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  • 201.
    Fischer, M Dominik
    et al.
    University of Pennsylvania School of Medicine.
    Gorospe, J Rafael
    George Washington University, Washington.
    Felder, Edward
    University of Pennsylvania School of Medicine, Philadelphia.
    Bogdanovich, Sasha
    University of Pennsylvania School of Medicine.
    Pedrosa-Domellöf, Fatima
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Ahima, Rexford S
    University of Pennsylvania School of Medicine, Philadelphia.
    Rubinstein, Neal A
    University of Pennsylvania School of Medicine, Philadelphia.
    Hoffman, Eric P
    George Washington University, Washington.
    Khurana, Tejvir S
    University of Pennsylvania School of Medicine.
    Expression profiling reveals metabolic and structural components of extraocular muscles2002Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 9, nr 2, s. 71-84Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The extraocular muscles (EOM) are anatomically and physiologically distinct from other skeletal muscles. EOM are preferentially affected in mitochondrial myopathies, but spared in Duchenne's muscular dystrophy. The anatomical and pathophysiological properties of EOM have been attributed to their unique molecular makeup: an allotype. We used expression profiling to define molecular features of the EOM allotype. We found 346 differentially expressed genes in rat EOM compared with tibialis anterior, based on a twofold difference cutoff. Genes required for efficient, fatigue-resistant, oxidative metabolism were increased in EOM, whereas genes for glycogen metabolism were decreased. EOM also showed increased expression of genes related to structural components of EOM such as vessels, nerves, mitochondria, and neuromuscular junctions. Additionally, genes related to specialized functional roles of EOM such as the embryonic and EOM-specific myosin heavy chains and genes for muscle growth, development, and/or regeneration were increased. The EOM expression profile was validated using biochemical, structural, and molecular methods. Characterization of the EOM expression profile begins to define gene transcription patterns associated with the unique anatomical, metabolic, and pathophysiological properties of EOM.

  • 202.
    Flanagan, J Randall
    et al.
    Queen's University, Kingston, Ontario.
    Vetter, Philipp
    University College London, Queen Square, London.
    Johansson, Roland S
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Wolpert, Daniel M
    University College London, Queen Square, London.
    Prediction precedes control in motor learning2003Inngår i: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 13, nr 2, s. 146-150, Article Number: PII S0960-9822(03)00007-1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Skilled motor behavior relies on the brain learning both to control the body and predict the consequences of this control. Prediction turns motor commands into expected sensory consequences, whereas control turns desired consequences into motor commands. To capture this symmetry, the neural processes underlying prediction and control are termed the forward and inverse internal models, respectively. Here, we investigate how these two fundamental processes are related during motor learning. We used an object manipulation task in which subjects learned to move a hand-held object with novel dynamic properties along a prescribed path. We independently and simultaneously measured subjects' ability to control their actions and to predict their consequences. We found different time courses for predictor and controller learning, with prediction being learned far more rapidly than control. In early stages of manipulating the object, subjects could predict the consequences of their actions, as measured by the grip force they used to grasp the object, but could not generate appropriate actions for control, as measured by their hand trajectory. As predicted by several recent theoretical models of sensorimotor control, our results indicate that people can learn to predict the consequences of their actions before they can learn to control their actions.

  • 203.
    Florea, Cristina
    et al.
    "Politehnica” University of Timisoara, Mechanical Engineering Faculty, Mechatronics Department, Timisoara, Romania; University of Eastern Finland, Department of Applied Physics, Kuopio, Finland.
    Jakorinne, Asmo
    Savonia University of Applied Sciences, School of Engineering and Technology, Kuopio, Finland.
    Lammi, Mikko
    University of Eastern Finland, Department of Biosciences, Kuopio, Finland.
    Davidescu, Arjana
    “Politehnica” University of Timisoara, Mechanical Engineering Faculty, Mechatronics Department, Timisoara, Romania.
    Korhonen, Rami
    University of Eastern Finland, Department of Applied Physics, Kuopio, Finland.
    Determination of mechanical properties of chondrocytes in articular cartilage using atomic force microscopy2014Inngår i: Solid State Phenomena, ISSN 1012-0394, E-ISSN 1662-9779, Vol. 216, s. 134-139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Atomic Force Microscopy (AFM) based nanoindentation is a widely used technique for measuring mechanical properties of living cells, providing information for understanding their mechanobiological behavior. However, very local properties of cell surfaces have not been characterized earlier. The goal of this study was to develop an AFM-based technique to determine local elastic properties of bovine articular chondrocytes. The Youngs modulus of chondrocytes was 19.3 ± 5.6 kPa for spread cells and 10 ± 4.1 kPa for the round cells. The results were compared to previous studies in which different techniques were used to obtain more global properties of chondrocytes. Our findings suggest that using nanosized AFM tips, the very local cell properties can be measured.

  • 204.
    Florea, Cristina
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Tanska, Petri
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Mononen, Mika
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Qu, Chengjuan
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Lammi, Mikko
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). School of Public Health, Health Science Center of Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Laasanen, Mikko
    School of Engineering and Technology, Savonia University of Applied Sciences, Kuopio, Finland.
    Korhonen, Rami
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland; Diagnostic Imaging Center, Kuopio University Hospital, Kuopio, Finland.
    A combined experimental atomic force microscopy-based nanoindentation and computational modeling approach to unravel the key contributors to the time-dependent mechanical behavior of single cells2017Inngår i: Biomechanics and Modeling in Mechanobiology, ISSN 1617-7959, E-ISSN 1617-7940, Vol. 16, nr 1, s. 297-311, artikkel-id 27554263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cellular responses to mechanical stimuli are influenced by the mechanical properties of cells and the surrounding tissue matrix. Cells exhibit viscoelastic behavior in response to an applied stress. This has been attributed to fluid flow-dependent and flow-independent mechanisms. However, the particular mechanism that controls the local time-dependent behavior of cells is unknown. Here, a combined approach of experimental AFM nanoindentation with computational modeling is proposed, taking into account complex material behavior. Three constitutive models (porohyperelastic, viscohyperelastic, poroviscohyperelastic) in tandem with optimization algorithms were employed to capture the experimental stress relaxation data of chondrocytes at 5 % strain. The poroviscohyperelastic models with and without fluid flow allowed through the cell membrane provided excellent description of the experimental time-dependent cell responses (normalized mean squared error (NMSE) of 0.003 between the model and experiments). The viscohyperelastic model without fluid could not follow the entire experimental data that well (NMSE = 0.005), while the porohyperelastic model could not capture it at all (NMSE = 0.383). We also show by parametric analysis that the fluid flow has a small, but essential effect on the loading phase and short-term cell relaxation response, while the solid viscoelasticity controls the longer-term responses. We suggest that the local time-dependent cell mechanical response is determined by the combined effects of intrinsic viscoelasticity of the cytoskeleton and fluid flow redistribution in the cells, although the contribution of fluid flow is smaller when using a nanosized probe and moderate indentation rate. The present approach provides new insights into viscoelastic responses of chondrocytes, important for further understanding cell mechanobiological mechanisms in health and disease.

  • 205.
    Fong, Gloria
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Influence of neuromodulators and mechanical loading on pathological cell and tissue characteristics in tendinosis2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: Tendinosis is a painful chronic, degenerative condition characterized by objective changes in the tissue structure of a tendon. Hallmark features in tendinosis tendons include increased number of cells (hypercellularity), extracellular matrix (ECM) degradation and disorganized collagen. The progression of these pathological changes seen in tendinosis is neither well characterized nor fully understood.

    Studies have suggested that there are biochemical and mechanical elements involved in tendinosis. From a biochemical perspective, studies have shown that the tendon cells, tenocytes, produce a number of neuronal signal substances/neuromodulators, such as substance P (SP) and acetylcholine (ACh), traditionally thought to be confined to the nervous system. Furthermore, it has been shown that the expression of these neuromodulators is elevated in tendinosis tendons as compared to normal healthy tendons. Interestingly, studies on other tissue types have revealed that both SP and ACh can induce tissue changes seen in tendinosis, such as hypercellularity and collagen disorganization. From a mechanical angle, it has been suggested that overload of tendons, including extensive strain on the primary tendon cells (tenocytes), causes the degenerative processes associated with tendinosis. In vivo studies have shown that in overloaded tendons, the presence of neuromodulators is elevated, not least SP, which also precedes the development of the tissue changes seen in tendinosis. This further supports the importance of combining biochemical factors and mechanical factors in the pathogenesis of tendinosis.

    Hypotheses: In this thesis project, we hypothesize: 1) that neuromodulators, such as SP and ACh when stimulating their preferred receptors, the neurokinin 1 (NK-1 R) and muscarinic receptors (mAChRs), respectively, can cause increased tenocyte proliferation; 2) that the effects of SP and ACh on tenocyte proliferation converge mechanistically via a shared signalling pathway; 3) that mechanical loading of tenocytes results in increased production of SP by the tenocytes; and 4) that SP enhances collagen remodelling by tenocytes via NK-1 R.

    Model system: In vitro studies offer insight into the function of healthy tendon matrix and the etiology of tendinopathy. Using a cell culture model of human primary tendon cells, highly controlled experiments were performed in this thesis project to study a subset of biological and mechanical parameters that are implicated in tendinosis. The FlexCell® Tension System was used to study the influence of mechanical loading on tenocytes. As well, a collagen gel contraction assay was used to examine the intrinsic ability of tenocytes to reorganise type I collagen matrices under the influence of the neuromodulator SP.

    Results: The studies showed that exogenous administration of SP and ACh results in increased tenocyte proliferation that is mediated via activation of the ERK1/2 mitogenic pathway when the preferred receptors of SP and ACh, the NK-1 R and mAChRs, respectively, are stimulated. Furthermore, the studies resulted in the novel finding that SP and ACh both converge mechanistically via transforming growth factor (TGF)-β1 and that a negative feedback mechanism is present in which TGF-β1 downregulates the expression of mAChRs and NK-1 R. The studies also showed that SP can increase collagen remodelling and upregulate expression of genes related to tendinosis. Finally, it was established that tenocytes are mechanoresponsive by showing that cyclic mechanical loading increases the expression of SP by human tenocytes.

    Conclusions: This thesis work concludes that stimulation of NK-1 R and mAChRs results in proliferation of human tenocytes, which both involve the ERK1/2 signalling pathway. It also shows that SP and ACh converge mechanistically via TGF-β1 in their contribution to tenocyte proliferation. The role of hypercellularity in tendinosis tissue is unknown. Possibly, it has different roles at different stages of the disease. The findings also show that SP increases collagen remodelling, suggesting that increased SP not only results in hypercellularity but also contributes to the collagen morphology in tendinosis.

  • 206.
    Fong, Gloria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Idrottsmedicin.
    Scott, Alex
    Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    The Effects of Substance P and Acetylcholine on Human Tenocyte Proliferation Converge Mechanistically via TGF-β12017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 3, artikkel-id e0174101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous in vitro studies on human tendon cells (tenocytes) have demonstrated that the exogenous administration of substance P (SP) and acetylcholine (ACh) independently result in tenocyte proliferation, which is a prominent feature of tendinosis. Interestingly, the possible link between SP and ACh has not yet been explored in human tenocytes. Recent studies in other cell types demonstrate that both SP and ACh independently upregulate TGF-β1 expression via their respective receptors, the neurokinin 1 receptor (NK-1R) and muscarinic ACh receptors (mAChRs). Furthermore, TGF-β1 has been shown to downregulate NK-1R expression in human keratocytes. The aim of this study was to examine if TGF-β1 is the intermediary player involved in mediating the proliferative pathway shared by SP and ACh in human tenocytes. The results showed that exogenous administration of SP and ACh both caused significant upregulation of TGF-β1 at the mRNA and protein levels. Exposing cells to TGF-β1 resulted in increased cell viability of tenocytes, which was blocked in the presence of the TGFβRI/II kinase inhibitor. In addition, the proliferative effects of SP and ACh on tenocytes were reduced by the TGFβRI/II kinase inhibitor; this supports the hypothesis that the proliferative effects of these signal substances are mediated via the TGF-β axis. Furthermore, exogenous TGF-β1 downregulated NK-1R and mAChRs expression at both the mRNA and protein levels, and these effects were negated by simultaneous exposure to the TGFβRI/II kinase inhibitor, suggesting a negative feedback loop. In conclusion, the results indicate that TGF-β1 is the intermediary player through which the proliferative actions of both SP and ACh converge mechanistically.

  • 207.
    Forsgren, Stina
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Mechanisms of lymphocyte selection in physiology and autoimmune pathology1991Doktoravhandling, med artikler (Annet vitenskapelig)
  • 208.
    Francis, Matthew
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    The pathogenic Yersiniae: advances in the understanding of physiology and virulence2013Inngår i: Frontiers in Cellular and Infection Microbiology, ISSN 2235-2988, Vol. 3, nr 51, s. 2s. 1-2Artikkel, forskningsoversikt (Fagfellevurdert)
  • 209.
    Francis, Monika K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Regulation of GRAF1 membrane sculpting function during cell movement2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    All eukaryotic cells rely on endocytic events to satisfy a constant need for nutrient and fluid uptake from their surroundings. Endocytosis-dependent turnover of cell surface constituents also serves to control signal transduction and establish morphological changes in response to extracellular stimuli. During endocytosis, distinct protein machineries re-sculpt the plasma membrane into vesicular carriers that enclose molecules that are to be taken up into the cell. Besides those produced from the canonical clathrin-mediated endocytic machinery, it is becoming increasingly clear that other membrane carriers exist. The indisputable connection between the function of these uptake systems and various disease states, highlights why it is so important to increase our knowledge about the underlying molecular machineries.

    The aim of this thesis was therefore to characterise the function of GRAF1, a protein suggested to be a tumour suppressor due to that the gene has been found to be mutated in certain cancer patients. My work focused on understanding how this protein operates during formation of clathrin-independent carriers, with possible implications for disease development.

    Previous in vitro studies showed that GRAF1 harbours a GTPase activating domain to inactivate Rho GTPase Cdc42, a major actin cytoskeleton regulator. Herein, microscopy based approaches used to analyse HeLa cells demonstrated the importance of a transient interaction between GRAF1 and Cdc42 for proper processing of GRAF1-decorated carriers. Although GRAF1-mediated inactivation of Cdc42 was not vital for the budding of carriers from the plasma membrane, it was important for carrier maturation. In addition, studies of purified GRAF1 and its association with lipid bilayers identified a membrane scaffolding-dependent oligomerisation mechanism, with the ability to sculpt membranes. This was consistent with the assumption that GRAF1 possesses an inherent banana shaped membrane binding domain. Remarkably, this function was autoinhibited and in direct competition with the Cdc42 interaction domain.

    Finally, other novel GRAF1 interaction partners were identified in this study. Interestingly, many of these partners are known to be associated with protein complexes involved in cell adherence, spreading and migration. Although never actually seen localising to mature focal adhesions that anchor cells to their growth surface, dynamic GRAF1 carriers were captured travelling to and from such locations. Moreover, GRAF1 was recruited specifically to smaller podosome-like structures. Consistent with this, the tracking of GRAF1 in live cells uncovered a clear pattern of dynamic carrier formation at sites of active membrane turnover – notably protrusions at the cell periphery. Furthermore, the silencing of GRAF1 gave rise to cells defective in spreading and migration, indicating a targeting of GRAF1-mediated endocytosis to aid in rapid plasma membrane turnover needed for morphological changes that are a prerequisite for cell movement. Since these cells exhibited an increase in active Rab8, a GTPase responsible for polarised vesicle transport, the phenotype could also be explained by a defect in Rab8 trafficking that results in hyperpolarisation.

    Taken together, the spatial and temporal regulation of GRAF1 membrane sculpting function is likely to be accomplished via its membrane binding propensity, in concert with various protein interactions. The importance of GRAF1 in aiding membrane turnover during cell movement spans different functional levels – from its local coordination of membrane and actin dynamics by interacting with Cdc42, to its global role in membrane lipid trafficking.

  • 210. Friant, S
    et al.
    Heyman, T
    Byström, Anders S
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wilhelm, M
    Wilhelm, F X
    Interactions between Ty1 retrotransposon RNA and the T and D regions of the tRNA(iMet) primer are required for initiation of reverse transcription in vivo1998Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 18, nr 2, s. 799-806Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Reverse transcription of the Saccharomyces cerevisiae Ty1 retrotransposon is primed by tRNA(iMet) base paired to the primer binding site (PBS) near the 5' end of Ty1 genomic RNA. The 10-nucleotide PBS is complementary to the last 10 nucleotides of the acceptor stem of tRNA(iMet). A structural probing study of the interactions between the Ty1 RNA template and the tRNA(iMet) primer showed that besides interactions between the PBS and the 3' end of tRNA(iMet), three short regions of Ty1 RNA, named boxes 0, 1, and 2.1, interact with the T and D stems and loops of tRNA(iMet). To determine if these sequences are important for the reverse transcription pathway of the Ty1 retrotransposon, mutant Ty1 elements and tRNA(iMet) were tested for the ability to support transposition. We show that the Ty1 boxes and the complementary sequences in the T and D stems and loops of tRNA(iMet) contain bases that are critical for Ty1 retrotransposition. Disruption of 1 or 2 bp between tRNA(iMet) and box 0, 1, or 2.1 dramatically decreases the level of transposition. Compensatory mutations which restore base pairing between the primer and the template restore transposition. Analysis of the reverse transcription intermediates generated inside Ty1 virus-like particles indicates that initiation of minus-strand strong-stop DNA synthesis is affected by mutations disrupting complementarity between Ty1 RNA and primer tRNA(iMet).

  • 211.
    Frisan, Teresa
    Dept. Cell and Molecular Biology, Karolinska Institutet.
    Bacterial genotoxins: the long journey to the nucleus of mammalian cells2016Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1858, nr 3, s. 567-575, artikkel-id S0005-2736(15)00267-9Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Bacterial protein genotoxins target the DNA of eukaryotic cells, causing DNA single and double strand breaks. The final outcome of the intoxication is induction of DNA damage responses and activation of DNA repair pathways. When the damage is beyond repair, the target cell either undergoes apoptosis or enters a permanent quiescent stage, known as cellular senescence. In certain instances, intoxicated cells can survive and proliferate. This event leads to accumulation of genomic instability and acquisition of malignant traits, underlining the carcinogenic potential of these toxins. The toxicity is dependent on the toxins' internalization and trafficking from the extracellular environment to the nucleus, and requires a complex interaction with several cellular membrane compartments: the plasma membrane, the endosomes, the trans Golgi network and the endoplasmic reticulum, and finally the nucleus. This review will discuss the current knowledge of the bacterial genotoxins internalization pathways and will highlight the issues that still remain unanswered. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.

  • 212.
    Frisan, Teresa
    et al.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Coppotelli, Giuseppe
    Dryselius, Rikard
    Masucci, Maria G
    Ubiquitin C-terminal hydrolase-L1 interacts with adhesion complexes and promotes cell migration, survival, and anchorage independent growth2012Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, nr 12, s. 5060-5070Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a deubiquitinating enzyme of unknown function that is highly expressed in neurons and overexpressed in several human cancers. UCH-L1 has been implicated in the regulation of phenotypic properties associated with malignant cell growth but the underlying mechanisms have not been elucidated. By comparing cells expressing catalytically active or inactive versions of UCH-L1, we found that the active enzyme enhances cell adhesion, spreading, and migration; inhibits anoikis; and promotes anchorage independent growth. UCH-L1 accumulates at the motile edge of the cell membrane during the initial phases of adhesion, colocalizes with focal adhesion kinase (FAK), p120-catenin, and vinculin, and enhances the formation of focal adhesions, which correlates with enhanced FAK activation. The involvement of UCH-L1 in the regulation of focal adhesions and adherens junctions is supported by coimmunoprecipitation with key components of these complexes, including FAK, paxillin, p120-catenin, β-catenin, and vinculin. UCH-L1 stabilizes focal adhesion signaling in the absence of adhesion, as assessed by reduced caspase-dependent cleavage of FAK following cell detachment and sustained activity of the AKT signaling pathway. These findings offer new insights on the molecular interactions through which the deubiquitinating enzyme regulates the survival, proliferation, and metastatic potential of malignant cells.

  • 213.
    Frisan, Teresa
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Department of Cell and Molecular Biology Karolinska Institutet, Stockholm, Sweden.
    Nagy, Noemi
    Chioureas, Dimitrios
    Terol, Marie
    Grasso, Francesca
    Masucci, Maria G.
    A bacterial genotoxin causes virus reactivation and genomic instability in Epstein-Barr virus infected epithelial cells pointing to a role of co-infection in viral oncogenesis2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, nr 1, s. 98-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have addressed the role of bacterial co-infection in viral oncogenesis using as model Epstein-Barr virus (EBV), a human herpesvirus that causes lymphoid malignancies and epithelial cancers. Infection of EBV carrying epithelial cells with the common oral pathogenic Gram-negative bacterium Aggregatibacter actinomycetemcomitans (Aa) triggered reactivation of the productive virus cycle. Using isogenic Aa strains that differ in the production of the cytolethal distending toxin (CDT) and purified catalytically active or inactive toxin, we found that the CDT acts via induction of DNA double strand breaks and activation of the Ataxia Telangectasia Mutated (ATM) kinase. Exposure of EBV-negative epithelial cells to the virus in the presence of sub-lethal doses of CDT was accompanied by the accumulation of latently infected cells exhibiting multiple signs of genomic instability. These findings illustrate a scenario where co-infection with certain bacterial species may favor the establishment of a microenvironment conducive to the EBV-induced malignant transformation of epithelial cells.

  • 214.
    Frisan, Teresa
    et al.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Sebo, Peter
    Editorial: Why still study bacterial toxins in the third millennium?2016Inngår i: Pathogens and Disease, E-ISSN 2049-632X, Vol. 74, nr 3, artikkel-id ftw009Artikkel i tidsskrift (Fagfellevurdert)
  • 215. Fuchino, Katsuya
    et al.
    Bagchi, Sonchita
    Cantlay, Stuart
    Sandblad, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Wu, Di
    Bergman, Jessica
    Kamali-Moghaddam, Masood
    Flardh, Klas
    Ausmees, Nora
    Dynamic gradients of an intermediate filament-like cytoskeleton are recruited by a polarity landmark during apical growth2013Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 21, s. E1889-E1897Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intermediate filament (IF)-like cytoskeleton emerges as a versatile tool for cellular organization in all kingdoms of life, underscoring the importance of mechanistically understanding its diverse manifestations. We showed previously that, in Streptomyces (a bacterium with a mycelial lifestyle similar to that of filamentous fungi, including extreme cell and growth polarity), the IF protein FilP confers rigidity to the hyphae by an unknown mechanism. Here, we provide a possible explanation for the IF-like function of FilP by demonstrating its ability to self-assemble into a cis-interconnected regular network in vitro and its localization into structures consistent with a cytoskeletal network in vivo. Furthermore, we reveal that a spatially restricted interaction between FilP and DivIVA, the main component of the Streptomyces polarisome complex, leads to formation of apical gradients of FilP in hyphae undergoing active tip extension. We propose that the coupling between the mechanism driving polar growth and the assembly of an IF cytoskeleton provides each new hypha with an additional stress-bearing structure at its tip, where the nascent cell wall is inevitably more flexible and compliant while it is being assembled and matured. Our data suggest that recruitment of cytoskeleton around a cell polarity landmark is a broadly conserved strategy in tip-growing cells.

  • 216.
    Fällman, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Schedin, Staffan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Jass, Jana
    Department of Microbiology and Immunology, The Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
    Uhlin, Bernt Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Axner, Ove
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    The unfolding of the P pili quaternary structure by stretching is reversible, not plastic2005Inngår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 6, nr 1, s. 52-56Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    P pili are protein filaments expressed by uropathogenic Escherichia coli that mediate binding to glycolipids on epithelial cell surfaces, which is a prerequisite for bacterial infection. When a bacterium, attached to a cell surface, is exposed to external forces, the pili, which are composed of ∼103PapA protein subunits arranged in a helical conformation, can elongate by unfolding to a linear conformation. This property is considered important for the ability of a bacterium to withstand shear forces caused by urine flow. It has hitherto been assumed that this elongation is plastic, thus constituting a permanent conformational deformation. We demonstrate, using optical tweezers, that this is not the case; the unfolding of the helical structure to a linear conformation is fully reversible. It is surmised that this reversibility helps the bacteria regain close contact to the host cells after exposure to significant shear forces, which is believed to facilitate their colonization.

  • 217.
    Fällman, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Deleuil, Fabienne
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    McGee, Karen
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Resistance to phagocytosis by Yersinia2002Inngår i: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 291, nr 6-7, s. 501-509Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Enteropathogenic species of the genus Yersinia penetrate the intestinal epithelium and then spread to the lymphatic system, where they proliferate extracellularly. At this location, most other bacteria are effectively ingested and destroyed by the resident phagocytes. Yersinia, on the other hand binds to receptors on the external surface of phagocytes, and from this location it blocks the capacity of these cells to exert their phagocytic function via different receptors. The mechanism behind the resistance to phagocytosis involves the essential virulence factor YopH, a protein tyrosine phosphatase that is translocated into interacting target cells via a type III secretion machinery. YopH disrupts peripheral focal complexes of host cells, seen as a rounding up of infected cells. The focal complex proteins that are dephosphorylated by YopH are focal adhesion kinase and Crk-associated substrate, the latter of which is a common substrate in both professional and non-professional phagocytes. In macrophages additional substrates have been found, the Fyn-binding/SLP-76-associated protein and SKAP-HOM. Phagocytosis is a rapid process that is activated when the bacterium interacts with the phagocyte. Consequently, the effect exerted by a microbe to block this process has to be rapid and precise. This review deals with the mechanisms involved in impeding uptake as well as with the role of the YopH substrates and focal complex structures in normal cell function.

  • 218.
    Fällman, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Persson, Cathrine
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Schesser, K.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wolf-Watz, Hans
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Bidirectional signaling between Yersinia and its target cell1998Inngår i: Folia microbiologica (Prague), ISSN 0015-5632, E-ISSN 1874-9356, Vol. 43, nr 3, s. 263-273Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Preventing the early host immune defense allows pathogenic Yersinia to proliferate in lymphatic tissue. This ability depends on signaling that occurs between the bacteria and the host cells. Following intimate contact with the target cell a signal is generated within the bacterium that results in increased expression of virulence-associated proteins that are subsequently delivered into the infected cell. These proteins, designated Yops, interfere with the host-cell signaling pathways that are normally activated to eliminate infectious agents.

  • 219.
    Fällman, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Persson, Cathrine
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wolf-Watz, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Yersinia proteins that target host cell signaling pathways1997Inngår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 99, nr 6, s. 1153-1157Artikkel, forskningsoversikt (Fagfellevurdert)
  • 220. Gan, Haiyun
    et al.
    Yu, Chuanhe
    Devbhandari, Sujan
    Sharma, Sushma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Han, Junhong
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Remus, Dirk
    Zhang, Zhiguo
    Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress2017Inngår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 68, nr 2, s. 446-455Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The checkpoint kinase Rad53 is activated during replication stress to prevent fork collapse, an essential but poorly understood process. Here we show that Rad53 couples leading- and lagging-strand synthesis under replication stress. In rad53-1 cells stressed by dNTP depletion, the replicative DNA helicase, MCM, and the leading-strand DNA polymerase, Pol ε, move beyond the site of DNA synthesis, likely unwinding template DNA. Remarkably, DNA synthesis progresses further along the lagging strand than the leading strand, resulting in the exposure of long stretches of single-stranded leading-strand template. The asymmetric DNA synthesis in rad53-1 cells is suppressed by elevated levels of dNTPs in vivo, and the activity of Pol ε is compromised more than lagging-strand polymerase Pol δ at low dNTP concentrations in vitro. Therefore, we propose that Rad53 prevents the generation of excessive ssDNA under replication stress by coordinating DNA unwinding with synthesis of both strands.

  • 221.
    Ganai, Rais Ahmad
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Structural and biochemical basis for the high fidelity and processivity of DNA polymerase ε2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    DNA polymerase epsilon (Pol ε) is a multi-subunit B-family DNA polymerase that is involved in leading strand DNA replication in eukaryotes. DNA Pol ε in yeast consists of four subunits, Pol2, Dpb2, Dpb3, and Dpb4. Pol2 is the catalytic subunit and Dpb2, Dpb3, and Dpb4 are the accessory subunits. Pol2 can be further divided into an N-terminal catalytic core (Pol2core) containing both the polymerase and exonuclease active sites and a C-terminus domain. We determined the X-ray crystal structure of Pol2core at 2.2 Å bound to DNA and with an incoming dATP. Pol ε has typical fingers, palm, thumb, exonuclease, and N-terminal domains in common with all other B-family DNA polymerases. However, we also identified a seemingly novel domain we named the P-domain that only appears to be present in Pol ε. This domain partially encircles the nascent duplex DNA as it leaves the active site and contributes to the high intrinsic processivity of Pol ε.

    To ask if the crystal structure of Pol2core can serve as a model for catalysis by Pol ε, we investigated how the C-terminus of Pol2 and the accessory subunits of Pol ε influence the enzymatic mechanism by which Pol ε builds new DNA efficiently and with high fidelity. Pre-steady state kinetics revealed that the exonuclease and polymerization rates were comparable between Pol2core and Pol ε. However, a global fit of the data over five nucleotide-incorporation events revealed that Pol ε is slightly more processive than Pol2 core. The largest differences were observed when measuring the time for loading the polymerase onto a 3' primer-terminus and the subsequent incorporation of one nucleotide. We found that Pol ε needed less than a second to incorporate the first nucleotide, but it took several seconds for Pol2core to incorporate similar amounts of the first nucleotide.

    B-family polymerases have evolved an extended β-hairpin loop that is important for switching the primer terminus between the polymerase and exonuclease active sites. The high-resolution structure of Pol2core revealed that Pol ε does not possess an extended β-hairpin loop. Here, we show that Pol ε can processively transfer a mismatched 3' primer-terminus between the polymerase and exonuclease active sites despite the absence of a β-hairpin loop. Additionally we have characterized a series of amino acid substitutions in Pol ε that lead to altered partitioning of the 3'primer-terminus between the two active sites.

    In a final set of experiments, we investigated the ability of Pol ε to displace the downstream double-stranded DNA while carrying out DNA synthesis. Pol ε displaced only one base pair when encountering double-stranded DNA after filling a gap or a nick. However, exonuclease deficient Pol ε carries out robust strand displacement synthesis and can reach the end of the templates tested here. Similarly, an abasic site or a ribonucleotide on the 5'-end of the downstream primer was efficiently displaced but still only by one nucleotide. However, a flap on the 5'-end of the blocking primer resembling a D-loop inhibited Pol ε before it could reach the double-stranded junction. Our results are in agreement with the possible involvement of Pol ε in short-patch base excision repair and ribonucleotide excision repair but not in D-loop extension or long-patch base excision repair.

  • 222. Garbacz, Marta A.
    et al.
    Cox, Phillip B.
    Sharma, Sushma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lujan, Scott A.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kunkel, Thomas A.
    The absence of the catalytic domains of Saccharomyces cerevisiae DNA polymerase ϵ strongly reduces DNA replication fidelity2019Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, nr 8, s. 3986-3995Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The four B-family DNA polymerases α, δ, ϵ and ζ cooperate to accurately replicate the eukaryotic nuclear genome. Here, we report that a Saccharomyces cerevisiae strain encoding the pol2-16 mutation that lacks Pol ϵ's polymerase and exonuclease activities has increased dNTP concentrations and an increased mutation rate at the CAN1 locus compared to wild type yeast. About half of this mutagenesis disappears upon deleting the REV3 gene encoding the catalytic subunit of Pol ζ. The remaining, still strong, mutator phenotype is synergistically elevated in an msh6Δ strain and has a mutation spectrum characteristic of mistakes made by Pol δ. The results support a model wherein slow-moving replication forks caused by the lack of Pol ϵ's catalytic domains result in greater involvement of mutagenic DNA synthesis by Pol ζ as well as diminished proofreading by Pol δ during replication.

  • 223. Garcia-Aljaro, Cristina
    et al.
    Melado-Rovira, Silvia
    Milton, Debra L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Blanch, Anicet R.
    Quorum-sensing regulates biofilm formation in Vibrio scophthalmi2012Inngår i: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 12, s. 287-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In a previous study, we demonstrated that Vibrio scophthalmi, the most abundant Vibrio species among the marine aerobic or facultatively anaerobic bacteria inhabiting the intestinal tract of healthy cultured turbot (Scophthalmus maximus), contains at least two quorum-sensing circuits involving two types of signal molecules (a 3-hydroxy-dodecanoyl-homoserine lactone and the universal autoinducer 2 encoded by luxS). The purpose of this study was to investigate the functions regulated by these quorum sensing circuits in this vibrio by constructing mutants for the genes involved in these circuits.

    Results: The presence of a homologue to the Vibrio harveyi luxR gene encoding a main transcriptional regulator, whose expression is modulated by quorum-sensing signal molecules in other vibrios, was detected and sequenced. The V. scophthalmi LuxR protein displayed a maximum amino acid identity of 82% with SmcR, the LuxR homologue found in Vibrio vulnificus. luxR and luxS null mutants were constructed and their phenotype analysed. Both mutants displayed reduced biofilm formation in vitro as well as differences in membrane protein expression by mass-spectrometry analysis. Additionally, a recombinant strain of V. scophthalmi carrying the lactonase AiiA from Bacillus cereus, which causes hydrolysis of acyl homoserine lactones, was included in the study.

    Conclusions: V. scophthalmi shares two quorum sensing circuits, including the main transcriptional regulator luxR, with some pathogenic vibrios such as V. harveyi and V. anguillarum. However, contrary to these pathogenic vibrios no virulence factors (such as protease production) were found to be quorum sensing regulated in this bacterium. Noteworthy, biofilm formation was altered in luxS and luxR mutants. In these mutants a different expression profile of membrane proteins were observed with respect to the wild type strain suggesting that quorum sensing could play a role in the regulation of the adhesion mechanisms of this bacterium.

  • 224. Garzón, J.
    et al.
    Rodríguez, R.
    Kong, Ziqing
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Rodríguez-Acebes, S.
    Méndez, J.
    Moreno, S.
    García-Higuera, I.
    Shortage of dNTPs underlies altered replication dynamics and DNA breakage in the absence of the APC/C cofactor Cdh12017Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 36, nr 42, s. 5808-5818Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The APC/C-Cdh1 ubiquitin-ligase complex targets cell cycle regulators for proteosomal degradation and helps prevent tumor development and accumulation of chromosomal aberrations. Replication stress has been proposed to be the main driver of genomic instability in the absence of Cdh1, but the real contribution of APC/C-Cdh1 to efficient replication, especially in normal cells, remains unclear. Here we show that, in primary MEFs, acute depletion or permanent ablation of Cdh1 slowed down replication fork movement and increased origin activity. Partial inhibition of origin firing does not accelerate replication forks, suggesting that fork progression is intrinsically limited in the absence of Cdh1. Moreover, exogenous supply of nucleotide precursors, or ectopic overexpression of RRM2, the regulatory subunit of Ribonucleotide Reductase, restore replication efficiency, indicating that dNTP availability could be impaired upon Cdh1 loss. Indeed, we found reduced dNTP levels in Cdh1-deficient MEFs. Importantly, DNA breakage is also significantly alleviated by increasing intracellular dNTP pools, strongly suggesting that genomic instability is the result of aberrant replication. These observations highlight the relevance of APC/C-Cdh1 activity during G1 to ensure an adequate supply of dNTPs to the replisome, prevent replication stress and the resulting chromosomal breaks and, ultimately, suppress tumorigenesis.

  • 225. Gause, Maria
    et al.
    Hovhannisyan, Hayk
    Kan, Tatiana
    Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
    Kuhfittig, Steffi
    Mogila, Vladic
    Georgiev, Pavel
    hobo Induced rearrangements in the yellow locus influence the insulation effect of the gypsy su(Hw)-binding region in Drosophila melanogaster1998Inngår i: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 149, nr 3, s. 1393-1405Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The su(Hw) protein is responsible for the insulation mediated by the su(Hw)-binding region present in the gypsy retrotransposon. In the y2 mutant, su(Hw) protein partially inhibits yellow transcription by repressing the function of transcriptional enhancers located distally from the yellow promoter with respect to gypsy. y2 mutation derivatives have been induced by the insertion of two hobo copies on the both sides of gypsy: into the yellow intron and into the 5' regulatory region upstream of the wing and body enhancers. The hobo elements have the same structure and orientation, opposite to the direction of yellow transcription. In the sequence context, where two copies of hobo are separated by the su(Hw)-binding region, hobo-dependent rearrangements are frequently associated with duplications of the region between the hobo elements. Duplication of the su(Hw)-binding region strongly inhibits the insulation of the yellow promoter separated from the body and wing enhancers by gypsy. These results provide a better insight into mechanisms by which the su(Hw)-binding region affects the enhancer function.

  • 226.
    Gerpe, M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Kling, P.
    Berg, A. H.
    Olsson, P.-E.
    Arctic char (Salvelinus alpinus) metallothionein: cDNA sequence, expression, and tissue-specific inhibition of cadmium-mediated metallothionein induction by 17ß-estradiol, 4-OH-PCB 30, and PCB 1042000Inngår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 19, nr 3, s. 638-645Artikkel i tidsskrift (Fagfellevurdert)
  • 227.
    Gharibyan, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Amyloids here, amyloids there…What’s wrong with them?2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Amyloid formation is inherent property of proteins which under certain circumstances can become a pathologic feature of a group of diseases called amyloidosis. There are about 30 known human amyloidosis and more than 27 identified proteins involved in these pathologies.  Besides these proteins, there are a growing number of proteins non-related to diseases shown to form amyloid-like structures in vitro, which make them excellent tools for studying amyloid formation mechanisms, physicochemical properties of different amyloid species and the nature of their influence on tissues and cells.  It is important to understand the mechanisms by which amyloids interact with different types of cells, as the leading hypothesis in amyloid field suggests that amyloids and especially their intermediate states are the main harmful, toxic species causing tissue and cell degeneration.

    Using de-novo synthesized protein albebetin as a model of amyloidogenic protein, we demonstrated that it forms amyloid-like structures under physiological conditions (pH 7 and 37°C). During aggregation it forms 2 different types of intermediate oligomers — cross-b sheet containing and lacking β-sheet oligomers. Only the former induces cellular toxicity in a dose dependent manner. Further aggregation leads to the formation of fully mature amyloid-like fibrils, which are not toxic to the cells during studied period of incubation.

    Another model protein in our studies was hen egg white lysozyme, which readily forms amyloid under denaturing conditions (pH 2,2 and 57°C). In contrast to albebetin and many other proteins reported in the literature, we showed that both oligomers and mature fibrils from hen lysozyme affect cell viability. Targeting different mechanisms involved in cellular death, we revealed that oligomers induce slow and apoptotic-like cell death, while mature fibrils cause rapid and mainly necrotic-like cellular death.   

    One of the important aspects of amyloid studies is to develop measures for inhibiting or re-directing the process of amyloid formation to abolish or neutralize toxic amyloid species. Among the agents having inhibitory or modulatory properties small, phenol containing molecules are widely studied. We investigated the effect of the novel nootropic drug noopept on amyloid formation process of α-synuclein, as this drug is a small dipeptide containing a phenol ring. We showed that noopept is able to modulate amyloid formation process by accelerating it to rapid conversion of α-synuclein into fully mature fibrils, thus eliminating the stage of population of toxic oligomeric species.  Using wide range of cytotoxicity assays we showed that amyloid-like fibrils formed in the presence of noopept have no cytotoxic properties.  As this medicine is becoming popular and freely available in some countries as a cognitive enhancer, neuroprotective and nootropic agent, further detailed investigations and clinical trials are needed to assess the safety and benefit of noopept in particular for the patients with amyloid related neurodegenerative diseases (such as Parkinson’s or Alzheimer’s diseases).    

    While in vitro models are useful to study some specific aspects of protein aggregation, their properties and effects on cell viability, it is very difficult or practically impossible to create an absolutely accurate model of in vivo situation. Therefore, it is important to turn to in vivo/ex vivo studies to relate the knowledge accumulated from in vitro studies to the real situation in the body.

    Using human brain hippocampus tissues from individuals with Alzheimer’s disease, we found that besides well-known and widely accepted main pathological hallmark — Ab peptide deposition, S100A9 and S100A8 pro-inflammatory calcium-binding proteins are also localized in the plaques and in surrounding tissues and very explicitly co-localized with Ab. Moreover, we found the presence of S100A9 within the neuronal cells, which has not been reported before and can be an important clue for understanding the mechanisms of neurodegeneration. In vitro cytotoxicity studies showed that S100A9 protein can efficiently induce cytotoxicity when added exogenously to the neuronal cell culture. These findings suggest that S100A8 and S100A9 proteins play an important role in Alzheimer’s pathology, and potentially can be candidates for the amyloid plaque formation and neurodegeneration. Whether they are associated with inflammatory processes underlying the early onset of disease or produced and accumulated as a consequence of A-beta induced pathology remain to be clarified.

    We found that Alzheimer’s disease is not the only pathology associated with A-beta and S100A9 deposition in a form of plaques. Immunohistochemical studies of an aortic valve surgically removed from a patient with aortic stenosis revealed plaque-like structures positively stained with A-beta and S100A9 proteins. These areas are also positively stained with fibril-specific antibodies as well as with Congo red, which also shows very distinct apple-green birefringence under the polarized light. Besides, there is intracellular localization and co-localization of both proteins in interstitial cells throughout the whole fibrous tissue of the valve. The presented case report is the first finding suggesting inflammatory protein S100A9 as well as A-beta peptide as potential candidates for amyloid formation in aortic stenosis valves.  We suggest that there is a specific interaction between A-beta and S100A9 during amyloid formation, which can be involved in amyloid-associated pathology in various tissues and organs in the body, which can potentially be caused by inflammatory processes, particularly by its chronic, long lasting forms.

  • 228.
    Gharibyan, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Narayana, Vinod
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ankarcrona, Maria
    Karolinska Institute.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Emerging role of inflammatory S100A9 in Alzheimer’s disease amyloid growth and neurodegenerationManuskript (preprint) (Annet vitenskapelig)
  • 229.
    Gharibyan, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Narayana, Vinod
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Habib, Ahsan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sulniute, Rima
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Henein, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Inflammatory S100A9 and Aβ amyloids in heart valve of patient with aortic stenosisManuskript (preprint) (Annet vitenskapelig)
  • 230. Gisterå, Anton
    et al.
    Robertson, Anna-Karin L
    Andersson, John
    Ketelhuth, Daniel FJ
    Ovchinnikova, Olga
    Nilsson, Stefan K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Lundberg, Anna M
    Li, Ming O
    Flavell, Richard A
    Hansson, Göran K
    Transforming growth factor-beta signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway2013Inngår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 5, nr 196, s. 196ra100-Artikkel i tidsskrift (Fagfellevurdert)
  • 231. Gnanasundram, Sivakumar Vadivel
    et al.
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Translation Stress Regulates Ribosome Synthesis and Cell Proliferation2018Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, nr 12, artikkel-id 3757Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Ribosome and protein synthesis are major metabolic events that control cellular growth and proliferation. Impairment in ribosome biogenesis pathways and mRNA translation is associated with pathologies such as cancer and developmental disorders. Processes that control global protein synthesis are tightly regulated at different levels by numerous factors and linked with multiple cellular signaling pathways. Several of these merge on the growth promoting factor c-Myc, which induces ribosome biogenesis by stimulating Pol I, Pol II, and Pol III transcription. However, how cells sense and respond to mRNA translation stress is not well understood. It was more recently shown that mRNA translation stress activates c-Myc, through a specific induction of E2F1 synthesis via a PI3K delta-dependent pathway. This review focuses on how this novel feedback pathway stimulates cellular growth and proliferation pathways to synchronize protein synthesis with ribosome biogenesis. It also describes for the first time the oncogenic activity of the mRNA, and not the encoded protein.

  • 232. Goldberg, Emily L.
    et al.
    Asher, Jennifer L.
    Molony, Ryan D.
    Shaw, Albert C.
    Zeiss, Caroline J.
    Wang, Chao
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Herzog, Raimund I.
    Iwasaki, Akiko
    Dixit, Vishwa Deep
    beta-Hydroxybutyrate deactivates Neutrophil NLRP3 inflammasome to relieve gout flares2017Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, nr 9, s. 2077-2087Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1 beta (IL-1 beta) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases beta-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1 beta in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.

  • 233.
    Goldsteins, Gundars
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Persson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Andersson, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Dacklin, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Edvinsson, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Saraiva, Maria João
    Lundgren, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants1999Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 96, nr 6, s. 3108-3113Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The structural requirements for generation of amyloid from the plasma protein transthyretin (TTR) are not known, although it is assumed that TTR is partly misfolded in amyloid. In a search for structural determinants important for amyloid formation, we generated a TTR mutant with high potential to form amyloid. We demonstrated that the mutant represents an intermediate in a series of conformational changes leading to amyloid. Two monoclonal antibodies were generated against this mutant; each displayed affinity to ex vivo TTR and TTR mutants with amyloidogenic folding but not to wild-type TTR or mutants exhibiting the wild-type fold. Two cryptic epitopes were mapped to a domain of TTR, where most mutations associated with amyloidosis occur and which we propose is displaced at the initial phase of amyloid formation, opening up new surfaces necessary for autoaggregation of TTR monomers. The results provide direct biochemical evidence for structural changes in an amyloidogenic intermediate of TTR.

  • 234. Gomzikova, Marina O.
    et al.
    Zhuravleva, Margarita N.
    Miftakhova, Regina R.
    Arkhipova, Svetlana S.
    Evtugin, Vladimir G.
    Khaiboullina, Svetlana F.
    Kiyasov, Andrey P.
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Mongan, Nigel P.
    Pestell, Richard G.
    Rizvanov, Albert A.
    Cytochalasin B-induced membrane vesicles convey angiogenic activity of parental cells2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 41, s. 70496-70507Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Naturally occurring extracellular vesicles (EVs) play essential roles in intracellular communication and delivery of bioactive molecules. Therefore it has been suggested that EVs could be used for delivery of therapeutics. However, to date the therapeutic application of EVs has been limited by number of factors, including limited yield and full understanding of their biological activities. To address these issues, we analyzed the morphology, molecular composition, fusion capacity and biological activity of Cytochalasin B-induced membrane vesicles (CIMVs). The size of these vesicles was comparable to that of naturally occurring EVs. In addition, we have shown that CIMVs from human SH-SY5Y cells contain elevated levels of VEGF as compared to the parental cells, and stimulate angiogenesis in vitro and in vivo.

  • 235.
    Grabbe, Caroline
    et al.
    Goethe University Frankfurt am Main, Germany.
    Dikic, Ivan
    Goethe University Frankfurt am Main, Germany.
    Functional roles of ubiquitin-like domain (ULD) and ubiquitin-binding domain (UBD) containing proteins2009Inngår i: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 109, nr 4, s. 1481-1494Artikkel i tidsskrift (Fagfellevurdert)
  • 236.
    Grabowski, Pawel
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Telomere length as prognostic parameter in chronic lymphocytic leukemia2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia among the adult population in western countries and accounts for 30-40% of all leukemias. With survival time ranging from months to decades, the clinical course of individual CLL patients is highly variable. This heterogeneity and in the end the need for means to identify the patients with less favorable disease has encouraged the search for biomarkers that can predict the prognosis.

    Telomeres are repetitive structures protecting the chromosomal endings and shorten at each cell division. Telomere length (TL) has been indicated as a prognostic factor both in hematological malignancies and solid tumors. In B-CLL, TL is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and with clinical course. In the present thesis the main aim was to evaluate TL as a biomarker in B-CLL using a quantitative PCR-based method for TL determination.

    In paper I, TL was shown to be a prognostic factor for stage A and stage B/C patients, whereas IGHV mutation status predicted outcome only in stage A patients. Moreover, IGHV mutated CLL cases were subdivided by TL into two groups with different prognosis, a subdivision not seen for unmutated cases. Interestingly, the IGHV-mutated group with short telomeres had en overall survival close to that of the unmutated cases. Thus, a combination of IGHV mutation status and telomere length gave an improved subclassification of CLL identifying previously unrecognized patient groups with different outcomes.

    TL correlates with cellular origin of B-cell malignancies in relation to the germinal center (GC). In paper II different B-cell lymphoma/leukemia subtypes were analyzed. Shortest telomeres were found in IGHV unmutated CLLs, differing significantly from IGHV mutated cases. Contrary to this, mantle cell lymphomas (MCL) demonstrated similar TL regardless of IGHV mutation status. TL differed significantly between GC-like and non-GC-like diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas (FL) had shorter telomeres than GC-like DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. In conclusion, TL seemed not to simply correlate with GC origin.

    Paper III presents a B-CLL cohort assessed for TL, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression. An inverse correlation existed between TL and IGHV homology, CD38 and ZAP-70 expression. The presence of genomic aberrations was similar among patients regardless of TL. In contrast, 13q deletion, a favorable biomarker, was more frequent in patients with long telomeres, while 11q and 17p deletions (markers of less favorable outcome) were more frequent in the subgroup with short telomeres.

    In paper IV a large group of mainly indolent CLL cases from a population based cohort was studied again showing an association between TL and prognosis, especially in “good” prognosis cases as defined by other biomarkers. Multivariate analysis indicated a strong connection between IGHV mutation status, lipoprotein lipase (LPL) expression and TL. A comparison of TL in diagnostic and follow up samples demonstrated a significant correlation, and also in the follow samples TL constituted a significant biomarker for survival.

  • 237.
    Grabowski, Pawel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Karlsson, Karin
    Tobin, Gerard
    Aleskog, Anna
    Thunberg, Ulf
    Laurell, Anna
    Sundström, Christer
    Rosenquist, Richard
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status2005Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, nr 12, s. 4807-4812Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.

  • 238.
    Graffmo, Karin Sixtensdotter
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap.
    Of mice and men: SOD1 associated human amyotrophic lateral sclerosis and transgenic mouse models2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Amyotrophic lateral sclerosis, ALS, is a progressive fatal neurodegenerative disorder affecting motor neurones in motor cortex, brain stem and spinal cord. This inevitably leads to paralysis, respiratory failure and death. In about 5% of patients with ALS there is an association with mutations in gene for the abundant intracellular scavenging enzyme superoxide dismutase1, SOD1. The noxious property of SOD1 is proposed to be due to gain of function. In familial cases the inheritance is most commonly dominant.

    This study focus on two disparate SOD1 mutations occurring in Scandinavia. The recessive D90A mutation which has properties similar to that of the normal wild-type human SOD1. The dominantly inherited G127insTGGG mutation, G127X, causes a C-terminal truncation of the last 21 amino acids and is a highly unstable protein.

    Transgenic mice were created expressing D90A and G127X mutated human SOD1. Results from studies of tissue from the central nervous system of patients carrying either of these mutations were compared with similar tissue collected from transgenic mice generated with the same mutations. Tissue from the mice were also compared to central nervous tissue from several other transgenic mouse strains expressing human wild type SOD1 as well as other ALS associated human SOD1 mutations.

    The transgenic mice expressing D90A respectively G127X mutated human SOD1 develop motor neurone disease. Microscopic studies of central nervous tissues from G127X transgenic mice reveals inclusions of aggregated misfolded SOD1 in motor neurones and adjacent supporting cells. These inclusions are composed of detergent resistant aggregates and preceded by accumulations of minute quantities of detergent-soluble aggregates. The inclusions mimic those found in G127X patients.

    In D90A transgenic mice the progression, as in the humans, was slower and the mice, as the patients, showed bladder disturbance. In the D90A patients, the SOD1 inclusions mimic those found in sporadic ALS patients.

    Aggregation of SOD1 in central nervous tissue appears to be related to severity of disease. Degenerative features as vacuolization and gliosis precedes phenotypic alterations. Changes are seen not only in motor areas but also in higher centres of the telencephalon.

  • 239.
    Granberg, I
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Lindell, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Eriksson, Per-Olof
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Klinisk oral fysiologi.
    Pedrosa-Domellöf, Fatima
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Stål, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Capillary supply in relation to myosin heavy chain fibre composition of human intrinsic tongue muscles2010Inngår i: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 192, nr 5, s. 303-313Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The capillary supply and myosin heavy chain (MyHC) composition of three different intrinsic tongue muscles was analysed in the anterior and posterior regions of the human tongue with biochemical and immunohistochemical techniques. Mean capillary density for the whole tongue was 796 ± 82 cap/mm², without regional differences. The overall number of capillaries around each fibre (CAF) was higher in the posterior than in the anterior region (2.5 vs. 2.1, p = 0.009). However, correcting for regional differences in fibre size, CAF per fibre area was higher in the anterior region (4.3 vs. 3.0, p < 0.001). Muscle fibres containing fast MyHCs predominated in the anterior region (78.7%), consisting of MyHCIIa (58.5%), MyHCIIx (1.0%), MyHCIIa+MyHCIIx (11.3%) and MyHCI+MyHCIIa (7.9%). Fibres containing slow MyHC predominated in the posterior region (65.2%), consisting of MyHCI (45.5%) and MyHCI+MyHCIIa (19.7%). A minor fibre population (<2%) contained unusual MyHC isoforms, namely MyHC foetal, MyHC slow-tonic, MyHC α-cardiac or MyHC embryonic. The microvascularization of the human tongue was twice as high as in human limb muscles. Regional similarities in capillary supply, but differences in fibre phenotype composition, suggest that human tongue muscle fibres are fatigue resistant independently of MyHC content. High frequency of hybrid fibres, that is fibres co-expressing two or more MyHC isoforms, indicates a wider spectrum of fibre contractile properties than in limb muscles. In conclusion, human intrinsic tongue muscles showed internal specialization in distribution of MyHC isoforms and capillary supply, but not in the expression of unusual MyHCs.

  • 240.
    Granholm, Susanne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Henning, Petra
    Göteborgs universitet.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Comparisons between the effects of calcitonin receptor-stimulating peptide and intermedin and other peptides in the calcitonin family on bone resorption and osteoclastogenesis2011Inngår i: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 112, nr 11, s. 3300-3312Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Calcitonin receptor-stimulating peptide (CRSP) and intermedin (IMD) are two recently discovered peptides in the calcitonin (CT) family of peptides. CRSP and IMD, similar to CT, calcitonin gene-related peptide (CGRP) and amylin (AMY), but in contrast to adrenomedullin (ADM), inhibited bone resorption in mouse calvarial bones. CRSP and IMD, similar to CT, CGRP, AMY, but in contrast to ADM, decreased formation of osteoclasts and number of pits in bone marrow macrophage cultures stimulated by M-CSF and RANKL, with no effect on the expression of a number of genes associated with osteoclast progenitor cell differentiation. CRSP and IMD inhibited osteoclastogenesis at a late stage but had no effect on DC-STAMP mRNA. IMD, similar to CGRP, AMY and ADM stimulated cyclic AMP formation in M-CSF expanded osteoclast progenitor cells lacking CT receptors. RANKL induced CT receptors and a cyclic AMP response also to CT and CRSP, and increased the cyclic AMP response to CGRP, AMY and IMD but decreased the response to ADM. Our data demonstrate that CRSP and IMD share several functional properties of peptides in the CT family of peptides, including inhibition of bone resorption and osteoclast formation. The data also show that the reason why ADM does not inhibit osteoclast activity or formation is related to the fact that RANKL decreases ADM receptor signalling through the adenylate cyclase-cyclic AMP pathway. Finally, the findings indicate that activation by CGRP, AMY and IMD may include activation of both CT and CT receptor-like receptors. J. Cell. Biochem. © 2011 Wiley-Liss, Inc.

  • 241. Grasso, Francesca
    et al.
    Frisan, Teresa
    Department Cell and Molecular Biology, Karolinska Institutet.
    Bacterial Genotoxins: Merging the DNA Damage Response into Infection Biology2015Inngår i: Biomolecules, E-ISSN 2218-273X, Vol. 5, nr 3, s. 1762-1782Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Bacterial genotoxins are unique among bacterial toxins as their molecular target is DNA. The consequence of intoxication or infection is induction of DNA breaks that, if not properly repaired, results in irreversible cell cycle arrest (senescence) or death of the target cells. At present, only three bacterial genotoxins have been identified. Two are protein toxins: the cytolethal distending toxin (CDT) family produced by a number of Gram-negative bacteria and the typhoid toxin produced by Salmonella enterica serovar Typhi. The third member, colibactin, is a peptide-polyketide genotoxin, produced by strains belonging to the phylogenetic group B2 of Escherichia coli. This review will present the cellular effects of acute and chronic intoxication or infection with the genotoxins-producing bacteria. The carcinogenic properties and the role of these effectors in the context of the host-microbe interaction will be discussed. We will further highlight the open questions that remain to be solved regarding the biology of this unusual family of bacterial toxins.

  • 242.
    Grimsholm, Ola
    Umeå universitet, Medicinsk fakultet, Integrativ medicinsk biologi.
    Neuropeptides and neurotrophins in arthritis: studies on the human and mouse knee joint2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Neuropeptides, such as substance P (SP) and bombesin/gastrin-releasing peptide (BN/GRP), and neurotrophins are involved in neuro-immunomodulatory processes and have marked trophic, growth-promoting and inflammation-modulating properties. The impact of these modulators in rheumatoid arthritis (RA) is, however, unclear. An involvement of the innervation, including the peptidergic innervation, is frequently proposed as an important factor for arthritic disease. Many patients with RA, but not all, benefit from treatment with anti-TNF medications.

    The studies presented here aimed to investigate the roles of neuropeptides, with an emphasis on BN/GRP and SP, and neurotrophins, especially with attention to brain-derived neurotrophic factor (BDNF), in human and murine knee joint tissue. The expression patterns of these substances and their receptors in synovial tissue from patients with either RA or osteoarthritis (OA) were studied in parallel with the levels of these factors in blood and synovial fluid from patients with RA and from healthy controls. Correlation studies were also performed comparing the levels of neuropeptides with those of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)]. Furthermore, the impact of anti-TNF treatment on the levels of BDNF in blood was investigated. In a murine model of RA, the expression of these substances on articular chondrocytes along with their expression in synovial tissue was investigated.

    The expression of BN/GRP in human synovial tissue was confined to fibroblast-like and mononuclear-like cells whereas SP was detected in nerve-related structures. Receptors for these neuropeptides (GRP-R and NK-1R) were frequently present in blood vessel walls, and on fibroblast-like and mononuclear-like cells. The expression of BDNF and its receptors, p75 neurotrophin receptor and TrkB, was mainly confined to nerve structures. The levels of SP, and particularly those of BN/GRP, in synovial fluid and peripheral blood correlated with the levels of pro-inflammatory cytokines. There were clearly more correlations between SP-BN/GRP and inflammatory parameters than between BDNF and these factors. Plasma levels of BDNF were decreased following anti-TNF-treatment. In the joints of the murine model, there was a marked expression of neurotrophins, neurotrophin receptors and NK-1R/GRP-R in the articular chondrocytes. The expression was down-regulated in the arthritic animals. A neurotrophin system was found to develop in the inflammatory infiltrates of the synovium in the arthritic mice.

    The results presented suggest that there is a local, and not nerve-related, supply of BN/GRP in the human synovial tissue. Furthermore, BN/GRP and SP have marked effects in the synovial tissue of patients with RA, i.e., there were abundant receptor expressions, and these neuropeptides are, together with cytokines, likely to be involved in the neuro-immunomodulation that occurs in arthritis. The observations do on the whole suggest that the neuropeptides, rather than BDNF, are related to inflammatory processes in the human knee joint. A new effect of anti-TNF treatment; i.e., lowering plasma levels of BDNF, was observed. Severe arthritis, as in the murine model, lead to a decrease in the levels of neurotrophin, and neurotrophin and neuropeptide receptor expressions in the articular cartilage. This fact might be a drawback for the function of the chondrocytes. Certain differences between the expression patterns in the synovial tissue of the murine model and those of human arthritic synovial tissue were noted. It is obvious that local productions in the synovial tissue, nerve-related supply in this tissue and productions in chondrocytes to different extents occur for the investigated substances.

  • 243. Grong, Eivind
    et al.
    Kulseng, Bård
    Arbo, Ingerid Brænne
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mårvik, Ronald
    Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography2016Inngår i: Surgical Endoscopy, ISSN 0930-2794, E-ISSN 1432-2218, Vol. 30, nr 2, s. 532-542Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background In type 2 diabetes mellitus, there is a progressive loss of beta-cell mass. Bariatric surgery has in recent investigations showed promising results in terms of diabetes remission, but little is established regarding the effect of surgery on the survival or regeneration of pancreatic beta-cells. In this study, we aim to explore how bariatric surgery with its subsequent hormonal alterations affects the islets of Langerhans.

    Methods Twenty-four Goto-Kakizaki rats were operated with duodenojejunostomy (DJ), sleeve gastrectomy (SG) or sham operation. From the 38th week after surgery, body weight, fasting blood glucose, glycosylated hemoglobin, mixed meal tolerance with repeated measures of insulin, glucagon-like peptide 1, gastrin and total ghrelin were evaluated. Forty-six weeks after surgery, the animals were euthanized and the total beta-cell mass in all animals was examined by three-dimensional volume quantification by optical projection tomography based on the signal from insulin-specific antibody staining.

    Results Body weight did not differ between groups (Pg = 0.37). SG showed lower fasting blood glucose compared to DJ and sham (Pg = 0.037); HbA1c levels in SG were lower compared to DJ only (p\0.05). GLP-1 levels were elevated for DJ compared to SG and sham (Pg = 0.001), whereas gastrin levels were higher in SG compared to the two other groups (Pg = 0.002). Beta-cell mass was significantly greater in animals operated with SG compared to both DJ and sham (p = 0.036).

    Conclusion Sleeve gastrectomy is superior to duodenojejunostomy and sham operation when comparing the preservation of beta-cell mass 46 weeks after surgery in Goto-Kakizaki rats. This could be related to both the increased gastrin levels and the long-term improvement in glycemic parameters observed after this procedure.

  • 244.
    Grubbström, Olivia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Biomedicinprogrammet.
    In vitro study of drugs against mammalian ribonucleotide reductase2014Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 245.
    Grundström, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Is DNA polymerase ε a new driver in cancer development?: Functional studies of cancer associated mutations2015Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 246.
    Grundström, Thomas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Hauser, Jannek
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Grundström, Christine
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Kumar, Ramesh
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ahmed, Tanzeel
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Mechanisms controlling diversification and affinity maturation of antibodies2015Inngår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 36, s. S43-S43Artikkel i tidsskrift (Annet vitenskapelig)
  • 247.
    Gu, Weigang
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rosqvist, Roland
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wester, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Cell division in the cerebral cortex of adult rats after photothrombotic ring stroke.2009Inngår i: Stem Cell Research, ISSN 1876-7753, Vol. 2, nr 1, s. 68-77Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurogenesis has been shown to occur in the cerebral cortex in adult rats after ischemic stroke. The origin of the newborn neurons is largely unknown. This study aimed to explore cell division in the poststroke penumbral cortex. Adult male Wistar rats were subjected to photothrombotic ring stroke. After repeated delivery of the DNA duplication marker BrdU, the animals were sacrificed at various times poststroke. BrdU was detected by immunohistochemistry/immunofluorescence labeling, as was the M-phase marker Phos H3 and the spindle components alpha-tubulin/gamma-tubulin. DNA damage was examined by TUNEL staining. Cell type was ascertained by double immunolabeling with the neuronal markers Map-2ab/beta-tubulin III and NeuN/Hu or the astrocyte marker GFAP. From 16h poststroke, BrdU-immunolabeled cells appeared in the penumbral cortex. From 24h, Phos H3 was colocalized with BrdU in the nuclei. Mitotic spindles immunolabeled by alpha-tubulin/gamma-tubulin appeared inside the cortical cells containing BrdU-immunopositive nuclei. Unexpectedly, the markers of neuronal differentiation, Map-2ab/beta-tubulin III/NeuN/Hu, were expressed in the Phos H3-immunolabeled cells, and NeuN was detected in some cells containing spindles. This study suggests that in response to a sublethal ischemic insult, endogenous cells with neuronal immunolabeling may duplicate their nuclear DNA and commit cell mitosis to generate daughter neurons in the penumbral cortex in adult rats.

  • 248.
    Gu, Xiaolian
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    p63 and epithelial homeostasis: studies of p63 under normal, hyper-proliferative and malignant conditions2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: The p63 gene is a member of the p53 transcription factor family and can produce six different proteins using two promoters and differential splicing. Expression of p63 is required for proper formation of epithelial tissues. Studies on the transcriptional control of specific genes involved in cell survival, proliferation, differentiation and adhesion have revealed the contributions of p63 to the continuously renewing stratified epithelium. In this thesis, the aim was to improve our understanding of the roles of p63 in epithelial homeostasis by investigating expression of p63 in normal and benign hyper-proliferative epithelia and exploring the influence of p63 deregulation on cancer progression.

    Materials and methods: Using quantitative real time RT-PCR and immunohistochemistry, we first examined the expression of different p63 isoforms in patients diagnosed with psoriasis - a benign hyper-proliferative and inflammatory skin disease. Afterwards, we investigated responses of p63 in psoriatic epidermis upon Narrowband-UVB (NB-UVB) phototherapy. At the same time, we studied the potential impact of p63 in carcinogenesis by searching for p63 transcriptional targets in a cell line derived from squamous cell carcinoma of the head and neck (SCCHN) - the sixth most common cancer worldwide with over-expression of the ∆Np63α protein as a common feature. p63 gene silencing and microarray were used to identify p63 regulated genes. Real time RT-PCR, western blot, immunohistochemistry, chromatin immunoprecipitation, transient transfection and reporter assays were performed to confirm specific genes as direct p63 targets.

    Results: Significant down-regulation of p63 mRNA levels was found in psoriatic lesions compared to patients’ own clinically normal skin. Moreover, a trend of decreased TAp63 mRNA levels was seen in patients’ normal skin compared to age- and sex-matched healthy controls. Following NB-UVB phototherapy, an effective first line therapy for psoriasis, expression of p63 was not significantly affected. However, significant changes in p53, FABP5, miR-21 and miR-125b were found. Surprisingly, location and expression levels of p63 proteins detected by immunohistochemistry were similar under all skin conditions. A direct transcriptional regulation of TRAF4 by p63 was seen in the SCCHN cell line and we further found that the localization of the TRAF4 protein was associated with histological differentiation of SCCHN cells. However, unlike its over-expression in SCCHN, similar TRAF4 mRNA expression levels were seen in psoriatic lesions as compared to healthy controls. Besides TRAF4, a total of 127 genes were identified as potentially p63 regulated in the SCCHN cell line and strikingly, about 20% of these genes are involved in cell adhesion or migration.

    Conclusions: Dysregulation of p63 isoforms in psoriatic epidermis, especially decreased TAp63 expression, and their resistance to NB-UVB phototherapy implicated a contribution of p63 to the psoriasis phenotype. Transcriptional regulation of genes involved in multiple biological pathways indicated that over-expression of p63 in SCCHN might account for altered cell differentiation, adhesion and migration, thus contributing to SCCHN. In conclusion, our studies have found additional mechanisms through which p63 guarded homeostasis of the established epithelium. Deregulation of p63 might play a role in distinct pathological conditions by participating in diverse cellular pathways under different microenvironments.

  • 249.
    Gu, Xiaolian
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip J
    Boldrup, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    p63 contributes to cell invasion and migration in squamous cell carcinoma of the head and neck2008Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 263, nr 1, s. 26-34Artikkel i tidsskrift (Fagfellevurdert)
  • 250.
    Gu, Xiaolian
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip
    MacCallum, Stephanie
    Boldrup, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Sjöström, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN2007Inngår i: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 6, nr 12, s. 1979-1983Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    p63, a member of the p53 family, is overexpressed in squamous cell carcinoma of the head and neck (SCCHN) and some other tumors of epithelial origin. As a transcription factor, p63 can bind to p53-type response elements and there is some overlap between p53 family transcriptional targets. Tumor necrosis factor receptor associated factor 4 (TRAF4) is a p53 regulated gene which is overexpressed in many human carcinomas. We investigated the involvement of p63 in regulation of TRAF4 and the expression of the TRAF4 protein in SCCHN. Disrupting endogenous p63 expression resulted in downregulation of TRAF4 mRNA and protein in an SCCHN cell line. Endogenous p63 bound to the TRAF4 promoter in vivo and reporter assays showed that p63, p73 and p53 can all transactivate TRAF4, with TAp63 isoforms being the most potent activators. The level of TRAF4 activation by TAp63 was two-fold higher than by p53, and TRAF4 was ten-fold more responsive to TAp63 than another p63-target, IGFBP3. Nuclear expression of TRAF4 was seen in normal oral epithelium and highly/moderately differentiated SCCHN, whereas cytoplasmic expression of TRAF4 was seen in poorly differentiated SCCHN. These results indicate that TRAF4 is a common target of p53 family members and that localization of TRAF4 is associated with differentiation of SCCHN cells.

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