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  • 1.
    Abreu-Vieira, Gustavo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fischer, Alexander W.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Hamburg, Germany.
    Mattsson, Charlotte
    de Jong, Jasper M. A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ryden, Mikael
    Laurencikiene, Jurga
    Arner, Peter
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cidea improves the metabolic profile through expansion of adipose tissue2015In: Nature Communications, E-ISSN 2041-1723, Vol. 6, article id 7433Article in journal (Refereed)
    Abstract [en]

    In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.

  • 2.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    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 Organogenesis2016In: Traffic: the International Journal of Intracellular Transport, ISSN 1398-9219, E-ISSN 1600-0854, Vol. 17, no 1, p. 66-79Article in journal (Refereed)
    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.

  • 3.
    Achour, Cyrinne
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Canonical and non-canonical functions of METTL3 in breast cancer2022Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Gene expression is spatially and temporally regulated at multiple levels. N6-methyladenosine (m6A) is the most prevalent internal modification in messenger RNA (mRNA) and long noncoding RNA (lncRNAs). m6A plays important roles in multiple cellular processes including stem cell pluripotency, adipogenesis, spermatogenesis, neurogenesis, circadian rhythm and development by modulating RNA splicing, export, stability, degradation and translation. Although aberrant m6A methylation has been reported in various types of cancer, the underlying molecular functions of METTL3, the solely catalytic subunit of the m6A-methylase complex, has yet to be defined.

    m6A has been recently identified in nascent pre-mRNA, and more specifically intronic m6A has been linked to exon skipping events. The occurrence of impaired alternative splicing (AS) is frequently found during the development of cancer. We performed transcriptome wide analysis in breast cancer cell lines and explored AS events. Our results define an AS signature for breast tumorigenesis. We found that METTL3 modulates AS directly through m6A deposition at the intron-exon junctions or indirectly by the m6A deposition in transcripts encoding for splicing factors and transcription factors. In particular, we show that MYC mRNA harbours the m6A mark, suggesting that METTL3 regulates AS indirectly via the regulation of MYC expression. Indeed, the targets of MYC overlapped with METTL3-associated AS events. Importantly, five of the AS events identified and validated in vitro, are linked to a worse prognosis in breast cancer patients. Additionally, we show that METTL3 enhances the breast cancer phenotype through a dual mechanism depending on its sub-cellular localization. We find that the canonical nuclear function of METTL3 decorates transcripts that are involved in cell proliferation and migration. We observe that METTL3 is highly expressed in the cytoplasmic compartment of breast cancer cells from patients. Remarkably, we uncover that the cytoplasmic METTL3 interacts with subunits of the exocyst, whose subunit EXOC7 has been linked to cell adhesion, migration and invasion. Notably, we show that breast cancer cell lines depleted of METTL3 display less gelatinase activity and invadopodia formation, supporting the role of METTL3 in cell invasion via exocytosis.

    m6A is a reversible modification, which can be demethylated by the erasers FTO and ALKBH5. Depletion of FTO has been shown to increase the level of m6A in mRNA, however recent studies have reported that FTO could demethylate N6,2´-O-dimethyladenosine (m6Am), adjacent to the 7-methylguanosine cap on mRNA. In the cellular model of colorectal cancer CRC1, depletion of FTO leads to a cancer stem cell phenotype and confers chemotherapy resistance. By performing m6A-RNA immunoprecipitation followed by sequencing (MeRIP), we show that knockdown of FTO in CRC1 cells does not affect the global level of m6A in mRNA but of m6Am level.

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    The full text will be freely available from 2024-12-13 07:00
  • 4.
    Achour, Cyrinne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Bhattarai, Devi Prasad
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Esteva-Socias, Margalida
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rodriguez-Barrueco, Ruth
    Malla, Sandhya
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Seier, Kerstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Marchand, Virginie
    Motorine, Yuri
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marzese, Diego Matias
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Roman, Angel-Carlos
    Pich, Andreas
    Aguilo, Francesca
    Reshaping the role of METTL3 in breast tumorigenesisManuscript (preprint) (Other academic)
  • 5.
    Ademovski, Emir
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV).
    In vitro effects of skincare ingredients on keratinocytes2023Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The skin has several functions as the largest and one of the most complex organs of the body. One of the skin’s primary functions is to prevent water loss by retaining water to allow the skin to function in dry environments. The outermost layer, stratum corneum (SC), retains water loss as rehydration by natural moisturizing factors (NMFs). In this project, HaCaT cells were incubated with commonly used skincare ingredients such as urea, glycerol, transcutol, salicylic acid, and polyethylene glycol 4000 Da (PEG-4000) to evaluate their impact on cell viability, MTT proliferation assay and gene expression measurements by qPCR. The relationship between cell viability, gene expression, and water activity was also studied. The excipients showed a dose-dependent decrease in cell viability because osmotic pressure increased. One finding was that transcutol exhibited a protective effect against concentrations where osmotic pressure harmed the cells. PEG-4000, with a concentration of 10 % (w/v), showed an upregulation of elongation of very long chain fatty acid 4 (ELOVL-4). Gene expression of serine palmitoyltransferase (SPT) was low, with 10 mM transcutol, even though the cells had a viability of >100 %. It should have conducted an upregulation of SPT from the high metabolic activity in the cells. In conclusion, the viability and gene expression were most likely related to osmotic stress but should be further analyzed with digital holographic microscopy (DHM) and Western blot. 

  • 6.
    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.2008In: Journal of Microscopy, ISSN 0022-2720, E-ISSN 1365-2818, Vol. 230, no Pt 1, p. 121-33Article in journal (Refereed)
  • 7.
    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.2007In: Journal of Microscopy, Vol. 227, no Pt 1, p. 83; author reply 84-5Article in journal (Other academic)
  • 8.
    Adler, Jeremy
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Parmryd, Ingela
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Plasma membrane topology and membrane models2009In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 3, no Supplement 1, p. 282a-282a, article id 1435-PosArticle in journal (Other academic)
  • 9.
    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 Coefficient2010In: CYTOMETRY PART A, ISSN 1552-4922, Vol. 77A, no 8, p. 733-742Article in journal (Refereed)
    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.

  • 10.
    Adler, Jeremy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    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 correlation2019In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 132, no 1, article id UNSP jcs222455Article in journal (Other academic)
  • 11.
    Adler, Jeremy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Quantifying colocalization: thresholding, void voxels and the H-coef2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 11, p. e111983-Article in journal (Refereed)
    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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  • 12. Adler, Jeremy
    et al.
    Shevchuk, Andrew I
    Novak, Pavel
    Korchev, Yuri E
    Parmryd, Ingela
    Plasma membrane topography and interpretation of single-particle tracks.2010In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 7, no 3, p. 170-1Article in journal (Refereed)
  • 13.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Teichmann, Martin
    Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux 2, rue , Robert Escarpit, 33607 Pessac, France..
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Smit, Arian
    Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Singh, Umashankar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs2016In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, p. 1558-1571Article in journal (Refereed)
    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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  • 14.
    Agrillo, Caroline
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    DNA methylation modifications in human mesenchymal stem cells  induced by exposure to endocrine disrupting plasticiser metabolites MBP, MEP, MBzP, MEHP and MINCH2022Independent thesis Advanced level (degree of Master (Two Years)), 80 credits / 120 HE creditsStudent thesis
    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.

    The full text will be freely available from 2026-01-01 15:14
  • 15.
    Aguilera, Anabella
    et al.
    Fundación para Investigaciones Biológicas Aplicadas (CIB-FIBA), Argentina.
    Berdun, Federico
    Fundación para Investigaciones Biológicas Aplicadas (CIB-FIBA), Argentina.
    Bartoli, Carlos
    Universidad Nacional de La Plata, Argentina.
    Steelheart, Charlotte
    Universidad Nacional de La Plata, Argentina.
    Alegre, Matías
    Universidad Nacional de La Plata, Argentina.
    Bayir, Hülya
    University of Pittsburgh, USA.
    Tyurina, Yulia Y.
    University of Pittsburgh, USA.
    Kagan, Valerian E.
    University of Pittsburgh, USA;IM Sechenov Moscow State Medical University, Russia.
    Salerno, Graciela
    Fundación para Investigaciones Biológicas Aplicadas (CIB-FIBA), Argentina.
    Pagnussat, Gabriela
    Universidad Nacional de Mar del Plata, Argentina.
    Martin, María Victoria
    Fundación para Investigaciones Biológicas Aplicadas (CIB-FIBA), Argentina.
    C-ferroptosis is an iron-dependent form of regulated cell death in cyanobacteria2021In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 221, no 2, article id e201911005Article in journal (Refereed)
    Abstract [en]

    Ferroptosis is an oxidative and iron-dependent form of regulated cell death (RCD) recently described in eukaryotic organisms like animals, plants, and parasites. Here, we report that a similar process takes place in the photosynthetic prokaryote Synechocystis sp. PCC 6803 in response to heat stress. After a heat shock, Synechocystis sp. PCC 6803 cells undergo a cell death pathway that can be suppressed by the canonical ferroptosis inhibitors, CPX, vitamin E, Fer-1, liproxstatin-1, glutathione (GSH), or ascorbic acid (AsA). Moreover, as described for eukaryotic ferroptosis, this pathway is characterized by an early depletion of the antioxidants GSH and AsA, and by lipid peroxidation. These results indicate that all of the hallmarks described for eukaryotic ferroptosis are conserved in photosynthetic prokaryotes and suggest that ferroptosis might be an ancient cell death program.

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  • 16.
    Aguilera, Anabella
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Distéfano, Ayelén
    Universidad Nacional de Mar del Plata, Argentina.
    Jauzein, Cécile
    Ifremer, France.
    Correa-Aragunde, Natalia
    Universidad Nacional de Mar del Plata, Argentina.
    Martinez, Dana
    Universidad Nacional de La Plata, Argentina.
    Martin, María Victoria
    Fundación para InveUniversidad Nacional de Mar del Plata, Argentina.
    Sueldo, Daniela J
    Norwegian University of Science and Technology, Norway.
    Do photosynthetic cells communicate with each other during cell death? From cyanobacteria to vascular plants2022In: Journal of Experimental Botany, ISSN 0022-0957, E-ISSN 1460-2431, Vol. 73, no 22, p. 7219-7242Article, review/survey (Refereed)
    Abstract [en]

    As in metazoans, life in oxygenic photosynthetic organisms relies on the accurate regulation of cell death. During development and in response to the environment, photosynthetic cells activate and execute cell death pathways that culminate in the death of a specific group of cells, a process known as regulated cell death (RCD). RCD control is instrumental, as its misregulation can lead to growth penalties and even the death of the entire organism. Intracellular molecules released during cell demise may act as ‘survival’ or ‘death’ signals and control the propagation of cell death to surrounding cells, even in unicellular organisms. This review explores different signals involved in cell-cell communication and systemic signalling in photosynthetic organisms, in particular Ca2+, reactive oxygen species, lipid derivates, nitric oxide, and eATP. We discuss their possible mode-of-action as either ‘survival’ or ‘death’ molecules and their potential role in determining cell fate in neighbouring cells. By comparing the knowledge available across the taxonomic spectrum of this coherent phylogenetic group, from cyanobacteria to vascular plants, we aim at contributing to the identification of conserved mechanisms that control cell death propagation in oxygenic photosynthetic organisms 

    The full text will be freely available from 2024-11-01 17:54
  • 17.
    Aguilo, Francesca
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Walsh, Martin J.
    The N6-Methyladenosine RNA modification in pluripotency and reprogramming2017In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 46, p. 77-82Article, review/survey (Refereed)
    Abstract [en]

    Chemical modifications of RNA provide a direct and rapid way to manipulate the existing transcriptome, allowing rapid responses to the changing environment further enriching the regulatory capacity of RNA. N-6-Methyladenosine(m(6)A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. M(6)A modification affects a broad spectrum of cellular functions, including maintenance of the pluripotency of embryonic stem cells (ESCs) and the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). In this review, we summarize the most recent findings on m(6)A modification with special focus on the different studies describing how m(6)A is implicated in ESC self-renewal, cell fate specification and iPSC generation.

  • 18.
    Agurell, Eva
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Comparative studies of alkylating and N-heterocyclic compounds on different genetic endpoints with special emphasis on amplification of minisatellite sequences1992Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Several mutational events are involved in the multistage process of cancer. Genetic instability of tumor DNA is shown in a variety of genetic changes such as point mutations, chromosomal aberrations, aneuploidy, DNA amplification and somatic recombination. Highly repetitive sequences, minisatellite DNA, have been changed in tumors, most probably by DNA amplification.

    To better predict carcinogens all these genetic changes should be considered. The present investigation has focused on the study of genetic changes especially DNA amplification with the use of genetic instability of minisatellites. DNA alterations in human bladder tumors were examined. A new in vitro test system was developed to study DNA amplification.

    In this study DNA fingerprint analysis, with the use of minisatellite DNA, of 22 bladder tumor patients is performed. DNA alterations were determined in approximately 50% of the examined bladder tumor patients. In eight of these ten patients a loss of bands was demonstrated.

    To study DNA amplifications an in vitro test system was developed. A haploid yeast strain was constructed, the TR(MS1)-1, which carries a chromosomal integration of the human minisatellite sequence MSI. The spontaneous frequency of new MSI length alleles was approximately 30%. Both amplifications and deamplifications can be detected in this system without selection. A plasmid pop-out frequency can also be meausured.

    A number of model compounds was used during this study, namely three alkylating agents, a nongenotoxic carcinogen and several nitrogen heterocyclic compounds. To compare genotoxicity and the mechanism of action, these compounds are tested in several in vitro test systems. Ethylene oxide (EO) was demonstrated to be more potent than propylene oxide (PO) in several of the measured endpoints in yeast. EO induced changes in the amplification spectrum of new MSI length alleles in TR(MS1)-1 while PO increased the plasmid pop-out frequency. 2,3,7,8-Tetrachlorodibenzo(p)dioxin (TCDD) was also seen to induce changes in the amplification spectrum of new MSI length alleles, thus demonstrating an effect of TCDD at the DNA level. Among the N-heterocyclic compounds, camptothecin increased the plasmid pop-out frequency in TR(MS1)-1. Two tryptophan photoproducts, "284" and "312", were shown to bind to the A A-receptor. They were demonstrated to be nongenotoxic and antimutagenic in bacteria and slightly genotoxic in yeast. These two compounds are antimutagenic by inhibiting the cytochrome P450IA1. "284" increased cell survival or cell division. These two tryptophan photoproducts, ”284" and "312", are postulated to be biological signal substances by being the endogenous ligand to the Ah -receptor.

  • 19. 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 vesicles2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 5, p. e63474-Article in journal (Refereed)
    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.

  • 20.
    Akkuratov, Evgeny E.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    The Biophysics of Na+,K+-ATPase in neuronal health and disease2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Na+,K+-ATPase is one of the most important proteins in the mammalian cell. It creates sodium and potassium gradients which are fundamental for the membrane potential and sodium-dependent secondary active transport. It has a second role in the cell as a receptor that by binding chemicals from the cardiotonic steroids family, the most knowledgeable of them is ouabain, triggers various signaling pathways in the cell which regulate gene activation, proliferation, apoptosis, etc. It has been shown that several severe neurological diseases are associated with mutations in the Na+,K+-ATPase encoding genes. Although Na+,K+-ATPase was discovered already in 1957 by the Danish scientist Jens Skou, the knowledge about the function of this enzyme  is still not complete.

     

    In the studies included in the thesis, we have learned more about the function of Na+,K+-ATPase in different aspects of health and disease. In study I we showed a mechanism of ouabain-dependent regulation of the NMDA receptor, one of the most important receptors in the nervous system, via binding with Na+,K+-ATPase. This allows us to look at the Na+,K+-ATPase as regulator via protein-protein interaction. In study II we investigated a different aspect of Na+,K+-ATPase functioning – to look at how binding of ouabain to Na+,K+-ATPase activates a number of signaling cascades by looking at the phosphoproteome status of the cells. This allows us to see the whole picture of ouabain-mediated cascades and further characterize them. In study III we focused on the role of Na+,K+-ATPase in severe epileptic encephalopathy caused by a mutation in the ATP1A1 gene. We performed a molecular and cellular study to describe how mutations affects protein structure and function and found that this mutation converts the ion pump to a nonspecific leak channel. In study IV we performed a translational study of the most common mutation for rapid-onset dystonia-parkinsonism. We studied how this mutation affects the nervous system on the protein-, cellular-, and organism level and found that the complete absence of ultraslow afterhyperpolarization (usAHP) could explain gait disturbances found in patients. In the on-going study we showed that Na+,K+-ATPase can oligomerize and that this effect is triggered by ouabain binding to the Na+,K+-ATPase. In this study, we utilized a novel fluorescence labelling approach and used biophysical techniques with single molecule sensitivity to track Na+,K+-ATPase interactions.

     

    In summary, we applied biophysical and molecular methods to study different aspects of the function of Na+,K+-ATPase, and gained insights that could be helpful not only for answering fundamental questions about Na+,K+-ATPase but also to find a treatment for patients with diseases associated with mutations in this protein.

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  • 21.
    Akkuratov, Evgeny E.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Sorrell, Frankie
    Souza, Vasco
    Paukar, Martin
    Picton, Laurence
    Jans, Daniel
    Andersson, Magnus
    Fritz, Nicolas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Zhang, Xiaoqun
    Liebmann, Thomas
    KTH.
    Lindskog, Maria
    KTH.
    Svenningsson, Per
    Miles, Gareth
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Aperia, Anita
    KTH.
    Mechanisms by which the T613M mutation causes mobility and gait disturbances in Rapid-Onset Dystonia-ParkinsonismManuscript (preprint) (Other academic)
  • 22.
    Akkuratov, Evgeny E.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Westin, Linda
    Vazquez-Juarez, Erika
    de Marothy, Minttu
    Melnikova, Aleksandra K
    Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia, 119234.
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindskog, Maria
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Aperia, Anita
    Ouabain Modulates the Functional Interaction Between Na,K-ATPase and NMDA Receptor.2020In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 57, no 10, p. 4018-4030Article in journal (Refereed)
    Abstract [en]

    The N-methyl-D-aspartate (NMDA) receptor plays an essential role in glutamatergic transmission and synaptic plasticity and researchers are seeking for different modulators of NMDA receptor function. One possible mechanism for its regulation could be through adjacent membrane proteins. NMDA receptors coprecipitate with Na,K-ATPase, indicating a potential interaction of these two proteins. Ouabain, a mammalian cardiotonic steroid that specifically binds to Na,K-ATPase and affects its conformation, can protect from some toxic effects of NMDA receptor activation. Here we have examined whether NMDA receptor activity and downstream effects can be modulated by physiological ouabain concentrations. The spatial colocalization between NMDA receptors and the Na,K-ATPase catalytic subunits on dendrites of cultured rat hippocampal neurons was analyzed with super-resolution dSTORM microscopy. The functional interaction was analyzed with calcium imaging of single hippocampal neurons exposed to 10 μM NMDA in presence and absence of ouabain and by determination of the ouabain effect on NMDA receptor-dependent long-term potentiation. We show that NMDA receptors and the Na,K-ATPase catalytic subunits alpha1 and alpha3 exist in same protein complex and that ouabain in nanomolar concentration consistently reduces the calcium response to NMDA. Downregulation of the NMDA response is not associated with internalization of the receptor or with alterations in its state of Src phosphorylation. Ouabain in nanomolar concentration elicits a long-term potentiation response. Our findings suggest that ouabain binding to a fraction of Na,K-ATPase molecules that cluster with the NMDA receptors will, via a conformational effect on the NMDA receptors, cause moderate but consistent reduction of NMDA receptor response at synaptic activation.

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  • 23.
    Akuwudike, Pamela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lopez Riego, Milagrosa
    Marczyk, Michal
    Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.
    Brückner, Fabian
    Biberach University of Applied Sciences.
    Polanska, Joanna
    Department of Data Science and Engineering, Silesian University of Technology, .
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Institute of Biology, Jan Kochanowski University, Kielce, Poland.
    Lundholm, Lovisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Short- and long-term effects of radiation exposure  at low dose and low dose rate on normal human  VH10 fibroblastsManuscript (preprint) (Other academic)
    Abstract [en]

    Experimental studies complement epidemiological data on the biological effects of low doses and dose rates of ionizing radiation and help in determining the dose and dose rate effectiveness factor.  Here, human VH10 skin fibroblasts exposed to 25, 50 and 100 mGy of 137Cs gamma radiation at 1.6, 8, 12 mGy/h, and at a high dose rate of 23.4 Gy/h, were analyzed for radiation-induced short- and long-term effects. Two sample cohorts, i.e. discovery (n=30) and validation (n=12), were subjected to RNA sequencing. Results from the pool of those samples with shared conditions among six experiments constituted a third cohort (n=12). The 100 mGy-exposed cells at all the abovementioned dose rates, harvested at early and late time points after exposure, showed no strong gene expression changes. DMXL2, involved in the regulation of the NOTCH signalling pathway, presented a consistent upregulation among both the discovery and validation cohorts. Gene set enrichment analysis revealed that the NOTCH pathway was upregulated in the pooled cohort (p=0.76, NES=0.86). Apart from upregulated apical junction and downregulated DNA repair, few pathways were consistently changed across exposed cohorts. In agreement, cell viability assays, performed 1-, 3-, and 6-days post-irradiation, and colony forming assay, seeded just after exposure, did not reveal any statistically significant early effects in cell growth or survival patterns. Tendencies of increased growth and reduced colony size were observed at 12 mGy/h and 23.4 Gy/min. Furthermore, no long-term changes were observed in cell growth curves generated up to 70 days after exposure. In conclusion, low doses of gamma radiation given at low dose rates had no strong cytotoxic effects on VH10 cells.

  • 24.
    Akuwudike, Pamela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    López Riego, Milagrosa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ginter, Józef
    Cheng, Lei
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wieczorek, Anna
    Życieńska, Katarzyna
    Łysek-Gładysińska, Małgorzata
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brzozowska, Beata
    Lundholm, Lovisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mechanistic insights from high resolution DNA damage analysis to understand mixed radiation exposure2023In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 130, article id 103554Article in journal (Refereed)
    Abstract [en]

    Cells exposed to densely ionising high and scattered low linear energy transfer (LET) radiation (50 % dose of each) react more strongly than to the same dose of each separately. The relationship between DNA double strand break location inside the nucleus and chromatin structure was evaluated, using high-resolution transmission electron microscopy (TEM) in breast cancer MDA-MB-231 cells at 30 min post 5 Gy. Additionally, response to high and/or low LET radiation was assessed using single (1 ×1.5 Gy) versus fractionated dose delivery (5 ×0.3 Gy). By TEM analysis, the highest total number of γH2AX nanobeads were found in cells irradiated with alpha radiation just prior to gamma radiation (called mixed beam), followed by alpha, then gamma radiation. γH2AX foci induced by mixed beam radiation tended to be surrounded by open chromatin (lighter TEM regions), yet foci containing the highest number of beads, i.e. larger foci representing complex damage, remained in the heterochromatic areas. The γH2AX large focus area was also greater in mixed beam-treated cells when analysed by immunofluorescence. Fractionated mixed beams given daily induced the strongest reduction in cell viability and colony formation in MDA-MB-231 and osteosarcoma U2OS cells compared to the other radiation qualities, as well as versus acute exposure. This may partially be explained by recurring low LET oxidative DNA damage by every fraction together with a delay in recompaction of chromatin after high LET, demonstrated by low levels of heterochromatin marker H3K9me3 at 2 h after the last mixed beam fraction in MDA-MB-231. In conclusion, early differences in response to complex DNA damage may lead to a stronger cell kill induced by fractionated exposure, which suggest a therapeutic potential of combined high and low LET irradiation.

  • 25.
    Alakpa, Enateri V.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Bahrd, Anton
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Wiklund, Krister
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Andersson, Magnus
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Ljungberg, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kelk, Peyman
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Bioprinted schwann and mesenchymal stem cell co-cultures for enhanced spatial control of neurite outgrowth2023In: Gels, E-ISSN 2310-2861, Vol. 9, no 3, article id 172Article in journal (Refereed)
    Abstract [en]

    Bioprinting nerve conduits supplemented with glial or stem cells is a promising approach to promote axonal regeneration in the injured nervous system. In this study, we examined the effects of different compositions of bioprinted fibrin hydrogels supplemented with Schwann cells and mesenchymal stem cells (MSCs) on cell viability, production of neurotrophic factors, and neurite outgrowth from adult sensory neurons. To reduce cell damage during bioprinting, we analyzed and optimized the shear stress magnitude and exposure time. The results demonstrated that fibrin hydrogel made from 9 mg/mL of fibrinogen and 50IE/mL of thrombin maintained the gel’s highest stability and cell viability. Gene transcription levels for neurotrophic factors were significantly higher in cultures containing Schwann cells. However, the amount of the secreted neurotrophic factors was similar in all co-cultures with the different ratios of Schwann cells and MSCs. By testing various co-culture combinations, we found that the number of Schwann cells can feasibly be reduced by half and still stimulate guided neurite outgrowth in a 3D-printed fibrin matrix. This study demonstrates that bioprinting can be used to develop nerve conduits with optimized cell compositions to guide axonal regeneration.

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  • 26.
    Alakpa, Enateri V.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Saeed, Anwer
    Chung, Peter
    Riehle, Mathis O.
    Gadegaard, Nikolaj
    Dalby, Matthew J.
    Cusack, Maggie
    The Prismatic Topography of Pinctada maxima Shell Retains Stem Cell Multipotency and Plasticity In Vitro2018In: Advanced Biosystems, ISSN 2366-7478, Vol. 2, no 6, article id 1800012Article in journal (Refereed)
    Abstract [en]

    The shell of the bivalve mollusc Pinctada maxima is composed of the calcium carbonate polymorphs calcite and aragonite (nacre). Mother-of-pearl, or nacre, induces vertebrate cells to undergo osteogenesis and has good osteointegrative qualities in vivo. The calcite counterpart, however, is less researched in terms of the response of vertebrate cells. This study shows that isolation of calcite surface topography from the inherent chemistry allows viable long-term culture of bone marrow derived mesenchymal stem cells (MSCs). Self-renewal is evident from the increased gene expression of the self-renewal markers CD63, CD166, and CD271 indicating that cells cultured on the calcite topography maintain their stem cell phenotype. MSCs also retain their multipotency and can undergo successful differentiation into osteoblasts and adipocytes. When directed to adipogenesis, MSCs cultured on prism replicas are more amenable to differentiation than MSCs cultured on tissue culture polystyrene indicating a higher degree of plasticity in MSCs growing on calcite P. maxima prismatic topography. The study highlights the potential of the calcite topography of P. maxima as a biomimetic design for supporting expansion of MSC populations in vitro, which is of fundamental importance if it meets the demands for autologous MSCs for therapeutic use.

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  • 27.
    Alarcón-Riquelme, Marta E.
    Stockholm University, Faculty of Science.
    Murine Systemic Lupus erythematosus: cellular regulation and molecular mechanisms behind the formation of autoantibodies in autoimmune disease1994Doctoral thesis, comprehensive summary (Other academic)
  • 28.
    Alberti, Esteban
    et al.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Garcia, Rocio
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Fraga, JL
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Serrano, T.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Hernandez, E.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Macías, R.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Martinez, L.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Castillo, L.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    de la Cuétara, K.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba.
    Prolonged Survival and expression of neural markers by bone marrow-derived stem cells transplanted into brain lesions2009In: Medical Science Monitor, ISSN 1234-1010, E-ISSN 1643-3750, Vol. 15, no 2, p. BR47-BR54Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bone marrow-derived stem cell transplantation is a potentially viable therapeutic option for the treatment of neurodegenerative disease. MATERIAL/METHODS: We have isolated bone marrow stem cells by standard method. We then evaluated the survival of rats' bone marrow mononuclear cells implanted in rats' brain. The cells were extracted from rats' femurs, and marked for monitoring purposes by adenoviral transduction with Green Fluorescent Protein (GFP). Labeled cells were implanted within the area of rats' striatum lesions that were induced a month earlier employing quinolinic acid-based method. The implants were phenotyped by monitoring CD34; CD38; CD45 and CD90 expression. Bone marrow stromal cells were extracted from rats' femurs and cultivated until monolayer bone marrow stromal cells were obtained. The ability of bone marrow stromal cells to express NGF and GDNF was evaluated by RT-PCR. RESULTS: Implanted cells survived for at least one month after transplantation and dispersed from the area of injection towards corpus callosum and brain cortex. Interestingly, passaged rat bone marrow stromal cells expressed NGF and GDNF mRNA. CONCLUSIONS: The bone marrow cells could be successfully transplanted to the brain either for the purpose of trans-differentiation, or for the expression of desired growth factors.

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  • 29.
    Alfaro-Moreno, Ernesto
    et al.
    Örebro University, School of Science and Technology.
    Quintana-Belmares, R.
    Instituto Nacional de Cancerologia, Investigacion Basica, Mexico City, Mexico.
    Montiel-Davalos, A.
    Instituto Nacional de Cancerologia, Investigacion Basica, Mexico City, Mexico.
    Gustafsson, A.
    Örebro University, Man-Technology-Environment Research Center, Örebro, Sweden.
    Miranda, J.
    Universidad Nacional Autonoma de Mexico, Instituto de Fisica, Mexico City, Mexico.
    Lopez-Marure, R.
    Instituto Nacional de Cardiologia, Investigacion, Mexico City, Mexico.
    Rosas-Perez, I.
    Universidad Nacional Autonoma de Mexico, Centro de Ciencias de la Atmosfera, Mexico City, Mexico.
    Expression of receptors for adhesion molecules in monocytes exposed to urban particulate matter is independent of size and composition of the particles2019In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 314, no Suppl., p. S232-S233Article in journal (Other academic)
  • 30.
    Al-Furoukh, Natalie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ianni, Alessandro
    Nolte, Hendrik
    Hölper, Soraya
    Krüger, Marcus
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Braun, Thomas
    ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells2015In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1853, no 10, p. 2580-2591Article in journal (Refereed)
    Abstract [en]

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

  • 31.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. 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 carcinoma2022In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 304, article id 120699Article in journal (Refereed)
    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.

  • 32.
    Alijagic, Andi
    et al.
    Örebro University, School of Science and Technology.
    Sinisalu, Lisanna
    Örebro University, School of Science and Technology.
    Duberg, Daniel
    Örebro University, School of Science and Technology.
    Kotlyar, Oleksandr
    Örebro University, School of Science and Technology.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland; Department of Life Technologies, University of Turku, FI-20014 Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Metabolic and phenotypic changes induced by PFAS exposure in two human hepatocyte cell models2024In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 190, article id 108820Article in journal (Refereed)
    Abstract [en]

    PFAS are ubiquitous industrial chemicals with known adverse health effects, particularly on the liver. The liver, being a vital metabolic organ, is susceptible to PFAS-induced metabolic dysregulation, leading to conditions such as hepatotoxicity and metabolic disturbances. In this study, we investigated the phenotypic and metabolic responses of PFAS exposure using two hepatocyte models, HepG2 (male cell line) and HepaRG (female cell line), aiming to define phenotypic alterations, and metabolic disturbances at the metabolite and pathway levels. The PFAS mixture composition was selected based on epidemiological data, covering a broad concentration spectrum observed in diverse human populations. Phenotypic profiling by Cell Painting assay disclosed predominant effects of PFAS exposure on mitochondrial structure and function in both cell models as well as effects on F-actin, Golgi apparatus, and plasma membrane-associated measures. We employed comprehensive metabolic characterization using liquid chromatography combined with high-resolution mass spectrometry (LC-HRMS). We observed dose-dependent changes in the metabolic profiles, particularly in lipid, steroid, amino acid and sugar and carbohydrate metabolism in both cells as well as in cell media, with HepaRG cell line showing a stronger metabolic response. In cells, most of the bile acids, acylcarnitines and free fatty acids showed downregulation, while medium-chain fatty acids and carnosine were upregulated, while the cell media showed different response especially in relation to the bile acids in HepaRG cell media. Importantly, we observed also nonmonotonic response for several phenotypic features and metabolites. On the pathway level, PFAS exposure was also associated with pathways indicating oxidative stress and inflammatory responses. Taken together, our findings on PFAS-induced phenotypic and metabolic disruptions in hepatocytes shed light on potential mechanisms contributing to the broader comprehension of PFAS-related health risks.

  • 33.
    Alizadeh, Javad
    et al.
    University of Manitoba, Canada.
    Zeki, Amir A.
    Centre Comparat Resp Biol and Med, CA USA.
    Mirzaei, Nima
    University of Manitoba, Canada.
    Tewary, Sandipan
    University of Manitoba, Canada.
    Rezaei Moghadam, Adel
    University of Manitoba, Canada; University of Manitoba, Canada.
    Glogowska, Aleksandra
    University of Manitoba, Canada.
    Nagakannan, Pandian
    University of Manitoba, Canada.
    Eftekharpour, Eftekhar
    University of Manitoba, Canada.
    Wiechec, Emilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Speech language pathology, Audiology and Otorhinolaryngology. Linköping University, Faculty of Medicine and Health Sciences.
    Gordon, Joseph W.
    University of Manitoba, Canada; University of Manitoba, Canada; University of Manitoba, Canada.
    Xu, Fred. Y.
    University of Manitoba, Canada; University of Manitoba, Canada.
    Field, Jared T.
    University of Manitoba, Canada.
    Yoneda, Ken Y.
    Centre Comparat Resp Biol and Med, CA USA.
    Kenyon, Nicholas J.
    Centre Comparat Resp Biol and Med, CA USA.
    Hashemi, Mohammad
    Zehedan University of Medical Science, Iran.
    Hatch, Grant M.
    University of Manitoba, Canada; University of Manitoba, Canada.
    Hombach-Klonisch, Sabine
    University of Manitoba, Canada.
    Klonisch, Thomas
    University of Manitoba, Canada.
    Ghavami, Saeid
    University of Manitoba, Canada; University of Manitoba, Canada; Shiraz University of Medical Science, Iran.
    Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 44841Article in journal (Refereed)
    Abstract [en]

    The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP-and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB231( breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.

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  • 34. 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 University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Westerlund, Fredrik
    Nanoconfined Circular and Linear DNA: Equilibrium Conformations and Unfolding Kinetics2015In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 48, no 3, p. 871-878Article in journal (Refereed)
    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.

  • 35. Al-Khalili Szigyarto, Cristina
    et al.
    Sibbons, P.
    Williams, G.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics.
    Metcalfe, S. M.
    The E3 Ligase Axotrophin/MARCH-7: Protein Expression Profiling of Human Tissues Reveals Links to Adult Stem Cells2010In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 58, no 4, p. 301-308Article in journal (Refereed)
    Abstract [en]

    Axotrophin/MARCH-7 was first identified in mouse embryonic stem cells as a neural stem cell gene. Using the axotrophin/MARCH-7 null mouse, we discovered profound effects on T lymphocyte responses, including 8-fold hyperproliferation and 5-fold excess release of the stem cell cytokine leukemia inhibitory factor (LIF). Our further discovery that axotrophin/MARCH-7 is required for targeted degradation of the LIF receptor subunit gp190 implies a direct role in the regulation of LIF signaling. Bioinformatics studies revealed a highly conserved RING-CH domain in common with the MARCH family of E3-ubiquitin ligases, and accordingly, axotrophin was renamed "MARCH-7." To probe protein expression of human axotrophin/MARCH-7, we prepared antibodies against different domains of the protein. Each antibody bound its specific target epitope with high affinity, and immunohistochemistry cross-validated target specificity. Forty-eight human tissue types were screened. Epithelial cells stained strongly, with trophoblasts having the greatest staining. In certain tissues, specific cell types were selectively positive, including neurons and neuronal progenitor cells in the hippocampus and cerebellum, endothelial sinusoids of the spleen, megakaryocytes in the bone marrow, crypt stem cells of the small intestine, and alveolar macrophages in the 7 lung. Approximately 20% of central nervous system neuropils were positive. Notably, axotrophin/MARCH-7 has an expression profile that is distinct from that of other MARCH family members. This manuscript contains online supplemental material at http://www.jhc. org. Please visit this article online to view these materials. (J Histochem Cytochem 58:301-308, 2010)

  • 36. Alkharusi, Amira
    et al.
    Yu, Shengze
    KTH, School of Biotechnology (BIO).
    Landazuri, Natalia
    Zadjali, Fahad
    Davodi, Belghis
    Nystrom, Thomas
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Protein Technology.
    Rahbar, Afsar
    Norstedt, Gunnar
    Stimulation of prolactin receptor induces STAT-5 phosphorylation and cellular invasion in glioblastoma multiforme2016In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 48, p. 79558-79569Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans and is characterized with poor outcome. In this study, we investigated components of prolactin (Prl) system in cell models of GBM and in histological tissue sections obtained from GBM patients. Expression of Prolactin receptor (PrlR) was detected at high levels in U251-MG, at low levels in U87-MG and barely detectable in U373 cell lines and in 66% of brain tumor tissues from 32 GBM patients by immunohistochemical technique. In addition, stimulation of U251-MG and U87-MG cells but not U373 with Prl resulted in increased STAT5 phosphorylation and only in U251-MG cells with increased cellular invasion. Furthermore, STAT5 phosphorylation and cellular invasion induced in Prl stimulated cells were significantly reduced by using a Prl receptor antagonist that consists of Prl with four amino acid replacements. We conclude that Prl receptor is expressed at different levels in the majority of GBM tumors and that blocking of PrlR in U251-MG cells significantly reduce cellular invasion.

  • 37.
    Alm, Tove L.
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    The Affinity Binder Knockdown Initiative.2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 38.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Vicente-Carrillo, Alejandro
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Exogenous Individual Lecithin-Phospholipids (Phosphatidylcholine and Phosphatidylglycerol) Cannot Prevent the Oxidative Stress Imposed by Cryopreservation of Boar Sperm.2017In: Journal of veterinary medicine and surgery, ISSN 2574-2868, Vol. 1, no 1Article in journal (Refereed)
    Abstract [en]

    Objective: Despite the use of high proportions of the chemically undefined lipoprotein/phospholipid-rich egg-yolk in extenders, boar sperm are highly sensitive to cooling, which induces ROS generation and disrupts the plasma membrane.

    Here, we studied whether replacement of hen egg-yolk by commercially defined lecithin phospholipids, derived from egg (LPGE: phosphatidyl glycerol, LPCE: phosphatidyl choline) or soybean (LPCS: phosphatidyl choline), could individually ameliorate such oxidative effects during cryopreservation of ejaculated (sperm rich fraction, SRF) or of cauda-epididymal sperm, retrieved post-mortem from the same males.

    Methods: A conventional extender (lactose buffer, with 20% egg-yolk, 0.5% OEP and 3% glycerol) was used as control. Cryodamage was assessed as loss of sperm motility, membrane and acrosome intactness, early membrane destabilization changes, mitochondrial potential, superoxide and ROS production, to finally determine lipid peroxidation (LPO) using specific probes.

    Results and conclusion: In general, the exogenous phospholipids assayed were unable of maintaining neither sperm motility nor viability post-thaw compared to controls, owing to increased ROS production and lipid peroxidation. In our study, mitochondrial superoxide production resulted in very high levels for all groups, whereas both ROS production and lipid peroxidation were reduced in the control group, containing emulsified hen egg yolk. Further studies using various dosage and combination of LPCS should be followed for their eventual protective effect.

    Keywords: Cryodamage; Sperm; Boar; Mitochondrial activation; Mitochondrial superoxide; ROS production; Lipid peroxidation

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  • 39.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. 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 Carcinogens2018In: Pharmacognosy Magazine, ISSN 0973-1296, E-ISSN 0976-4062, Vol. 14, no 58, p. 548-553Article in journal (Refereed)
    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.

  • 40.
    Amirhosseini, Mehdi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Aseptic Loosening of Orthopedic Implants: Osteoclastogenesis Regulation and Potential Therapeutics2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aseptic loosening is the main cause of failure of orthopedic prostheses. With no pharmaceuticals to prevent or mitigate periprosthetic bone degradation, a surgery to replace the loose implant with a new one is the only choice to restore patients’ function. Most studies on mechanisms for aseptic loosening investigate wear debris particle-induced osteolysis. However, pathological loading conditions around unstable implants can also trigger osteoclast differentiation and bone loss.

    In the first study, global gene expression changes induced by mechanical instability of implants, and by titanium particles were compared in a validated rat model for aseptic loosening. Microarray analysis showed that similar signaling pathways and gene expression patterns are involved in particle- and instability-induced periprosthetic osteolysis with an early onset innate immune response as a hallmark of osteolysis induced by mechanical instability.

    Further, effects of potential therapeutics on restriction of excessive osteoclast differentiation were evaluated. Wnt signaling pathway is known to regulate bone remodeling. In the second study, effects of inactivation of glycogen synthase kinase 3 beta (GSK-3β), a negative regulator of canonical Wnt signaling, on instability-induced periprosthetic osteolysis were examined using our rat model for aseptic loosening. Inhibition of GSK-3β led to a decrease in osteoclast numbers in the periprosthetic bone tissue exposed to mechanical instability while osteoblast perimeter showed an increase. This was accompanied by higher bone volume fraction (BV/TV) in animals treated with the GSK-3β inhibitor.

    In the third study, potential beneficial effects of two selective inhibitors of cyclindependent kinase 8/19 (CDK8/19) on bone tissue were evaluated. CDK8/19 is a Mediator complex-associated transcriptional regulator involved in several signaling pathways. CDK8/19 inhibitors, mainly under investigation as treatments for tumors, are reported to enhance osteoblast differentiation and bone formation. We show in this study, for the first time, that inhibition of CDK8/19 led to marked suppression of osteoclast differentiation from bone marrow macrophages in vitro through disruption of the RANK signaling. In mouse primary osteoblasts downregulation of osteopontin mRNA, a negative regulator of mineralization, together with increased alkaline phosphatase activity and calcium deposition indicated that osteoblast mineralization was promoted by CDK8/19 inhibition. Moreover, local administration of a CDK8/19 inhibitor promoted cancellous bone regeneration in a rat model for bone healing.

    These studies contribute to better understanding of mechanisms behind mechanical instability-induced periprosthetic osteolysis and propose potential therapeutics to restrict bone loss with effects on both osteoclasts and osteoblasts.

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  • 41.
    Andersson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Developing a protocol for RT-qPCR of wing-tissue gene expression and investigating the dynamics of photoperiodically induced polyphenism in the water strider Gerris buenoi2023Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    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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  • 42.
    Andersson, Hanna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    The Effect of Chemotherapy Treatment on Bone Marrow Mesenchymal Stromal Cell Adipocyte Differentiation2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In an effort to understand the cause of late onset cardiac, metabolic, and musculoskeletal conditions in paediatric acute lymphoblastic leukaemia (ALL) survivors, the adipogenic differentiation of bone marrow (BM) mesenchymal stromal cells (MSCs) has been studied. There is a complex network of factors influencing adipogenesis, which to date is not completely understood. Hence, the overall aim is to better understand the cellular and molecular basis behind the development of these conditions in survivors. To this end, we asked whether treating BM MSCs in vitro with cancer drugs, Doxorubicin and Dexamethasone, will initiate a skewed differentiation towards adipogenesis. BM MSCs were analysed with respect to lipid accumulation, gene expression, and adipokine production. In general, our hypothesis was not confirmed. No lipid accumulations were detected in the cells. In analysis of gene expression of the adipogenic transcription factors PPARγ and C/EBPα, certain changes were seen; however, due to lack of biological replicates, no statistical analyses could be applied to the results. Lastly, the inflammation and adipogenesis associated cytokine IL-6 displayed a slight increase, whereas the cytokines IL-8 and TNF-α were undetectable.

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  • 43.
    Andersson, Hanna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    The Effect of Chemotherapy Treatment on Bone Marrow Mesenchymal Stromal Cell Adipocyte Differentiation2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In an effort to understand the cause of late onset cardiac, metabolic, and musculoskeletal conditions in paediatric acute lymphoblastic leukaemia (ALL) survivors, the adipogenic differentiation of bone marrow (BM) mesenchymal stromal cells (MSCs) has been studied. There is a complex network of factors influencing adipogenesis, which to date is not completely understood. Hence, the overall aim is to better understand the cellular and molecular basis behind the development of these conditions in survivors. To this end, we asked whether treating BM MSCs in vitro with cancer drugs, Doxorubicin and Dexamethasone, will initiate a skewed differentiation towards adipogenesis. BM MSCs were analysed with respect to lipid accumulation, gene expression, and adipokine production. In general, our hypothesis was not confirmed. No lipid accumulations were detected in the cells. In analysis of gene expression of the adipogenic transcription factors PPARγ and C/EBPα, certain changes were seen; however, due to lack of biological replicates, no statistical analyses could be applied to the results. Lastly, the inflammation and adipogenesis associated cytokine IL-6 displayed a slight increase, whereas the cytokines IL-8 and TNF-α were undetectable.

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  • 44.
    Andersson, Linn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Exploring the post-transcriptional regulation of flagellar genes by small RNAs and RNA-binding proteins in Salmonella enterica serovar Typhimurium2024Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
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  • 45.
    Andersson, Linnea
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sjöström, Dick J.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Quach, Huy Quang
    Mayo Clin, USA.
    Hägerström, Kim
    Region Kalmar County, Sweden.
    Hurler, Lisa
    Semmelwe Univ, Hungary.
    Kajdacsi, Erika
    Semmelwe Univ, Hungary.
    Cervenak, Laszlo
    Semmelwe Univ, Hungary.
    Prohaszka, Zoltan
    Semmelwe Univ, Hungary.
    Toonen, Erik J. M.
    Hycult Biotechnology, Netherlands.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Nordland Hosp, Norway.
    Sandgren, Per
    Karolinska Institutet, Sweden.
    Tjernberg, Ivar
    Region Kalmar County, Sweden;Linköping University, Sweden.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Storage of Transfusion Platelet Concentrates is Associated with Complement Activation and Reduced Ability of Platelets to Respond to Protease-Activated Receptor-1 and Thromboxane A2 Receptor2024In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, no 2, article id 1091Article in journal (Refereed)
    Abstract [en]

    Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 degrees C for seven days and assessed daily for complement and platelet activation markers. Additionally, platelet function was analyzed in terms of their responsiveness to protease-activated receptor-1 (PAR-1) and thromboxane A2 receptor (TXA(2)R) activation and their capacity to adhere to collagen. Complement activation increased over the storage period for all analyzed markers, including the C1rs/C1-INH complex (fold change (FC) = 1.9; p < 0.001), MASP-1/C1-INH complex (FC = 2.0; p < 0.001), C4c (FC = 1.8, p < 0.001), C3bc (FC = 4.0; p < 0.01), and soluble C5b-9 (FC = 1.7, p < 0.001). Furthermore, the levels of soluble platelet activation markers increased in the concentrates over the seven-day period, including neutrophil-activating peptide-2 (FC = 2.5; p < 0.0001), transforming growth factor beta 1 (FC = 1.9; p < 0.001) and platelet factor 4 (FC = 2.1; p < 0.0001). The ability of platelets to respond to activation, as measured by surface expression of CD62P and CD63, decreased by 19% and 24% (p < 0.05) for PAR-1 and 69-72% (p < 0.05) for TXA(2)R activation, respectively, on Day 7 compared to Day 1. The extent of platelet binding to collagen was not significantly impaired during storage. In conclusion, we demonstrated that complement activation increased during the storage of platelets, and this correlated with increased platelet activation and a reduced ability of the platelets to respond to, primarily, TXA(2)R activation.

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  • 46.
    Andersson, Marie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Cellular transport and secretion of the cyanobacterial neurotoxin BMAA into milk and egg: Implications for developmental neurotoxicity2015Doctoral thesis, comprehensive summary (Other academic)
    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.

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  • 47.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Ersson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Potential transfer of neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA) from mother to infant during breast-feeding: Predictions from human cell lines2017In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 320, p. 40-50Article in journal (Refereed)
    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.

  • 48.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Correction: Maternal Transfer of the Cyanobacterial Neurotoxin β-N-Methylamino-L-Alanine (BMAA) via Milk to Suckling Offspring2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 10, article id e78133Article in journal (Refereed)
  • 49. Andersson, Rebecca
    et al.
    Eisele-Burger, Anna Maria
    Hanzen, Sarah
    Vielfort, Katarina
    Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Oling, David
    Eisele, Frederik
    Johansson, Gustav
    Gustafsson, Tobias
    Kvint, Kristian
    Nystrom, Thomas
    Differential role of cytosolic Hsp70s in longevity assurance and protein quality control2021In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 17, no 1, article id e1008951Article in journal (Refereed)
    Abstract [en]

    70 kDa heat shock proteins (Hsp70) are essential chaperones of the protein quality control network; vital for cellular fitness and longevity. The four cytosolic Hsp70's in yeast, Ssa1-4, are thought to be functionally redundant but the absence of Ssa1 and Ssa2 causes a severe reduction in cellular reproduction and accelerates replicative aging. In our efforts to identify which Hsp70 activities are most important for longevity assurance, we systematically investigated the capacity of Ssa4 to carry out the different activities performed by Ssa1/2 by overproducing Ssa4 in cells lacking these Hsp70 chaperones. We found that Ssa4, when overproduced in cells lacking Ssa1/2, rescued growth, mitigated aggregate formation, restored spatial deposition of aggregates into protein inclusions, and promoted protein degradation. In contrast, Ssa4 overproduction in the Hsp70 deficient cells failed to restore the recruitment of the disaggregase Hsp104 to misfolded/aggregated proteins, to fully restore clearance of protein aggregates, and to bring back the formation of the nucleolus-associated aggregation compartment. Exchanging the nucleotide-binding domain of Ssa4 with that of Ssa1 suppressed this 'defect' of Ssa4. Interestingly, Ssa4 overproduction extended the short lifespan of ssa1 Delta ssa2 Delta mutant cells to a lifespan comparable to, or even longer than, wild type cells, demonstrating that Hsp104-dependent aggregate clearance is not a prerequisite for longevity assurance in yeast.

    Author summary: All organisms have proteins that network together to stabilize and protect the cell throughout its lifetime. One of these types of proteins are the Hsp70s (heat shock protein 70). Hsp70 proteins take part in folding other proteins to their functional form, untangling proteins from aggregates, organize aggregates inside the cell and ensure that damaged proteins are destroyed. In this study, we investigated three closely related Hsp70 proteins in yeast; Ssa1, 2 and 4, in an effort to describe the functional difference of Ssa4 compared to Ssa1 and 2 and to answer the question: What types of cellular stress protection are necessary to reach a normal lifespan? We show that Ssa4 can perform many of the same tasks as Ssa1 and 2, but Ssa4 doesn't interact in the same manner as Ssa1 and 2 with other types of proteins. This leads to a delay in removing protein aggregates created after heat stress. Ssa4 also cannot ensure that misfolded proteins aggregate correctly inside the nucleus of the cell. However, this turns out not to be necessary for yeast cells to achieve a full lifespan, which shows us that as long as cells can prevent aggregates from forming in the first place, they can reach a full lifespan.

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  • 50. Andersson, Sandra
    et al.
    Konrad, Anna
    KTH, School of Biotechnology (BIO), Protein Technology.
    Ashok, Nikhil
    Pontén, Fredrik
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Protein Technology.
    Asplund, Anna
    Antibodies Biotinylated Using a Synthetic Z-domain from Protein A Provide Stringent In Situ Protein Detection2013In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 61, no 11, p. 773-784Article in journal (Refereed)
    Abstract [en]

    Antibody-based protein profiling on a global scale using immunohistochemistry constitutes an emerging strategy for mapping of the human proteome, which is crucial for an increased understanding of biological processes in the cell. Immunohistochemistry is often performed indirectly using secondary antibodies for detection, with the benefit of signal amplification. Direct immunohistochemistry instead brings the advantage of multiplexing; however, it requires labeling of the primary antibody. Many antibody-labeling kits do not specifically target IgG and may therefore cause labeling of stabilizing proteins present in the antibody solution. A new conjugation method has been developed that utilizes a modified Z-domain of protein A (ZBPA) to specifically target the Fc part of antibodies. The aim of the present study was to compare the ZBPA conjugation method and a commercially available labeling kit, Lightning-Link, for in situ protein detection. Fourteen antibodies were biotinylated with each method and stained using immunohistochemistry. For all antibodies tested, ZBPA biotinylation resulted in distinct immunoreactivity without off-target staining, regardless of the presence of stabilizing proteins in the buffer, whereas the majority of the Lightning-Link biotinylated antibodies displayed a characteristic pattern of nonspecific staining. We conclude that biotinylated ZBPA domain provides a stringent method for antibody biotinylation, advantageous for in situ protein detection in tissues.

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