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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, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Parmryd, Ingela
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Ingela Parmryd, Box 440, S-40530 Gothenburg, Sweden.
    Quantifying colocalization: the MOC is a hybrid coefficient - an uninformative mix of co-occurrence and correlation2019Ingår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 132, nr 1, artikel-id UNSP jcs222455Artikel i tidskrift (Övrigt vetenskapligt)
  • 6.
    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, 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.

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  • 7. 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)
  • 8.
    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.

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  • 9.
    Agrillo, Caroline
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    DNA methylation modifications in human mesenchymal stem cells  induced by exposure to endocrine disrupting plasticiser metabolites MBP, MEP, MBzP, MEHP and MINCH2022Självständigt arbete på avancerad nivå (masterexamen), 80 poäng / 120 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Endocrine disrupting chemicals (EDCs) are exogenous substances which can modify the function of the endocrine system and lead to adverse health effects. Humans experience daily uncontrolled exposure to EDC mixtures. Predicting mixture effects is complicated since the chemicals may produce different effects when combined together. EDCs may produce epigenetic effects such as alterations of the DNA methylation, which could modify the expression of the gene. Previously, 14 chemicals linked to metabolism (mixture G1) were reported to induce DNA methylation changes in an in vitro model. Mixture G1 were based on a Swedish longitudinal study which had identified the chemical burden of >2300 pregnant women. This project aimed to study single chemical driver effects of five individual chemicals from mixture G1, namely the four phthalate metabolites monobutyl phthalate (MBP), monoethyl phthalate (MEP), monobenzyl pthtalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP) and the non-phthalate plasticiser Bis(7-methyloctyl) Cyclohexane-1,2-dicarboxylate (DINCH) metabolite 2-4-methyl-7-oxyoctyl-oxycarbonyl-cyclohexane carboxylic acid (MINCH). Human mesenchymal stem cells (hMSCs) were exposed to the five compounds individually at the same concentrations as in mixture G1. After exposure, DNA methylation changes in four CpG sites within PGM1, MYOF and HCFC1 genes were analysed. While som chemicals did not show statistically significant effects, one chemical showed significant effects and thus could be a potential driver. The discrepancy between the observed DNA methylation alterations in the analysed genes and the alterations in mixture G1 highlights the need for comparing mixture to single chemical effects to identify drivers within mixes and for increased understanding of mixture effects.

    Publikationen är tillgänglig i fulltext från 2026-01-01 15:14
  • 10. 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, 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.

  • 11.
    Alhamad, Dima W.
    et al.
    Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates..
    Elgendy, Sara M.
    Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates..
    Hersi, Fatema
    Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Med, Sharjah, U Arab Emirates..
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm 32512, Egypt..
    Omar, Hany A.
    Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates.;Beni Suef Univ, Fac Pharm, Dept Pharmacol & Toxicol, Bani Suwayf 62514, Egypt.;Univ Sharjah, Coll Pharm, Dept Pharm Practice & Pharmacotherapeut, Sharjah, U Arab Emirates..
    The inhibition of autophagy by spautin boosts the anticancer activity of fingolimod in multidrug-resistant hepatocellular carcinoma2022Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 304, artikel-id 120699Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The contribution of autophagy to drug resistance has been studied in several cancers. However, there is no clear evidence about the role of autophagy in the resistance to chemotherapy in cancers, such as hepatocellular carcinoma (HCC). HCC is characterized by a poor prognosis and limited therapeutic options. Moreover, the emergence of multidrug-resistance (MDR) hinders successful treatment. Therefore, understanding how autophagy is regulated in resistant HCC is essential for sensitizing this malignancy to chemotherapy. This work demonstrated that basal and induced autophagy differ between parental and resistant Hep3B cells. In optimum growth conditions, the basal level of autophagy was low in resistant Hep3B (Hep3B-R) cells compared to the wild-type Hep3B (Hep3B-P) cells. However, in metabolic or therapeutic stress conditions, the rate of autophagy flux was much faster in the resistant cells. The work also confirmed the pro-survival function of autophagy in HCC. Besides, it demonstrated that the autophagy inhibitor, spautin, acted synergistically with fingolimod (FTY720) to promote cell death. The combination treatment resulted in superior reactive oxygen species (ROS) production and significant induction of apoptosis. In addition, spautin potentiated the effect of FTY720 against cell survival pathways like the Akt and ERK. Interestingly, the results indicated that Hep3B-R cells were more sensitive to autophagy inhibition than their parental counterparts. Collectively, this work revealed that combining spautin with chemotherapeutic agents that induce cytoprotective autophagy such as FTY720 is a promising approach to overcome MDR in HCC.

  • 12. 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.

  • 13.
    Amin, Kawa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning. Univ Sulaimani, Dept Microbiol Immunol, Coll Med, Sulaimani, Iraq.
    Ali, Kosar Muhammad
    Univ Sulaimani, Dept Med, Coll Med, Sulaimani, Iraq.
    Saeed, Amanj
    Minist Higher Educ & Sci Res, Erbil, Iraq.
    Rahman, Heshu Sulaiman
    Univ Sulaimani, Coll Vet Med, Sulaimani, Iraq.
    Byström, Jonas
    Barts & London Queen Mary Univ London, William Harvey Res Inst, Ctr Expt Med & Rheumatol, Charterhouse Sq, London EC1M 6BQ, England.
    Hepatic Immune Response to Environmental Carcinogens2018Ingår i: Pharmacognosy Magazine, ISSN 0973-1296, E-ISSN 0976-4062, Vol. 14, nr 58, s. 548-553Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Environmental carcinogenic substances contribute to increasing incidence of hepatocellular carcinoma (HCC). We employed a sensitive method for the detection of DNA damage combined with analysis of the immune response to gain better knowledge how environmental carcinogens mediate pathology.

    Materials and Methods: Rat hepatocytes were isolated and stimulated with carcinogenic substances for the assessment of DNA damage. The mycotoxin aflatoxin B-1 (AFB(1)), two heterocyclic amines from the cooking of meat amino-3-methylimidazo[4,5-f] quinoline (IQ) and 3-amino-1-methyl-5H-pyr ido-(4,3-b)-indole (TRP-P-2), and protein extract from the fungus Lactarius necator were assayed. Unscheduled DNA synthesis in hepatocytes was measured by the incorporation of radioactive thymidine during DNA repair. Stimulation of hepatocyte/immune cell preparation with the substances and measurement of IFN gamma release at different time points determined their ability to induce an inflammatory response.

    Results: DNA repair in the hepatocytes was induced in response to 10(-7) M AFB(1) and 10(-9) M IQ. TRP-P-2 did not induce DNA repair; however, at 10(-4) M, the fungus extract did this. Furthermore, liver-resident immune cells responded with differential production of IFN gamma over time in response to stimulation by all the carcinogens, with AFB(1) being the most potent. TRP-P-2 showed the most significant reduction in IFN gamma response over time.

    Conclusion: DNA damage in hepatocytes induced by environmental substances was detected at low molecular concentrations. The system did provide novel evidence for hepatic carcinogenicity by the fungus L. necator. Analysis of the response by liver-resident immune cells to the substances suggested that highly mutagenic substances induce prolonged inflammatory response.

  • 14.
    Andersson, Elin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Developing a protocol for RT-qPCR of wing-tissue gene expression and investigating the dynamics of photoperiodically induced polyphenism in the water strider Gerris buenoi2023Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Wing polyphenism in insects is a type of phenotypic plasticity where environmental factors trigger the development of a set of discrete wing morphologies. In the water strider Gerris buenoi, photoperiods are the main environmental cue that trigger wing morph determination. The genetic mechanisms connecting environmental cues and the determination of wing morph in G. buenoi are not clear. However, recent experimental work suggests that engagement of the Hippo pathway via ecdysone signalling is a promising model for further investigation. In this study, a reverse-transcription quantitative PCR (RT-qPCR) protocol was developed, aimed at elucidating this potential transduction pathway by quantifying gene expression of Fat, Dachsous, Yorkie, EcR, E75 and E74. This was done using melt curve analysis, gel electrophoresis, sequencing of RT-qPCR products and qPCR standard curves. Additionally, wing morph distribution in extreme and intermediate photoperiods were examined. Wing morph proportions were significantly different between adults emerging in the intermediate photoperiods 15.30:8.30 and 15:9 (hours light : hours dark). An effect of sex was observed, with a higher probability of males becoming long-winged compared to females. This has likely evolved as a result of a dispersal-reproduction trade-off. Taken together, this study provided insight for future investigations of periodically induced wing morph determination and its genetic mechanisms in G. buenoi that will contribute to the understanding of phenotypic plasticity.

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  • 15.
    Andersson, Linn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Exploring the post-transcriptional regulation of flagellar genes by small RNAs and RNA-binding proteins in Salmonella enterica serovar Typhimurium2024Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
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  • 16.
    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, 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: 2021-06-14Bibliografiskt 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: 2019-12-19Bibliografiskt 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
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  • 17.
    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.

  • 18.
    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, E-ISSN 1932-6203, Vol. 8, nr 10, artikel-id e78133Artikel i tidskrift (Refereegranskat)
  • 19.
    Annika, Staffas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Novel radiosensitization strategies in cancer2024Självständigt arbete på avancerad nivå (masterexamen), 40 poäng / 60 hpStudentuppsats (Examensarbete)
    Abstract [en]

    The aim of this thesis was to investigates the potential of using Onalespib (AT13387) and KRIBB11 in combination with radiotherapy as a novel treatment approach for head and neck cancer (HN), squamous cell carcinoma (SCC) and glioblastoma. Current clinical therapies for these cancer types have limitations, including resistance and unwanted side effects that reduce the quality of life and the likelihood of long-term survival. Radiation is often used in the treatment of HN+SCC and brain tumors, but the addition of novel drugs could eradicate resistant cells and may reduce toxicity due to dose reduction while keeping the efficacy. To evaluate cell lines’ survival, cell based assays such as colony formation, migration, and spheroids were used. Western blot was performed to determine key protein expressions in drug and radiation treated samples. Cell cycle analysis was performed by flow cytometry. Confocal microscopy was used to analyze DNA damage. U87 and U343 glioblastoma cell lines displayed decreased cell survival, arrested cell cycles and increased DNA damage from combination treatment of radiotherapy and Onalespib treatment. SCC cell line A431 and HN cell line SCC-25 showed decreased colony formation for combination therapy (radiotherapy+Onalespib+KRIBB11) and all tested HN+SCC cell lines displayed less migration in cells treated with all therapies combined. The study found conclusive evidence of synergistic effects of radiotherapy and Onalespib on all tested cell lines. The results for the combination therapy in the HN+SCC cell lines showed variations in efficacy and cell survival mainly due to KRIBB11. Combination treatments are a promising strategy to overcome resistance and improve treatment outcomes, however more studies are needed to further improve combination therapies as potential treatment for cancer.

  • 20.
    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.

  • 21.
    Aspenström, Pontus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    The Intrinsic GDP/GTP Exchange Activities of Cdc42 and Rac1 Are A Critical Determinants for Their Specific Effects on Mobilization of the Actin Filament System2019Ingår i: Cells, E-ISSN 2073-4409, Vol. 8, nr 7, artikel-id 759Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Rho GTPases comprise a subfamily of the Ras superfamily of small GTPases. Their importance in regulation of cell morphology and cell migration is well characterized. According to the prevailing paradigm, Cdc42 regulates the formation of filopodia, Rac1 regulates the formation of lamellipodia, and RhoA triggers the assembly of focal adhesions. However, this scheme is clearly an oversimplification, as the Rho subfamily encompasses 20 members with diverse effects on a number of vital cellular processes, including cytoskeletal dynamics and cell proliferation, migration, and invasion. This article highlights the importance of the catalytic activities of the classical Rho GTPases Cdc42 and Rac1, in terms of their specific effects on the dynamic reorganization of the actin filament system. GTPase-deficient mutants of Cdc42 and Rac1 trigger the formation of broad lamellipodia and stress fibers, and fast-cycling mutations trigger filopodia formation and stress fiber dissolution. The filopodia response requires the involvement of the formin family of actin nucleation promotors. In contrast, the formation of broad lamellipodia induced by GTPase-deficient Cdc42 and Rac1 is mediated through Arp2/3-dependent actin nucleation.

    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 22.
    Astvaldsson, Asgeir
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Hultenby, Kjell
    Svärd, Staffan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Jerlstrom-Hultqvist, Joel
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Proximity Staining using Enzymatic Protein Tagging in Diplomonads2019Ingår i: mSphere, E-ISSN 2379-5042, Vol. 4, nr 2, artikel-id e00153-19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The diplomonads are a group of understudied eukaryotic flagellates whose most prominent member is the human pathogen Giardia intestinalis. Methods commonly used in other eukaryotic model systems often require special optimization in diplomonads due to the highly derived character of their cell biology. We have optimized a proximity labeling protocol using pea ascorbate peroxidase (APEX) as a reporter for transmission electron microscopy (TEM), to enable study of ultrastructural cellular details in diplomonads. Currently available TEM-compatible tags requires light-induced activation (1, 2) or are inactive in many cellular compartments (3) while ascorbate peroxidase has not been shown to have those limitations. Here we have optimized the in vivo activity of two versions of pea ascorbate peroxidase (APXW41F and APEX) using the diplomonad fish parasite Spironucleus salmonicida, a relative of G. intestinalis. We exploited the well-known peroxidase substrates, Amplex UltraRed and 3,3’-diaminobenzidine (DAB), to validate the activity of the two tags and argue that APEX is the most stable version to use in Spironucleus salmonicida. Next, we fused APEX to proteins with established localization to evaluate the activity of APEX in different cellular compartments of the diplomonad cell and used Amplex UltraRed as well as antibodies along with super-resolution microscopy to confirm the protein-APEX localization. The ultrastructural details of protein-APEX fusions were determined by TEM and we observed marker activity in all cellular compartments tested when using the DAB substrate. Finally, we show that the optimized conditions established for S. salmonicida can be used in the related diplomonad G. intestinalis.

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    fulltext
  • 23.
    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.

  • 24. Bailleul, Benjamin
    et al.
    Berne, Nicolas
    Murik, Omer
    Petroutsos, Dimitris
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Fysiologi och miljötoxikologi.
    Prihoda, Judit
    Tanaka, Atsuko
    Villanova, Valeria
    Bligny, Richard
    Flori, Serena
    Falconet, Denis
    Krieger-Liszkay, Anja
    Santabarbara, Stefano
    Rappaport, Fabrice
    Joliot, Pierre
    Tirichine, Leila
    Falkowski, Paul G
    Cardol, Pierre
    Bowler, Chris
    Finazzi, Giovanni
    Energetic coupling between plastids and mitochondria drives CO2 assimilation in diatoms.2015Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 524, nr 7565, s. 366-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diatoms are one of the most ecologically successful classes of photosynthetic marine eukaryotes in the contemporary oceans. Over the past 30 million years, they have helped to moderate Earth's climate by absorbing carbon dioxide from the atmosphere, sequestering it via the biological carbon pump and ultimately burying organic carbon in the lithosphere. The proportion of planetary primary production by diatoms in the modern oceans is roughly equivalent to that of terrestrial rainforests. In photosynthesis, the efficient conversion of carbon dioxide into organic matter requires a tight control of the ATP/NADPH ratio which, in other photosynthetic organisms, relies principally on a range of plastid-localized ATP generating processes. Here we show that diatoms regulate ATP/NADPH through extensive energetic exchanges between plastids and mitochondria. This interaction comprises the re-routing of reducing power generated in the plastid towards mitochondria and the import of mitochondrial ATP into the plastid, and is mandatory for optimized carbon fixation and growth. We propose that the process may have contributed to the ecological success of diatoms in the ocean.

  • 25.
    Bajic, Andrej
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi och Handkirurgi.
    Andersson, Brittmarie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi och Handkirurgi.
    Ossinger, Alexander
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi och Handkirurgi.
    Tavakoli, Shima
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Makromolekylär kemi.
    Varghese, Oommen P.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Makromolekylär kemi.
    Schizas, Nikos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi och Handkirurgi.
    Physically and Chemically Crosslinked Hyaluronic Acid-Based Hydrogels Differentially Promote Axonal Outgrowth from Neural Tissue Cultures2024Ingår i: Biomimetics, E-ISSN 2313-7673, Vol. 9, nr 3, artikel-id 140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our aim was to investigate axonal outgrowth from different tissue models on soft biomaterials based on hyaluronic acid (HA). We hypothesized that HA-based hydrogels differentially promote axonal outgrowth from different neural tissues. Spinal cord sliced cultures (SCSCs) and dorsal root ganglion cultures (DRGCs) were maintained on a collagen gel, a physically crosslinked HA-based hydrogel (Healon 5®) and a novel chemically crosslinked HA-based hydrogel, with or without the presence of neurotrophic factors (NF). Time-lapse microscopy was performed after two, five and eight days, where axonal outgrowth was assessed by automated image analysis. Neuroprotection was investigated by PCR. Outgrowth was observed in all groups; however, in the collagen group, it was scarce. At the middle timepoint, outgrowth from SCSCs was superior in both HA-based groups compared to collagen, regardless of the presence of NF. In DRGCs, the outgrowth in Healon 5® with NF was significantly higher compared to the rest of the groups. PCR revealed upregulation of NeuN gene expression in the HA-based groups compared to controls after excitotoxic injury. The differences in neurite outgrowth from the two different tissue models suggest that axons differentially respond to the two types of biomaterials.

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  • 26. 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.

  • 27.
    Barbera, Stefano
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy..
    Lugano, Roberta
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Pedalina, Alessia
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy..
    Mongiat, Maurizio
    Ctr Riferimento Oncol Aviano CRO IRCCS, Dept Res & Diag, Div Mol Oncol, Aviano, Italy..
    Santucci, Annalisa
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy..
    Tosi, Gian Marco
    Univ Siena, Dept Med Surg & Neurosci, Ophthalmol Unit, Siena, Italy..
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Galvagni, Federico
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy..
    Orlandini, Maurizio
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy..
    The C-type lectin CD93 controls endothelial cell migration via activation of the Rho family of small GTPases2021Ingår i: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 99, s. 1-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Endothelial cell migration is essential to angiogenesis, enabling the outgrowth of new blood vessels both in physiological and pathological contexts. Migration requires the activation of several signaling pathways, the elucidation of which expands the opportunity to develop new drugs to be used in antiangiogenic therapy. In the proliferating endothelium, the interaction between the transmembrane glycoprotein CD93 and the extra cellular matrix activates signaling pathways that regulate cell adhesion, migration, and vascular maturation. Here we identify a pathway, comprising CD93, the adaptor proteins Cbl and Crk, and the small GTPases Rac1, Cdc42, and RhoA, which we propose acts as a regulator of cytoskeletal movements responsible for endothelial cell migration. In this framework, phosphorylation of Cbl on tyrosine 774 leads to the interaction with Crk, which acts as a downstream integrator in the CD93-mediated signaling regulating cell polarity and migration. Moreover, confocal microscopy analyses of GTPase biosensors show that CD93 drives coordinated activation of Rho-proteins at the cell edge of migratory endothelial cells. In conclusion, together with the demonstration of the key contribution of CD93 to the migratory process in living cells, these findings suggest that the signaling triggered by CD93 converges to the activation and modulation of the Rho GTPase signaling pathways regulating cell dynamics.

  • 28.
    Barbera, Stefano
    et al.
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Nardi, Federica
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Elia, Ines
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Realini, Giulia
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Lugano, Roberta
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Santucci, Annalisa
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Tosi, Gian Marco
    Univ Siena, Dept Med Surg & Neurosci, Ophthalmol Unit, Policlin Le Scotte, Viale Bracci, I-53100 Siena, Italy.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Galvagni, Federico
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Orlandini, Maurizio
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    The small GTPase Rab5c is a key regulator of trafficking of the CD93/Multimerin-2/1 integrin complex in endothelial cell adhesion and migration2019Ingår i: Cell Communication and Signaling, E-ISSN 1478-811X, Vol. 17, artikel-id 55Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    In the endothelium, the single-pass membrane protein CD93, through its interaction with the extracellular matrix protein Multimerin-2, activates signaling pathways that are critical for vascular development and angiogenesis. Trafficking of adhesion molecules through endosomal compartments modulates their signaling output. However, the mechanistic basis coordinating CD93 recycling and its implications for endothelial cell (EC) function remain elusive.

    Methods

    Human umbilical vein ECs (HUVECs) and human dermal blood ECs (HDBEC) were used in this study. Fluorescence confocal microscopy was employed to follow CD93 retrieval, recycling, and protein colocalization in spreading cells. To better define CD93 trafficking, drug treatments and transfected chimeric wild type and mutant CD93 proteins were used. The scratch assay was used to evaluate cell migration. Gene silencing strategies, flow citometry, and quantification of migratory capability were used to determine the role of Rab5c during CD93 recycling to the cell surface.

    Results

    Here, we identify the recycling pathway of CD93 following EC adhesion and migration. We show that the cytoplasmic domain of CD93, by its interaction with Moesin and F-actin, is instrumental for CD93 retrieval in adhering and migrating cells and that aberrant endosomal trafficking of CD93 prevents its localization at the leading edge of migration. Moreover, the small GTPase Rab5c turns out to be a key component of the molecular machinery that is able to drive CD93 recycling to the EC surface. Finally, in the Rab5c endosomal compartment CD93 forms a complex with Multimerin-2 and active 1 integrin, which is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis.

    Conclusions

    Our findings, focusing on the pro-angiogenic receptor CD93, unveil the mechanisms of its polarized trafficking during EC adhesion and migration, opening novel therapeutic opportunities for angiogenic diseases.

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  • 29.
    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)
  • 30.
    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.

  • 31.
    Bazi, Hadi
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning. Karolinska Institute.
    Investigating The Nuclear Translocation of Mitochondrial Factor (MF) Upon Low Insulin/IGF Signaling In C. elegans2023Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Publikationen är tillgänglig i fulltext från 2033-08-14 00:28
  • 32.
    Beljanski, Vladimir
    et al.
    Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA.
    Grinnemo, Karl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi. Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Div Cardiothorac Surg & Anesthesiol, Stockholm, Sweden.
    Österholm, Cecilia
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Div Cardiothorac Surg & Anesthesiol, Stockholm, Sweden.
    Pleiotropic roles of autophagy in stem cell-based therapies2019Ingår i: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 21, nr 4, s. 380-392Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Stem cells (SCs) have been proven to possess regenerative and immunomodulatory properties and can be used to treat diseases that involve loss of cells due to tissue damage or inflammation. For this approach to succeed, SCs or their derivatives should be able to engraft in the target tissue at least for a short period of time. Unfortunately, once injected, therapeutic SCs will encounter a hostile environment, including hypoxia, lack of nutrients and stromal support, and cells may also be targeted and rejected by the immune system. Therefore, SC's stress-response mechanisms likely play a significant role in survival of injected cells and possibly contribute to their therapeutic efficacy. Autphagy, a stress-response pathway, is involved in many different cellular processes, such as survival during hypoxia and nutrient deprivation, cellular differentiation and de-differentiation, and it can also contribute to their immunovisibility by regulating antigen presentation and cytokine secretion. Autophagy machinery interacts with many proteins and signaling pathways that regulate SC properties, including PI3K/Akt, mammalian target of rapamycin (mTOR), Wnt, Hedgehog and Notch, and it is also involved in regulating intracellular reactive oxygen species (ROS) levels. In this review, we contend that autophagy is an important therapeutic target that can be used to improve the outcome of SC-based tissue repair and regeneration. Further research should reveal whether inhibition or stimulation of autophagy increases the therapeutic utility of SCs and it should also identify appropriate therapeutic regimens that can be applied in the clinic.

  • 33. 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)
  • 34.
    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, 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: 2022-09-15Bibliografiskt 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
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    (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
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  • 35.
    Bergero, Roberta
    et al.
    Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland..
    Ellis, Peter
    Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England..
    Haerty, Wilfried
    Earlham Inst, Norwich Res Pk, Norwich NR4 7UZ, Norfolk, England..
    Larcombe, Lee
    Appl Exom Ltd, Stevenage Biosci Catalyst, Stevenage SG1 2FX, Herts, England..
    Macaulay, Iain
    Earlham Inst, Norwich Res Pk, Norwich NR4 7UZ, Norfolk, England..
    Mehta, Tarang
    Earlham Inst, Norwich Res Pk, Norwich NR4 7UZ, Norfolk, England..
    Mogensen, Mette
    Univ East Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England..
    Murray, David
    Univ East Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England..
    Nash, Will
    Earlham Inst, Norwich Res Pk, Norwich NR4 7UZ, Norfolk, England..
    Neale, Matthew J.
    Univ Sussex, Sch Life Sci, Genome Damage & Stabil Ctr, Brighton BN1 9RH, E Sussex, England..
    O'Connor, Rebecca
    Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England..
    Ottolini, Christian
    Evewell, 61 Harley St, London W1G 8QU, England..
    Peel, Ned
    Earlham Inst, Norwich Res Pk, Norwich NR4 7UZ, Norfolk, England..
    Ramsey, Luke
    James Hutton Inst, Dundee DD2 5DA, Scotland..
    Skinner, Ben
    Univ Essex, Sch Life Sci, Colchester CO4 3SQ, Essex, England..
    Suh, Alexander
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Systematisk biologi. Univ East Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England..
    Summers, Michael
    Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England.;Bridge Ctr, 1 St Thomas St, London SE1 9RY, England..
    Sun, Yu
    Univ East Anglia, Norwich Med Sch, Norwich Res Pk,Colney Ln, Norwich NR4 7UG, Norfolk, England..
    Tidy, Alison
    Univ Nottingham, Sch Biosci, Plant Sci, Sutton Bonington Campus, Loughborough LE12 5RD, England..
    Rahbari, Raheleh
    Wellcome Sanger Inst, Cambridge CB10 1SA, England..
    Rathje, Claudia
    Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England..
    Immler, Simone
    Univ East Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England..
    Meiosis and beyond - understanding the mechanistic and evolutionary processes shaping the germline genome2021Ingår i: Biological Reviews, ISSN 1464-7931, E-ISSN 1469-185X, Vol. 96, nr 3, s. 822-841Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The separation of germ cell populations from the soma is part of the evolutionary transition to multicellularity. Only genetic information present in the germ cells will be inherited by future generations, and any molecular processes affecting the germline genome are therefore likely to be passed on. Despite its prevalence across taxonomic kingdoms, we are only starting to understand details of the underlying micro-evolutionary processes occurring at the germline genome level. These include segregation, recombination, mutation and selection and can occur at any stage during germline differentiation and mitotic germline proliferation to meiosis and post-meiotic gamete maturation. Selection acting on germ cells at any stage from the diploid germ cell to the haploid gametes may cause significant deviations from Mendelian inheritance and may be more widespread than previously assumed. The mechanisms that affect and potentially alter the genomic sequence and allele frequencies in the germline are pivotal to our understanding of heritability. With the rise of new sequencing technologies, we are now able to address some of these unanswered questions. In this review, we comment on the most recent developments in this field and identify current gaps in our knowledge.

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  • 36. 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.

  • 37.
    Bergstrand, Jan
    et al.
    Royal Inst Technol KTH, Dept Appl Phys, Albanova Univ Ctr, Expt Biomol Phys, SE-10691 Stockholm, Sweden.
    Xu, Lei
    Royal Inst Technol KTH, Dept Appl Phys, Albanova Univ Ctr, Expt Biomol Phys, SE-10691 Stockholm, Sweden.
    Miao, Xinyan
    Royal Inst Technol KTH, Dept Appl Phys, Albanova Univ Ctr, Expt Biomol Phys, SE-10691 Stockholm, Sweden.
    Li, Nailin
    Karolinska Inst, Dept Med Solna, Karolinska Univ Hosp Solna, Clin Pharmacol, L7 03, SE-17176 Stockholm, Sweden.
    Oktem, Ozan
    Royal Inst Technol KTH, Dept Math, Lindstedsvagen 25, SE-10044 Stockholm, Sweden.
    Franzen, Bo
    Karolinska Inst, Dept Oncol Pathol, Karolinska Univ Hosp, K7,Z1 00, S-17176 Stockholm, Sweden.
    Auer, Gert
    Karolinska Inst, Dept Oncol Pathol, Karolinska Univ Hosp, K7,Z1 00, S-17176 Stockholm, Sweden.
    Lomnytska, Marta
    Karolinska Inst, Dept Oncol Pathol, Karolinska Univ Hosp, K7,Z1 00, S-17176 Stockholm, Sweden;Acad Univ Hosp, Dept Obstet & Gynaecol, SE-75185 Uppsala, Sweden.
    Widengren, Jerker
    Royal Inst Technol KTH, Dept Appl Phys, Albanova Univ Ctr, Expt Biomol Phys, SE-10691 Stockholm, Sweden.
    Super-resolution microscopy can identify specific protein distribution patterns in platelets incubated with cancer cells2019Ingår i: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 11, nr 20, s. 10023-10033Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein contents in platelets are frequently changed upon tumor development and metastasis. However, how cancer cells can influence protein-selective redistribution and release within platelets, thereby promoting tumor development, remains largely elusive. With fluorescence-based super-resolution stimulated emission depletion (STED) imaging we reveal how specific proteins, implicated in tumor progression and metastasis, re-distribute within platelets, when subject to soluble activators (thrombin, adenosine diphosphate and thromboxane A2), and when incubated with cancer (MCF-7, MDA-MB-231, EFO21) or non-cancer cells (184A1, MCF10A). Upon cancer cell incubation, the cell-adhesion protein P-selectin was found to re-distribute into circular nano-structures, consistent with accumulation into the membrane of protein-storing alpha-granules within the platelets. These changes were to a significantly lesser extent, if at all, found in platelets incubated with normal cells, or in platelets subject to soluble platelet activators. From these patterns, we developed a classification procedure, whereby platelets exposed to cancer cells, to non-cancer cells, soluble activators, as well as non-activated platelets all could be identified in an automatic, objective manner. We demonstrate that STED imaging, in contrast to electron and confocal microscopy, has the necessary spatial resolution and labelling efficiency to identify protein distribution patterns in platelets and can resolve how they specifically change upon different activations. Combined with image analyses of specific protein distribution patterns within the platelets, STED imaging can thus have a role in future platelet-based cancer diagnostics and therapeutic monitoring. The presented approach can also bring further clarity into fundamental mechanisms for cancer cell-platelet interactions, and into non-contact cell-to-cell interactions in general.

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  • 38.
    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, 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.

  • 39.
    Bernier-Latmani, Jeremiah
    et al.
    Ludwig Inst Canc Res Lausanne, Dept Oncol, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Mauri, Cristina
    Ludwig Inst Canc Res Lausanne, Dept Oncol, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Marcone, Rachel
    SIB Swiss Inst Bioinformat, Bioinformat Core Facil, Lausanne, Switzerland..
    Renevey, Francois
    Univ Lausanne, Dept Immunobiol, Lausanne, Switzerland..
    Durot, Stephan
    ETH, Inst Mol Syst Biol, Zurich, Switzerland..
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Vanlandewijck, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Dept Med Huddinge, Huddinge, Sweden..
    Maclachlan, Catherine
    Ecole Polytech Fed Lausanne, Bio Electron Microscopy Lab, Sch Life Sci, Lausanne, Switzerland..
    Davanture, Suzel
    Ludwig Inst Canc Res Lausanne, Dept Oncol, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Zamboni, Nicola
    ETH, Inst Mol Syst Biol, Zurich, Switzerland..
    Knott, Graham W.
    Ecole Polytech Fed Lausanne, Bio Electron Microscopy Lab, Sch Life Sci, Lausanne, Switzerland..
    Luther, Sanjiv A.
    Univ Lausanne, Dept Immunobiol, Lausanne, Switzerland..
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Dept Med Huddinge, Huddinge, Sweden..
    Delorenzi, Mauro
    Ludwig Inst Canc Res Lausanne, Dept Oncol, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland.;SIB Swiss Inst Bioinformat, Bioinformat Core Facil, Lausanne, Switzerland..
    Brisken, Cathrin
    Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res ISREC, Sch Life Sci, Lausanne, Switzerland..
    Petrova, Tatiana, V
    Ludwig Inst Canc Res Lausanne, Dept Oncol, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland.;Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res ISREC, Sch Life Sci, Lausanne, Switzerland..
    ADAMTS18+ villus tip telocytes maintain a polarized VEGFA signaling domain and fenestrations in nutrient-absorbing intestinal blood vessels2022Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 13, nr 1, artikel-id 3983Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The small intestinal villus tip is the first point of contact for lumen-derived substances including nutrients and microbial products. Electron microscopy studies from the early 1970s uncovered unusual spatial organization of small intestinal villus tip blood vessels: their exterior, epithelial-facing side is fenestrated, while the side facing the villus stroma is non-fenestrated, covered by pericytes and harbors endothelial nuclei. Such organization optimizes the absorption process, however the molecular mechanisms maintaining this highly specialized structure remain unclear. Here we report that perivascular LGR5(+) villus tip telocytes (VTTs) are necessary for maintenance of villus tip endothelial cell polarization and fenestration by sequestering VEGFA signaling. Mechanistically, unique VTT expression of the protease ADAMTS18 is necessary for VEGFA signaling sequestration through limiting fibronectin accumulation. Therefore, we propose a model in which LGR5(+) ADAMTS18(+) telocytes are necessary to maintain a "just-right" level and location of VEGFA signaling in intestinal villus blood vasculature to ensure on one hand the presence of sufficient endothelial fenestrae, while avoiding excessive leakiness of the vessels and destabilization of villus tip epithelial structures. The molecular mechanisms ensuring the specialized structure of small intestinal villus tip blood vessels are incompletely understood. Here the authors show that ADAMTS18(+) telocytes maintain a "just-right" level and location of VEGFA signaling on intestinal villus blood vessels, thereby ensuring the presence of endothelial fenestrae for nutrient absorption, while avoiding excessive leakiness and destabilization of villus tip epithelial structures.

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  • 40.
    Bertilsson, Filippa
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Spatial mapping of motile cilia proteins in respiratory and female reproductive tissues2024Självständigt arbete på avancerad nivå (masterexamen), 40 poäng / 60 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Motile cilia play critical roles in the human body, including expelling mucus from the lungs and facilitating the transport of oocytes and sperm through the fallopian tubes. Understanding the complex structure and motility of cilia, as well as the diseases associated with them, is of big importance. This study investigates the proteins expressed in ciliated cells from both respiratory and reproductive tissues using multiplex immunofluorescence. We determined the subcellular localization of 134 proteins in the fallopian tube, endometrium, cervix, nasopharynx, and bronchus, focusing on five subcellular regions: the cilia tip, transition zone, basal body, cytoplasm, and nucleus. This analysis was conducted using an automated image analysis method developed specifically for this project. Our findings revealed a high correlation in protein expression across all tissues, although several proteins exhibited distinct expression patterns between different tissues. Notably, the fallopian tube showed a higher correlation with the nasopharynx and bronchus than with the endometrium and cervix. Within these proteins, six gene clusters were identified, with the two largest clusters being strongly associated with ciliary structure. This study enhances our understanding of motile ciliary structures and ciliated cells, identifying key proteins for further research into cilia motion, function, and related diseases.

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  • 41.
    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, 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.

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  • 42.
    Björnör, Saga
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för biologisk grundutbildning.
    Investigating the unknown CdiA-CT-2 toxin used by E. coli D12 to outcompete other bacteria2024Självständigt arbete på avancerad nivå (masterexamen), 30 poäng / 45 hpStudentuppsats (Examensarbete)
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  • 43.
    Blanc, Caroline
    et al.
    Laboratory of Biology and Modeling of the Cell, Ecole Normale Supérieure de Lyon, CNRS UMR 5239, Inserm U1293, University Claude Bernard Lyon 1, Lyon, France..
    Saclier, Nathanaelle
    Institut des Sciences de l'Evolution, Université Montpellier, Institut de Recherche pour le Développement, 34090 Montpellier, France..
    Le Faou, Ehouarn
    University of Rennes, CNRS, ECOBIO (Ecologie, Biodiversité, Evolution)–UMR 6553, F-35000 Rennes, France..
    Marie-Orleach, Lucas
    University of Rennes, CNRS, ECOBIO (Ecologie, Biodiversité, Evolution)–UMR 6553, F-35000 Rennes, France..
    Wenger, Eva
    Laboratory of Biology and Modeling of the Cell, Ecole Normale Supérieure de Lyon, CNRS UMR 5239, Inserm U1293, University Claude Bernard Lyon 1, Lyon, France..
    Diblasi, Celian
    Institut des Sciences de l'Evolution, Université Montpellier, Institut de Recherche pour le Développement, 34090 Montpellier, France..
    Glémin, Sylvain
    University of Rennes, CNRS, ECOBIO (Ecologie, Biodiversité, Evolution)–UMR 6553, F-35000 Rennes, France.;Department of Ecology and Genetics, Evolutionary Biology Centre, Uppsala University, 75236 Uppsala, Sweden..
    Galtier, Nicolas
    Institut des Sciences de l'Evolution, Université Montpellier, Institut de Recherche pour le Développement, 34090 Montpellier, France..
    Delattre, Marie
    Laboratory of Biology and Modeling of the Cell, Ecole Normale Supérieure de Lyon, CNRS UMR 5239, Inserm U1293, University Claude Bernard Lyon 1, Lyon, France..
    Cosegregation of recombinant chromatids maintains genome-wide heterozygosity in an asexual nematode2023Ingår i: Science Advances, E-ISSN 2375-2548, Vol. 9, nr 34Artikel i tidskrift (Refereegranskat)
  • 44.
    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, 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.

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  • 45. 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.

  • 46.
    Bogatikov, Evgenii
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Rostedt Punga: Klinisk neurofysiologi.
    Lindblad, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Rostedt Punga: Klinisk neurofysiologi.
    Punga, Tanel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rostedt Punga, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Rostedt Punga: Klinisk neurofysiologi.
    miR-1933-3p is upregulated in skeletal muscles of MuSK+ EAMG mice and affects Impa1 and Mrpl272020Ingår i: Neuroscience research, ISSN 0168-0102, E-ISSN 1872-8111, Vol. 151, s. 46-52Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    MuSK antibody seropositive (MuSK+) Myasthenia Gravis (MG) typically affects skeletal muscles of the bulbar area, including the omohyoid muscle, causing focal fatigue, weakness and atrophy. The profile of circulating extracellular microRNA (miRNA) is changed in MuSK + MG, but the intracellular miRNA profile in skeletal muscles of MuSK + MG and MuSK + experimental autoimmune MG (EAMG) remains unknown. This study elucidated the intracellular miRNA profile in the omohyoid muscle of mice with MuSK + EAMG. The levels of eleven mouse miRNAs were elevated and two mouse miRNAs were reduced in muscles of MuSK + EAMG mice. Transient expression of miR-1933-3p and miR-1930-5p in mouse muscle (C2C12) cells revealed several downregulated genes, out of which five had predicted binding sites for miR-1933-3p. The mRNA expression of mitochondrial ribosomal protein L27 (Mrpl27) and Inositol monophosphatase I (Impa1) was reduced in miR-1933-3p transfected C2C12 cells compared to control cells (p = 0.032 versus p = 0.020). Further, transient expression of miR-1933-3p reduced Impa1 protein accumulation in C2C12 cells. These findings provide novel insights of dysregulated miRNAs and their intracellular pathways in muscle tissue afflicted with MuSK + EAMG, providing a possible link to mitochondrial dysfunction and muscle atrophy observed in MuSK + MG.

  • 47.
    Bogatikov, Evgenii
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Rostedt Punga: Klinisk neurofysiologi.
    Rostedt Punga, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Rostedt Punga: Klinisk neurofysiologi.
    Evaluation of motor unit potential parameters in relation to morphology of skeletal muscles culture on MEA chipsManuskript (preprint) (Övrigt vetenskapligt)
  • 48.
    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
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  • 49.
    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.

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  • 50.
    Bonagas, Nadilly
    et al.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Gustafsson, Nina M. S.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Henriksson, Martin
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Marttila, Petra
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Gustafsson, Robert
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Wiita, Elisee
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Borhade, Sanjay
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Green, Alanna C.
    Univ Sheffield, Med Sch, Dept Oncol & Metab, Weston Pk Canc Ctr, Sheffield, S Yorkshire, England..
    Vallin, Karl S. A.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Sarno, Antonio
    Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway..
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gokturk, Camilla
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Pham, Therese
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Jemth, Ann-Sofie
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Loseva, Olga
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Cookson, Victoria
    Univ Sheffield, Med Sch, Dept Oncol & Metab, Weston Pk Canc Ctr, Sheffield, S Yorkshire, England..
    Kiweler, Nicole
    Luxembourg Inst Hlth, Dept Oncol, Canc Metab Grp, Luxembourg, Luxembourg..
    Sandberg, Lars
    Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Rasti, Azita
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Unterlass, Judith E.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Haraldsson, Martin
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Andersson, Yasmin
    Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Scaletti, Emma R.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.;Lund Univ, Dept Expt Med Sci, Lund, Sweden..
    Bengtsson, Christoffer
    Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Paulin, Cynthia B. J.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Sanjiv, Kumar
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Abdurakhmanov, Eldar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pudelko, Linda
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Kunz, Ben
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Desroses, Matthieu
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Iliev, Petar
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Farnegardh, Katarina
    Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Kramer, Andreas
    Goethe Univ, Inst Pharmaceut Chem, Frankfurt, Germany..
    Garg, Neeraj
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Michel, Maurice
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Haggblad, Sara
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, Solna, Sweden..
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kalderen, Christina
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Jensen, Amanda Bogedahl
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Almlof, Ingrid
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Karsten, Stella
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Zhang, Si Min
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Haggblad, Maria
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, Solna, Sweden..
    Eriksson, Anders
    Karolinska Inst, Karolinska High Throughput Ctr, Dept Biosci & Nutr, Huddinge, Sweden..
    Liu, Jianping
    Karolinska Inst, Karolinska High Throughput Ctr, Dept Biosci & Nutr, Huddinge, Sweden..
    Glinghammar, Bjorn
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Nekhotiaeva, Natalia
    Karolinska Inst, Karolinska High Throughput Ctr, Dept Biosci & Nutr, Huddinge, Sweden..
    Klingegard, Fredrik
    Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Koolmeister, Tobias
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Martens, Ulf
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, Solna, Sweden..
    Llona-Minguez, Sabin
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Moulson, Ruth
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Nordström, Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Parrow, Vendela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Dahllund, Leif
    Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Sjoberg, Birger
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Vargas, Irene L.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Vo, Duy Duc
    Uppsala Univ, Dept Med Chem, Sci Life Lab, Uppsala, Sweden..
    Wannberg, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Knapp, Stefan
    Goethe Univ, Inst Pharmaceut Chem, Frankfurt, Germany..
    Krokan, Hans E.
    Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway..
    Arvidsson, Per, I
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden..
    Scobie, Martin
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Meiser, Johannes
    Luxembourg Inst Hlth, Dept Oncol, Canc Metab Grp, Luxembourg, Luxembourg..
    Stenmark, Pal
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.;Lund Univ, Dept Expt Med Sci, Lund, Sweden..
    Berglund, Ulrika Warpman
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Homan, Evert J.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
    Helleday, Thomas
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.;Univ Sheffield, Med Sch, Dept Oncol & Metab, Weston Pk Canc Ctr, Sheffield, S Yorkshire, England..
    Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress2022Ingår i: NATURE CANCER, ISSN 2662-1347, Vol. 3, nr 2, s. 156-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.

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