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  • 301.
    Fontana, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fritz, Nicolas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Aperia, Anita
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Apoptosis caused by excessive mitochondrial albumin uptake in renal cells is initiated by increased mitochondrial calcium concentration2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29Article in journal (Other academic)
  • 302.
    Fontana, Jacopo M.
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Bernhem, Kristoffer
    KTH, School of Engineering Sciences (SCI), Applied Physics. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Zhang, L.
    Karolinska Inst, Dept Pediat Cell Mol Biol, Stockholm, Sweden..
    Nilsson, Linnea
    KTH, School of Engineering Sciences (SCI), Applied Physics. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics. Royal Inst Technol, Dept Appl Phys, Stockholm, Sweden..
    Aperia, A.
    Karolinska Inst, Dept Pediat Cell Mol Biol, Stockholm, Sweden..
    Ouabain, a Na, K-ATPase ligand, intervenes with the onset of glucose-triggered apoptosis2015In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 26Article in journal (Other academic)
  • 303.
    Fontana, Jacopo M.
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Sci Life Labs, Appl Phys, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden..
    Jess, David Unnersjö
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Sci Life Labs, Appl Phys, Stockholm, Sweden..
    Blom, Hans
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Sci Life Labs, Appl Phys, Stockholm, Sweden..
    Brismar, Hjalmar
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Sci Life Labs, Appl Phys, Stockholm, Sweden.;Karolinska Inst, Womens & Childrens Hlth, Stockholm, Sweden..
    Aperia, Anita
    Karolinska Inst, Womens & Childrens Hlth, Stockholm, Sweden..
    Role of calcium signaling for GDNF secretion, ureter branching and early nephron formation2016In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 30Article in journal (Other academic)
  • 304.
    Fontana, Jacopo M.
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Khodus, Georgiy R.
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Unnersjö Jess, David
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blom, Hans
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Aperia, Anita
    Karolinska Inst, Sci Life Lab, Dept Womens & Childrens Hlth, Solna, Sweden..
    Brismar, Hjalmar
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney2019In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 3, p. 4089-4096Article in journal (Refereed)
    Abstract [en]

    The central role of calcium signaling during development of early vertebrates is well documented, but little is known about its role in mammalian embryogenesis. We have used immunofluorescence and time-lapse calcium imaging of cultured explanted embryonic rat kidneys to study the role of calcium signaling for branching morphogenesis. In mesenchymal cells, we recorded spontaneous calcium activity that was characterized by irregular calcium transients. The calcium signals were dependent on release of calcium from intracellular stores in the endoplasmic reticulum. Down-regulation of the calcium activity, both by blocking the sarco-endoplasmic reticulum Ca2+-ATPase and by chelating cytosolic calcium, resulted in retardation of branching morphogenesis and a reduced formation of primitive nephrons but had no effect on cell proliferation. We propose that spontaneous calcium activity contributes with a stochastic factor to the self-organizing process that controls branching morphogenesis, a major determinant of the ultimate number of nephrons in the kidney.Fontana, J. M., Khodus, G. R., Unnersjo-Jess, D., Blom, H., Aperia, A., Brismar, H. Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney.

  • 305.
    Fontana, Jacopo Maria
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yin, Huijuan
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Chen, Yun
    Florez, Ricardo
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fu, Ying
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Transport and release of colloidal 3-mercaptopropionic acid-coated CdSe-CdS/ZnS core-multishell quantum dots in human umbilical vein endothelial cells2017In: International Journal of Nanomedicine, ISSN 1176-9114, E-ISSN 1178-2013, Vol. 12, p. 8615-8629Article in journal (Refereed)
    Abstract [en]

    Colloidal semiconductor quantum dots (QDs) have been extensively researched and developed for biomedical applications, including drug delivery and biosensing assays. Hence, it is pivotal to understand their behavior in terms of intracellular transport and toxicological effects. In this study, we focused on 3-mercaptopropionic acid-coated CdSe-CdS/ZnS core-multishell quantum dots (3MPA-QDs) converted from the as-grown octadecylamine-coated quantum dots (ODA-QDs) and their direct and dynamic interactions with human umbilical vein endothelial cells (HUVECs). Live cell imaging using confocal fluorescence microscopy showed that 3MPAQDs first attached to and subsequently aggregated on HUVEC plasma membrane similar to 25 min after QD deposition. The aggregated QDs started being internalized at similar to 2 h and reached their highest internalization degree at similar to 24 h. They were released from HUVECs after similar to 48 h. During the 48 h period, the HUVECs responded normally to external stimulations, grew, proliferated and wound healed without any perceptible apoptosis. Furthermore, 1) 3MPA-QDs were internalized in newly formed LysoTracker-stained early endosomes; 2) adenosine 5'-triphosphateinduced [Ca2+](i) modulation caused a transient decrease in the fluorescence of 3MPA-QDs that were attached to the plasma membrane but a transient increase in the internalized 3MPA-QDs; and 3) fluorescence signal modulations of co-stained LysoTracker and QDs induced by the lysosomotropic agent Gly-Phe-beta-naphthylamide were spatially co-localized and temporally synchronized. Our findings suggest that 3MPA-QDs converted from ODA-QDs are a potential nontoxic fluorescent probe for future use in clinical applications. Moreover, the photophysical strategy and techniques reported in this work are easily applicable to study of direct interactions between other nanoparticles and live cells; contributing to awareness and implementation of the safe applications of nanoparticles.

  • 306. Fornell, Anna
    et al.
    Nilsson, Johan
    Jonsson, Linus
    Periyannan Rajeswari, Prem Kumar
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jönsson, Håkan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tenje, Maria
    Particle enrichment in two-phase microfluidic systems using acoustophoresis2016In: Acoustofluidics 2016, Kongens Lyngby, Denmark, September 22-23 2016, 2016Conference paper (Refereed)
  • 307. Forslund, Elin
    et al.
    Sohlberg, Ebba
    Enqvist, Monika
    Olofsson, Per E.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Malmberg, Karl-Johan
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Sci Life Lab, Dept Microbiol Tumor & Cell Biol, S-17165 Stockholm, Sweden.
    Microchip-Based Single-Cell Imaging Reveals That CD56(dim) CD57(-)KIR(-)NKG2A(+) NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56(dim)CD57(-)KIR(-)NKG2A(-) NK Cells2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 7, p. 3374-3381Article in journal (Refereed)
    Abstract [en]

    NK cells are functionally educated by self-MHC specific receptors, including the inhibitory killer cell Ig-like receptors (KIRs) and the lectin-like CD94/NKG2A heterodimer. Little is known about how NK cell education influences qualitative aspects of cytotoxicity such as migration behavior and efficacy of activation and killing at the single-cell level. In this study, we have compared the behavior of FACS-sorted CD56(dim)CD57(-)KIR(-)NKG2A(+) (NKG2A(+)) and CD56(dim)CD57(-)KIR(-)NKG2A(+) (lacking inhibitory receptors; IR-) human NK cells by quantifying migration, cytotoxicity, and contact dynamics using microchip-based live cell imaging. NKG2A(+) NK cells displayed a more dynamic migration behavior and made more contacts with target cells than IR-NK cells. NKG2A(+) NK cells also more frequently killed the target cells once a conjugate had been formed. NK cells with serial killing capacity were primarily found among NKG2A(+) NK cells. Conjugates involving IR- NK cells were generally more short-lived and IR- NK cells did not become activated to the same extent as NKG2A(+) NK cells when in contact with target cells, as evident by their reduced spreading response. In contrast, NKG2A(+) and IR- NK cells showed similar dynamics in terms of duration of conjugation periods and NK cell spreading response in conjugates that led to killing. Taken together, these observations suggest that the high killing capacity of NKG2A(+) NK cells is linked to processes regulating events in the recognition phase of NK-target cell contact rather than events after cytotoxicity has been triggered.

  • 308.
    Forsström, Bjorn
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Axnäs, Barbara Bislawska
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Rockberg, Johan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Danielsson, Hanna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Bohlin, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Dissecting antibodies withregards to linear and conformational epitopesManuscript (preprint) (Other academic)
  • 309.
    Forsström, Bjorn
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Axnäs, Barbara Bislawska
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Stengele, Klaus-Peter
    Buehler, Jochen
    Albert, Thomas J.
    Richmond, Todd A.
    Hu, Francis Jingxin
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hudson, Elton Paul
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Rockberg, Johan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Proteome-wide Epitope Mapping of Antibodies Using Ultra-dense Peptide Arrays2014In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 13, no 6, p. 1585-1597Article in journal (Refereed)
    Abstract [en]

    Antibodies are of importance for the field of proteomics, both as reagents for imaging cells, tissues, and organs and as capturing agents for affinity enrichment in mass-spectrometry-based techniques. It is important to gain basic insights regarding the binding sites (epitopes) of antibodies and potential cross-reactivity to nontarget proteins. Knowledge about an antibody's linear epitopes is also useful in, for instance, developing assays involving the capture of peptides obtained from trypsin cleavage of samples prior to mass spectrometry analysis. Here, we describe, for the first time, the design and use of peptide arrays covering all human proteins for the analysis of antibody specificity, based on parallel in situ photolithic synthesis of a total of 2.1 million overlapping peptides. This has allowed analysis of on-and off-target binding of both monoclonal and polyclonal antibodies, complemented with precise mapping of epitopes based on full amino acid substitution scans. The analysis suggests that linear epitopes are relatively short, confined to five to seven residues, resulting in apparent off-target binding to peptides corresponding to a large number of unrelated human proteins. However, subsequent analysis using recombinant proteins suggests that these linear epitopes have a strict conformational component, thus giving us new insights regarding how antibodies bind to their antigens.

  • 310.
    Forsström, Björn
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Axnäs, Barbara Bislawska
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Rockberg, Johan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Danielsson, Hanna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Bohlin, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Dissecting Antibodies with Regards to Linear and Conformational Epitopes2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0121673Article in journal (Refereed)
    Abstract [en]

    An important issue for the performance and specificity of an antibody is the nature of the binding to its protein target, including if the recognition involves linear or conformational epitopes. Here, we dissect polyclonal sera by creating epitope-specific antibody fractions using a combination of epitope mapping and an affinity capture approach involving both synthesized peptides and recombinant protein fragments. This allowed us to study the relative amounts of antibodies to linear and conformational epitopes in the polyclonal sera as well as the ability of each antibody-fraction to detect its target protein in Western blot assays. The majority of the analyzed polyclonal sera were found to have most of the target-specific antibodies directed towards linear epitopes and these were in many cases giving Western blot bands of correct molecular weight. In contrast, many of the antibodies towards conformational epitopes did not bind their target proteins in the Western blot assays. The results from this work have given us insights regarding the nature of the antibody response generated by immunization with recombinant protein fragments and has demonstrated the advantage of using antibodies recognizing linear epitopes for immunoassay involving wholly or partially denatured protein targets.

  • 311.
    Fourati, Zaineb
    et al.
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Heusser, Stephanie A.
    Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Hu, Haidai
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France.;UPMC Univ Paris 6, Sorbonne Univ, F-75005 Paris, France..
    Ruza, Reinis R.
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Sauguet, Ludovic
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.
    Delarue, Marc
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels2018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 23, no 4, p. 993-1004Article in journal (Refereed)
    Abstract [en]

    Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

  • 312. Fransson, Martin N.
    et al.
    Brugård, Jan
    Aronsson, Peter
    Gréen, Henrik
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Semi-physiologically based pharmacokinetic modeling of paclitaxel metabolism and in silico-based study of the dynamic sensitivities in pathway kinetics2012In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 47, no 4, p. 759-767Article in journal (Refereed)
    Abstract [en]

    Purpose: To build a semi-physiologically based pharmacokinetic model describing the uptake, metabolism and efflux of paclitaxel and its metabolites and investigate the effect of hypothetical genetic polymorphisms causing reduced uptake, metabolism or efflux in the pathway by model simulation and sensitivity analysis. Methods: A previously described intracellular pharmacokinetic model was used as a starting point for model development. Kinetics for metabolism, transport, binding and systemic and output compartments were added to mimic a physiological model with hepatic elimination. Model parameters were calibrated using constraints postulated as ratios of concentrations and amounts of metabolites and drug in the systemic plasma and output compartments. The sensitivity in kinetic parameters was tested using dynamic sensitivity analysis. Results: Predicted plasma concentrations of drug and metabolites were in the range of what has been observed in clinical studies. Given the final model, plasma concentrations of paclitaxel seems to be relatively little affected by changes in metabolism or transport, while its main metabolite may be largely affected even by small changes. If metabolites prove to be clinically relevant, genetic polymorphisms may play an important role for individualizing paclitaxel treatment.

  • 313.
    Fredolini, Claudia
    et al.
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Byström, Sanna
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Pin, Elisa
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Edfors, Fredrik
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tamburro, Davide
    Iglesias, Maria Jesus
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Häggmark, Anna
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hong, Mun-Gwan
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Immunocapture strategies in translational proteomics2016In: Expert Review of Proteomics, ISSN 1478-9450, E-ISSN 1744-8387, Vol. 13, no 1, p. 83-98Article, review/survey (Refereed)
    Abstract [en]

    Aiming at clinical studies of human diseases, antibody-assisted assays have been applied to biomarker discovery and toward a streamlined translation from patient profiling to assays supporting personalized treatments. In recent years, integrated strategies to couple and combine antibodies with mass spectrometry-based proteomic efforts have emerged, allowing for novel possibilities in basic and clinical research. Described in this review are some of the field's current and emerging immunocapture approaches from an affinity proteomics perspective. Discussed are some of their advantages, pitfalls and opportunities for the next phase in clinical and translational proteomics.

  • 314.
    Fredolini, Claudia
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Byström, Sanna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sanchez-Rivera, Laura
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ioannou, Marina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tamburro, Davide
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, Canc Prote, S-17121 Solna, Sweden..
    Pontén, Fredrik
    Uppsala Univ, Rudbeck Lab, Sci Life Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Branca, Rui M.
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, Canc Prote, S-17121 Solna, Sweden..
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lehtio, Janne
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, Canc Prote, S-17121 Solna, Sweden..
    Schwenk, Jochen M.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Systematic assessment of antibody selectivity in plasma based on a resource of enrichment profiles2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 8324Article in journal (Refereed)
    Abstract [en]

    There is a strong need for procedures that enable context and application dependent validation of antibodies. Here, we applied a magnetic bead assisted workflow and immunoprecipitation mass spectrometry (IP-MS/MS) to assess antibody selectivity for the detection of proteins in human plasma. A resource was built on 414 IP experiments using 157 antibodies (targeting 120 unique proteins) in assays with heat-treated or untreated EDTA plasma. For each protein we determined their antibody related degrees of enrichment using z-scores and their frequencies of identification across all IP assays. Out of 1,313 unique endogenous proteins, 426 proteins (33%) were detected in >20% of IPs, and these background components were mainly comprised of proteins from the complement system. For 45% (70/157) of the tested antibodies, the expected target proteins were enriched (z-score >= 3). Among these 70 antibodies, 59 (84%) co-enriched other proteins beside the intended target and mainly due to sequence homology or protein abundance. We also detected protein interactions in plasma, and for IGFBP2 confirmed these using several antibodies and sandwich immunoassays. The protein enrichment data with plasma provide a very useful and yet lacking resource for the assessment of antibody selectivity. Our insights will contribute to a more informed use of affinity reagents for plasma proteomics assays.

  • 315. Friboulet, Luc
    et al.
    Barrios-Gonzales, Daniel
    Commo, Frederic
    Olaussen, Ken Andre
    Vagner, Stephan
    Adam, Julien
    Goubar, Aicha
    Dorvault, Nicolas
    Lazar, Vladimir
    Job, Bastien
    Besse, Benjamin
    Validire, Pierre
    Girard, Philippe
    Lacroix, Ludovic
    Hasmats, Johanna
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Dufour, Fabienne
    Andre, Fabrice
    Soria, Jean-Charles
    Molecular Characteristics of ERCC1-Negative versus ERCC1-Positive Tumors in Resected NSCLC2011In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 17, no 17, p. 5562-5572Article in journal (Refereed)
    Abstract [en]

    Purpose: Excision repair cross-complementation group 1 (ERCC1) is a protein involved in repair of DNA platinum adducts and stalled DNA replication forks. We and others have previously shown the influence of ERCC1 expression upon survival rates and benefit of cisplatin-based chemotherapy in patients with resected non-small-cell lung cancer (NSCLC). However, little is known about the molecular characteristics of ERCC1-positive and ERCC1-negative tumors. Experimental Design: We took advantage of a cohort of 91 patients with resected NSCLC, for which we had matched frozen and paraffin-embedded samples to explore the comparative molecular portraits of ERCC1-positive and ERCC1-negative tumors of NSCLC. We carried out a global molecular analysis including assessment of ERCC1 expression levels by using both immunohistochemistry (IHC) and quantitative reverse transcriptase PCR (qRT-PCR), genomic instability, global gene and miRNA expression, and sequencing of selected key genes involved in lung carcinogenesis. Results: ERCC1 protein and mRNA expression were significantly correlated. However, we observed several cases with clear discrepancies. We noted that ERCC1-negative tumors had a higher rate of genomic abnormalities versus ERCC1-positive tumors. ERCC1-positive tumors seemed to share a common DNA damage response (DDR) phenotype with the overexpression of seven genes linked to DDR. The miRNA expression analysis identified miR-375 as significantly underexpressed in ERCC1-positive tumors. Conclusions: Our data show inconsistencies in ERCC1 expression between IHC and qRT-PCR readouts. Furthermore, ERCC1 status is not linked to specific mutational patterns or frequencies. Finally, ERCC1negative tumors have a high rate of genomic aberrations that could consequently influence prognosis in patients with resected NSCLC. Clin Cancer Res; 17(17); 5562-72.

  • 316. Fridberg, M.
    et al.
    Nodin, B.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jirström, K.
    Dachshund homologue 2 is a marker of good prognosis in breast cancer2012In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 61, p. 19-19Article in journal (Other academic)
  • 317. Fridberg, Marie
    et al.
    Nodin, Björn
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jirström, Karin
    Dachshund homologue 2 is a marker of good prognosis in breast cancer2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, p. 87-87Article in journal (Other academic)
  • 318. Frings, O.
    et al.
    Alexeyenko, Andrey
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm Bioinformatics Centre, Science for Life Laboratory, Solna, Sweden .
    Sonnhammer, E. L. L.
    MGclus: Network clustering employing shared neighbors2013In: Molecular BioSystems, ISSN 1742-206X, Vol. 9, no 7, p. 1670-1675Article in journal (Refereed)
    Abstract [en]

    Network analysis is an important tool for functional annotation of genes and proteins. A common approach to discern structure in a global network is to infer network clusters, or modules, and assume a functional coherence within each module, which may represent a complex or a pathway. It is however not trivial to define optimal modules. Although many methods have been proposed, it is unclear which methods perform best in general. It seems that most methods produce far from optimal results but in different ways. MGclus is a new algorithm designed to detect modules with a strongly interconnected neighborhood in large scale biological interaction networks. In our benchmarks we found MGclus to outperform other methods when applied to random graphs with varying degree of noise, and to perform equally or better when applied to biological protein interaction networks. MGclus is implemented in Java and utilizes the JGraphT graph library. It has an easy to use command-line interface and is available for download from http://sonnhammer.sbc.su.se/download/software/ MGclus/.

  • 319.
    Frings, Oliver
    et al.
    Stockholm Univ, Science for life laboratory.
    Mank, Judith E.
    Alexeyenko, Andrey
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sonnhammer, Erik L. L.
    Network Analysis of Functional Genomics Data: Application to Avian Sex-Biased Gene Expression2012In: Scientific World Journal, ISSN 1537-744X, E-ISSN 1537-744X, p. 130491-Article in journal (Refereed)
    Abstract [en]

    Gene expression analysis is often used to investigate the molecular and functional underpinnings of a phenotype. However, differential expression of individual genes is limited in that it does not consider how the genes interact with each other in networks. To address this shortcoming we propose a number of network-based analyses that give additional functional insights into the studied process. These were applied to a dataset of sex-specific gene expression in the chicken gonad and brain at different developmental stages. We first constructed a global chicken interaction network. Combining the network with the expression data showed that most sex-biased genes tend to have lower network connectivity, that is, act within local network environments, although some interesting exceptions were found. Genes of the same sex bias were generally more strongly connected with each other than expected. We further studied the fates of duplicated sex-biased genes and found that there is a significant trend to keep the same pattern of sex bias after duplication. We also identified sex-biased modules in the network, which reveal pathways or complexes involved in sex-specific processes. Altogether, this work integrates evolutionary genomics with systems biology in a novel way, offering new insights into the modular nature of sex-biased genes.

  • 320. Fristedt, Richard
    et al.
    Elebro, Jacob
    Gaber, Alexander
    Jonsson, Liv
    Heby, Margareta
    Yudina, Yulyana
    Nodin, Bjorn
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. AlbaNova University, Sweden.
    Eberhard, Jakob
    Jirstrom, Karin
    Reduced Expression of the Polymeric Immunoglobulin Receptor in Pancreatic and Periampullary Adenocarcinoma Signifies Tumour Progression and Poor Prognosis2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112728-Article in journal (Refereed)
    Abstract [en]

    The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmo and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p<0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71-5.25) and early recurrence (HR = 2.89, 95% CI 1.67-4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57). These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies a more favourable tumour phenotype and that low expression independently predicts a shorter survival in patients with pancreatic and periampullary cancer. The mechanistic basis for the putative tumour suppressing properties of pIgR in these cancers merits further study.

  • 321.
    Fritz, Nicolas
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Akkuratov, Evgeny
    KTH.
    Liebmann, Thomas
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindskog, Maria
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Aperia, Anita
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Functional consequences of the disease-causing T613M mutation of NKAalpha3 for hippocampal neurons2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29Article in journal (Other academic)
  • 322.
    Fritzell, Kajsa
    et al.
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Svante Arrheniusvag 20C, S-10691 Stockholm, Sweden..
    Xu, Li-Di
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Svante Arrheniusvag 20C, S-10691 Stockholm, Sweden..
    Lagergren, Jens
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Electrical Engineering and Computer Science (EECS).
    Ohman, Marie
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Svante Arrheniusvag 20C, S-10691 Stockholm, Sweden..
    ADARs and editing: The role of A-to-I RNA modification in cancer progression2018In: Seminars in Cell and Developmental Biology, ISSN 1084-9521, E-ISSN 1096-3634, Vol. 79, p. 123-130Article, review/survey (Refereed)
    Abstract [en]

    Cancer arises when pathways that control cell functions such as proliferation and migration are dysregulated to such an extent that cells start to divide uncontrollably and eventually spread throughout the body, ultimately endangering the survival of an affected individual. It is well established that somatic mutations are important in cancer initiation and progression as well as in creation of tumor diversity. Now also modifications of the transcriptome are emerging as a significant force during the transition from normal cell to malignant tumor. Editing of adenosine (A) to inosine (I) in double-stranded RNA, catalyzed by adenosine deaminases acting on RNA (ADARs), is one dynamic modification that in a combinatorial manner can give rise to a very diverse transcriptome. Since the cell interprets inosine as guanosine (G), editing can result in non-synonymous codon changes in transcripts as well as yield alternative splicing, but also affect targeting and disrupt maturation of microRNA. ADAR editing is essential for survival in mammals but its dysregulation can lead to cancer. ADAR1 is for instance overexpressed in, e.g., lung cancer, liver cancer, esophageal cancer and chronic myoelogenous leukemia, which with few exceptions promotes cancer progression. In contrast, ADAR2 is lowly expressed in e.g. glioblastoma, where the lower levels of ADAR2 editing leads to malignant phenotypes. Altogether, RNA editing by the ADAR enzymes is a powerful regulatory mechanism during tumorigenesis. Depending on the cell type, cancer progression seems to mainly be induced by ADAR1 upregulation or ADAR2 downregulation, although in a few cases ADAR1 is instead downregulated. In this review, we discuss how aberrant editing of specific substrates contributes to malignancy. 

  • 323. Frostegård, J.
    et al.
    Hellström, Cecilia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Frostegård, A. G.
    Ajeganova, S.
    Autoantibody profiling reveals four protein candidate autoantigens associated with systemic lupus erythematosus2018In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 27, no 10, p. 1670-1678Article in journal (Refereed)
    Abstract [en]

    Objectives In systemic lupus erythematosus (SLE) there are typically many autoantibodies. The disease heterogeneity could be better understood with discovery of phenotype-specific antigens targeted by autoantibodies. We here aimed to identify novel autoantigens potentially related to SLE disease and a major complication, atherosclerosis. Methods Antigen microarrays were used to profile IgG autoantibody reactivity against 77 protein fragments (20-140 amino acids (aa) long, median 89 aa) produced within the Human Protein Atlas project, in serum samples from SLE patients (n=107) and age- and sex-matched population-based controls (n=107). Common carotid intima-media thickness, plaque occurrence and echogenicity were determined by B-mode ultrasound. Results We determined significant differences between patients and controls in IgG reactivity against four proteins. In patients compared to controls, there was an increase of IgG reactivity against zinc finger protein 688 (ZNF688), early B cell factor 2 (EBF2), crystallin, alpha B (CRYAB) and tumor necrosis factor receptor superfamily member 13C (TNFRSF13C). Of these four antigens, only anti-ZNF688 was associated with carotid atherosclerosis (plaque occurrence) and vulnerable plaques in SLE. There was a weak association between anti-EBF2 and SLE disease activity but no significant associations were determined for other measured IgG reactivity. Conclusions In this discovery screening we here demonstrate new candidate autoantigens with differential reactivity (reflecting autoantibody levels) in SLE patients and in controls and in relation to atherosclerosis in SLE.

  • 324. Frånberg, Mattias
    et al.
    Gertow, Karl
    Hamsten, Anders
    Lagergren, Jens
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Sennblad, Bengt
    Discovering Genetic Interactions in Large-Scale Association Studies by Stage-wise Likelihood Ratio Tests2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 9, article id e1005502Article in journal (Refereed)
    Abstract [en]

    Despite the success of genome-wide association studies in medical genetics, the underlying genetics of many complex diseases remains enigmatic. One plausible reason for this could be the failure to account for the presence of genetic interactions in current analyses. Exhaustive investigations of interactions are typically infeasible because the vast number of possible interactions impose hard statistical and computational challenges. There is, therefore, a need for computationally efficient methods that build on models appropriately capturing interaction. We introduce a new methodology where we augment the interaction hypothesis with a set of simpler hypotheses that are tested, in order of their complexity, against a saturated alternative hypothesis representing interaction. This sequential testing provides an efficient way to reduce the number of non-interacting variant pairs before the final interaction test. We devise two different methods, one that relies on a priori estimated numbers of marginally associated variants to correct for multiple tests, and a second that does this adaptively. We show that our methodology in general has an improved statistical power in comparison to seven other methods, and, using the idea of closed testing, that it controls the family-wise error rate. We apply our methodology to genetic data from the PRO-CARDIS coronary artery disease case/control cohort and discover three distinct interactions. While analyses on simulated data suggest that the statistical power may suffice for an exhaustive search of all variant pairs in ideal cases, we explore strategies for a priori selecting subsets of variant pairs to test. Our new methodology facilitates identification of new disease-relevant interactions from existing and future genome-wide association data, which may involve genes with previously unknown association to the disease. Moreover, it enables construction of interaction networks that provide a systems biology view of complex diseases, serving as a basis for more comprehensive understanding of disease pathophysiology and its clinical consequences.

  • 325.
    Frånberg, Mattias
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS). KTH, Centres, Science for Life Laboratory, SciLifeLab. Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden ; Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden.
    Lagergren, Jens
    KTH, School of Electrical Engineering and Computer Science (EECS), Computational Science and Technology (CST). KTH, Centres, SeRC - Swedish e-Science Research Centre.
    Sennblad, Bengt
    Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden ; Dept of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    BESIQ: A tool for discovering gene-gene and gene-environment interactions in genome-wide association studiesManuscript (preprint) (Other academic)
  • 326.
    Frånberg, Mattias
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS). KTH, Centres, Science for Life Laboratory, SciLifeLab. Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden ; .
    Sabater-Lleal, Maria
    Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Unit of Genomics of Complex Diseases, Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain.
    Hamsten, Anders
    Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lagergren, Jens
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Electrical Engineering and Computer Science (EECS).
    Sennblad, Bengt
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; .
    Discovering gene-environment interactions with LassoManuscript (preprint) (Other academic)
  • 327.
    Fu, Ying
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jussi, Johnny Israelsson
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Elmlund, Louise
    Swedish Natl Forens Ctr, SE-58194 Linkoping, Sweden..
    Dunne, Simon
    Swedish Natl Forens Ctr, SE-58194 Linkoping, Sweden..
    Wang, Qin
    RISE Res Inst Sweden AB, Box 1070, SE-16425 Kista, Sweden..
    Brismar, Hjalmar
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Intrinsic blinking characteristics of single colloidal CdSe-CdS/ZnS core-multishell quantum dots2019In: Physical Review B, ISSN 2469-9950, E-ISSN 2469-9969, Vol. 99, no 3, article id 035404Article in journal (Refereed)
    Abstract [en]

    Fluorescence blinking of single colloidal semiconductor quantum dots (QDs) has been extensively studied, and several sophisticated models have been proposed. In this work, we derive Heisenberg equations of motion to carefully study principal transition processes, i.e., photoexcitation, energy relaxation, impact ionization and Auger recombination, radiative and nonradiative recombinations, and tunneling between core states and surface states, of the electron-hole pair in single CdSe-CdS/ZnS core-multishell QDs and show that the on-state probability density distribution of the QD fluorescence obeys the random telegraph signal theory because of the random radiative recombination of the photoexcited electron-hole pair in the QD core, while the off-state probability density distribution obeys the inverse power law distribution due to the series of random walks of the photoexcited electron in the two-dimensional surface-state network after the electron tunnels from the QD core to the QD surface. These two different blinking characteristics of the single QD are resolved experimentally by properly adjusting the optical excitation power and the bin time.

  • 328.
    Gabrielsson, Anders
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Liin, Sara
    Elinder, Fredrik
    Lindahl, Erik
    Binding Structure & Dynamics for Toxins Modifying the Gating Mechanism of Kv Channels2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 738A-738AArticle in journal (Other academic)
  • 329. Gallus, S.
    et al.
    Hallström, Björn M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Senckenberg Gesellschaft für Naturforschung, Germany .
    Kumar, V.
    Dodt, W. G.
    Janke, A.
    Schumann, G. G.
    Nilsson, M. A.
    Evolutionary histories of transposable elements in the genome of the largest living marsupial carnivore, the tasmanian devil2015In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 32, no 5, p. 1268-1283Article in journal (Refereed)
    Abstract [en]

    The largest living carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii), is the sole survivor of a lineage originating about 12 Ma. We set out to investigate the spectrum of transposable elements found in the Tasmanian devil genome, the first high-coverage genome of an Australian marsupial. Marsupial genomes have been shown to have the highest amount of transposable elements among vertebrates. We analyzed the horizontally transmitted DNA transposons OC1 and hAT-1-MEu in the Tasmanian devil genome. OC1 is present in all carnivorous marsupials, while having a very limited distribution among the remaining Australian marsupial orders. In contrast, hAT-1-MEu is present in all Australian marsupial orders, and has so far only been identified in a few placental mammals. We screened 158 introns for phylogenetically informative retrotransposons in the order Dasyuromorphia, and found that the youngest SINE (Short INterspersed Element), WSINE1, is no longer active in the subfamily Dasyuridae. The lack of detectable WSINE1 activity in this group may be due to a retrotransposon inactivation event approximately 30 Ma. We found that the Tasmanian devil genome contains a relatively low number of continuous full-length LINE-1 (Long INterspersed Element 1, L1) retrotransposons compared with the opossum genome. Furthermore, all L1 elements in the Tasmanian devil appeared to be nonfunctional. Hidden Markov Model approaches suggested that other potential sources of functional reverse transcriptase are absent from the genome. We discuss the issues associated with assembling long, highly similar L1 copies from short read Illumina data and describe how assembly artifacts can potentially lead to erroneous conclusions.

  • 330. Gan, Z.
    et al.
    Pan, P.
    Chen, Z.
    Meng, M.
    Xu, Hao
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yu, Z.
    Chang, C.
    Tao, Y.
    Ultraviolet Photoluminescence of Carbon Nanospheres and its Surface Plasmon-Induced Enhancement2018In: Small, ISSN 1613-6810, E-ISSN 1613-6829, Vol. 14, no 16, article id 1704239Article in journal (Refereed)
    Abstract [en]

    Ultraviolet (UV) light can be used in versatile applications ranging from photoelectronic devices to biomedical imaging. In the development of new UV light sources, in this study, stable UV emission at ≈350 nm is unprecedentedly obtained from carbon nanospheres (CNSs). The origin of the UV fluorescence is comprehensively investigated via various characterization methods, including Raman and Fourier transform infrared analyses, with comparison to the visible emission of carbon nanodots. Based on the density functional calculations, the UV fluorescence is assigned to the carbon nanostructures bonded to bridging O atoms and dangling –OH groups. Moreover, a twofold enhancement in the UV emission is acquired for Au-carbon core-shell nanospheres (Au-CNSs). This remarkable modification of the UV emission is primarily ascribed to charge transfer between the CNSs and the Au surface.

  • 331. Gan, Zhixing
    et al.
    Wu, Xinghong
    Xu, Hao
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zhang, Ning
    Nie, Shouping
    Fu, Ying
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Electron transition pathways of photoluminescence from 3C-SiC nanocrystals unraveled by steady-state, blinking and time-resolved photoluminescence measurement2016In: Journal of Physics D: Applied Physics, ISSN 0022-3727, E-ISSN 1361-6463, Vol. 49, no 27Article in journal (Refereed)
    Abstract [en]

    The cubic phase SiC nanocrystals (3C-SiC NCs) have been extensively studied for electronics and photonics applications. In this work we study the electron transition pathways of photoluminescence (PL) from 3C-SiC NCs. It is found through measuring the steady-state, blinking and time-resolved PL spectra that surface passivation by glycerol improved the steady-state PL intensity (it does not modify the emission wavelength) and the NCs fluoresced more steadily. The PL decay lifetimes are shown to be the same when the detection wavelength is modified to scan the broad PL peak, implying that the broad PL peak is originated from the distribution of NCs' sizes. Furthermore, the PL decay lifetimes are not modified by the surface passivation. It is concluded that for PL, the electron is photoexcited from the ground state in the NC to a high-energy excited state, relaxes to the first excited state then radiatively recombines to the ground state to emit a photon. The photoexcited electron at the high-energy excited state could transit to the surface state, resulting in a reduced PL intensity and a decreased on-state dwell time in the blinking trajectory. The PL decay lifetime data implies that the two principal electron transition pathways of (a) high-energy excited state double right arrow the first excited state double right arrow the ground state, and (b) high-energy excited state double right arrow surface state double right arrow the ground state are independent from each other. We strongly believe that such a deep knowledge about 3C-SiC NCs will open new doors to harness them for novel applications.

  • 332. Gan, Zhixing
    et al.
    Xu, Hao
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Ningbo University, China.
    Photoluminescence of Diphenylalanine Peptide Nano/Microstructures: From Mechanisms to Applications2017In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 38, no 22, article id 1700370Article, review/survey (Refereed)
    Abstract [en]

    Diphenylalanine (Phe-Phe, FF) molecules, which can self-assemble into highly ordered nano/microstructures, have increasingly aroused intense interests due to their special optical properties. In this review, recent advances in photoluminescence (PL) of supramolecular architectures of FF-based peptide and the underlying mechanisms are highlighted. Mainly deep ultraviolet emission at around 285 nm and/or blue emission at approximate to 450 nm are observed in various FF peptide structures and its derivatives, which are primarily interpreted by quantum confinement effects, shallow radiative traps, and electron delocalization via hydrogen bonds in beta-sheet structures. Furthermore, current applications of such fluorescent peptide nano/microstructures are also reviewed here, e.g., probing the number of water molecules confined in FF, temperature sensing, and visualization of deep ultraviolet beam. Yet, the PL mechanism is still under fierce debate and the application based on fluorescence is constantly under exploration. Thus, this review is endeavored to boost future explorations on the PL of the bioinspired FF peptide nano/microstructures.

  • 333. Gan, Zhixing
    et al.
    Xu, Hao
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fu, Ying
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Photon Reabsorption and Nonradiative Energy-Transfer-Induced Quenching of Blue Photoluminescence from Aggregated Graphene Quantum Dots2016In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 120, no 51, p. 29432-29438Article in journal (Refereed)
    Abstract [en]

    A deep understanding of the photoluminescence (PL) from aggregated graphene quantum dots (GQDs) is very important for their practical applications. Here the PL spectra from GQDs solutions at different concentrations are studied. We find that the intensity of the green emission (ca. 530560 nm) linearly relies on the concentration of GQDs, whereas the blue PL (ca. 425 nm) intensity is below the linear relationship, indicating a concentration-induced partial quenching of blue PL. Confocal fluorescence images explicitly demonstrate the aggregation of GQDs at high concentration. The concentration-induced PL quenching is successfully interpreted by a model of photon reabsorption and nonradiative energy transfer, indicating that, at the aggregated states, the excited electrons of GQDs may nonradiatively relax to ground states through couplings with neighboring ones. Simulated fluorescence decay results show that the energy transfer between neighboring GQDs results in a prolonged dwell time of electron on high-energy state and thus increases the decay time of 425 nm emission, while 550 nm emission remains unaffected, which is consistent with the experimental results. This work will contribute to a deep understanding on PL of GQDs and is also of huge importance to extend GQDs applications.

  • 334. Gan, Zhixing
    et al.
    Xu, Hao
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hao, Yanling
    Mechanism for excitation-dependent photoluminescence from graphene quantum dots and other graphene oxide derivates: consensus, debates and challenges2016In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 8, no 15, p. 7794-7807Article, review/survey (Refereed)
    Abstract [en]

    Luminescent nanomaterials, with wide applications in biosensing, bioimaging, illumination and display techniques, have been consistently garnering enormous research attention. In particular, those with wavelength-controllable emissions could be highly beneficial. Carbon nanostructures, including graphene quantum dots (GQDs) and other graphene oxide derivates (GODs), with excitation-dependent photoluminescence (PL), which means their fluorescence color could be tuned simply by changing the excitation wavelength, have attracted lots of interest. However the intrinsic mechanism for the excitation-dependent PL is still obscure and fiercely debated presently. In this review, we attempt to summarize the latest efforts to explore the mechanism, including the quantum confinement effect, surface traps model, giant red-edge effect, edge states model and electronegativity of heteroatom model, as well as the newly developed synergistic model, to seek some clues to unravel the mechanism. Meanwhile the controversial difficulties for each model are further discussed. Besides this, the challenges and potential influences of the synthetic methodology and development of the materials are illustrated extensively to elicit more thought and constructive attempts toward their application.

  • 335.
    Gantelius, Jesper
    et al.
    KTH, School of Biotechnology (BIO), Nano Biotechnology (closed 20130101).
    Bass, Tarek
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101).
    Sjöberg, Ronald
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Andersson-Svahn, Helene
    KTH, School of Biotechnology (BIO), Nano Biotechnology (closed 20130101).
    A Lateral Flow Protein Microarray for Rapid and Sensitive Antibody Assays2011In: International Journal of Molecular Sciences, ISSN 1661-6596, Vol. 12, no 11, p. 7748-7759Article in journal (Refereed)
    Abstract [en]

    Protein microarrays are useful tools for highly multiplexed determination of presence or levels of clinically relevant biomarkers in human tissues and biofluids. However, such tools have thus far been restricted to laboratory environments. Here, we present a novel 384-plexed easy to use lateral flow protein microarray device capable of sensitive (<30 ng/mL) determination of antigen-specific antibodies in ten minutes of total assay time. Results were developed with gold nanobeads and could be recorded by a cell-phone camera or table top scanner. Excellent accuracy with an area under curve (AUC of 98% was achieved in comparison with an established glass microarray assay for 26 antigen-specific antibodies. We propose that the presented framework could find use in convenient and cost-efficient quality control of antibody production, as well as in providing a platform for multiplexed affinity-based assays in low-resource or mobile settings.

  • 336. Gantner, S
    et al.
    Andersson, Anders F.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Alonso-Saez, L
    Bertilsson, S
    Novel primers for 16S rRNA-based archaeal community analyses in environmental samples2011In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 84, no 1, p. 12-18Article in journal (Refereed)
    Abstract [en]

    Next generation sequencing technologies for in depth analyses of complex microbial communities rely on rational primer design based on up-to-date reference databases. Most of the 16S rRNA-gene based analyses of environmental Archaea community composition use PCR primers developed from small data sets several years ago, making an update long overdue. Here we present a new set of archaeal primers targeting the 16S rRNA gene designed from 8500 aligned archaeal sequences in the SILVA database. The primers 340F-1000R showed a high archaeal specificity (<1% bacteria amplification) covering 93 and 97% of available sequences for Crenarchaeota and Euryarchaeota respectively. In silico tests of the primers revealed at least 38% higher coverage for Archaea compared to other commonly used primers. Empirical tests with clone libraries confirmed the high specificity of the primer pair to Archaea in three biomes: surface waters in the Arctic Ocean, the pelagic zone of a temperate lake and a methanogenic bioreactor. The clone libraries featured both Euryarchaeota and Crenarchaeota in variable proportions and revealed dramatic differences in the archaeal community composition and minimal phylogenetic overlap between samples.

  • 337. Gardberg, M.
    et al.
    Kaipio, K.
    Lehtinen, L.
    Mikkonen, P.
    Heuser, V. D.
    Talvinen, K.
    Iljin, K.
    Kampf, C.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Grénman, R.
    Koivisto, M.
    Carpén, O.
    FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74923-Article in journal (Refereed)
    Abstract [en]

    Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.

  • 338. Gardberg, Maria
    et al.
    Heuser, Vanina D.
    Iljin, Kristiina
    Kampf, Caroline
    Uhlen, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Carpen, Olli
    Characterization of Leukocyte Formin FMNL1 Expression in Human Tissues2014In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 62, no 6, p. 460-470Article in journal (Refereed)
    Abstract [en]

    Formins are cytoskeleton regulating proteins characterized by a common FH2 structural domain. As key players in the assembly of actin filaments, formins direct dynamic cytoskeletal processes that influence cell shape, movement and adhesion. The large number of formin genes, fifteen in the human, suggests distinct tasks and expression patterns for individual family members, in addition to overlapping functions. Several formins have been associated with invasive cell properties in experimental models, linking them to cancer biology. One example is FMNL1, which is considered to be a leukocyte formin and is known to be overexpressed in lymphomas. Studies on FMNL1 and many other formins have been hampered by a lack of research tools, especially antibodies suitable for staining paraffin-embedded formalin-fixed tissues. Here we characterize, using bioinformatics tools and a validated antibody, the expression pattern of FMNL1 in human tissues and study its subcellular distribution. Our results indicate that FMNL1 expression is not restricted to hematopoietic tissues and that neoexpression of FMNL1 can be seen in epithelial cancer.

  • 339. Ge, Changrong P
    et al.
    Tong, Dongmei R
    Liang, Bibo T
    Lonnblom, Erik S
    Schneider, Nadine K
    Hagert, Cecilia U
    Viljanen, Johan V
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Stawikowska, Roma T
    Nilsson, Peter C.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fields, Gregg B
    Skogh, Thomas A
    Kastbom, Alf R
    Kihlberg, Jan T
    Burkhardt, Harald T
    Dobritzsch, Doreen C
    Holmdahl, Rikard K
    Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage2017In: JCI INSIGHT, ISSN 2379-3708, Vol. 2, no 13, article id e93688Article in journal (Refereed)
    Abstract [en]

    Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.

  • 340.
    Ge, Changrong
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Xu, Bingze
    Karolinska Inst, Stockholm, Sweden..
    Liang, Bibo
    Karolinska Inst, Stockholm, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Lonnblom, Erik
    Karolinska Inst, Stockholm, Sweden..
    Lundstrom, Susanna L.
    Karolinska Inst, Stockholm, Sweden..
    Zubarev, Roman A.
    Karolinska Inst, Stockholm, Sweden..
    Ayoglu, Burcu
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Skogh, Thomas
    Linkoping Univ, Linkoping, Sweden..
    Kastbom, Alf
    Linkoping Univ, Linkoping, Sweden..
    Malmstrom, Vivianne
    Karolinska Inst, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Klareskog, Lars
    Karolinska Inst, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Toes, Rene E. M.
    Leiden Univ, Med Ctr, Leiden, Netherlands..
    Rispens, Theo
    Univ Amsterdam, Amsterdam, Netherlands..
    Dobritzsch, Doreen
    Uppsala Univ, Uppsala, Sweden..
    Holmdahl, Rikard
    Karolinska Inst, Stockholm, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies2019In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 71, no 2, p. 210-221Article in journal (Refereed)
    Abstract [en]

    Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.

  • 341. Geiger, T.
    et al.
    Velic, A.
    MacEk, B.
    Lundberg, E.
    Kampf, C.
    Nagaraj, N.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Cox, J.
    Mann, M.
    Initial quantitative proteomic map of 28 mouse tissues using the SILAC mouse2013In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 12, no 6, p. 1709-1722Article in journal (Refereed)
    Abstract [en]

    Identifying the building blocks of mammalian tissues is a precondition for understanding their function. In particular, global and quantitative analysis of the proteome of mammalian tissues would point to tissue-specific mechanisms and place the function of each protein in a whole-organism perspective. We performed proteomic analyses of 28 mouse tissues using high-resolution mass spectrometry and used a mix of mouse tissues labeled via stable isotope labeling with amino acids in cell culture as a "spike-in" internal standard for accurate protein quantification across these tissues. We identified a total of 7,349 proteins and quantified 6,974 of them. Bioinformatic data analysis showed that physiologically related tissues clustered together and that highly expressed proteins represented the characteristic tissue functions. Tissue specialization was reflected prominently in the proteomic profiles and is apparent already in their hundred most abundant proteins. The proportion of strictly tissue-specific proteins appeared to be small. However, even proteins with household functions, such as those in ribosomes and spliceosomes, can have dramatic expression differences among tissues. We describe a computational framework with which to correlate proteome profiles with physiological functions of the tissue. Our data will be useful to the broad scientific community as an initial atlas of protein expression of a mammalian species.

  • 342. Ghaffari, Pouyan
    et al.
    Mardinoglu, Adil
    Asplund, Anna
    Shoaie, Saeed
    Kampf, Caroline
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers, Dept Biol & Biol Engn, Sweden.
    Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8183-Article in journal (Refereed)
    Abstract [en]

    Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines based on RNA-Seq data and validated the functionality of these models with data from metabolite profiling. We used cell line-specific GEMs to analyze the differences in the metabolism of cancer cell lines, and to explore the heterogeneous expression of the metabolic subsystems. Furthermore, we predicted 85 antimetabolites that can inhibit growth of, or even kill, any of the cell lines, while at the same time not being toxic for 83 different healthy human cell types. 60 of these antimetabolites were found to inhibit growth in all cell lines. Finally, we experimentally validated one of the predicted antimetabolites using two cell lines with different phenotypic origins, and found that it is effective in inhibiting the growth of these cell lines. Using immunohistochemistry, we also showed high or moderate expression levels of proteins targeted by the validated antimetabolite. Identified anti-growth factors for inhibition of cell growth may provide leads for the development of efficient cancer treatment strategies.

  • 343. Ghaffari, Pouyan
    et al.
    Mardinoglu, Adil
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Nielsen, Jens
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden; Technical University of Denmark, Denmark.
    Cancer Metabolism: A Modeling Perspective2015In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, article id 382Article, review/survey (Refereed)
    Abstract [en]

    Tumor cells alter their metabolism to maintain unregulated cellular proliferation and survival, but this transformation leaves them reliant on constant supply of nutrients and energy. In addition to the widely studied dysregulated glucose metabolism to fuel tumor cell growth, accumulating evidences suggest that utilization of amino acids and lipids contributes significantly to cancer cell metabolism. Also recent progresses in our understanding of carcinogenesis have revealed that cancer is a complex disease and cannot be understood through simple investigation of genetic mutations of cancerous cells. Cancer cells present in complex tumor tissues communicate with the surrounding microenvironment and develop traits which promote their growth, survival, and metastasis. Decoding the full scope and targeting dysregulated metabolic pathways that support neoplastic transformations and their preservation requires both the advancement of experimental technologies for more comprehensive measurement of omics as well as the advancement of robust computational methods for accurate analysis of the generated data. Here, we review cancer-associated reprogramming of metabolism and highlight the capability of genome-scale metabolic modeling approaches in perceiving a system-level perspective of cancer metabolism and in detecting novel selective drug targets.

  • 344.
    Giacomello, Stefania
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochemestry & Biophys, Stockholm, Sweden..
    Asp, Michaela
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wardell, Eva
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Reimegard, Johan
    Uppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden..
    Salmén, Fredrik
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Grinnemo, Karl-Henrik
    Uppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden..
    Mansson-Broberg, Agneta
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Corbascio, Cecilia Osterholm
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Sylven, Christer
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ståhl, Patrik
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Corbascio, Matthias
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lundeberg, Joakim
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    New insights into the human heart development using a combined spatial and single-cell transcriptomics approach2018In: HUMAN GENOMICS, ISSN 1473-9542, Vol. 12Article in journal (Other academic)
  • 345.
    Giacomello, Stefania
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Stockholm, Sweden..
    Lundeberg, Joakim
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Preparation of plant tissue to enable Spatial Transcriptomics profiling using barcoded microarrays2018In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 13, no 11, p. 2425-2446Article in journal (Refereed)
    Abstract [en]

    Elucidation of the complex processes involved in plant growth requires analysis of the spatial gene expression patterns in all affected tissues. This protocol extension is an adaptation of a protocol that describes how to use barcoded oligo-dT microarrays to evaluate spatial global gene expression profiles in mammalian tissue to enable it to be applied to plant material. Here, we explain the required adjustments for preparing and treating plant tissue sections on the array surface, specifically in regard to how to permeabilize and remove the tissue. Once the tissue has been removed, the cDNA-mRNA hybrid that is left on the slide is processed in the same way as cDNA obtained during experiments on mammalian tissue; thus the later stages of the protocol are not included here, and readers should follow the accompanying protocol for those. We have previously used our protocol to generate high-quality sequencing libraries for Arabidopsis thaliana inflorescence, Populus tremula developing and dormant leaf buds, and Picea abies female cones. However, we anticipate that the protocol can be adapted to other tissue types and species. The entire protocol for preparing samples and processing libraries can be completed in 3-4 d.

  • 346.
    Giacomello, Stefania
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm University, Sweden.
    Salmén, Fredrik
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Terebieniec, B. K.
    Vickovic, Sanja
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Navarro, J. F.
    Alexeyenko, A.
    Reimegård, J.
    McKee, Lauren S.
    KTH, School of Biotechnology (BIO), Glycoscience.
    Mannapperuma, C.
    Bulone, Vincent
    KTH, School of Biotechnology (BIO), Glycoscience. University of Adelaide, Australia.
    Ståhl, P. L.
    Sundström, J. F.
    Street, N. R.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spatially resolved transcriptome profiling in model plant species2017In: Nature Plants, ISSN 2055-0278, Vol. 3, article id 17061Article in journal (Refereed)
    Abstract [en]

    Understanding complex biological systems requires functional characterization of specialized tissue domains. However, existing strategies for generating and analysing high-throughput spatial expression profiles were developed for a limited range of organisms, primarily mammals. Here we present the first available approach to generate and study high-resolution, spatially resolved functional profiles in a broad range of model plant systems. Our process includes high-throughput spatial transcriptome profiling followed by spatial gene and pathway analyses. We first demonstrate the feasibility of the technique by generating spatial transcriptome profiles from model angiosperms and gymnosperms microsections. In Arabidopsis thaliana we use the spatial data to identify differences in expression levels of 141 genes and 189 pathways in eight inflorescence tissue domains. Our combined approach of spatial transcriptomics and functional profiling offers a powerful new strategy that can be applied to a broad range of plant species, and is an approach that will be pivotal to answering fundamental questions in developmental and evolutionary biology.

  • 347. Gioti, Anastasia
    et al.
    Nystedt, Björn
    Li, Wenjun
    Xu, Jun
    Andersson, Anna
    Averette, Anna F.
    Muench, Karin
    Wang, Xuying
    Kappauf, Catharine
    Kingsbury, Joanne M.
    Kraak, Bart
    Walker, Louise A.
    Johansson, Henrik J.
    Holm, Tina
    Lehtiö, Janne
    Stajich, Jason E.
    Mieczkowski, Piotr
    Kahmann, Regine
    Kennell, John C.
    Cardenas, Maria E.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Saunders, Charles W.
    Boekhout, Teun
    Dawson, Thomas L.
    Munro, Carol A.
    de Groot, Piet W. J.
    Butler, Geraldine
    Heitman, Joseph
    Scheynius, Annika
    Genomic Insights into the Atopic Eczema-Associated Skin Commensal Yeast Malassezia sympodialis2013In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 4, no 1, p. e00572-12-Article in journal (Refereed)
    Abstract [en]

    Malassezia commensal yeasts are associated with a number of skin disorders, such as atopic eczema/dermatitis and dandruff, and they also can cause systemic infections. Here we describe the 7.67-Mbp genome of Malassezia sympodialis, a species associated with atopic eczema, and contrast its genome repertoire with that of Malassezia globosa, associated with dandruff, as well as those of other closely related fungi. Ninety percent of the predicted M. sympodialis protein coding genes were experimentally verified by mass spectrometry at the protein level. We identified a relatively limited number of genes related to lipid biosynthesis, and both species lack the fatty acid synthase gene, in line with the known requirement of these yeasts to assimilate lipids from the host. Malassezia species do not appear to have many cell wall-localized glycosylphosphatidylinositol (GPI) proteins and lack other cell wall proteins previously identified in other fungi. This is surprising given that in other fungi these proteins have been shown to mediate interactions (e. g., adhesion and biofilm formation) with the host. The genome revealed a complex evolutionary history for an allergen of unknown function, Mala s 7, shown to be encoded by a member of an amplified gene family of secreted proteins. Based on genetic and biochemical studies with the basidiomycete human fungal pathogen Cryptococcus neoformans, we characterized the allergen Mala s 6 as the cytoplasmic cyclophilin A. We further present evidence that M. sympodialis may have the capacity to undergo sexual reproduction and present a model for a pseudobipolar mating system that allows limited recombination between two linked MAT loci. IMPORTANCE Malassezia commensal yeasts are associated with a number of skin disorders. The previously published genome of M. globosa provided some of the first insights into Malassezia biology and its involvement in dandruff. Here, we present the genome of M. sympodialis, frequently isolated from patients with atopic eczema and healthy individuals. We combined comparative genomics with sequencing and functional characterization of specific genes in a population of clinical isolates and in closely related model systems. Our analyses provide insights into the evolution of allergens related to atopic eczema and the evolutionary trajectory of the machinery for sexual reproduction and meiosis. We hypothesize that M. sympodialis may undergo sexual reproduction, which has important implications for the understanding of the life cycle and virulence potential of this medically important yeast. Our findings provide a foundation for the development of genetic and genomic tools to elucidate host-microbe interactions that occur on the skin and to identify potential therapeutic targets.

  • 348. Gliga, Anda R.
    et al.
    Edoff, Karin
    Caputo, Fanny
    Kallman, Thomas
    Blom, Hans
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Karlsson, Hanna L.
    Ghibelli, Lina
    Traversa, Enrico
    Ceccatelli, Sandra
    Fadeel, Bengt
    Cerium oxide nanoparticles inhibit differentiation of neural stem cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 9284Article in journal (Refereed)
    Abstract [en]

    Cerium oxide nanoparticles (nanoceria) display antioxidant properties and have shown cytoprotective effects both in vitro and in vivo. Here, we explored the effects of nanoceria on neural progenitor cells using the C17.2 murine cell line as a model. First, we assessed the effects of nanoceria versus samarium (Sm) doped nanoceria on cell viability in the presence of the prooxidant, DMNQ. Both particles were taken up by cells and nanoceria, but not Sm-doped nanoceria, elicited a temporary cytoprotective effect upon exposure to DMNQ. Next, we employed RNA sequencing to explore the transcriptional responses induced by nanoceria or Sm-doped nanoceria during neuronal differentiation. Detailed computational analyses showed that nanoceria altered pathways and networks relevant for neuronal development, leading us to hypothesize that nanoceria inhibits neuronal differentiation, and that nanoceria and Sm-doped nanoceria both interfere with cytoskeletal organization. We confirmed that nanoceria reduced neuron specific beta 3-tubulin expression, a marker of neuronal differentiation, and GFAP, a neuroglial marker. Furthermore, using super-resolution microscopy approaches, we could show that both particles interfered with cytoskeletal organization and altered the structure of neural growth cones. Taken together, these results reveal that nanoceria may impact on neuronal differentiation, suggesting that nanoceria could pose a developmental neurotoxicity hazard.

  • 349.
    Gonzalez-Granillo, Marcela
    et al.
    Karolinska Inst, Ctr Endocrinol Metab & Diabet, Dept Med, Metab & Mol Nutr Unit, S-14186 Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Med, Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr, C2-94, S-14186 Stockholm, Sweden..
    Helguero, Luisa A.
    Univ Aveiro, Inst Biomed, Dept Med Sci, Aveiro, Portugal..
    Alves, Eliana
    Univ Aveiro, Mass Spectrometry Ctr, Dept Chem QOPNA CESAM & ECOMARE, Aveiro, Portugal..
    Archer, Amena
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, Huddinge, Sweden.
    Savva, Christina
    Karolinska Inst, Ctr Endocrinol Metab & Diabet, Dept Med, Metab & Mol Nutr Unit, S-14186 Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Med, Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr, C2-94, S-14186 Stockholm, Sweden..
    Pedrelli, Matteo
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, Huddinge, Sweden.;Karolinska Univ, Hosp Huddinge, Karolinska Inst, Dept Lab Med,Div Clin Chem, Huddinge, Sweden..
    Ahmed, Osman
    Karolinska Univ, Hosp Huddinge, Karolinska Inst, Dept Lab Med,Div Clin Chem, Huddinge, Sweden..
    Li, Xidan
    Karolinska Inst, Ctr Endocrinol Metab & Diabet, Dept Med, Metab & Mol Nutr Unit, S-14186 Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Med, Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr, C2-94, S-14186 Stockholm, Sweden..
    Domingues, Maria Rosario
    Univ Aveiro, Mass Spectrometry Ctr, Dept Chem QOPNA CESAM & ECOMARE, Aveiro, Portugal..
    Parini, Paolo
    Karolinska Univ, Hosp Huddinge, Karolinska Inst, Dept Lab Med,Div Clin Chem, Huddinge, Sweden..
    Gustafsson, Jan-Ake
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, Huddinge, Sweden.;Univ Houston, Ctr Nucl Receptors & Cell Signalling, Dept Biol & Biochem, Houston, TX USA..
    Korach-Andre, Marion
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, Huddinge, Sweden.;Karolinska Inst, Ctr Endocrinol Metab & Diabet, Dept Med, Metab & Mol Nutr Unit, S-14186 Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Med, Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr, C2-94, S-14186 Stockholm, Sweden..
    Sex-specific lipid molecular signatures in obesity-associated metabolic dysfunctions revealed by lipidomic characterization in ob/ob mouse2019In: Biology of Sex Differences, ISSN 2042-6410, Vol. 10, article id 11Article in journal (Refereed)
    Abstract [en]

    The response to overfeeding is sex dependent, and metabolic syndrome is more likely associated to obesity in men or postmenopausal women than in young fertile women. We hypothesized that obesity-induced metabolic syndrome is sex dependent due to a sex-specific regulation of the fatty acid (FA) synthesis pathways in liver and white adipose depots. We aimed to identify distinctive molecular signatures between sexes using a lipidomics approach to characterize lipid species in liver, perigonadal adipose tissue, and inguinal adipose tissue and correlate them to the physiopathological responses observed. Males had less total fat but lower subcutaneous on visceral fat ratio together with higher liver weight and higher liver and serum triglyceride (TG) levels. Males were insulin resistant compared to females. Fatty acid (FA) and TG profiles differed between sexes in both fat pads, with longer chain FAs and TGs in males compared to that in females. Remarkably, hepatic phospholipid composition was sex dependent with more abundant lipotoxic FAs in males than in females. This may contribute to the sexual dimorphism in response to obesity towards more metaflammation in males. Our work presents an exhaustive novel description of a sex-specific lipid signature in the pathophysiology of metabolic disorders associated with obesity in ob/ob mice. These data could settle the basis for future pharmacological treatment in obesity.

  • 350. Gossmann, Toni I.
    et al.
    Shanmugasundram, Achchuthan
    Boerno, Stefan
    Duvaux, Ludovic
    Lemaire, Christophe
    Kuhl, Heiner
    Klages, Sven
    Roberts, Lee D.
    Schade, Sophia
    Gostner, Johanna M.
    Hildebrand, Falk
    Vowinckel, Jakob
    Bichet, Coraline
    Muelleder, Michael
    Calvani, Enrica
    Zelezniak, Aleksej
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Griffin, Julian L.
    Bork, Peer
    Allaine, Dominique
    Cohas, Aurelie
    Welch, John J.
    Timmermann, Bernd
    Ralser, Markus
    Ice-Age Climate Adaptations Trap the Alpine Marmot in a State of Low Genetic Diversity2019In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 29, no 10, p. 1712-+Article in journal (Refereed)
    Abstract [en]

    Some species responded successfully to prehistoric changes in climate [1,2], while others failed to adapt and became extinct [3]. The factors that determine successful climate adaptation remain poorly understood. We constructed a reference genome and studied physiological adaptations in the Alpine marmot (Marmota marmota), a large ground-dwelling squirrel exquisitely adapted to the "ice-age" climate of the Pleistocene steppe [4,5]. Since the disappearance of this habitat, the rodent persists in large numbers in the high-altitude Alpine meadow [6,7]. Genome and metabolome showed evidence of adaptation consistent with cold climate, affecting white adipose tissue. Conversely, however, we found that the Alpine marmot has levels of genetic variation that are among the lowest for mammals, such that deleterious mutations are less effectively purged. Our data rule out typical explanations for low diversity, such as high levels of consanguineous mating, or a very recent bottleneck. Instead, ancient demographic reconstruction revealed that genetic diversity was lost during the climate shifts of the Pleistocene and has not recovered, despite the current high population size. We attribute this slow recovery to the marmot's adaptive life history. The case of the Alpine marmot reveals a complicated relationship between climatic changes, genetic diversity, and conservation status. It shows that species of extremely low genetic diversity can be very successful and persist over thousands of years, but also that climate-adapted life history can trap a species in a persistent state of low genetic diversity.

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