The increased mutation rate in dpb3Δdpb4Δ strains is partly dependent on REV3, as well as the proofreading capacity of Pol δ. Finally, biochemical studies demonstrate that the absence of Dpb3 and Dpb4 destabilizes the interaction between Pol ε and the template DNA during processive DNA synthesis and during processive 3' to 5'exonucleolytic degradation of DNA. Collectively, these data suggest a model wherein Dpb3 and Dpb4 do not directly influence replication fidelity per se, but rather contribute to normal replication fork progression. In their absence, a defective replisome may more frequently leave gaps on the leading strand that are eventually filled by Pol ζ or Pol δ, in a post-replication process that generates errors not corrected by the DNA mismatch repair system.

  • 14. Al Azzawi, Tiba Nazar Ibrahim
    et al.
    Khan, Murtaza
    Hussain, Adil
    Shahid, Muhammad
    Imran, Qari Muhammad
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. School of Applied Biosciences, Kyungpook National University, Korea.
    Mun, Bong-Gyu
    Lee, Sang-Uk
    Yun, Byung-Wook
    Evaluation of Iraqi Rice Cultivars for Their Tolerance to Drought Stress2020Ingår i: Agronomy, E-ISSN 2073-4395, Vol. 10, nr 11, artikel-id 1782Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Drought stress is a serious problem around the globe and particularly in the Republic of Iraq. Rice is the third most consumed crop for the Iraqi people; however, its cultivation and production is very low due to several challenges including drought. The current study was performed to evaluate five Iraqi rice cultivars along with relevant (drought-tolerant and drought-susceptible) controls under drought stress, either by treatment with 10% PEG (polyethylene glycol) or through water withholding to induce natural drought stress. The phenotypes of all the cultivars were evaluated and the transcriptional responses of key drought-responsive candidate genes, identified through the EST-SSR marker-based approach, were studied. We also studied transcript accumulation of drought-related transcriptional factors, such as OsGRASS23, OsbZIP12, and OsDREB2A. Moreover, the reference cultivars also included a drought-tolerant inter-specific cultivar Nerica 7 (a cross between Oryza sativa ssp. indica X O. glaberrima). Among the cultivars, the more drought-tolerant phenotypic characteristics and higher transcript accumulation of drought-related marker genes OsE647 and OsE1899 and transcriptional factors OsGRASS23, OsbZIP12, and OsDREB2A were observed in four (out of five) significantly drought-tolerant Iraqi cultivars; Mashkab, followed by Furat, Yasmen, and Amber 33. On another note, Amber Barka was found to be significantly drought susceptible. Mashkab and Amber Barka were found to be the most drought-tolerant and-susceptible cultivars, respectively. The identified tolerant cultivars may potentially serve as a genetic source for the incorporation of drought-tolerant phenotypes in rice.

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  • 15.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nilsson, Anna Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sharpe, James
    Larefalk, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 7, s. 1756-1764Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

    Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

    Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

    Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

  • 16. Al-Behadili, Ali
    et al.
    Uhler, Jay P.
    Berglund, Anna-Karin
    Peter, Bradley
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Reyes, Aurelio
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zeviani, Massimo
    Falkenberg, Maria
    A two-nuclease pathway involving RNase H1 is required for primer removal at human mitochondrial OriL2018Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr 18, s. 9471-9483Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of Ribonuclease H1 (RNase H1) during primer removal and ligation at the mitochondrial origin of light-strand DNA synthesis (OriL) is a key, yet poorly understood, step in mitochondrial DNA maintenance. Here, we reconstitute the replication cycle of L-strand synthesis in vitro using recombinant mitochondrial proteins and model OriL substrates. The process begins with initiation of DNA replication at OriL and ends with primer removal and ligation. We find that RNase H1 partially removes the primer, leaving behind the last one to three ribonucleotides. These 5′-end ribonucleotides disturb ligation, a conclusion which is supported by analysis of RNase H1-deficient patient cells. A second nuclease is therefore required to remove the last ribonucleotides and we demonstrate that Flap endonuclease 1 (FEN1) can execute this function in vitro. Removal of RNA primers at OriL thus depends on a two-nuclease model, which in addition to RNase H1 requires FEN1 or a FEN1-like activity. These findings define the role of RNase H1 at OriL and help to explain the pathogenic consequences of disease causing mutations in RNase H1.

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  • 17. Alcocer, M. J. C.
    et al.
    Murtagh, G. J.
    Mirotti, L.
    Brans, A.
    Harnett, W.
    Rundqvist, Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Larsson, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The allergenicity of 2S plant albumins2011Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 41, nr 12, s. 1827-1827Artikel i tidskrift (Refereegranskat)
  • 18. Alcocer, Marcos
    et al.
    Rundqvist, Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Larsson, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ber e 1 protein: the versatile major allergen from Brazil nut seeds.2012Ingår i: Biotechnology letters, ISSN 0141-5492, E-ISSN 1573-6776, Vol. 34, nr 4, s. 597-610Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Due mainly to its extremely high content of sulphur amino acids, Ber e 1 protein, the major allergen from Brazil nut, has attracted much scientific and press attention. Ber e 1 was the main target protein in early biotechnology transgenic work, in early processing studies of plant storage proteins, in plant vacuolar targeting studies and as the main protein in early nutritional supplementation experiments. Ber e 1 was also one of the first food allergens to be unintentionally transferred from one plant to another and was involved in the first reported case of systemic allergic reaction caused by a food allergen transferred in semen. In this review, many of the Ber e 1 unique biotechnological and structural functions are discussed with a particular emphasis on its use as model protein for studies of intrinsic allergenicity of food proteins.

  • 19. Aleshkov, S B
    et al.
    Fa, M
    Karolin, J
    Strandberg, L
    Johansson, L B
    Wilczynska, M
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Biochemical and biophysical studies of reactive center cleaved plasminogen activator inhibitor type 1. The distance between P3 and P1' determined by donor-donor fluorescence energy transfer.1996Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 271, nr 35, s. 21231-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Plasminogen activator inhibitor type 1 (PAI-1) is a fast acting inhibitor of plasminogen activators (PAs). In accordance with other serpins, PAI-1 is thought to undergo a conformational change upon reactive center cleavage. In this study we have developed methods to produce and purify reactive center cleaved wild-type PAI-1 and characterized this molecular form of PAI-1 by biochemical and biophysical methods. Incubation with Sepharose-bound trypsin caused cleavage only at the P1-P1' bond in the reactive center and resulted in 39- and 4-kDa polypeptides, strongly held together by noncovalent interactions. Circular dichroism measurements suggest that the reactive center cleavage triggers larger conformational changes than the conversion from the active to the latent form. Cleaved PAI-1 did not bind to either PAs or vitronectin but retained the heparin-binding capacity. To study the structure of cleaved PAI-1 by polarized fluorescence spectroscopy and to measure intramolecular distances, we used cysteine substitution mutants to which extrinsic fluorescence probes were attached. These studies revealed increasing orientational freedom of probes in the P3 and P1' positions upon cleavage. Distance measurements based on fluorescence energy transfer between probes in positions P3 and P1' indicate that these residues are separated by at least 68 +/- 10 A in cleaved PAI-1.

  • 20.
    Al-Furoukh, Natalie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ianni, Alessandro
    Nolte, Hendrik
    Hölper, Soraya
    Krüger, Marcus
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Braun, Thomas
    ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells2015Ingår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1853, nr 10, s. 2580-2591Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Proteostasis is crucial for life and maintained by cellular chaperones and proteases. One major mitochondrial protease is the ClpXP complex, which is comprised of a catalytic ClpX subunit and a proteolytic ClpP subunit. Based on two separate observations, we hypothesized that ClpX may play a leading role in the cellular function of ClpXP. Therefore, we analyzed the effect of ClpX overexpression on a myoblast proteome by quantitative proteomics. ClpX overexpression results in the upregulation of markers of the mitochondria( proteostasis pathway, known as the "mitochondrial unfolded protein response" (UPRmt). Although this pathway is described in detail in Caenorhabditis elegans, it is not clear whether it is conserved in mammals. Therefore, we compared features of the classical nematode UPRmt with our mammalian ClpX-triggered UPRmt dataset. We show that they share the same retrograde mitochondria-to-nucleus signaling pathway that involves the key UPRmt transcription factor CHOP (also known as Ddit3, CEBPZ or GADD153). In conclusion, our data confirm the existence of a mammalian UPRmt that has great similarity to the C elegans pathway. Furthermore, our results illustrate that ClpX overexpression is a good and simple model to study the underlying mechanisms of the UPRmt in mammalian cells.

  • 21. Andersen, Gorm
    et al.
    Björnberg, Olof
    Polakova, Silvia
    Pynyaha, Yuriy
    Rasmussen, Anna
    Møller, Kasper
    Hofer, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Moritz, Thomas
    Sandrini, Michael Paolo Bastner
    Merico, Anna-Maria
    Compagno, Concetta
    Akerlund, Hans-Erik
    Gojković, Zoran
    Piskur, Jure
    A second pathway to degrade pyrimidine nucleic acid precursors in eukaryotes.2008Ingår i: Journal of Molecular Biology, ISSN 1089-8638, Vol. 380, nr 4, s. 656-66Artikel i tidskrift (Övrigt vetenskapligt)
  • 22. Andersson, J
    et al.
    Westman, M
    Hofer, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Sjoberg, B M
    Allosteric regulation of the class III anaerobic ribonucleotide reductase from bacteriophage T4.2000Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 275, nr 26, s. 19443-8Artikel i tidskrift (Refereegranskat)
  • 23.
    Andersson, Jesper
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Low frequency of sequence variants in EEF1A1 in clear cell Renal Cell Carcinoma2014Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
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  • 24.
    Andersson, Jesper
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Role of pro-inflammatory S100A8 and S100A9 proteins in the neuro-inflammatory amyloid cascade in traumatic brain injury and age-dependent diseases2016Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Ladda ner (pdf)
    bilaga
  • 25.
    Andersson, Simon
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The role of RPA and MRN complex as sensors of DNA damage. A studie of aRPA and tRPA´s interaction with DNA and MRN subunits.2014Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 26.
    Andrade-Talavera, Yuniesky
    et al.
    Neuronal Oscillations Laboratory, Center for Alzheimer Research, Departments of NVS and KBH, Karolinska Institutet, Solna, Sweden.
    Chen, Gefei
    Department of Biosciences and Nutrition, Neo, Karolinska Institutet, 141 83 Huddinge, Sweden.
    Pansieri, Jonathan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Arroyo-García, Luis Enrique
    Neuronal Oscillations Laboratory, Center for Alzheimer Research, Departments of NVS and KBH, Karolinska Institutet, Solna, Sweden.
    Toleikis, Zigmantas
    Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
    Smirnovas, Vytautas
    Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
    Johansson, Jan
    Department of Biosciences and Nutrition, Neo, Karolinska Institutet, 141 83 Huddinge, Sweden.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Fisahn, André
    Neuronal Oscillations Laboratory, Center for Alzheimer Research, Departments of NVS and KBH, Karolinska Institutet, Solna, Sweden.
    S100A9 amyloid growth and S100A9 fibril-induced impairment of gamma oscillations in area CA3 of mouse hippocampus ex vivo is prevented by Bri2 BRICHOS2022Ingår i: Progress in Neurobiology, ISSN 0301-0082, E-ISSN 1873-5118, Vol. 219, artikel-id 102366Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The pro-inflammatory and highly amyloidogenic protein S100A9 is central to the amyloid-neuroinflammatory cascade in neurodegenerative diseases leading to cognitive impairment. Molecular chaperone activity of Bri2 BRICHOS has been demonstrated against a range of amyloidogenic polypeptides. Using a combination of thioflavin T fluorescence kinetic assay, atomic force microscopy and immuno electron microscopy we show here that recombinant Bri2 BRICHOS effectively inhibits S100A9 amyloid growth by capping amyloid fibrils. Using ex-vivo neuronal network electrophysiology in mouse brain slices we also show that both native S100A9 and amyloids of S100A9 disrupt cognition-relevant gamma oscillation power and rhythmicity in hippocampal area CA3 in a time- and protein conformation-dependent manner. Both effects were associated with Toll-like receptor 4 (TLR4) activation and were not observed upon TLR4 blockade. Importantly, S100A9 that had co-aggregated with Bri2 BRICHOS did not elicit degradation of gamma oscillations. Taken together, this work provides insights on the potential influence of S100A9 on cognitive dysfunction in Alzheimer's disease (AD) via gamma oscillation impairment from experimentally-induced gamma oscillations, and further highlights Bri2 BRICHOS as a chaperone against detrimental effects of amyloid self-assembly.

  • 27. Andrews, Robert K.
    et al.
    Wolberg, Alisa
    Lip, Gregory Y. H.
    Eikelboom, John
    De Meyer, Simon F.
    Mast, Alan
    Flick, Matthew
    Urano, Tetsumei
    Ny, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Cutler, Daniel
    Ju, Lining A.
    Zhu, Cheng
    Randi, Anna M.
    O'Donnell, James S.
    O'Brien, Sarah H.
    Fijnvandraat, Karin
    Shima, Midori
    Nathwani, Amit
    Luyendyk, Jim
    Vanhoorelbeke, Karen
    Barco, Stefano
    Chuansumrit, Ampaiwan
    Stanworth, Simon J.
    Curry, Nicola
    Del Rio, J. Mauricio
    Battinelli, Elisabeth M.
    Bos, Mettine H. A.
    Reinhardt, Christoph
    Peter, Karlheinz
    Gomez, Keith
    Danese, Elisa
    Rak, Janusz
    Flaumenhaft, Robert
    Di Paola, Jorge
    Nilsson, Susie
    Severin, Sonia
    Eto, Koji
    Hitchcock, Ian S.
    Ni, Heyu
    Despotovic, Jenny
    Boilard, Eric
    Rondina, Matthew
    Mangin, Pierre
    Hamilton, Justin R.
    Suzuki-Inoue, Katsue
    Tsukiji, Nagaharu
    Conway, Edward M.
    Maas, Coen
    Emsley, Jonas
    Jenne, Craig N.
    Fuchs, Tobias A.
    Weitz, Jeffrey
    Johnsen, Jill M.
    Rauova, Lubica
    Spyropoulos, Alex
    Goto, Shinya
    Verhamme, Peter
    Miranda, Sebastien
    Rodger, Marc
    Ni Ainle, Fionnuala
    Schreiber, Karen
    Thomas, Moumneh
    Le Gal, Gregoire
    Zentner, Dominica
    McLintock, Claire
    Magnusson, Maria
    Illustrated State-of-the-Art Capsules of the ISTH 2019 Congress in Melbourne, Australia: Plasminogen in wound healing2019Ingår i: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS, ISSN 2475-0379, Vol. 3, nr 3, s. 431-497Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6-10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or 'Capsules' consisting of short text, three references and a figure, with topics including stroke, cancer-associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure-function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.

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  • 28.
    Andréasson, Måns
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Donzel, Maxime
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Clinical Genetics Unit, Department of Women and Children’s Health, Padua University, Padua, Italy.
    Quiroga, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Eriksson, Anna U.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chao, Yu-Kai
    Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
    Overman, Jeroen
    Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
    Pemberton, Nils
    Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), Bio Pharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands2024Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 67, nr 3, s. 2202-2219Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.

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  • 29.
    Andréasson, Måns
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Donzel, Maxime
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Quiroga, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pemberton, Nils
    AstraZeneca, Gothenburg, Sweden.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    The Synergism of the Dispersion and Electrostatic Components in the Arene-Arene Interactions Between Ligands and G4 DNAManuskript (preprint) (Övrigt vetenskapligt)
  • 30.
    Arabuli, Lili
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of Natural Sciences, School of Science and Technology, University of Georgia, Tbilisi, Georgia.
    Iashchishyn, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Romanova, Nina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Musteikyte, Greta
    Smirnovas, Vytautas
    Chaudhary, Himanshu
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Svedružić, Željko M.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Co-aggregation of S100A9 with DOPA and cyclen-based compounds manifested in amyloid fibril thickening without altering rates of self-assembly2021Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, nr 16, artikel-id 8556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer’s and Parkinson’s, and remains the focus of much current research. S100A9 protein drives the amyloid-neuroinflammatory cascade in these diseases. DOPA and cyclen-based compounds were used as amyloid modifiers and inhibitors previously, and DOPA is also used as a precursor of dopamine in Parkinson’s treatment. Here, by using fluorescence titration experiments we showed that five selected ligands: DOPA-D-H-DOPA, DOPA-H-H-DOPA, DOPA-D-H, DOPA-cyclen, and H-E-cyclen, bind to S100A9 with apparent Kd in the sub-micromolar range. Ligand docking and molecular dynamic simulation showed that all compounds bind to S100A9 in more than one binding site and with different ligand mobility and H-bonds involved in each site, which all together is consistent with the apparent binding determined in fluorescence experiments. By using amyloid kinetic analysis, monitored by thioflavin-T fluorescence, and AFM imaging, we found that S100A9 co-aggregation with these compounds does not hinder amyloid formation but leads to morphological changes in the amyloid fibrils, manifested in fibril thickening. Thicker fibrils were not observed upon fibrillation of S100A9 alone and may influence the amyloid tissue propagation and modulate S100A9 amyloid assembly as part of the amyloid-neuroinflammatory cascade in neurodegenerative diseases.

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  • 31.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Roles of the BabA and the SabA adhesins in gastroduodenal diseases2016Ingår i: Helicobacter pylori research: from bench to bedside / [ed] Steffen Backert; Yoshio Yamaoka, Tokyo: Springer, 2016, s. 143-164Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Adhesion is an important prerequisite for colonization and it is the initial step in infections with pathogenic bacteria. Adherence to host epithelial surfaces is the result of bacterial surface proteins, called adhesins, and their specific interaction with cognate protein- or glycoconjugate receptors on the host cells. Often, the bacteria have a set of complementary adhesins that are specific for different host receptors. Alternative mechanism has been suggested to mediate H. pylori adhesion, and this chapter will focus on the two well-characterized adhesins BabA and SabA. In the healthy gastric mucosa, the Lewis b antigen (Leb) is present in the gastric epithelial lining of blood group O (H-antigen), B, and A individuals. H. pylori binding to ABO/Leb is mediated by the blood group antigen-binding BabA adhesin. As the inflammation develops, Leb is downregulated and the levels of sialylated antigens increase. Sialyl-Lewis x/a antigens (sLex/a) are specifically recognized by the H. pylori sialic acid-binding adhesin SabA. Even though bacterial adherence per se cannot cause disease, adherence is considered as a crucial step in pathogenesis since it is needed for bacterial delivery of effector molecules into the host cell. The presence of receptors and host-immune responses are two factors that differently affect adhesion. To achieve long-term colonization, H. pylori must regulate the expression of a cognate adhesin to fit the available receptors. Adhesion to the gastric epithelial cells promotes gain of nutrients, but too tight adhesion may be intimidating because of the risk of clearance by the bacteria for life-threatening immune responses. Thus, expression levels of the adhesins must be fine-tuned in accord to host receptor expression levels. This chapter will also discuss H. pylori adhesion in relation to severe gastric diseases.

  • 32.
    Asalya, Kamal K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Funktionella studier av cancervarianter hos DNA Polymeras epsilon2023Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 33. Aspholm, Marina
    et al.
    Kalia, Awdhesh
    Ruhl, Stefan
    Schedin, Staffan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lindén, Sara
    Sjöström, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gerhard, Markus
    Semino-Mora, Cristina
    Dubois, Andre
    Unemo, Magnus
    Danielsson, Dan
    Teneberg, Susann
    Lee, Woo-Kon
    Berg, Douglas E
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Helicobacter pylori adhesion to carbohydrates.2006Ingår i: Methods in enzymology, ISSN 0076-6879, Vol. 417, s. 293-339Artikel i tidskrift (Refereegranskat)
  • 34. Aspholm, Marina
    et al.
    Olfat, Farzad O
    Nordén, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sondén, Berit
    Lundberg, Carina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sjöström, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Altraja, Siiri
    Odenbreit, Stefan
    Haas, Rainer
    Wadström, Torkel
    Engstrand, Lars
    Semino-Mora, Cristina
    Liu, Hui
    Dubois, André
    Teneberg, Susann
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans.2006Ingår i: PLoS Pathog, ISSN 1553-7374, Vol. 2, nr 10, s. e110-Artikel i tidskrift (Refereegranskat)
  • 35.
    Aspholm-Hurtig, Marina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Dailide, Giedrius
    Lahmann, Martina
    Kalia, Awdhesh
    Ilver, Dag
    Roche, Niamh
    Vikström, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Sjöström, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Lindén, Sara
    Bäckström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Lundberg, Carina
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Arnqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi. Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Mahdavi, Jafar
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Nilsson, Ulf J
    Velapatiño, Billie
    Gilman, Robert H
    Gerhard, Markus
    Alarcon, Teresa
    López-Brea, Manuel
    Nakazawa, Teruko
    Fox, James G
    Correa, Pelayo
    Dominguez-Bello, Maria Gloria
    Perez-Perez, Guillermo I
    Blaser, Martin J
    Normark, Staffan
    Carlstedt, Ingemar
    Oscarson, Stefan
    Teneberg, Susann
    Berg, Douglas E
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin2004Ingår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 305, nr 5683, s. 519-522Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.

  • 36. Asturias, Francisco J
    et al.
    Cheung, Iris K
    Sabouri, Nasim
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Chilkova, Olga
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Wepplo, Daniel
    Johansson, Erik
    Umeå universitet, Medicinsk fakultet, Medicinsk kemi och biofysik.
    Structure of Saccharomyces cerevisiae DNA polymerase epsilon by cryo-electron microscopy.2006Ingår i: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 13, nr 1, s. 35-43Artikel i tidskrift (Refereegranskat)
  • 37.
    Augusti, Angela
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Betson, Tatiana R.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jurgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Deriving correlated climate and physiological signals from deuterium isotopomers in tree rings2008Ingår i: Chemical Geology, ISSN 0009-2541, E-ISSN 1872-6836, Vol. 252, nr 1-2, s. 1-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    he deuterium (D) abundance of tree-ring cellulose archives past climatic conditions, but previous attempts to access this archive have led to conflicting results. Based on an overview of D fractionation mechanisms in plants, we explain why past measurements of D abundance yield unreliable paleo signals. Our data show that variation in D abundance among the C–H groups (isotopomer variation) of tree-ring cellulose is generally greater than variation in D abundance due to climatic influences. A comparison of the D isotopomer abundances of soluble sugars of annual plants and of trees, and of tree-ring cellulose shows that an “isotopomer pattern” of the C3 photosynthetic pathway is transmitted from soluble sugars to tree-ring cellulose. Differences in this pattern between oaks and conifers appear to be related to differences in metabolism. Furthermore, the patterns are modified by hydrogen isotope exchange between C–H groups and source water during cellulose synthesis. Based on these results, we propose a strategy to simultaneously reconstruct climate signals and signals related to tree physiology from D isotopomers of tree rings. Combination of climate signals and physiological signals may allow the detection of century-time-scale adaptations of trees to past environmental change, and help to forecast future adaptations.

  • 38.
    Augusti, Angela
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Betson, Tatiana R.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Deuterium isotopomers record a CO2 response of plants in leaves and tree ringsManuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
  • 39.
    Augusti, Angela
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Betson, Tatiana R
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hydrogen exchange during cellulose synthesis distinguishes climatic and biochemical isotope fractionations in tree rings.2006Ingår i: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 172, nr 3, s. 490-499Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    • The abundance of the hydrogen isotope deuterium (D) in tree rings is an attractive record of climate; however, use of this record has proved difficult so far, presumably because climatic and physiological influences on D abundance are difficult to distinguish.

    • Using D labelling, we created a D gradient in trees. Leaf soluble sugars of relatively low D abundance entered cellulose synthesis in stems containing strongly D-labelled water. We used nuclear magnetic resonance (NMR) spectroscopy to quantify D in the C-H groups of leaf glucose and of tree-ring cellulose.

    • Ratios of D abundances of individual C-H groups of leaf glucose depended only weakly on leaf D labelling, indicating that the D abundance pattern was determined by physiological influences. The D abundance pattern of tree-ring cellulose revealed C-H groups that exchanged strongly (C(2)-H) or weakly (C(6)-H2) with water during cellulose synthesis.

    • We propose that strongly exchanging C-H groups of tree-ring cellulose adopt a climate signal stemming from the D abundance of source water. C-H groups that exchange weakly retain their D abundance established in leaf glucose, which reflects physiological influences. Combining both types of groups may allow simultaneous reconstruction of climate and physiology from tree rings.

  • 40. Augusti, Angela
    et al.
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The ins and outs of stable isotopes in plants.2007Ingår i: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 174, nr 3, s. 473-475Artikel i tidskrift (Refereegranskat)
  • 41. Azevedo, M
    et al.
    Eriksson, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mendes, N
    Serpa, J
    Figueiredo, C
    Resende, LP
    Ruvoën-Clouet, N
    Haas, R
    Borén, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Le Pendu, J
    David, L
    Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype2008Ingår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, nr 3, s. 308-316Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Helicobacter pylori (Hp) infects half the world's population and causes diverse gastric lesions, from gastritis to gastric cancer. Our aim was to evaluate the significance of secretor and Lewis status in infection and in vitro adherence by Hp expressing BabA adhesin. We enrolled 304 Hp-infected individuals from Northern Portugal. Gastric biopsies, blood and saliva were collected. Polymerase chain reaction (PCR) and immunofluorescence were used to detect BabA+ Hp in gastric biopsies. In vitro adherence by a BabA expressing Hp strain to gastric biopsies was performed. Secretor status was identified by Ulex, a lectin that recognizes secretor-dependent glycan structures in saliva and in gastric mucosa, and by Lewis(a/b) antibodies, and indirectly by identification of an inactivating mutation in the FUT2 gene (G428A). BabA status of infecting Hp was associated with CagA and VacAs1 (p < 0.05), intercellular localization of Hp (p < 0.01) and the presence of intestinal metaplasia (p < 0.05) and degenerative alterations (p < 0.005) in the biopsies. BabA was associated (p < 0.05) with Ulex staining of gastric biopsies and, although not significantly, to absence of homozygosity for FUT2 G428A inactivating polymorphism. In vitro Hp adherence was higher in cases wild-type or heterozygous for FUT2 G428A mutation (p < 0.0001), cases staining for Ulex (p < 0.0001) and a(-)b+ and a(-)b(-) secretor phenotypes (p < 0.001). In conclusion, BabA+ Hp infection/adhesion is secretor-dependent and associated with the severity of gastric lesions.

  • 42. Bacal, Julien
    et al.
    Moriel-Carretero, María
    Pardo, Benjamin
    Barthe, Antoine
    Sharma, Sushma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Lengronne, Armelle
    Pasero, Philippe
    Mrc1 and Rad9 cooperate to regulate initiation and elongation of DNA replication in response to DNA damage2018Ingår i: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 37, nr 21, artikel-id e99319Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The S-phase checkpoint maintains the integrity of the genome in response to DNA replication stress. In budding yeast, this pathway is initiated by Mec1 and is amplified through the activation of Rad53 by two checkpoint mediators: Mrc1 promotes Rad53 activation at stalled forks, and Rad9 is a general mediator of the DNA damage response. Here, we have investigated the interplay between Mrc1 and Rad9 in response to DNA damage and found that they control DNA replication through two distinct but complementary mechanisms. Mrc1 rapidly activates Rad53 at stalled forks and represses late-firing origins but is unable to maintain this repression over time. Rad9 takes over Mrc1 to maintain a continuous checkpoint signaling. Importantly, the Rad9-mediated activation of Rad53 slows down fork progression, supporting the view that the S-phase checkpoint controls both the initiation and the elongation of DNA replication in response to DNA damage. Together, these data indicate that Mrc1 and Rad9 play distinct functions that are important to ensure an optimal completion of S phase under replication stress conditions.

  • 43. Bagnato, Paola
    et al.
    Castagnino, Alessia
    Cortese, Katia
    Bono, Maria
    Grasso, Silvia
    Bellese, Grazia
    Daniele, Tiziana
    Lundmark, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Defilippi, Paola
    Castagnola, Patrizio
    Tacchetti, Carlo
    Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells2017Ingår i: Oncotarget, E-ISSN 1949-2553, Vol. 8, nr 36, s. 60109-60122Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ERBB2 receptor belongs to the ERBB tyrosine kinase receptor family. At variance to the other family members, ERBB2 is a constitutively active orphan receptor. Upon ligand binding and activation, ERBB receptors form homo-or hetero-dimers with the other family members, including ERBB2, promoting an intracellular signaling cascade. ERBB2 is the preferred dimerization partner and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. The specific contribution of ERBB2 in heterodimer signaling is still undefined. Here we report the formation of circular dorsal ruffles (CDRs) upon treatment of the ERBB2-overexpressing breast cancer cell lines SK-BR-3 and ZR751 with Trastuzumab, a therapeutic humanized monoclonal antibody directed against ERBB2. We found that in SK-BR-3 cells Trastuzumab leads to surface redistribution of ERBB2 and ERBB1 in CDRs, and that the ERBB2-dependent ERK1/2 phosphorylation and ERBB1 expression are both required for CDR formation. In particular, in these cells CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin depolymerizing protein cofilin, mediated by ERBB1. Furthermore, we suggest that this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. In conclusion, here we show for the first time an ERBB2-specific signaling contribution to an ERBB2/ERBB1 heterodimer, in the activation of a complex biological process such as the formation of CDRs.

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  • 44.
    Bai, Qiao
    et al.
    Chongqing Medical University, 1 Medical College Road, Yu Zhong District, Chongqing, China.
    Sun, Dan
    State Key Laboratory of Photon-Technology in Western China Energy, Institute of Photonics and Photon-Technology, Northwest University, Xi’an, Shaanxi, China.
    Zeng, Yang
    State Key Laboratory of Photon-Technology in Western China Energy, Institute of Photonics and Photon-Technology, Northwest University, Xi’an, Shaanxi, China.
    Zhu, Jie
    State Key Laboratory of Photon-Technology in Western China Energy, Institute of Photonics and Photon-Technology, Northwest University, Xi’an, Shaanxi, China.
    Zhang, Ce
    State Key Laboratory of Photon-Technology in Western China Energy, Institute of Photonics and Photon-Technology, Northwest University, Xi’an, Shaanxi, China.
    Zhang, Xiaoyin
    Chongqing Medical University, 1 Medical College Road, Yu Zhong District, Chongqing, China.
    Chen, Li
    Chongqing Medical University, 1 Medical College Road, Yu Zhong District, Chongqing, China.
    Zhou, Xin
    Chongqing Medical University, 1 Medical College Road, Yu Zhong District, Chongqing, China.
    Ye, Liu
    Chongqing Medical University, 1 Medical College Road, Yu Zhong District, Chongqing, China.
    Tang, Yong
    Chongqing Medical University, 1 Medical College Road, Yu Zhong District, Chongqing, China.
    Liu, Yonggang
    Chongqing Medical University, 1 Medical College Road, Yu Zhong District, Chongqing, China.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Effect of proinflammatory S100A9 protein on migration and proliferation of microglial cells2023Ingår i: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 73, nr 11-12, s. 983-995Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer’s disease (AD) is a multifactorial disease affecting aging population worldwide. Neuroinflammation became a focus of research as one of the major pathologic processes relating to the disease onset and progression. Proinflammatory S100A9 is the central culprit in the amyloid-neuroinflammatory cascade implicated in AD and other neurodegenerative diseases. We studied the effect of S100A9 on microglial BV-2 cell proliferation and migration. The responses of BV-2 cells to S100A9 stimulation were monitored in real-time using live cell microscopy, transcriptome sequencing, immunofluorescence staining, western blot analysis, and ELISA. We observed that a low dose of S100A9 promotes migration and proliferation of BV-2 cells. However, acute inflammatory condition (i.e., high S100A9 doses) causes diminished cell viability; it is uncovered that S100A9 activates TLR-4 and TLR-7 signaling pathways, leading to TNF-α and IL-6 expression, which affect BV-2 cell migration and proliferation in a concentration-dependent manner. Interestingly, the effects of S100A9 are not only inhibited by TNF-α and IL-6 antibodies. The addition of amyloid-β (Aβ) 1–40 peptide resumes the capacities of BV-2 cells to the level of low S100A9 concentrations. Based on these results, we conclude that in contrast to the beneficial effects of low S100A9 dose, high S100A9 concentration leads to impaired mobility and proliferation of immune cells, reflecting neurotoxicity at acute inflammatory conditions. However, the formation of Aβ plaques may be a natural mechanism that rescues cells from the proinflammatory and cytotoxic effects of S100A9, especially considering that inflammation is one of the primary causes of AD.

  • 45. Balciunas, Darius
    et al.
    Hallberg, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Björklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ronne, Hans
    Functional interactions within yeast mediator and evidence of differential subunit modifications2003Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, nr 6, s. 3831-3839Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It is possible to recruit RNA polymerase II to a target promoter and, thus, activate transcription by fusing Mediator subunits to a DNA binding domain. To investigate functional interactions within Mediator, we have tested such fusions of the lexA DNA binding domain to Med1, Med2, Gal11, Srb7, and Srb10 in wild type, med1, med2, gal11, sin4, srb8, srb10, and srb11 strains. We found that lexA-Med2 and lexA-Gal11 are strong activators that are independent of all Mediator subunits tested. lexA-Srb10 is a weak activator that depends on Srb8 and Srb11. lexA-Med1 and lexA-Srb7 are both cryptic activators that become active in the absence of Srb8, Srb10, Srb11, or Sin4. An unexpected finding was that lexA-VP16 differs from Gal4-VP16 in that it is independent of the activator binding Mediator module. Both lexA-Med1 and lexA-Srb7 are stably associated with Med4 and Med8, which suggests that they are incorporated into Mediator. Med4 and Med8 exist in two mobility forms that differ in their association with lexA-Med1 and lexA-Srb7. Within purified Mediator, Med4 is present as a phosphorylated lower mobility form. Taken together, these results suggest that assembly of Mediator is a multistep process that involves conversion of both Med4 and Med8 to their low mobility forms.

  • 46. Baldassarre, Maurizio
    et al.
    Baronio, Cesare M.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Barth, Andreas
    Amyloid beta-peptides 1-40 and 1-42 form oligomers with mixed beta-sheets2017Ingår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 8, nr 12, s. 8247-8254Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two main amyloid-beta peptides of different length (A beta(40) and A beta(42)) are involved in Alzheimer's disease. Their relative abundance is decisive for the severity of the disease and mixed oligomers may contribute to the toxic species. However, little is know about the extent of mixing. To study whether A beta(40) and A beta(42) co-aggregate, we used Fourier transform infrared spectroscopy in combination with C-13-labeling and spectrum calculation and focused on the amide I vibration, which is sensitive to backbone structure. Mixtures of monomeric labeled A beta(40) and unlabeled A beta(42) (and vice versa) were co-incubated for similar to 20 min and their infrared spectrum recorded. The position of the main C-13-amide I' band shifted to higher wavenumbers with increasing admixture of C-12-peptide due to the presence of C-12-amides in the vicinity of C-13-amides. The results indicate that A beta(40) and A beta(42) form mixed oligomers with a largely random distribution of A beta(40) and A beta(42) strands in their beta-sheets. The structures of the mixed oligomers are intermediate between those of the pure oligomers. There is no indication that one of the peptides forces the backbone structure of its oligomers on the other peptide when they are mixed as monomers. We also demonstrate that isotope-edited infrared spectroscopy can distinguish aggregation modulators that integrate into the backbone structure of their interaction partner from those that do not. As an example for the latter case, the pro-inflammatory calcium binding protein S100A9 is shown not to incorporate into the b-sheets of A beta(42).

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  • 47. Baldassarri, Cecilia
    et al.
    Falappa, Giulia
    Mazzara, Eugenia
    Acquaticci, Laura
    Ossoli, Elena
    Perinelli, Diego Romano
    Bonacucina, Giulia
    Dall’Acqua, Stefano
    Cappellacci, Loredana
    Maggi, Filippo
    Ranjbarian, Farahnaz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hofer, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Petrelli, Riccardo
    Antitrypanosomal Activity of Anthriscus Nemorosa Essential Oils and Combinations of Their Main Constituents2021Ingår i: Antibiotics, ISSN 0066-4774, E-ISSN 2079-6382, Vol. 10, nr 11, artikel-id 1413Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study aimed to investigate the susceptibility of Trypanosoma brucei to the Anthriscus nemorosa essential oils (EOs), isolated compounds from these oils, and artificial mixtures of the isolated compounds in their conventional and nanoencapsulated forms. The chemical composition of the essential oils from the aerial parts and roots of Anthriscus nemorosa, obtained from a wild population growing in central Italy, were analyzed by gas chromatography/mass spectrometry (GC/MS). In both cases, the predominant class of compounds was monoterpene hydrocarbons, which were more abundant in the EOs from the roots (81.5%) than the aerial parts (74.0%). The overall results of this work have shed light on the biological properties of A. nemorosa EO from aerial parts (EC50 = 1.17 μg/mL), farnesene (EC50 = 0.84 μg/mL), and artificial mixtures (Mix 3–5, EC50 in the range of 1.27 to 1.58 μg/mL) as relevant sources of antiprotozoal substances. Furthermore, the pool measurements of ADP (adenosine diphosphate) and NTPs (nucleoside triphosphates) in the cultivated bloodstream form of trypanosomes exposed to different concentrations of EOs showed a disturbed energy metabolism, as indicated by increased pools of ADP in comparison to ATP (adenosine triphosphate) and other NTPs. Ultimately, this study highlights the significant efficacy of A. nemorosa EO to develop long-lasting and effective antiprotozoal formulations, including nanoemulsions.

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  • 48.
    Barbari, Stephanie R.
    et al.
    Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE, Omaha, United States.
    Beach, Annette K.
    Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE, Omaha, United States.
    Markgren, Joel G.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Parkash, Vimal
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Moore, Elizabeth A.
    Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE, Omaha, United States.
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shcherbakova, Polina V
    Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, NE, Omaha, United States.
    Enhanced polymerase activity permits efficient synthesis by cancer-Associated DNA polymerase variants at low dNTP levels2022Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, nr 14, s. 8023-8040Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amino acid substitutions in the exonuclease domain of DNA polymerase (Pol) cause ultramutated tumors. Studies in model organisms suggested pathogenic mechanisms distinct from a simple loss of exonuclease. These mechanisms remain unclear for most recurrent Pol mutations. Particularly, the highly prevalent V411L variant remained a long-standing puzzle with no detectable mutator effect in yeast despite the unequivocal association with ultramutation in cancers. Using purified four-subunit yeast Pol, we assessed the consequences of substitutions mimicking human V411L, S459F, F367S, L424V and D275V. While the effects on exonuclease activity vary widely, all common cancer-Associated variants have increased DNA polymerase activity. Notably, the analog of Pol-V411L is among the strongest polymerases, and structural analysis suggests defective polymerase-To-exonuclease site switching. We further show that the V411L analog produces a robust mutator phenotype in strains that lack mismatch repair, indicating a high rate of replication errors. Lastly, unlike wild-Type and exonuclease-dead Pol, hyperactive variants efficiently synthesize DNA at low dNTP concentrations. We propose that this characteristic could promote cancer cell survival and preferential participation of mutator polymerases in replication during metabolic stress. Our results support the notion that polymerase fitness, rather than low fidelity alone, is an important determinant of variant pathogenicity.

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  • 49. Barfeld, Stefan J
    et al.
    Fazli, Ladan
    Persson, Margareta
    Marjavaara, Lisette
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Urbanucci, Alfonso
    Kaukoniemi, Kirsi M
    Rennie, Paul S
    Ceder, Yvonne
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Visakorpi, Tapio
    Mills, Ian G
    Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer2015Ingår i: Oncotarget, E-ISSN 1949-2553, Vol. 6, nr 14, s. 12587-12602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The androgen receptor is a key transcription factor contributing to the development of all stages of prostate cancer (PCa). In addition, other transcription factors have been associated with poor prognosis in PCa, amongst which c-Myc (MYC) is a well-established oncogene in many other cancers. We have previously reported that the AR promotes glycolysis and anabolic metabolism; many of these metabolic pathways are also MYC-regulated in other cancers. In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity. We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA). Treatment with MPA led to a significant reduction in cellular guanosine triphosphate (GTP) levels accompanied by nucleolar stress and p53 stabilization. In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.

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  • 50. Baskaran, Preetisri
    et al.
    Ekblad, Alf
    Soucémarianadin, Laure N.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. CNRS, Laboratoire de Géologie de l’ENS, Ecole Normale Supérieure, Paris, France.
    Hyvönen, Riitta
    Schleucher, Jürgen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lindahl, Björn D.
    Nitrogen dynamics of decomposing Scots pine needle litter depends on colonizing fungal species2019Ingår i: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 95, nr 6, artikel-id fiz059Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In boreal ecosystems plant production is often limited by low availability of nitrogen. Nitrogen retention in below-ground organic pools plays an important role in restricting recirculation to plants and thereby hampers forest production. Saprotrophic fungi are commonly assigned to different decomposer strategies, but how these relate to nitrogen cycling remains to be understood. Decomposition of Scots pine needle litter was studied in axenic microcosms with the ligninolytic litter decomposing basidiomycete Gymnopus androsaceus or the stress tolerant ascomycete Chalara longipes. Changes in chemical composition were followed by C-13 CP/MAS NMR spectroscopy and nitrogen dynamics was assessed by the addition of a N-15 tracer. Decomposition by C. longipes resulted in nitrogen retention in non-hydrolysable organic matter, enriched in aromatic and alkylic compounds, whereas the ligninolytic G. androsaceus was able to access this pool, counteracting nitrogen retention. Our observations suggest that differences in decomposing strategies between fungal species play an important role in regulating nitrogen retention and release during litter decomposition, implying that fungal community composition may impact nitrogen cycling at the ecosystem level.

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