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  • 1.
    Abu-Siniyeh, Ahmed
    et al.
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Owen, Dylan M.
    Kings Coll London, Dept Phys, London WC2R 2LS, England.;Kings Coll London, Randall Div Cell & Mol Biophys, London WC2R 2LS, England..
    Benzing, Carola
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Rinkwitz, Silke
    Becker, Thomas S.
    Univ Sydney, Brain & Mind Res Inst, Sydney Med Sch, Sydney, NSW 2006, Australia.;Univ Sydney, Dept Hlth Sci, Sydney, NSW 2006, Australia..
    Majumdar, Arindam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Gaus, Katharina
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis2016Ingår i: Traffic: the International Journal of Intracellular Transport, ISSN 1398-9219, E-ISSN 1600-0854, Vol. 17, nr 1, s. 66-79Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The differential distribution of lipids between apical and basolateral membranes is necessary for many epithelial cell functions, but how this characteristic membrane organization is integrated within the polarity network during ductal organ development is poorly understood. Here we quantified membrane order in the gut, kidney and liver ductal epithelia in zebrafish larvae at 3-11 days post fertilization (dpf) with Laurdan 2-photon microscopy. We then applied a combination of Laurdan imaging, antisense knock-down and analysis of polarity markers to understand the relationship between membrane order and apical-basal polarity. We found a reciprocal relationship between membrane order and the cell polarity network. Reducing membrane condensation by exogenously added oxysterol or depletion of cholesterol reduced apical targeting of the polarity protein, aPKC. Conversely, using morpholino knock down in zebrafish, we found that membrane order was dependent upon the Crb3 and Par3 polarity protein expression in ductal epithelia. Hence our data suggest that the biophysical property of membrane lipid packing is a regulatory element in apical basal polarity.

  • 2.
    Adler, J
    et al.
    Stockholms universitet, Wenner-Grens institut för experimentell biologi.
    Pagakis, S N
    Parmryd, I
    Stockholms universitet, Wenner-Grens institut för experimentell biologi.
    Replicate-based noise corrected correlation for accurate measurements of colocalization.2008Ingår i: Journal of Microscopy, ISSN 0022-2720, E-ISSN 1365-2818, Vol. 230, nr Pt 1, s. 121-33Artikel i tidskrift (Refereegranskat)
  • 3.
    Adler, Jeremy
    et al.
    Stockholms universitet, Wenner-Grens institut för experimentell biologi.
    Parmryd, Ingela
    Stockholms universitet, Wenner-Grens institut för experimentell biologi.
    In support of the Pearson correlation coefficient.2007Ingår i: Journal of Microscopy, Vol. 227, nr Pt 1, s. 83; author reply 84-5Artikel i tidskrift (Övrigt vetenskapligt)
  • 4.
    Adler, Jeremy
    et al.
    Stockholms universitet, Wenner-Grens institut.
    Parmryd, Ingela
    Stockholms universitet, Wenner-Grens institut.
    Quantifying Colocalization by Correlation: The Pearson Correlation Coefficient is Superior to the Mander's Overlap Coefficient2010Ingår i: CYTOMETRY PART A, ISSN 1552-4922, Vol. 77A, nr 8, s. 733-742Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Pearson correlation coefficient (PCC) and the Mander's overlap coefficient (MOC) are used to quantify the degree of colocalization between fluorophores. The MOC was introduced to overcome perceived problems with the PCC. The two coefficients are mathematically similar, differing in the use of either the absolute intensities (MOC) or of the deviation from the mean (PCC). A range of correlated datasets, which extend to the limits of the PCC, only evoked a limited response from the MOC. The PCC is unaffected by changes to the offset while the MOC increases when the offset is positive. Both coefficients are independent of gain. The MOC is a confusing hybrid measurement, that combines correlation with a heavily weighted form of co-occurrence, favors high intensity combinations, downplays combinations in which either or both intensities are low and ignores blank pixels. The PCC only measures correlation. A surprising finding was that the addition of a second uncorrelated population can substantially increase the measured correlation, demonstrating the importance of excluding background pixels. Overall, since the MOC is unresponsive to substantial changes in the data and is hard to interpret, it is neither an alternative to nor a useful substitute for the PCC. The MOC is not suitable for making measurements of colocalization either by correlation or co-occurrence.

  • 5.
    Adler, Jeremy
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Parmryd, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Quantifying colocalization: thresholding, void voxels and the H-coef2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, s. e111983-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A critical step in the analysis of images is identifying the area of interest e.g. nuclei. When the nuclei are brighter than the remainder of the image an intensity can be chosen to identify the nuclei. Intensity thresholding is complicated by variations in the intensity of individual nuclei and their intensity relative to their surroundings. To compensate thresholds can be based on local rather than global intensities. By testing local thresholding methods we found that the local mean performed poorly while the Phansalkar method and a new method based on identifying the local background were superior. A new colocalization coefficient, the Hcoef, highlights a number of controversial issues. (i) Are molecular interactions measurable (ii) whether to include voxels without fluorophores in calculations, and (iii) the meaning of negative correlations. Negative correlations can arise biologically (a) because the two fluorophores are in different places or (b) when high intensities of one fluorophore coincide with low intensities of a second. The cases are distinct and we argue that it is only relevant to measure correlation using pixels that contain both fluorophores and, when the fluorophores are in different places, to just report the lack of co-occurrence and omit these uninformative negative correlation. The Hcoef could report molecular interactions in a homogenous medium. But biology is not homogenous and distributions also reflect physico-chemical properties, targeted delivery and retention. The Hcoef actually measures a mix of correlation and co-occurrence, which makes its interpretation problematic and in the absence of a convincing demonstration we advise caution, favouring separate measurements of correlation and of co-occurrence.

  • 6. Adler, Jeremy
    et al.
    Shevchuk, Andrew I
    Novak, Pavel
    Korchev, Yuri E
    Parmryd, Ingela
    Plasma membrane topography and interpretation of single-particle tracks.2010Ingår i: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 7, nr 3, s. 170-1Artikel i tidskrift (Refereegranskat)
  • 7.
    Agarwal, Prasoon
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Teichmann, Martin
    Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux 2, rue , Robert Escarpit, 33607 Pessac, France..
    Jernberg Wiklund, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Smit, Arian
    Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Singh, Umashankar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs2016Ingår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, nr 12, s. 1558-1571Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

  • 8. Ahmed, Saheeb
    et al.
    Wittenmayer, Nina
    Kremer, Thomas
    Hoeber, Jan
    Kiran Akula, Asha
    Urlaub, Henning
    Islinger, Markus
    Kirsch, Joachim
    Dean, Camin
    Dresbach, Thomas
    Mover is a homomeric phospho-protein present on synaptic vesicles2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, s. e63474-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    With remarkably few exceptions, the molecules mediating synaptic vesicle exocytosis at active zones are structurally and functionally conserved between vertebrates and invertebrates. Mover was found in a yeast-2-hybrid assay using the vertebrate-specific active zone scaffolding protein bassoon as a bait. Peptides of Mover have been reported in proteomics screens for self-interacting proteins, phosphorylated proteins, and synaptic vesicle proteins, respectively. Here, we tested the predictions arising from these screens. Using flotation assays, carbonate stripping of peripheral membrane proteins, mass spectrometry, immunogold labelling of purified synaptic vesicles, and immuno-organelle isolation, we found that Mover is indeed a peripheral synaptic vesicle membrane protein. In addition, by generating an antibody against phosphorylated Mover and Western blot analysis of fractionated rat brain, we found that Mover is a bona fide phospho-protein. The localization of Mover to synaptic vesicles is phosphorylation dependent; treatment with a phosphatase caused Mover to dissociate from synaptic vesicles. A yeast-2-hybrid screen, co-immunoprecipitation and cell-based optical assays of homomerization revealed that Mover undergoes homophilic interaction, and regions within both the N- and C- terminus of the protein are required for this interaction. Deleting a region required for homomeric interaction abolished presynaptic targeting of recombinant Mover in cultured neurons. Together, these data prove that Mover is associated with synaptic vesicles, and implicate phosphorylation and multimerization in targeting of Mover to synaptic vesicles and presynaptic sites.

  • 9. Alizadehheidari, Mohammadreza
    et al.
    Werner, Erik
    Noble, Charleston
    Reiter-Schad, Michaela
    Nyberg, Lena K.
    Fritzsche, Joachim
    Mehlig, Bernhard
    Tegenfeldt, Jonas O.
    Ambjornsson, Tobias
    Persson, Fredrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Westerlund, Fredrik
    Nanoconfined Circular and Linear DNA: Equilibrium Conformations and Unfolding Kinetics2015Ingår i: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 48, nr 3, s. 871-878Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Studies of circular DNA confined to nanofluidic channels are relevant both from a fundamental polymer-physics perspective and due to the importance of circular DNA molecules in vivo. We here observe the unfolding of confined DNA from the circular to linear configuration as a light-induced double-strand break occurs, characterize the dynamics, and compare the equilibrium conformational statistics of linear and circular configurations. This is important because it allows us to determine to what extent existing statistical theories describe the extension of confined circular DNA. We find that the ratio of the extensions of confined linear and circular DNA configurations increases as the buffer concentration decreases. The experimental results fall between theoretical predictions for the extended de Gennes regime at weaker confinement and the Odijk regime at stronger confinement. We show that it is possible to directly distinguish between circular and linear DNA molecules by measuring the emission intensity from the DNA. Finally, we determine the rate of unfolding and show that this rate is larger for more confined DNA, possibly reflecting the corresponding larger difference in entropy between the circular and linear configurations.

  • 10.
    Andersson, Marie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Cellular transport and secretion of the cyanobacterial neurotoxin BMAA into milk and egg: Implications for developmental neurotoxicity2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA) is a neurotoxin implicated in the etiology of neurodegenerative diseases. Cyanobacteria are cosmopolitan organisms present in various environments. BMAA can cause long-term neurodegenerative alterations in rats exposed during the neonatal period, a period that corresponds to the last trimester and the first few years of life in humans. As BMAA has been reported to be bioaccumulated in the aquatic food chain and detected in mussels, crayfish and fish used for human consumption, the main aim of this thesis has been to investigate the final step in the mammalian food-chain, i.e. the transfer of BMAA into breast milk.

    Autoradiographic imaging and mass spectrometry analysis showed an enantiomer-selective uptake of BMAA and that the neurotoxin was transferred from lactating mice and rat, via the milk, to the brain of the nursed pups. The results show that transport of BMAA may be disproportional to dose. In addition, BMAA was found present both as free amino acid and tightly associated to proteins in rat brains. Surprisingly, however, no association to milk proteins was found. In vitro studies of murine (HC11) and human (MCF7) mammary epithelial cells suggest that BMAA can pass the human mammary epithelium into milk. Additional transport studies on human intestinal, glioblastoma and neuroblastoma cells showed that L-BMAA was consistently favored over D-BMAA and that the transport was mediated by several amino acid transporters. We also demonstrated that egg-laying quail transfer BMAA to its offspring by deposition in the eggs, particularly in the yolk but also in the albumen. Furthermore, comparative analysis of carboxyl- and methyl-labeled [14C]-BMAA suggested that BMAA was not metabolized to a large degree.

    Altogether, the results indicate that BMAA can be transferred from mothers, via the milk, to the brain of nursed human infants. Determinations of BMAA in mothers’ milk and cows’ milk are therefore warranted. We also propose that birds’ eggs could be an additional source of BMAA exposure in humans. It might therefore be of concern that mussels are increasingly used as feed in commercial egg production.

    Delarbeten
    1. Maternal Transfer of the Cyanobacterial Neurotoxin beta-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring
    Öppna denna publikation i ny flik eller fönster >>Maternal Transfer of the Cyanobacterial Neurotoxin beta-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring
    Visa övriga...
    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 10, s. e78133-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The cyanobacterial neurotoxin beta-N-methylamino-L-alanine (BMAA) has been implicated in the etiology of neurodegenerative disease and proposed to be biomagnified in terrestrial and aquatic food chains. We have previously shown that the neonatal period in rats, which in humans corresponds to the last trimester of pregnancy and the first few years of age, is a particularly sensitive period for exposure to BMAA. The present study aimed to examine the secretion of C-14-labeled L-and D-BMAA into milk in lactating mice and the subsequent transfer of BMAA into the developing brain. The results suggest that secretion into milk is an important elimination pathway of BMAA in lactating mothers and an efficient exposure route predominantly for L-BMAA but also for D-BMAA in suckling mice. Following secretion of [C-14] L-BMAA into milk, the levels of [C-14] L-BMAA in the brains of the suckling neonatal mice significantly exceeded the levels in the maternal brains. In vitro studies using the mouse mammary epithelial HC11 cell line confirmed a more efficient influx and efflux of L-BMAA than of D-BMAA in cells, suggesting enantiomer-selective transport. Competition experiments with other amino acids and a low sodium dependency of the influx suggests that the amino acid transporters LAT1 and LAT2 are involved in the transport of L-BMAA into milk. Given the persistent neurodevelopmental toxicity following injection of L-BMAA to neonatal rodent pups, the current results highlight the need to determine whether BMAA is enriched mother's and cow's milk.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-211448 (URN)10.1371/journal.pone.0078133 (DOI)000326037000089 ()
    Tillgänglig från: 2013-11-27 Skapad: 2013-11-25 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    2. Transfer of developmental neurotoxin beta-N-methylamino-L-alanine (BMAA) via milk to nursed offspring: Studies by mass spectrometry and image analysis
    Öppna denna publikation i ny flik eller fönster >>Transfer of developmental neurotoxin beta-N-methylamino-L-alanine (BMAA) via milk to nursed offspring: Studies by mass spectrometry and image analysis
    2016 (Engelska)Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, s. 108-114Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The cyanobacterial non-proteinogenic amino acid beta-N-methylamino-L-alanine (BMAA) is proposed to be involved in the etiology of amyotrophic lateral sclerosis/parkinsonism dementia complex. When administered as single doses to neonatal rats, BMAA gives rise to cognitive and neurodegenerative impairments in the adult animal. Here, we employed mass spectrometry (LC-MS/MS) and autoradiographic imaging to examine the mother-to-pup transfer of BMAA in rats. The results show that unchanged BMAA was secreted into the milk and distributed to the suckling pups. The concentration of BMAA in pup stomach milk and the neonatal liver peaked after 8 h, while the concentration in the pup brain increased throughout the study period. About 1 and 6% of the BMAA recovered from adult liver and brain were released following hydrolysis, suggesting that this fraction was associated with protein. No association to milk protein was observed. Injection of rat pups with [methyl-C-14]-L-BMAA or [carboxyl-C-14]-L-BMAA resulted in highly similar distribution patterns, indicating no or low metabolic elimination of the methylamino- or carboxyl groups. In conclusion, BMAA is transported as a free amino acid to rat milk and suckling pups. The results strengthen the proposal that mothers' milk could be a source of exposure for BMAA in human infants. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

    Nyckelord
    BMAA; Cyanobacterial neurotoxin, kinetics; Milk secretion; Developmental neurotoxicity; Mother-to-offspring transfer
    Nationell ämneskategori
    Utvecklingsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-265847 (URN)10.1016/j.toxlet.2016.06.015 (DOI)000381648300012 ()27320960 (PubMedID)
    Projekt
    Milk, secretion, BMAA, beta-N-methylamino-L-alanine, autoradiography, mass spectrometry
    Forskningsfinansiär
    Forskningsrådet Formas
    Tillgänglig från: 2015-11-03 Skapad: 2015-11-03 Senast uppdaterad: 2017-05-12Bibliografiskt granskad
    3. Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines
    Öppna denna publikation i ny flik eller fönster >>Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines
    2017 (Engelska)Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 320, s. 40-50Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    β-N-methylamino-alanine (BMAA) is a non-protein amino acid produced by cyanobacteria, diatoms and dinoflagellates. BMAA has potential to biomagnify in a terrestrial food chain, and to bioaccumulate in fish and shellfish. We have reported that administration of [14C]l-BMAA to lactating mice and rats results in a mother to off-spring transfer via the milk. A preferential enantiomer-specific uptake of [14C]l-BMAA has also been demonstrated in differentiated murine mammary epithelium HC11 cells. These findings, together with neurotoxic effects of BMAA demonstrated both in vitro and in vivo, highlight the need to determine whether such transfer could also occur in humans. Here, we used four cell lines of human origin to examine and compare the transport of the two BMAA enantiomers in vitro. The uptake patterns of [14C]l- and [14C]d-BMAA in the human mammary MCF7 cell line were in agreement with the results in murine HC11 cells, suggesting a potential secretion of BMAA into human breast milk. The permeability coefficients for both [14C]l- and [14C]d-BMAA over monolayers of human intestinal Caco2 cells supported an efficient absorption from the human intestine. As a final step, transport experiments confirmed that [14C]l-and [14C]d-BMAA can be taken up by human SHSY5Y neuroblastoma cells and even more efficiently by human U343 glioblastoma cells. In competition experiments with various amino acids, the ASCT2 specific inhibitor benzylserine was the most effective inhibitor of [14C]l-BMAA uptake tested here. Altogether, our results suggest that BMAA can be transferred from an exposed mother, via the milk, to the brain of the nursed infant.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2017
    Nyckelord
    BMAA, Cellular transport, Amino acid transporters, Breast milk, Neurodegeneration
    Nationell ämneskategori
    Cellbiologi Utvecklingsbiologi
    Forskningsämne
    Biologi med inriktning mot ekotoxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-265857 (URN)10.1016/j.taap.2017.02.004 (DOI)000396798200006 ()28174119 (PubMedID)
    Forskningsfinansiär
    Forskningsrådet Formas
    Tillgänglig från: 2015-11-03 Skapad: 2015-11-03 Senast uppdaterad: 2017-05-02Bibliografiskt granskad
    4. Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats
    Öppna denna publikation i ny flik eller fönster >>Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats
    Visa övriga...
    2014 (Engelska)Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 226, nr 1, s. 1-5Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is not an amino acid that is normally found in proteins. Our previous autoradiographic study of H-3-labeled BMAA in adult mice unexpectedly revealed a tissue distribution similar to that of protein amino acids. The aim of this study was to characterize the distribution of free and protein-bound BMAA in neonatal rat tissues following a short exposure using autoradiographic imaging and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The autoradiographic imaging of C-14-L-BMAA demonstrated a distinct uptake of radioactivity that was retained following acid extraction in tissues with a high rate of cell turnover and/or protein synthesis. The UHPLC-MS/MS analysis conclusively demonstrated a dose-dependent increase of protein-associated BMAA in neonatal rat tissues. The level of protein-associated BMAA in the liver was more than 10 times higher than that in brain regions not fully protected by the blood-brain barrier which may be due to the higher rate of protein synthesis in the liver. In conclusion, this study demonstrated that BMAA was associated with rat proteins suggesting that BMAA may be mis-incorporated into proteins. However, protein-associated BMAA seemed to be cleared over time, as none of the samples from adult rats had any detectable free or protein-associated BMAA.

    Nyckelord
    ALS/PDC, Cyanobacteria, Autoradiography, Mass spectrometry, Misincorporation, N-(2-aminoethyl) glycine
    Nationell ämneskategori
    Medicin och hälsovetenskap Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-222718 (URN)10.1016/j.toxlet.2014.01.027 (DOI)000332409000001 ()24472610 (PubMedID)
    Forskningsfinansiär
    Forskningsrådet Formas
    Tillgänglig från: 2014-04-17 Skapad: 2014-04-14 Senast uppdaterad: 2017-06-30Bibliografiskt granskad
    5. Deposition of cyanobacterial neurotoxin beta-N-methylamino-L-alanine (L-BMAA) in birds' egg: A potential source of BMAA exposure in humans
    Öppna denna publikation i ny flik eller fönster >>Deposition of cyanobacterial neurotoxin beta-N-methylamino-L-alanine (L-BMAA) in birds' egg: A potential source of BMAA exposure in humans
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    BMAA, beta-N-methylamino-L-alanine, quail, metabolism, autoradiography
    Nationell ämneskategori
    Utvecklingsbiologi
    Forskningsämne
    Biologi med inriktning mot ekotoxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-265859 (URN)
    Forskningsfinansiär
    Forskningsrådet Formas
    Tillgänglig från: 2015-11-03 Skapad: 2015-11-03 Senast uppdaterad: 2016-01-13
  • 11.
    Andersson, Marie
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Ersson, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Bergström, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines2017Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 320, s. 40-50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    β-N-methylamino-alanine (BMAA) is a non-protein amino acid produced by cyanobacteria, diatoms and dinoflagellates. BMAA has potential to biomagnify in a terrestrial food chain, and to bioaccumulate in fish and shellfish. We have reported that administration of [14C]l-BMAA to lactating mice and rats results in a mother to off-spring transfer via the milk. A preferential enantiomer-specific uptake of [14C]l-BMAA has also been demonstrated in differentiated murine mammary epithelium HC11 cells. These findings, together with neurotoxic effects of BMAA demonstrated both in vitro and in vivo, highlight the need to determine whether such transfer could also occur in humans. Here, we used four cell lines of human origin to examine and compare the transport of the two BMAA enantiomers in vitro. The uptake patterns of [14C]l- and [14C]d-BMAA in the human mammary MCF7 cell line were in agreement with the results in murine HC11 cells, suggesting a potential secretion of BMAA into human breast milk. The permeability coefficients for both [14C]l- and [14C]d-BMAA over monolayers of human intestinal Caco2 cells supported an efficient absorption from the human intestine. As a final step, transport experiments confirmed that [14C]l-and [14C]d-BMAA can be taken up by human SHSY5Y neuroblastoma cells and even more efficiently by human U343 glioblastoma cells. In competition experiments with various amino acids, the ASCT2 specific inhibitor benzylserine was the most effective inhibitor of [14C]l-BMAA uptake tested here. Altogether, our results suggest that BMAA can be transferred from an exposed mother, via the milk, to the brain of the nursed infant.

  • 12.
    Andersson, Marie
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Karlsson, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Brittebo, Eva B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Correction: Maternal Transfer of the Cyanobacterial Neurotoxin β-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 10, artikel-id e78133Artikel i tidskrift (Refereegranskat)
  • 13.
    Ashrafzadeh, Parham
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Parmryd, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Methods applicable to membrane nanodomain studies?2015Ingår i: Essays in Biochemistry, ISSN 0071-1365, E-ISSN 1744-1358, Vol. 57, s. 57-68Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Membrane nanodomains are dynamic liquid entities surrounded by another type of dynamic liquid. Diffusion can take place inside, around and in and out of the domains, and membrane components therefore continuously shift between domains and their surroundings. In the plasma membrane, there is the further complexity of links between membrane lipids and proteins both to the extracellular matrix and to intracellular proteins such as actin filaments. In addition, new membrane components are continuously delivered and old ones removed. On top of this, cells move. Taking all of this into account imposes great methodological challenges, and in the present chapter we discuss some methods that are currently used for membrane nanodomain studies, what information they can provide and their weaknesses.

  • 14.
    Bahram, Fuad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    VEGF-mediated signal transduction in lymphatic endothelial cells2010Ingår i: Pathophysiology : the official journal of the International Society for Pathophysiology / ISP, ISSN 0928-4680, Vol. 17, nr 4, s. 253-261Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The VEGF family of angiogenic ligands consists of VEGFA, VEGFB, VEGFC, VEGFD and placenta growth factor, PlGF. These growth factors bind in an overlapping pattern to three receptor tyrosine kinases, denoted VEGFR1, VEGFR2 and VEGFR3. Originally, VEGFA (the prototype VEGF) was described as a master regulator of vascular endothelial cell biology in vitro and in vivo, transducing its effect through VEGFR2. VEGFA, VEGFB and PlGF bind to VEGFR1, which is a negative regulator of endothelial cell function at least during embryogenesis. VEGFC and VEGFD were identified as lymphatic endothelial factors, acting via VEGFR3. With time, the very clear distinction between the roles of the VEGF ligands in angiogenesis/lymphangiogenesis has given way for a more complex pattern. It seems that the biology of the different VEGFR2 and VEGFR3 ligands overlaps quite extensively and that both receptor types contribute to angiogenesis as well as lymphangiogenesis. This paradigm shift in our understanding is due to the access to more sophisticated reagents and techniques revealing dynamic and plastic expression of ligands and receptors in different physiological and pathological conditions. Moreover, knowledge on the important role of VEGF coreceptors, the neuropilins, in regulating the responsiveness to VEGF has changed our perception on the mechanism of VEGF signal transduction. This review will primarily focus on the properties of VEGR3, its signal transduction and the resulting biology.

  • 15. Baltscheffsky, Herrick
    et al.
    Persson, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    On an Early Gene for Membrane-Integral Inorganic Pyrophosphatase in the Genome of an Apparently Pre-LUCA Extremophile, the Archaeon Candidatus Korarchaeum cryptofilum2014Ingår i: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 78, nr 2, s. 140-147Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A gene for membrane-integral inorganic pyrophosphatase (miPPase) was found in the composite genome of the extremophile archaeon Candidatus Korarchaeum cryptofilum (CKc). This korarchaeal genome shows unusual partial similarity to both major archaeal phyla Crenarchaeota and Euryarchaeota. Thus this Korarchaeote might have retained features that represent an ancestral archaeal form, existing before the occurrence of the evolutionary bifurcation into Crenarchaeota and Euryarchaeota. In addition, CKc lacks five genes that are common to early genomes at the LUCA border. These two properties independently suggest a pre-LUCA evolutionary position of this extremophile. Our finding of the miPPase gene in the CKc genome points to a role for the enzyme in the energy conversion of this very early archaeon. The structural features of its miPPase indicate that it can pump protons through membranes. An miPPase from the extremophile bacterium Caldicellulosiruptor saccharolyticus also has a sequence indicating a proton pump. Recent analysis of the three-dimensional structure of the miPPase from Vigna radiata has resulted in the recognition of a strongly acidic substrate (orthophosphate: Pi, pyrophosphate: PPi) binding pocket, containing 11 Asp and one Glu residues. Asp (aspartic acid) is an evolutionarily very early proteinaceous amino acid as compared to the later appearing Glu (glutamic acid). All the Asp residues are conserved in the miPPase of CKc, V. radiata and other miPPases. The high proportion of Asp, as compared to Glu, seems to strengthen our argument that biological energy conversion with binding and activities of orthophosphate (Pi) and energy-rich pyrophosphate (PPi) in connection with the origin and early evolution of life may have started with similar or even more primitive acidic peptide funnels and/or pockets.

  • 16.
    Barg, Sebastian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gandasi, Nikhil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Quantitative analysis of t-SNARE and Ca2+-channel clusters near secretory granules2010Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 53, nr Suppl. 1, s. S46-S46Artikel i tidskrift (Övrigt vetenskapligt)
  • 17.
    Barg, Sebastian
    et al.
    Department of Physiological Sciences, Lund University, Lund.
    Huang, Ping
    University of Chicago, Department of Neurobiology, Pharmacology and Physiology, Chicago.
    Eliasson, Lena
    Department of Physiological Sciences, Lund University, Lund.
    Nelson, Deborah J
    University of Chicago, Department of Neurobiology, Pharmacology and Physiology, Chicago.
    Obermüller, Stefanie
    Department of Physiological Sciences, Lund University, Lund.
    Rorsman, Patrik
    Department of Physiological Sciences, Lund University, Lund.
    Thévenod, Frank
    Physiologisches Institut, Universität des Saarlandes, Homburg/Saar.
    Renström, Erik
    Department of Physiological Sciences, Lund University, Lund.
    Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification2001Ingår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 114, nr Pt 11, s. 2145-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ATP-dependent priming of the secretory granules precedes Ca(2+)-regulated neuroendocrine secretion, but the exact nature of this reaction is not fully established in all secretory cell types. We have further investigated this reaction in the insulin-secreting pancreatic B-cell and demonstrate that granular acidification driven by a V-type H(+)-ATPase in the granular membrane is a decisive step in priming. This requires simultaneous Cl(-) uptake through granular ClC-3 Cl(-) channels. Accordingly, granule acidification and priming are inhibited by agents that prevent transgranular Cl(-) fluxes, such as 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and an antibody against the ClC-3 channels, but accelerated by increases in the intracellular ATP:ADP ratio or addition of hypoglycemic sulfonylureas. We suggest that this might represent an important mechanism for metabolic regulation of Ca(2+)-dependent exocytosis that is also likely to be operational in other secretory cell types.

  • 18. Bellomo, Claudia
    Fabregat, Isabel (Medarbetare/bidragsgivare)
    Mikulits, Wolfgang (Medarbetare/bidragsgivare)
    Kardassis, Dimitri
    Heldin, Carl-Henrik
    Moustakas, Aristidis
    Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinomaIngår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403Artikel i tidskrift (Refereegranskat)
  • 19.
    Bellomo, Claudia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    TGFβ and LXR signaling in hepatocellular carcinoma2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types in the Western world and in the Asia-pacific regions, with its incidence expected to rise up to 22 million cases till 2020. Hepatocellular carcinoma etiology is mainly due to hepatitis B (HBV) and hepatitis C (HCV) infections, and to a lesser extent it is determined by the development of alcohol-driven cirrhosis and non-alcoholic steatohepatitis (NASH). Furthermore, HCC is characterized by a high mortality rate, with poor prognostic expectance and limited therapeutic options currently available in the clinics.

    Transforming growth factor beta (TGFβ) is a pleiotropic cytokine with a janus-role in HCC and in other malignancies. TGFβ can in fact elicit either tumor-suppressive and tumor- promoting effects depending on tumor stage, microenvironmental and immunological cues. In HCC specifically, TGFβ determines cytostasis and cellular senescence during the first stages of tumor development, while it enhances HCC malignancy and progression in the later stages due to increased invasiveness, acquired resistance to cytostatic actions and tumor immunotolerance.

    Liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) are transcription factors of the nuclear hormone receptor family, which play an important role in oxysterol metabolism and reverse- cholesterol transport to the liver. Their involvement in malignancies has been studied so far to a limited extend, with evidence of both tumor-suppressive -via cytostatic mechanisms- and tumor- immunotolerance activities. Moreover, the potential crosstalk of LXR and TGFβ pathways has not been yet unraveled in the context of hepatocellular carcinoma.

    We have described (Paper I) a high-content imaging platform for the screening of small molecules able to revert the TGFβ-induced epithelial to mesenchymal transition (EMT) in human keratinocytes. This screening allowed us to identify LXR agonists as epithelial plasticity modulators in established terminally differentiated and mouse embryonic fibroblast, as well as in epithelial and mesenchymal HCC cell lines.

    We have identified (Paper II) the transcription factor SNAI1 (Snail) as the mediator of the crosstalk between TGFβ and LXRα pathways in epithelial and mesenchymal HCC cell models. LXRα activation diminishes the transcriptional induction of SNAI1 by TGFβ, thus antagonizing the induction of mesenchymal features and the production of reactive oxygen species by TGFβ. However, we have unraveled that LXRα and TGFβ signaling still positively interact in increasing cytostasis in HCC, in order to preserve liver epithelial features.

    We have described (Paper III) that LXRα activation counteracts the transcriptional induction of α smooth muscle actin (αSMA), a major hallmark of fibroblast activation, elicited by TGFβ in patient-derived primary liver fibroblasts.

    In conclusion, we herein report that the signaling crosstalk between TGFβ and LXRα pathways results in antagonistic effects either on parenchymal and fibroblast cell lines representative of the HCC disease, suggesting the potential future application of LXR agonists as clinical therapeutic options.

    Delarbeten
    1. Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
    Öppna denna publikation i ny flik eller fönster >>Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
    Visa övriga...
    2016 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 29868Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-301020 (URN)10.1038/srep29868 (DOI)000379878300001 ()27430378 (PubMedID)
    Forskningsfinansiär
    Cancerfonden, CAN 2006/1078, CAN 2009/900, CAN 2012/438Vetenskapsrådet, K2007-66X-14936-04-3, K2010-67X-14936-07-3, K2013-66X-14936-10-5EU, FP7, Sjunde ramprogrammet
    Tillgänglig från: 2016-08-17 Skapad: 2016-08-17 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
    2. Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
    Öppna denna publikation i ny flik eller fönster >>Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
    Visa övriga...
    (Engelska)Ingår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403Artikel i tidskrift (Refereegranskat) Accepted
    Nationell ämneskategori
    Cellbiologi Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-334443 (URN)
    Tillgänglig från: 2017-11-23 Skapad: 2017-11-23 Senast uppdaterad: 2017-12-05
    3. LXRα limits the pro-fibrotic action of TGFβ in liver cancer-associated fibroblasts
    Öppna denna publikation i ny flik eller fönster >>LXRα limits the pro-fibrotic action of TGFβ in liver cancer-associated fibroblasts
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Cellbiologi Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-334448 (URN)
    Tillgänglig från: 2017-11-23 Skapad: 2017-11-23 Senast uppdaterad: 2017-12-05
  • 20. Berglund, Erik
    et al.
    Akcakaya, Pinar
    Berglund, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Karlsson, Fredrik
    Vukojevic, Vladana
    Lee, Linkiat
    Bogdanovic, Darko
    Lui, Weng-Onn
    Larsson, Catharina
    Zedenius, Jan
    Frobom, Robin
    Branstrom, Robert
    Functional role of the Ca2+-activated Cl- channel DOG1/TMEM16A in gastrointestinal stromal tumor cells2014Ingår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 326, nr 2, s. 315-325Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DOG1, a Ca2+-activated Cl- channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl- currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target.

  • 21.
    Bernander, Rolf
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Lind, Anders E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Ettema, Thijs J.G.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    An archaeal origin for the actin cytoskeleton: implications for eukaryogenesis2011Ingår i: Communicative & Integrative Biology, ISSN 1942-0889, E-ISSN 1942-0889, Vol. 4, nr 6, s. 664-667Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A hallmark of the eukaryotic cell is the actin cytoskeleton, involved in a wide array of processes ranging from shape determination and phagocytosis to intracellular transport and cytokinesis. Recently, we reported the discovery of an actin-based cytoskeleton also in Archaea. The archaeal actin ortholog, Crenactin, was shown to belong to a conserved operon, Arcade (actin-related cytoskeleton in Archaea involved in shape determination), encoding an additional set of cytoskeleton-associated proteins. Here, we elaborate on the implications of these findings for the evolutionary relation between archaea and eukaryotes, with particular focus on the possibility that eukaryotic actin and actin-related proteins have evolved from an ancestral archaeal actin gene. Archaeal actin could thus have played an important role in cellular processes essential for the origin and early evolution of the eukaryotic lineage. Further exploration of uncharacterized archaeal lineages is necessary to find additional missing pieces in the evolutionary trajectory that ultimately gave rise to present-day organisms.

  • 22.
    Björnson, Elias
    et al.
    Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden..
    Mukhopadhyay, Bani
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA..
    Asplund, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pristovsek, Nusa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Cinar, Resat
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA..
    Romeo, Stefano
    Univ Gothenburg, Wallenberg Lab, Sahlgrenska Ctr Cardiovasc & Metab Res, Dept Mol & Clin Med, S-41345 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Cardiol, S-41650 Gothenburg, Sweden.;Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Clin Nutr Unit, I-88100 Catanzaro, Italy..
    Uhlen, Mathias
    KTH Royal Inst Technol, Dept Prote, S-10691 Stockholm, Sweden.;KTH Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden..
    Kunos, George
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA..
    Nielsen, Jens
    Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden.;KTH Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden..
    Mardinoglu, Adil
    Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden.;KTH Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden..
    Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization2015Ingår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 13, nr 9, s. 2014-2026Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC.

  • 23.
    Blikstad, Cecilia
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Ivarsson, Ylva
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    High-throughput methods for identification of protein-protein interactions involving short linear motifs2015Ingår i: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 13, artikel-id 38Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Interactions between modular domains and short linear motifs (3-10 amino acids peptide stretches) are crucial for cell signaling. The motifs typically reside in the disordered regions of the proteome and the interactions are often transient, allowing for rapid changes in response to changing stimuli. The properties that make domain-motif interactions suitable for cell signaling also make them difficult to capture experimentally and they are therefore largely underrepresented in the known protein-protein interaction networks. Most of the knowledge on domain-motif interactions is derived from low-throughput studies, although there exist dedicated high-throughput methods for the identification of domain-motif interactions. The methods include arrays of peptides or proteins, display of peptides on phage or yeast, and yeast-two-hybrid experiments. We here provide a survey of scalable methods for domain-motif interaction profiling. These methods have frequently been applied to a limited number of ubiquitous domain families. It is now time to apply them to a broader set of peptide binding proteins, to provide a comprehensive picture of the linear motifs in the human proteome and to link them to their potential binding partners. Despite the plethora of methods, it is still a challenge for most approaches to identify interactions that rely on post-translational modification or context dependent or conditional interactions, suggesting directions for further method development.

  • 24. Boesler, Carsten
    et al.
    Kruse, Janis
    Söderbom, Fredrik
    Department of Molecular Biology, Uppsala Biomedical Center, Swedish University of Agricultural Sciences, S-75124 Uppsala, Sweden .
    Hammann, Christian
    Sequence and generation of mature ribosomal RNA transcripts in Dictyostelium discoideum2011Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, nr 20, s. 17693-17703Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The amoeba Dictyostelium discoideum is a well established model organism for studying numerous aspects of cellular and developmental functions. Its ribosomal RNA (rRNA) is encoded in an extrachromosomal palindrome that exists in ∼100 copies in the cell. In this study, we have set out to investigate the sequence of the expressed rRNA. For this, we have ligated the rRNA ends and performed RT-PCR on these circular RNAs. Sequencing revealed that the mature 26 S, 17 S, 5.8 S, and 5 S rRNAs have sizes of 3741, 1871, 162, and 112 nucleotides, respectively. Unlike the published data, all mature rRNAs of the same type uniformly display the same start and end nucleotides in the analyzed AX2 strain. We show the existence of a short lived primary transcript covering the rRNA transcription unit of 17 S, 5.8 S, and 26 S rRNA. Northern blots and RT-PCR reveal that from this primary transcript two precursor molecules of the 17 S and two precursors of the 26 S rRNA are generated. We have also determined the sequences of these precursor molecules, and based on these data, we propose a model for the maturation of the rRNAs in Dictyostelium discoideum that we compare with the processing of the rRNA transcription unit of Saccharomyces cerevisiae.

  • 25.
    Bohman, Sara
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Microencapsulation of Pancreatic Islets: A Non-Vascularised Transplantation Model2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Transplantation of pancreatic islets is a potential treatment of type 1 diabetes that aims to restore normal blood glucose control. By encapsulating the islets in alginate, they can be protected from rejection. The aim of this thesis was to study the biology of encapsulated islets and to use the technique of microencapsulation to study the effect of transplantation in a system that is separated from direct contact with the vascular system and the host tissue at the transplantation site.

    Encapsulated islets can effectively reverse hyperglycaemia after transplantation into the peritoneal cavity of diabetic mice. A period of culture before encapsulation and transplantation did not affect their insulin release or curative capability. Pre-culture with exendin-4 improved insulin secretion, but not to the extent that the long term outcome in our transplantation model was improved. Despite being able to reach and retain normoglycaemia, microencapsulated islets transplanted intraperitoneally decreased in size. More specifically the number of beta cells in each individual islet was decreased. However, in contrast to previous studies using non-encapsulated islets, the alpha cell number was maintained, and thus the capsule seems to protect these peripherally located and otherwise exposed cells. As the capsule also prevents revascularisation of the islets, the model was used to study the importance of vascular supply for islet amyloid formation. Islet amyloid is a possible reason for the long-term failure of transplanted islets. It is likely that their low vascular density causes a disturbed local clearance of IAPP and insulin that starts the aggregation of IAPP. Indeed, encapsulated islets had an accelerated amyloid formation compared to normal islets, and might serve as a model for further studies of this process.

    In conclusion, although revascularisation is not a prerequisite for islet graft function, it plays an important role for islet transplantation outcome.

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    4. Extensive amyloid formation in transplanted microencapsulated mouse and human islets
    Öppna denna publikation i ny flik eller fönster >>Extensive amyloid formation in transplanted microencapsulated mouse and human islets
    2012 (Engelska)Ingår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 19, nr 2, s. 87-93Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: Deposition of cell toxic islet amyloid is a frequent finding in type 2 diabetes and also in transplanted human islets, where it is a possible explanation for their long-term failure. One suggested reason for amyloid in transplanted islets is that their low vascular density results in a disturbed local clearance of islet amyloid polypeptide (IAPP). To test this hypothesis we analysed accumulation of amyloid in microencapsulated islets, which exemplify a non-vascularised islet graft.

    Methods: Isolated islets from human or transgenic mice expressing human IAPP were microencapsulated in alginate and cultured in vitro or transplanted under the kidney capsule of normoglycemic nude mice. The degree of amyloid was determined after Congo red staining and subcellular alterations were analysed with electron microscopy.

    Results: Insulin and IAPP secretion from transgenic mouse islets were markedly increased during stimulation with glucose after one week of culture, but encapsulated islets in general released less insulin. Amyloid was detected after both one and three weeks of culture in the transgenic mouse islets and the encapsulated islets were most affected. After transplantation, electron microscopy displayed both intra-and extracellular amyloid in microencapsulated as well as in non-encapsulated human and transgenic mouse islet grafts. However, amyloid was more frequent in the encapsulated grafts.

    Conclusion: Micro-encapsulation of pancreatic islets might serve as an important tool for studies of amyloid formation under enhanced circumstances.

    Nyckelord
    Alginate, IAPP, islet amyloid, islet transplantation, islet amyloid polypeptide, microencapsulation
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97772 (URN)10.3109/13506129.2012.679988 (DOI)000304521800005 ()
    Tillgänglig från: 2008-11-13 Skapad: 2008-11-13 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
  • 26.
    Boije, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi. Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    Rulands, Steffen
    Univ Cambridge, Dept Phys, Cambridge CB3 0HE, England..
    Dudczig, Stefanie
    Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    Simons, Benjamin D.
    Univ Cambridge, Dept Phys, Cambridge CB3 0HE, England..
    Harris, William A.
    Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England..
    The Independent Probabilistic Firing of Transcription Factors: A Paradigm for Clonal Variability in the Zebrafish Retina2015Ingår i: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 34, nr 5, s. 532-543Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Early retinal progenitor cells (RPCs) in vertebrates produce lineages that vary greatly both in terms of cell number and fate composition, yet how this variability is achieved remains unknown. One possibility is that these RPCs are individually distinct and that each gives rise to a unique lineage. Another is that stochastic mechanisms play upon the determinative machinery of equipotent early RPCs to drive clonal variability. Here we show that a simple model, based on the independent firing of key fate-influencing transcription factors, can quantitatively account for the intrinsic clonal variance in the zebrafish retina and predict the distributions of neuronal cell types in clones where one or more of these fates are made unavailable.

  • 27.
    Brandhorst, Daniel
    et al.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Parnaud, Geraldine
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Friberg, Andrew
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Lavallard, Vanessa
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Demuylder-Mischler, Sandrine
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Hughes, Stephen
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Saphoerster, Julia
    SERVA Electrophoresis GmbH, Uetersen, Germany..
    Kurfuerst, Manfred
    SERVA Electrophoresis GmbH, Uetersen, Germany..
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Berney, Thierry
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Johnson, Paul R. V.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Multicenter Assessment of Animal-free Collagenase AF-1 for Human Islet Isolation2017Ingår i: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, nr 10, s. 1688-1693Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Animal-free (AF) SERVA Collagenase AF-1 and Neutral Protease (NP) AF GMP Grade have recently become available for human islet isolation. This report describes the initial experiences of 3 different islet transplant centers. Thirty-four human pancreases were digested using 1 vial of the 6 different lots of Collagenase AF-1 (2,000-2,583 PZ-U/vial) supplemented with 4 different lots of NP AF in a range of 50 to 160 DMC-U per pancreas. Isolation, culture, and quality assessment were performed using standard techniques as previously described. All data are presented as mean +/- standard error of the mean (SEM). Variability of pancreas weight was associated with a wide range of collagenase and NP activities, ranging from 12.7 to 46.6 PZ-U/g (26.0 +/- 1.5 PZ-U/g) and 0.4 to 3.0 DMC-U/g (1.5 +/- 0.1 DMC-U/g), respectively. Postpurification islet yield was 296,494 +/- 33,620 islet equivalents (IEQ) equivalent to 3,274 +/- 450 IEQ/g with a purity of 55.9% +/- 3.2%. Quality assessment performed after 2 to 4 d of culture demonstrated a viability of 88.1% +/- 1.5% and a stimulation index of 3.7 +/- 0.7. Eighteen of the 34 preparations were transplanted into type 1 diabetic patients equivalent to a transplantation rate of 52.9%. Six preparations, which were infused into patients as first transplant, could be analyzed and increased the fasting C-peptide level from 0.11 +/- 0.08 pretransplant to 1.23 +/- 0.24 and 2.27 +/- 0.31 ng/mL 3 and 6 mo posttransplant (P < 0.05), respectively. Insulin requirements were simultaneously reduced at the same time from 39.2 +/- 3.8 IU/d before transplantation to 10.8 +/- 4.1 and 4.0 +/- 2.3 IU/d, after 3 and 6 mo posttransplant (P < 0.05), respectively. This study demonstrates the efficiency of AF SERVA Collagenase AF-1 and NP AF for clinical islet isolation and transplantation. The new plant-based production process makes these products a safe new option for the islet field.

  • 28.
    Bryukhovetskiy, Igor
    et al.
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Ponomarenko, Arina
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Lyakhova, Irina
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Zaitsev, Sergey
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Zayats, Yulia
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Korneyko, Maria
    Far Eastern Fed Univ, Vladivostok 690091, Russia.
    Eliseikina, Marina
    Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Mischenko, Polina
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Shevchenko, Valerie
    Far Eastern Fed Univ, Vladivostok 690091, Russia;NN Blokhin Russian Canc Res Ctr, Moscow 115478, Russia.
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Khotimchenko, Yuri
    Far Eastern Fed Univ, Vladivostok 690091, Russia;Russian Acad Sci, Far Eastern Branch, Natl Sci Ctr Marine Biol, Vladivostok 690059, Russia.
    Personalized regulation of glioblastoma cancer stem cells based on biomedical technologies: From theory to experiment (Review)2018Ingår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 42, nr 2, s. 691-702Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. GBM represents >50% of primary tumors of the nervous system and similar to 20% of intracranial neoplasms. Standard treatment involves surgery, radiation and chemotherapy. However, the prognosis of GBM is usually poor, with a median survival of 15 months. Resistance of GBM to treatment can be explained by the presence of cancer stem cells (CSCs) among the GBM cell population. At present, there are no effective therapeutic strategies for the elimination of CSCs. The present review examined the nature of human GBM therapeutic resistance and attempted to systematize and put forward novel approaches for a personalized therapy of GBM that not only destroys tumor tissue, but also regulates cellular signaling and the morphogenetic properties of CSCs. The CSCs are considered to be an informationally accessible living system, and the CSC proteome should be used as a target for therapy directed at suppressing clonal selection mechanisms and CSC generation, destroying CSC hierarchy, and disrupting the interaction of CSCs with their microenvironment and extracellular matrix. These objectives can be achieved through the use of biomedical cellular products.

  • 29.
    Busse, Niels
    et al.
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Paroni, Federico
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Richardson, Sarah J.
    Univ Exeter, Islet Biol Exeter, Med, Exeter EX4 4QJ, Devon, England..
    Laiho, Jutta E.
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland..
    Oikarinen, Maarit
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland..
    Frisk, Gun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hyoty, Heikki
    Univ Tampere, Sch Med, Dept Virol, Tampere, Finland.;Pirkanmaa Hosp Dist, Fimlab Labs, Tampere, Finland..
    de Koning, Eelco
    Leiden Univ, Med Ctr, Dept Internal Med, Leiden, Netherlands.;Univ Med Ctr Utrecht, Hubrecht Inst, Utrecht, Netherlands..
    Morgan, Noel G.
    Univ Exeter, Islet Biol Exeter, Med, Exeter EX4 4QJ, Devon, England..
    Maedler, Kathrin
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Detection and localization of viral infection in the pancreas of patients with type 1 diabetes using short fluorescently-labelled oligonucleotide probes2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 8, s. 12620-12636Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Enteroviruses, specifically of the Coxsackie B virus family, have been implicated in triggering islet autoimmunity and type 1 diabetes, but their presence in pancreata of patients with diabetes has not been fully confirmed. To detect the presence of very low copies of the virus genome in tissue samples from T1D patients, we designed a panel of fluorescently labeled oligonucleotide probes, each of 17-22 nucleotides in length with a unique sequence to specifically bind to the enteroviral genome of the picornaviridae family. With these probes enteroviral RNA was detected with high sensitivity and specificity in infected cells and tissues, including in FFPE pancreas sections from patients with T1D. Detection was not impeded by variations in sample processing and storage thereby overcoming the potential limitations of fragmented RNA. Co-staining of small RNA probes in parallel with classical immunstaining enabled virus detection in a cell-specific manner and more sensitively than by viral protein.

  • 30.
    Caja, Laia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ortiz, Conrad
    Bertran, Esther
    Murillo, Miguel M
    Miró-Obradors, M Jesús
    Palacios, Evangelina
    Fabregat, Isabel
    Differential intracellular signalling induced by TGF-beta in rat adult hepatocytes and hepatoma cells: implications in liver carcinogenesis.2007Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 19, nr 4, s. 683-94Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The transforming growth factor-beta (TGF-beta) regulates hepatocyte growth, inhibiting proliferation and inducing apoptosis. Indeed, escaping from the TGF-beta suppressor actions might be a prerequisite for liver tumour progression. In this work we show that TGF-beta plays a dual role in regulating apoptosis in FaO rat hepatoma cells, since, in addition to its pro-apoptotic effect, TGF-beta also activates survival signals, such as AKT, the epidermal growth factor receptor (EGFR) being required for its activation. TGF-beta induces the expression of the EGFR ligands transforming growth factor-alpha (TGF-alpha) and heparin-binding EGF-like growth factor (HB-EGF) and induces intracellular re-localization of the EGFR. Cells that overcome the apoptotic effects of TGF-beta undergo morphological changes reminiscent of an epithelial-mesenchymal transition (EMT) process. In contrast, TGF-beta does not activate AKT in adult hepatocytes, which correlates with lack of EGFR transactivation and no response to EGFR inhibitors. Although TGF-beta induces TGF-alpha and HB-EGF in adult hepatocytes, these cells show very low expression of TACE/ADAM 17 (TNF-alpha converting enzyme), which is required for EGFR ligand proteolysis and activation. Furthermore, adult hepatocytes do not undergo EMT processes in response to TGF-beta, which might be due, at least in part, to the fact that F-actin re-organization induced by TGF-beta in FaO cells require the EGFR pathway. Finally, results indicate that EGFR transactivation does not block TGF-beta-induced cell cycle arrest in FaO cells, but must be interfering with the pro-apoptotic signalling. In conclusion, TGF-beta is a suppressor factor for adult quiescent hepatocytes, but not for hepatoma cells, where it plays a dual role, both suppressing and promoting carcinogenesis.

  • 31. Caja, Laia
    et al.
    Shahidi Dadras, Mahsa
    Tzavlaki, Kalliopi
    Tan, E-Jean
    Hatem, Gad
    Maturi, Nagaprathyusha
    Moren, Anita
    Wik, Lotta
    Watanabe, Yukihide
    Savary, Katia
    Kamali-Moghaddam, Masood
    Uhrbom, Lene
    Heldin, Carl-Henrik
    Moustakas, Aristidis
    Snail regulates BMP and TGF-β pathways to control the differentiation status of glioma initiating cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract
  • 32. Carthy, Jonathon
    Bellomo, Claudia ()
    Vanlandewijck, Michael ()
    Heldin, Angelos ()
    Moren, Anita ()
    Kardassis, Dimitri ()
    Gahman, Timothy ()
    Shiau, Andrew ()
    Bickle, Marc ()
    Zerial, Marino ()
    Heldin, Carl-Henrik ()
    Moustakas, Aristidis ()
    Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myo broblast di erentiation2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Artikel i tidskrift (Refereegranskat)
  • 33.
    Chacko, L. Johnson
    et al.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Blumer, M. J. F.
    Med Univ Innsbruck, Dept Anat Histol & Embryol, Div Clin & Funct Anat, Muellerstr 59, A-6020 Innsbruck, Austria..
    Pechriggl, E.
    Med Univ Innsbruck, Dept Anat Histol & Embryol, Div Clin & Funct Anat, Muellerstr 59, A-6020 Innsbruck, Austria..
    Rask-Andersen, Helge
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Dietl, W.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Haim, A.
    Med Univ Innsbruck, Dept Plast Reconstruct & Aesthet Surg, Innerkoflerstr 1, A-6020 Innsbruck, Austria..
    Fritsch, H.
    Med Univ Innsbruck, Dept Anat Histol & Embryol, Div Clin & Funct Anat, Muellerstr 59, A-6020 Innsbruck, Austria..
    Glueckert, R.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria.;Tirol Kliniken, Univ Clin Innsbruck, Anichstr 35, A-6020 Innsbruck, Austria..
    Dudas, J.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Schrott-Fischer, A.
    Med Univ Innsbruck, Dept Otorhinolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Role of BDNF and neurotrophic receptors in human inner ear development2017Ingår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, nr 3, s. 347-363Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The expression patterns of the neurotrophin, brain-derived neurotrophic factor, BDNF, and the neurotrophic receptors-p75NTR and Trk receptors-in the developing human fetal inner ear between the gestational weeks (GW) 9 to 12 are examined via in situ hybridization and immunohistochemistry. BDNF mRNA expression was highest in the cochlea at GW 9 but declined in the course of development. In contrast to embryonic murine specimens, a decline in BDNF expression from the apical to the basal turn of the cochlea could not be observed. p75NTR immunostaining was most prominent in the nerve fibers that penetrate into the sensory epithelia of the cochlea, the urticule and the saccule as gestational age progresses. TrkB and TrkC expression intensified towards GW 12, at which point the BDNF mRNA localization was at its lowest. TrkA expression was limited to fiber subpopulations of the facial nerve at GW 10. In the adult human inner ear, we observed BDNF mRNA expression in the apical poles of the cochlear hair cells and supporting cells, while in the adult human utricle, the expression was localized in the vestibular hair cells. We demonstrate the highly specific staining patterns of BDNF mRNA and its putative receptors over a developmental period in which multiple hearing disorders are manifested. Our findings suggest that BDNF and neurotrophin receptors are important players during early human inner ear development. In particular, they seem to be important for the survival of the afferent sensory neurons.

  • 34.
    Chen, Hongxin
    et al.
    Univ Helsinki, Dept Forest Sci, FIN-00014 Helsinki, Finland..
    Quintana, Julia
    Univ Helsinki, Dept Forest Sci, FIN-00014 Helsinki, Finland..
    Kovalchuk, Andriy
    Univ Helsinki, Dept Forest Sci, FIN-00014 Helsinki, Finland..
    Ubhayasekera, Wimal
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Asiegbu, Fred O.
    Univ Helsinki, Dept Forest Sci, FIN-00014 Helsinki, Finland..
    A cerato-platanin-like protein HaCPL2 from Heterobasidion annosum sensu stricto induces cell death in Nicotiana tabacum and Pinus sylvestris2015Ingår i: Fungal Genetics and Biology, ISSN 1087-1845, E-ISSN 1096-0937, Vol. 84, s. 41-51Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cerato-platanin family is a group of small secreted cysteine-rich proteins exclusive for filamentous fungi. They have been shown to be involved in the interactions between fungi and plants. Functional characterization of members from this family has been performed mainly in Ascomycota, except Moniliophthora perniciosa. Our previous phylogenetic analysis revealed that recent gene duplication of cerato-platanins has occurred in Basidiomycota but not in Ascomycota, suggesting higher functional diversification of this protein family in Basidiomycota than in Ascomycota. In this study, we identified three cerato-platanin homologues from the basidiomycete conifer pathogen Heterobasidion annosum sensu stricto. Expression of the homologues under various conditions as well as their roles in the H. annosum s.s.-Pinus sylvestris (Scots pine) pathosystem was investigated. Results showed that HaCPL2 (ceratoplatanin-like protein 2) had the highest sequence similarity to cerato-platanin from Ceratocystis platani and hacpl2 was significantly induced during nutrient starvation and necrotrophic growth. The treatment with recombinant HaCPL2 induced cell death, phytoalexin production and defense gene expression in Nicotiana tabacum. Eliciting and cell death-inducing ability accompanied by retardation of apical root growth was also demonstrated in Scots pine seedlings. Our results suggest that HaCPL2 might contribute to the virulence of H. annosum s.s. by promoting plant cell death.

  • 35.
    Chen, Hwei-yen
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi.
    Maklakov, Alexei A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi.
    Condition dependence of male mortality drives the evolution of sex differences in longevity2014Ingår i: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 24, nr 20, s. 2423-2427Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Males and females age at different rates and have different life expectancies across the animal kingdom, but what causes the longevity "gender gaps" remains one of the most fiercely debated puzzles among biologists and demographers [1-7]. Classic theory predicts that the sex experiencing higher rate of extrinsic mortality evolves faster aging and reduced longevity [1]. However, condition dependence of mortality [8, 9] can counter this effect by selecting against senescence in whole-organism performance [5, 10]. Contrary to the prevailing view but in line with an emerging new theory [7-9, 11], we show that the evolution of sex difference in longevity depends on the factors that cause sex-specific mortality and cannot be predicted from the mortality rate alone. Experimental evolution in an obligately sexual roundworm, Caenorhabditis remanei, in which males live longer than females, reveals that sexual dimorphism in longevity erodes rapidly when the extrinsic mortality in males is increased at random. We thus experimentally demonstrate evolution of the sexual monomorphism in longevity in a sexually dimorphic organism. Strikingly, when extrinsic mortalityis increased in a way that favors survival of fast-moving individuals, males evolve increased longevities, thereby widening the gender gap. Thus,sex-specific selection on whole-organism performance in males renders them less prone to the ravages of old age than females, despite higher rates of extrinsic mortality. Our results reconcile previous research with recent theoretical breakthroughs [8, 9] by showing that sexual dimorphism inlongevity evolves rapidly and predictably as a result of the sex-specific interactions between environmental hazard and organism's condition.

  • 36.
    Chen, Song
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Mestres, Gemma
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Lan, Weihua
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Xia, Wei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Engqvist, Håkan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Cytotoxicity of modified glass ionomer cement on odontoblast cells2016Ingår i: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 27, nr 7, artikel-id 116Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently a modified glass ionomer cement (GIC) with enhanced bioactivity due to the incorporation of wollastonite or mineral trioxide aggregate (MTA) has been reported. The aim of this study was to evaluate the cytotoxic effect of the modified GIC on odontoblast-like cells. The cytotoxicity of a conventional GIC, wollastonite modified GIC (W-mGIC), MTA modified GIC (M-mGIC) and MTA cement has been evaluated using cement extracts, a culture media modified by the cement. Ion concentration and pH of each material in the culture media were measured and correlated to the results of the cytotoxicity study. Among the four groups, conventional GIC showed the most cytotoxicity effect, followed by W-mGIC and M-mGIC. MTA showed the least toxic effect. GIC showed the lowest pH (6.36) while MTA showed the highest (8.62). In terms of ion concentration, MTA showed the largest Ca2+ concentration (467.3 mg/L) while GIC showed the highest concentration of Si4+ (19.9 mg/L), Al3+ (7.2 mg/L) and Sr2+ (100.3 mg/L). Concentration of F- was under the detection limit (0.02 mg/L) for all samples. However the concentrations of these ions are considered too low to be toxic. Our study showed that the cytotoxicity of conventional GIC can be moderated by incorporating calcium silicate based ceramics. The modified GIC might be promising as novel dental restorative cements.

  • 37.
    Cho, S. Ei
    et al.
    Stanford Univ, Biol, Stanford, CA USA.
    Roy, J.
    Stanford Univ, Biol, Stanford, CA USA.
    Ivarsson, Ylva
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Cyert, M. S.
    Stanford Univ, Biol, Stanford, CA USA.
    Investigating the phospho-regulation of ER shaping protein RTN1A (Reticulon-1A) by the Calcineurin phosphatase.2017Ingår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 28, nr 26, s. 3727-3727Artikel i tidskrift (Övrigt vetenskapligt)
  • 38.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    The neutrophil: one cell on many missions or many cells with different agendas?2018Ingår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 371, nr 3, s. 415-423Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The unique role of neutrophils in host defense is not only based on their abilities to kill bacteria but is also due to their abundance in circulation and their ability to quickly migrate and accumulate in great numbers at afflicted sites. The high number of circulating neutrophils is the result of regulated release of new neutrophils from bone marrow as well as from marginated pools to balance their recruitment to tissue. Marginated pools, such as the spleen and lung, have previously been attributed to passively delay neutrophil transit time due to their large capillary network, but recent reports demonstrate that they are comprised of neutrophils with specific functions. The spleen, for instance, holds neutrophil subpopulations at different anatomical locations with distinct functions important for, e.g., bacterial eradication, and the lung was recently shown to re-educate neutrophils that had trafficked from a site of sterile injury to home back to bone marrow for elimination. Further, recent reports demonstrate subpopulations of neutrophils with different actions during homeostasis, infection, tissue restitution and cancer. It is becoming increasingly clear that this cannot be due to different stages of neutrophil activation during their life span but instead points towards distinct subpopulations of neutrophils with different effector functions. Whether these cellular distinctions are due to different education or origin is, however, not yet known. Together, the accumulating information about the heterogeneous neutrophils presents important insights into their role in development of pathologies, as well as revealing novel targets in the form of certain subpopulations to treat disease.

  • 39. Crona, Mikael
    et al.
    Avesson, Lotta
    Sahlin, Margareta
    Lundin, Daniel
    Hinas, Andrea
    Klose, Ralph
    Söderbom, Fredrik
    Department of Molecular Biology, Swedish University of Agricultural Sciences, Uppsala Biomedical Center, SE-75124 Uppsala, Sweden .
    Sjöberg, Britt-Marie
    A Rare Combination of Ribonucleotide Reductases in the Social Amoeba Dictyostelium discoideum2013Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, nr 12, s. 8198-208Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ribonucleotide reductases (RNRs) catalyze the only pathway for de novo synthesis of deoxyribonucleotides needed for DNA replication and repair. The vast majority of eukaryotes encodes only a class I RNR, but interestingly some eukaryotes, including the social amoeba Dictyostelium discoideum, encode both a class I and a class II RNR. The amino acid sequence of the D. discoideum class I RNR is similar to other eukaryotic RNRs, whereas that of its class II RNR is most similar to the monomeric class II RNRs found in Lactobacillus spp. and a few other bacteria. Here we report the first study of RNRs in a eukaryotic organism that encodes class I and class II RNRs. Both classes of RNR genes were expressed in D. discoideum cells, although the class I transcripts were more abundant and strongly enriched during mid-development compared with the class II transcript. The quaternary structure, allosteric regulation, and properties of the diiron-oxo/radical cofactor of D. discoideum class I RNR are similar to those of the mammalian RNRs. Inhibition of D. discoideum class I RNR by hydroxyurea resulted in a 90% reduction in spore formation and decreased the germination viability of the surviving spores by 75%. Class II RNR could not compensate for class I inhibition during development, and an excess of vitamin B12 coenzyme, which is essential for class II activity, did not improve spore formation. We suggest that class I is the principal RNR during D. discoideum development and growth and is important for spore formation, possibly by providing dNTPs for mitochondrial replication.

  • 40.
    Dahl, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Mechanisms for Quantitative Regulation of TGF-ß Signaling2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Cancer is a widely spread disease, and many cancer variants are today still difficult to treat. Efforts are being made to understand the complexity of cancer, both at a clinical level but also at a pre-clinical level. The aim is of course to merge the research from both disciplines, as an example, find out how to treat a tumour in a patient and what molecular mechanisms are behind the origin of the tumour. Basic research provides a platform that in the long run will help to create treatments for many cancer variants that exist today. Transforming Growth Factor Beta (TGF-ß) is a cytokine that regulates many cellular events such as cell differentiation, cell proliferation and migration. TGF-ß signaling is important to study since many studies show that patients with cancer actually have accumulated mutations in proteins connected to the pathway. In this thesis I try to enhance the knowledge of the TGF-ß signaling pathway, looking in more detail how the signaling output is regulated by the response to the ligand, explained in paper four. Furthermore I try to reveal the protein network that control transmission of the signal from the cell surface to the nucleus. We found that PARP-1 (paper one and two) and PARP-2 (paper three) associates with the signaling pathway to regulate the Smad proteins and to negatively regulate the transcription of Smad target genes.

    Delarbeten
    1. PARP-1 attenuates Smad-mediated transcription
    Öppna denna publikation i ny flik eller fönster >>PARP-1 attenuates Smad-mediated transcription
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    2010 (Engelska)Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 40, nr 4, s. 521-532Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and orchestrate transcription. Termination of Smad-activated transcription involves Smad dephosphorylation, nuclear export, or ubiquitin-mediated degradation. In an unbiased proteomic screen, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a Smad-interacting partner. PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-β-induced epithelial-mesenchymal transition. Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-128847 (URN)10.1016/j.molcel.2010.10.029 (DOI)000284988400006 ()21095583 (PubMedID)
    Tillgänglig från: 2010-07-28 Skapad: 2010-07-27 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    2. Regulation of novel gene targets of TGFβ signaling by PARP-1
    Öppna denna publikation i ny flik eller fönster >>Regulation of novel gene targets of TGFβ signaling by PARP-1
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Naturvetenskap Cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-172851 (URN)
    Tillgänglig från: 2012-04-16 Skapad: 2012-04-16 Senast uppdaterad: 2012-08-01
    3. PARP-2 activation and association with Smads during regulation of TGFβ signaling
    Öppna denna publikation i ny flik eller fönster >>PARP-2 activation and association with Smads during regulation of TGFβ signaling
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Naturvetenskap Cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-172853 (URN)
    Tillgänglig från: 2012-04-16 Skapad: 2012-04-16 Senast uppdaterad: 2012-08-01
    4. Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics
    Öppna denna publikation i ny flik eller fönster >>Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics
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    2011 (Engelska)Ingår i: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 7, nr 492Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Mammalian cells can decode the concentration of extracellular transforming growth factor-beta (TGF-beta) and transduce this cue into appropriate cell fate decisions. How variable TGF-beta ligand doses quantitatively control intracellular signaling dynamics and how continuous ligand doses are translated into discontinuous cellular fate decisions remain poorly understood. Using a combined experimental and mathematical modeling approach, we discovered that cells respond differently to continuous and pulsating TGF-beta stimulation. The TGF-beta pathway elicits a transient signaling response to a single pulse of TGF-beta stimulation, whereas it is capable of integrating repeated pulses of ligand stimulation at short time interval, resulting in sustained phospho-Smad2 and transcriptional responses. Additionally, the TGF-beta pathway displays different sensitivities to ligand doses at different time scales. While ligand-induced short-term Smad2 phosphorylation is graded, long-term Smad2 phosphorylation is switch-like to a small change in TGF-beta levels. Correspondingly, the short-term Smad7 gene expression is graded, while long-term PAI-1 gene expression is switch-like, as is the long-term growth inhibitory response. Our results suggest that long-term switch-like signaling responses in the TGF-beta pathway might be critical for cell fate determination.

    Ort, förlag, år, upplaga, sidor
    EMBO and Macmillan Publishers Limited, 2011
    Nyckelord
    mathematical model, Smad, TGF-beta, ultrasensitivity
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-155228 (URN)10.1038/msb.2011.22 (DOI)000291351000003 ()
    Tillgänglig från: 2011-06-21 Skapad: 2011-06-20 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
  • 41. Dahl, Markus
    et al.
    Lönn, Peter
    Heldin, Carl-Henrik
    Moustakas, Aristidis
    Regulation of novel gene targets of TGFβ signaling by PARP-1Manuskript (preprint) (Övrigt vetenskapligt)
  • 42. Dahl, Markus
    et al.
    Lönn, Peter
    Vanlandewijck, Michael
    Zieba, Agata
    O. Hottiger, Michael
    Söderberg, Ola
    Heldin, Carl-Henrik
    Moustakas, Aristidis
    PARP-2 activation and association with Smads during regulation of TGFβ signalingManuskript (preprint) (Övrigt vetenskapligt)
  • 43. Daly, Craig J
    et al.
    Parmryd, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    McGrath, John C
    Visualization and analysis of vascular receptors using confocal laser scanning microscopy and fluorescent ligands2012Ingår i: Receptor Binding Techniques / [ed] Anthony P. Davenport, New York: Humana Press, 2012, Vol. 897, s. 95-107Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    The use of fluorescent ligands to analyze receptor distribution is increasing in popularity. This is due to the ever growing number of fluorescent ligands and the increased sensitivity of microscope-based technologies. Image-analysis methods have advanced to a stage where quantification of fluorescent signals is relatively simple (if used appropriately). In this chapter we describe a method of analyzing the 2D and 3D distribution of fluorescent ligands in segments of blood vessels. In addition, we introduce the issues surrounding the accurate analysis of colocalization of two different fluorescent ligands.

  • 44.
    Deng, Pan
    et al.
    Huazhong Univ Sci & Technol, State Key Lab Digital Mfg Equipment & Technol, Wuhan, Hubei, Peoples R China.
    Fu, Cheng-Jie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Systematisk biologi.
    Wu, Zhigang
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik. Huazhong Univ Sci & Technol, State Key Lab Digital Mfg Equipment & Technol, Wuhan, Hubei, Peoples R China.
    High purity and viability cell separation of a bacterivorous jakobid flagellate based on a steep velocity gradient induced soft inertial force2018Ingår i: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 8, nr 62, s. 35512-35520Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cell separation is one of the key limiting factors for precise analysis of non-axenic microbial lab cultures or environmental samples, and it remains a challenge to isolate target cells with high purity and viability via high-throughput cell sorting. During the past decade, hydrodynamic microfluidic platforms have attracted great attention in cell preparation for their high efficiency, robust performance and low cost. Here, we employ the use of a low-velocity sheath flow with high viscosity near the wall and a high-velocity sheath flow with low viscosity on the other side of the sample flow in a soft inertial separation chip. This not only prevents hard interactions between cells and chip walls but, in comparison to previous inertial separation methods, generates a significant increase in deflection of large cells while keeping the small ones in the original flow. We first conducted experiments on a mixture of small and large fluorescent particles (1.0 and 9.9 m, respectively) and removed over 99% of the small particles. The separation efficiency was then tested on a culture of a bacterivorous jakobid flagellate, Seculamonas ecuadoriensis fed on the live bacterium, Klebsiella sp. Using our microfluidic chip, over 94% of live bacteria were removed while maintaining high jakobid cell viability. For comparison, we also conducted size-based cell sorting of the same culture using flow cytometry, which is widely used as a rapid and automated separation tool. Compared with the latter, our chip showed more than 40% higher separation efficiency. Thus, our device provides high purity and viability for cell separation of a sensitive cell sample (jakobid cells). Potentially, the method can be further used for applications in diagnostics, biological analyses and environmental assessment of mixed microbial samples.

  • 45.
    Dinic, Jelena
    Stockholms universitet, Wenner-Grens institut.
    Plasma membrane order; the role of cholesterol and links to actin filaments2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The connection between T cell activation, plasma membrane order and actin filament dynamics was the main focus of this study. Laurdan and di-4-ANEPPDHQ, membrane order sensing probes, were shown to report only on lipid packing rather than being influenced by the presence of membrane-inserted peptides justifying their use in membrane order studies. These dyes were used to follow plasma membrane order in live cells at 37°C. Disrupting actin filaments had a disordering effect while stabilizing actin filaments had an ordering effect on the plasma membrane, indicating there is a basal level of ordered domains in resting cells. Lowering PI(4,5)P2 levels decreased the proportion of ordered domains strongly suggesting that the connection of actin filaments to the plasma membrane is responsible for the maintaining the level of ordered membrane domains. Membrane blebs, which are detached from the underlying actin filaments, contained a low fraction of ordered domains. Aggregation of membrane components resulted in a higher proportion of ordered plasma membrane domains and an increase in cell peripheral actin polymerization. This strongly suggests that the attachment of actin filaments to the plasma membrane induces the formation of ordered domains. Limited cholesterol depletion with methyl-beta-cyclodextrin triggered peripheral actin polymerization. Cholesterol depleted cells showed an increase in plasma membrane order as a result of actin filament accumulation underneath the membrane. Moderate cholesterol depletion also induced membrane domain aggregation and activation of T cell signaling events. The T cell receptor (TCR) aggregation caused redistribution of domains resulting in TCR patches of higher order and the bulk membrane correspondingly depleted of ordered domains. This suggests the preexistence of small ordered membrane domains in resting T cells that aggregate upon cell activation. Increased actin polymerization at the TCR aggregation sites showed that actin polymerization is strongly correlated with the changes in the distribution of ordered domains. The distribution of the TCR in resting cells and its colocalization with actin filaments is cell cycle dependent. We conclude that actin filament attachment to the plasma membrane, which is regulated via PI(4,5)P2, plays a crucial role in the formation of ordered domains.

  • 46.
    Dinic, Jelena
    et al.
    Stockholms universitet, Wenner-Grens institut.
    Biverståhl, Henrik
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Mäler, Lena
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Parmryd, Ingela
    Stockholms universitet, Wenner-Grens institut.
    Laurdan and di-4-ANEPPDHQ do not respond to membrane-inserted peptides and are good probes for lipid packing2011Ingår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1808, nr 1, s. 298-306Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Laurdan and di-4-ANEPPDHQ are used as probes for membrane order, with a blue shift in emission for membranes in liquid-ordered (lo) phase relative to membranes in liquid-disordered (ld) phase. Their use as membrane order probes requires that their spectral shifts are unaffected by membrane proteins, which we have examined by using membrane inserting peptides and large unilamellar vesicles (LUVs). The transmembrane polypeptides, mastoparan and bovine prion protein-derived peptide (bPrPp), were added to LUVs of either lo or ld phase, up to 1:10 peptide/total lipid ratio. The excitation and emission spectra of laurdan and di-4-ANEPPDHQ in both lipid phases were unaltered by peptide addition. The integrity and size distribution of the LUVs upon addition of the polypeptides were determined by dynamic light scattering. The insertion efficiency of the polypeptides into LUVs was determined by measuring their secondary structure by circular dichroism. Mastoparan had an α-helical and bPrPp a β-strand conformation compatible with insertion into the lipid bilayer. Our results suggest that the presence of proteins in biological membranes does not influence the spectra of laurdan and di-4-ANEPPDHQ, supporting that the dyes are appropriate probes for assessing lipid order in cells.

  • 47.
    Doudna, Jennifer
    et al.
    Univ Calif Berkeley, Berkeley, CA 94720 USA..
    Bar-Ziv, Roy
    Weizmann Inst Sci, IL-76100 Rehovot, Israel..
    Elf, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Noireaux, Vincent
    Univ Minnesota, Minneapolis, MN 55455 USA..
    Berro, Julien
    Yale Univ, New Haven, CT 06520 USA..
    Saiz, Leonor
    Univ Calif Davis, Davis, CA 95616 USA..
    Vavylonis, Dimitrios
    Lehigh Univ, Bethlehem, PA 18015 USA..
    Faulon, Jean-Loup
    INRA, Jouy En Josas, France..
    Fordyce, Polly
    Stanford Univ, Stanford, CA 94305 USA..
    How Will Kinetics and Thermodynamics Inform Our Future Efforts to Understand and Build Biological Systems?2017Ingår i: CELL SYSTEMS, ISSN 2405-4712, Vol. 4, nr 2, s. 144-146Artikel i tidskrift (Refereegranskat)
  • 48.
    Einarsson, Elin
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Troell, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Natl Vet Inst, Dept Microbiol, S-75007 Uppsala, Sweden.
    Höppner, Marc
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Univ Kiel, Inst Clin Mol Biol, Kiel, Germany.
    Grabherr, Mannfred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ribacke, Ulf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Svärd, Staffan G.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Coordinated Changes in Gene Expression Throughout Encystation of Giardia intestinalis2016Ingår i: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, nr 3, artikel-id e0004571Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Differentiation into infectious cysts through the process of encystation is crucial for transmission and survival of the intestinal protozoan parasite Giardia intestinalis. Hitherto the majority of studies have focused on the early events, leaving late encystation poorly defined. In order to further study encystation, focusing on the later events, we developed a new encystation protocol that generates a higher yield of mature cysts compared to standard methods. Transcriptome changes during the entire differentiation from trophozoites to cysts were thereafter studied using RNA sequencing (RNA-seq). A high level of periodicity was observed for up-and down-regulated genes, both at the level of the entire transcriptome and putative regulators. This suggests the trajectory of differentiation to be coordinated through developmentally linked gene regulatory activities. Our study identifies a core of 13 genes that are consistently up-regulated during initial encystation. Of these, two constitute previously uncharacterized proteins that we were able to localize to a new type of encystation-specific vesicles. Interestingly, the largest transcriptional changes were seen in the late phase of encystation with the majority of the highly up-regulated genes encoding hypothetical proteins. Several of these were epitope-tagged and localized to further characterize these previously unknown genetic components of encystation and possibly excystation. Finally, we also detected a switch of variant specific surface proteins (VSPs) in the late phase of encystation. This occurred at the same time as nuclear division and DNA replication, suggesting a potential link between the processes.

  • 49.
    Einarsson, Elin
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Ástvaldsson, Ásgeir
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Hultenby, Kjell
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Andersson, Jan O.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Svärd, Staffan G.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Jerlstrom-Hultqvist, Jon
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Comparative cell biology and evolution of Annexins in Diplomonads2016Ingår i: MSphere, ISSN 2379-5042, Vol. 1, nr 2, artikel-id e00032-15Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Annexins are multifunctional, calcium-binding proteins found in organisms across all kingdoms. Most studies of annexins from single-celled eukaryotes have focused on the alpha-giardins, proteins assigned to the group E annexins, expressed by the diplomonad Giardia intestinalis. We have characterized the annexin gene family in another diplomonad parasite, Spironucleus salmonicida, by phylogenetic and experimental approaches. We constructed a comprehensive phylogeny of the diplomonad group E annexins and found that they are abundant across the group with frequent gene duplications and losses. The annexins of S. salmonicida were found to be related to alpha-giardins but with better-preserved type II Ca2+ coordination sites. Two annexins were confirmed to bind phospholipids in a Ca2+-dependent fashion but with different specificities. Superresolution and confocal microscopy of epitope-tagged S. salmonicida annexins revealed localization to distinct parts of the cytoskeleton and membrane. The ultrastructural details of the localization of several annexins were determined by proximity labeling and transmission electron microscopy. Two annexins localize to a novel cytoskeletal structure in the anterior of the cell. Our results show that the annexin gene family is expanded in diplomonads and that these group E annexins are associated mostly with cytoskeletal and membrane structures. IMPORTANCE Annexins are proteins that associate with phospholipids in a Ca2+-dependent fashion. These proteins have been intensely studied in animals and plants because of their importance in diverse cellular processes, yet very little is known about annexins in single-celled eukaryotes, which represent the largest diversity of organisms. The human intestinal parasite Giardia intestinalis is known to have more annexins than humans, and they contribute to its pathogenic potential. In this study, we investigated the annexin complement in the salmon pathogen Spironucleus salmonicida, a relative of G. intestinalis. We found that S. salmonicida has a large repertoire of annexins and that the gene family has expanded separately across diplomonads, with members showing sequence diversity similar to that seen across kingdom-level groups such as plants and animals. S. salmonicida annexins are prominent components of the cytoskeleton and membrane. Two annexins are associated with a previously unrecognized structure in the anterior of the cell.

  • 50.
    Ekbom, Lisa H
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Evaluation of the ADVIA®60 on highvalue platelets2005Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats
    Abstract [en]

    Platelets are the smallest cells in the blood. They are formed in the bone-marrow and are important for the blood coagulation. Platelet tranfusions are given to patients propyhlactically before an operation but also in therapeutical purpose in connection with bleeding. It’s importent that the quality controls of the platelet concentrates are reliable.

    ADVIA®60 (Bayer HealthCare) is a fully automated cell counter which uses impedance principle to count platelets in blood samples. The purpose of the study was to evaluate this new instrument for use in the blood bank of Akademiska Sjukhuset in Uppsala. The instrument was bought to be used for quality control of platelet concentrates. 30 samples from platelet concentrates, from both apheresis and from buffy coats, were analyzed 10 times each on ADVIA®60 and the coefficient of variation (CV) was calculated for each sample. CV variated from 0,8 % to 2,9 % which is good considering that according to Bayer HealthCare the CV should be < 5 % for thrombocytes on ADVIA®60. The instrument was newly calibrated when the study was performed. Platelet count can also be performed by immunological or optical principles.

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