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

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

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

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

  • 3.
    Alm, Tove L.
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    The Affinity Binder Knockdown Initiative.2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 4. Andersson, Sandra
    et al.
    Konrad, Anna
    KTH, School of Biotechnology (BIO), Protein Technology.
    Ashok, Nikhil
    Pontén, Fredrik
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Protein Technology.
    Asplund, Anna
    Antibodies Biotinylated Using a Synthetic Z-domain from Protein A Provide Stringent In Situ Protein Detection2013In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 61, no 11, 773-784 p.Article in journal (Refereed)
    Abstract [en]

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

  • 5. Andrews, B. J.
    et al.
    Marian Walhout, A. J.
    Iyengar, R.
    Apweiler, R.
    Ardlie, K.
    Azeloglu, E. U.
    Birtwistle, M. R.
    Coon, J. J.
    Dolinski, K.
    Fan, T.
    FitzGerald, G. A.
    Gavin, A. -C
    Gingras, A. -C
    Gough, N. R.
    Hoffmann, A.
    Lee, M. J.
    Loew, L. M.
    CraigMak, H.
    Murphy, R. C.
    Myers, C.
    Snyder, M. P.
    Sorger, P. K.
    Stolovitzky, G.
    Subramaniam, S.
    Taipale, M.
    Travé, G.
    Troyanskaya, O. G.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Vidal, M.
    Quantitative human cell encyclopedia2016In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 443, mr1Article in journal (Refereed)
    Abstract [en]

    Scientists gathered to discuss the necessity, feasibility, and challenges of generating a quantitative catalog of the components in human cells that is essential for our understanding of human physiology in health and disease and to support future breakthroughs in treating diseases. This report summarizes the discussion that emerged at the Human Quantitative Dynamics Workshop held in Bethesda, MD, USA, in December 2015.

  • 6. Bartaula-Brevik, Sushma
    et al.
    Pedersen, Torbjorn O.
    Blois, Anna L.
    Papadakou, Panagiota
    Finne-Wistrand, Anna
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Xue, Ying
    Bolstad, Anne Isine
    Mustafa, Kamal
    Leukocyte transmigration into tissue-engineered constructs is influenced by endothelial cells through Toll-like receptor signaling2014In: Stem Cell Research & Therapy, E-ISSN 1757-6512, Vol. 5, 143- p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Inflammation plays a crucial role in tissue regeneration, wound healing, and the success of tissue-engineered constructs. The aim of this study was to investigate the influence of human umbilical vein endothelial cells (ECs) on leukocyte transmigration when co-cultured with primary human bone marrow-derived multipotent stromal cells (MSCs). Methods: MSCs with and without ECs were cultured in poly (L-lactide-co-1, 5-dioxepan-2-one) (poly (LLA-co-DXO)) scaffolds for 1 week in vitro in a bioreactor system, after which they were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. After 1 and 3 weeks, scaffolds were retrieved, and the mRNA expression of interleukin 1-beta (IL-1 beta), IL-6, IL-10, hypoxia-inducible factor 1-alpha (HIF-1 alpha), HIF-1 beta, and mammalian target of rapamycin was examined by real-time reverse transcription-polymerase chain reaction. Furthermore, immunofluorescent staining was performed for IL-1 beta, IL-6, neutrophils, and CD11b. In addition, Western blotting was done for IL-1 beta and IL-6. Leukocyte transmigration genes and genes in Toll-like receptor pathways, expressed by MSCs cultured in vitro with or without ECs, were further investigated with a microarray dataset. Results: In vitro, genes involved in leukocyte transmigration and Toll-like receptor pathways were clearly influenced by the addition of ECs. Platelet/endothelial cell adhesion molecule-1 (PECAM-1) and cadherin-5 (CDH5), both genes involved in leukocyte transmigration, were expressed significantly higher in the MSC/EC group. In vivo, the MSC/EC group showed higher mRNA expression of hypoxia-inducible factors HIF-1 alpha and HIF-1 beta. The mRNA expression of anti-inflammatory cytokine IL-10 showed no significant difference, whereas the mRNA and protein expression of pro-inflammatory cytokines IL-1 beta and IL-6 were lower in the MSC/EC group. The quantitative analysis of immunofluorescent staining revealed a significant difference in the number of neutrophils migrating into constructs, with the highest density found in the MSC/EC group. The number of macrophages positive for IL-6 and CD11b was significantly reduced in the MSC/EC group. Conclusions: The recruitment of leukocytes into tissue-engineered constructs with MSCs is strongly influenced by the addition of ECs via activation of leukocyte transmigration and Toll-like receptor pathways.

  • 7. Bartaula-Brevik, Sushma
    et al.
    Pedersen, Torbjorn O.
    Finne-Wistrand, Anna
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Bolstad, Anne Isine
    Mustafa, Kamal
    Angiogenic and Immunomodulatory Properties of Endothelial and Mesenchymal Stem Cells2016In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 22, no 3-4, 244-252 p.Article in journal (Refereed)
    Abstract [en]

    It has been suggested that the effect of implanted cells on the local environment is important when selecting the appropriate cell type for tissue regeneration. Our aim was to compare the local tissue response to implanted human mesenchymal stem cells (MSC) and human umbilical vein endothelial cells (EC). MSC and EC were cultured in poly(l-lactide-co-1,5-dioxepan-2-one) scaffolds for 1 week in a bioreactor system, after which they were implanted subcutaneously in NOD/SCID mice. After 3 weeks, scaffolds were retrieved, and the mRNA expression of selected genes involved in hypoxia and inflammation was examined by real-time reverse transcription polymerase chain reaction and correlated with immunofluorescent staining for corresponding proteins. The Toll-like receptor signaling pathway was examined by superarray hybridization. The expression of 53 angiogenesis-related proteins was investigated by a proteome profiler angiogenesis antibody array kit. Vascularization was quantified using immunohistochemistry for CD31. The expression of hypoxia-inducible factors and biomarkers for angiogenesis was more strongly upregulated in response to implanted EC than to MSC, suggesting a higher sensitivity to low oxygen tension among EC. Hypoxic signaling was increased after implantation of EC compared with MSC, leading to a prolonged acute inflammatory phase that promoted ingrowth of vascular cells and establishment of the circulation. Inflammatory cytokines were also differently expressed at the gene and protein levels in the two experimental groups, resulting in altered recruitment of acute and chronic inflammatory cells. The end result of these differences was increased vessel formation within the constructs in the EC group.

  • 8. Bjork, L.
    et al.
    Ait Blal, C.
    Alm, Tove L.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Bäckström, Anna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Gnann, C.
    Hjelmare, Martin
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schutten, Rutger
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Skogs, Marie
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Stadler, Charlotte
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Application specific antibody validation. The Human Protein Atlas validation scheme and how to confirm subcellular protein localization.2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 9. Bjornson, Elias
    et al.
    Mukhopadhyay, Bani
    Asplund, Anna
    Pristovsek, Nusa
    Cinar, Resat
    Romeo, Stefano
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kunos, George
    Nielsen, Jens
    Mardinoglu, Adil
    Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 13, no 9, 2014-2026 p.Article in journal (Refereed)
    Abstract [en]

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

  • 10. Blau, Helen M.
    et al.
    Gilbert, Penney M.
    Havenstrite, Karen
    Lutolf, Matthias P.
    Magnusson, Klas E. G.
    KTH, School of Electrical Engineering (EES), Signal Processing.
    Ramunas, John
    Elastic substrates and methods of use in cell manipulation and culture2010Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Methods are provided for the ex vivo manipulation of cells, stem cells and other reproductive cells, by manipulating the cells in a container or device comprising an elastic substrate, wherein the substrate has an elasticity that mimics the elasticity of a native microenvironment of the cell.

  • 11. Blom, M.
    et al.
    Reis, K.
    Nehru, V.
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gad, A. K. B.
    Aspenström, P.
    RhoD is a Golgi component with a role in anterograde protein transport from the ER to the plasma membrane2015In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 333, no 2, 208-219 p.Article in journal (Refereed)
    Abstract [en]

    RhoD is a member of the Rho GTPase family and it coordinates actin dynamics and membrane trafficking. Activation of RhoD results in formation of filopodia, dissolution of stress fibers, and the subsequent formation of short actin bundles. In addition, RhoD localizes to early endosomes and recycling endosomes, and has a regulatory role in endosome trafficking. In this study, we report on a function of RhoD in the regulation of Golgi homeostasis. We show that manipulation of protein and activation levels of RhoD, as well as of its binding partner WHAMM, result in derailed localization of Golgi stacks. Moreover, vesicle trafficking from the endoplasmic reticulum to the plasma membrane via the Golgi apparatus measured by the VSV-G protein is severely hampered by manipulation of RhoD or WHAMM. In summary, our studies demonstrate a novel role for this member of the Rho GTPases in the regulation of Golgi function.

  • 12.
    Bo, Stefano
    et al.
    KTH, Centres, Nordic Institute for Theoretical Physics NORDITA. Stockholm University, Sweden.
    Celani, A.
    Detecting Concentration Changes with Cooperative Receptors2015In: Journal of statistical physics, ISSN 0022-4715, E-ISSN 1572-9613, Vol. 162, no 5, 1365-1382 p.Article in journal (Refereed)
    Abstract [en]

    Cells constantly need to monitor the state of the environment to detect changes and timely respond. The detection of concentration changes of a ligand by a set of receptors can be cast as a problem of hypothesis testing, and the cell viewed as a Neyman–Pearson detector. Within this framework, we investigate the role of receptor cooperativity in improving the cell’s ability to detect changes. We find that cooperativity decreases the probability of missing an occurred change. This becomes especially beneficial when difficult detections have to be made. Concerning the influence of cooperativity on how fast a desired detection power is achieved, we find in general that there is an optimal value at finite levels of cooperation, even though easy discrimination tasks can be performed more rapidly by noncooperative receptors.

  • 13.
    Boräng, Stina
    et al.
    KTH, Superseded Departments, Biotechnology.
    Andersson, Tove
    KTH, Superseded Departments, Biotechnology.
    Thelin, A.
    Odeberg, Jacob
    KTH, Superseded Departments, Biotechnology.
    Lundeberg, Joakim
    KTH, Superseded Departments, Biotechnology.
    Vascular gene expression in atherosclerotic plaque-prone regions analyzed by representational difference analysis2004In: Pathobiology (Basel), ISSN 1015-2008, E-ISSN 1423-0291, Vol. 71, no 2, 107-114 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: Atherosclerotic plaques are known to develop and progress where the endothelium is subjected to turbulent blood flow. We have applied cDNA representational difference analysis (RDA) to study vascular gene expression in mouse aorta in a model for atherosclerosis. Methods: Gene expression profiles were investigated in plaque-prone and plaque-resistant localizations in the ascending aorta and arch in 8-week-oldApoE-/- and LDLR-/- mice. Total RNA was extracted and two rounds of subtraction were performed; the difference products were characterized in detail by shotgun cloning and analysis of more than 2,700 gene sequences. Results: The identified differentially expressed gene sequences include both genes with known involvement in vascular gene expression and genes previously not implicated in vascular processes. For example, CD36 and caveolin, previously reported for their participation in the progression of atherosclerosis, were found to have an increased expression in vessel localizations thought to be especially susceptible to plaque formation. Conclusions: This report provides new in vivo information of expressed genes that can be useful for further investigations of the molecular mechanisms in focal localization of atherosclerosis.

  • 14.
    Brismar, Hjalmar
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Astrid Lindgren Childrens Hosp, Dept Woman & Child Hlth, Sweden.
    Aperia, A
    Westin, L
    Moy, J
    Wang, M
    Guillermier, C
    Poczatek, C
    Lechene, C
    Study of protein and RNA in dendritic spines using multi-isotope imaging mass spectrometry (MIMS).2014In: Surface and Interface Analysis, ISSN 0142-2421, E-ISSN 1096-9918, Vol. 46, no Suppl 1Article in journal (Refereed)
    Abstract [en]

    The classical view of neuronal protein synthesis is that proteins are made in the cell body and then transported to their functional sites in the dendrites and the dendritic spines. Indirect evidence, however, suggests that protein synthesis can directly occur in the distal dendrites, far from the cell body. We are developing protocols for dual labeling of RNA and proteins using (15)N-uridine and (18)O- or (13)C-leucine pulse chase in cultured neurons to identify and localize both protein synthesis and fate of newly synthesized proteins. Pilot experiments show discrete localization of both RNA and newly synthesized proteins in dendrites, close to dendritic spines. We have for the first time directly imaged and measured the production of proteins at the subcellular level in the neuronal dendrites, close to the functional sites, the dendritic spines. This will open a powerful way to study neural growth and synapse plasticity in health and disease.

  • 15. Chen, D.
    et al.
    Liu, J.
    Rui, B.
    Gao, M.
    Zhao, Ningwei
    KTH, School of Biotechnology (BIO).
    Sun, S.
    Bi, A.
    Yang, T.
    Guo, Y.
    Yin, Z.
    Luo, L.
    GSTpi protects against angiotensin II-induced proliferation and migration of vascular smooth muscle cells by preventing signal transducer and activator of transcription 3 activation2014In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1843, no 2, 454-463 p.Article in journal (Refereed)
    Abstract [en]

    Angiotensin II (Ang II)-elicited excessive proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMCs) are vital to the pathogenesis of atheroclerosis. Glutathione S-transferase pi (GSTpi) exists extensively in various kinds of cells and protects cells against different stresses. However, knowledge remains limited about what GSTpi acts in VSMCs. We investigated the effect of GSTpi on Ang II-induced VSMC proliferation, hypertrophy and migration and its latent mechanism. Overexpression and RNAi experiments demonstrated that GSTpi inhibited Ang II-induced proliferation, hypertrophy and migration of VSMCs and arrested progression of cell cycle from G0/G1 to S phase. Immunoprecipitation, mass spectrometry and confocal microscopy analyses showed that GSTpi directly associated with signal transducer and activator of transcription 3 (STAT3) to prevent Ang II-triggered binding of Src to STAT3 and thus suppressed Ang II-stimulated phosphorylation and nuclear translocation of STAT3, as well as cyclin D1 expression. In contrast, GSTpi didn't affect Ang II-activated extracellular signal-regulated kinase (ERK1/2). GSTpi acts as a negative regulator to prevent Ang II-triggered proliferative signaling in VSMCs, suggesting that it may protect vessels against the stresses associated with atherosclerosis formation.

  • 16. Christensen, B M
    et al.
    Zelenina, M
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Aperia, A
    Nielsen, S
    Localization and regulation of PKA-phosphorylated AQP2 in response to V(2)-receptor agonist/antagonist treatment.2000In: American journal of physiology. Renal physiology, ISSN 1931-857X, Vol. 278, no 1, F29-42 p.Article in journal (Refereed)
    Abstract [en]

    Phosphorylation of Ser(256), in a PKA consensus site, in AQP2 (p-AQP2) appears to be critically involved in the vasopressin-induced trafficking of AQP2. In the present study, affinity-purified antibodies that selectively recognize AQP2 phosphorylated at Ser(256) were developed. These antibodies were used to determine 1) the subcellular localization of p-AQP2 in rat kidney and 2) changes in distribution and/or levels of p-AQP2 in response to [desamino-Cys(1),D-Arg(8)]vasopressin (DDAVP) treatment or V(2)-receptor blockade. Immunoelectron microscopy revealed that p-AQP2 was localized in both the apical plasma membrane and in intracellular vesicles of collecting duct principal cells. Treatment of rats with V(2)-receptor antagonist for 30 min resulted in almost complete disappearance of p-AQP2 labeling of the apical plasma membrane with only marginal labeling of intracellular vesicles remaining. Immunoblotting confirmed a marked decrease in p-AQP2 levels. In control Brattleboro rats (BB), lacking vasopressin secretion, p-AQP2 labeling was almost exclusively present in intracellular vesicles. Treatment of BB rats with DDAVP for 2 h induced a 10-fold increase in p-AQP2 labeling of the apical plasma membrane. The overall abundance of p-AQP2, however, was not increased, as determined both by immunoelectron microscopy and immunoblotting. Consistent with this, 2 h of DDAVP treatment of normal rats also resulted in unchanged p-AQP2 levels. Thus the results demonstrate that AQP2 phosphorylated in Ser(256) is present in the apical plasma membrane and in intracellular vesicles and that both the intracellular distribution/trafficking, as well as the abundance of p-AQP2, are regulated via V(2) receptors by altering phosphorylation and/or dephosphorylation of Ser(256) in AQP2.

  • 17.
    Danielsson, Frida
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Akesson, L.
    Skogs, Marie
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Profiling changes in response to hypoxia in a four-step cell line model for malignant transformation.2016In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27Article in journal (Refereed)
  • 18.
    Danielsson, Frida
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlen, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gad, A. K.
    Profiling the Molecular changes during malignant transformation and response to different oxygen levels, using a combined transcriptomics and proteomics approach2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, P1845Article in journal (Other academic)
  • 19. Dijksterhuis, Jacomijn P.
    et al.
    Arthofer, Elisa
    Marinescu, Voichita D.
    Nelander, Sven
    Uhlen, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Ponten, Frederik
    Mulder, Jan
    Schulte, Gunnar
    High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes2015In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 339, no 2, 280-288 p.Article in journal (Refereed)
    Abstract [en]

    Malignant gliomas are among the most severe types of cancer, and the most common primary brain tumors. Treatment options are limited and the prognosis is poor. WNT-5A, a member of the WNT family of lipoglycoproteins, plays a role in oncogenesis and tumor progression in various cancers, whereas the role of WNT-5A in glioma remains obscure. Based on the role of WNT-5A as an oncogene, its potential to regulate microglia cells and the glioma-promoting capacities of microglia cells, we hypothesize that WNT-5A has a role in regulation of immune functions in glioma. We investigated WNT-5A expression by in silico analysis of the cancer genome atlas (TCGA) transcript profiling of human glioblastoma samples and immunohistochemistry experiments of human glioma tissue microarrays (TMA). Our results reveal higher WNT-5A protein levels and mRNA expression in a subgroup of gliomas (WNT-5A(high)) compared to non-malignant control brain tissue. Furthermore, we show a significant correlation between WNT-5A in the tumor and presence of major histocompatibility complex Class II-positive microglia/monocytes. Our data pinpoint a positive correlation between WNT-5A and a proinflammatory signature in glioma. We identify increased presence of microglia/monocytes as an important aspect in the inflammatory transformation suggesting a novel role for WNT-5A in human glioma.

  • 20.
    Dånmark, Staffan
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Finne-Wistrand, Anna
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Albertsson, Ann-Christine
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Patarroyo, Manuel
    Institutionen for Odontologi, Karolinska Institute.
    Mustafa, Kamal
    Insititutt for klinisk Odontologi, Medicinska och Odontologiska Fakulteten, Universitetet i Bergen, Norge.
    Integrin-mediated adhesion of human mesenchymal stem cells to extracellular matrix proteins adsorbed to polymer surfaces2012In: Biomedical Materials, ISSN 1748-6041, E-ISSN 1748-605X, Vol. 7, no 3, 035011- p.Article in journal (Refereed)
    Abstract [en]

    In vitro, degradable aliphatic polyesters are widely used as cell carriers for bone tissue engineering, despite their lack of biological cues. Their biological active surface is rather determined by an adsorbed layer of proteins from the surrounding media. Initial cell fate, including adhesion and proliferation, which are key properties for efficient cell carriers, is determined by the adsorbed layer of proteins. Herein we have investigated the ability of human bone marrow derived stem cells (hBMSC) to adhere to extracellular matrix (ECM) proteins, including fibronectin and vitronectin which are present in plasma and serum. hBMSC expressed integrins for collagens, laminins, fibronectin and vitronectin. Accordingly, hBMSC strongly adhered to these purified ECM proteins by using the corresponding integrins. Although purified fibronectin and vitronectin adsorbed to aliphatic polyesters to a lower extent than to cell culture polystyrene, these low levels were sufficient to mediate adhesion of hBMSC. It was found that plasma- and serum-coated polystyrene adsorbed significant levels of both fibronectin and vitronectin, and fibronectin was identified as the major adhesive component of plasma for hBMSC; however, aliphatic polyesters adsorbed minimal levels of fibronectin under similar conditions resulting in impaired cell adhesion. Altogether, the results suggest that the efficiency of aliphatic polyesters cell carriers could be improved by increasing their ability to adsorb fibronectin.

  • 21.
    Dånmark, Staffan
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Finne-Wistrand, Anna
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Edlund, Ulrica
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Albertsson, Ann-Christine
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Mustafa, Kamal
    Insititutt for klinisk Odontologi, Medicinska och Odontologiska Fakulteten, Universitetet i Bergen, Norge.
    Enhanced Osteoconductivity of Degradable co-Polyester Scaffolds through Covalent Immobilization of BMP-2Manuscript (preprint) (Other academic)
  • 22.
    Dånmark, Staffan
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Gladnikoff, Micha
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Frisk, Thomas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Zelenina, Marina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Mustafa, Kamal
    Insititutt for klinisk Odontologi, Medicinska och Odontologiska Fakulteten, Universitetet i Bergen, Norge.
    Russom, Aman
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Finne-Wistrand, Anna
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
    Development of Novel Microfluidic Device for Long-Term in situ Monitoring of Live Cells in 3-dimensional MatricesManuscript (preprint) (Other academic)
  • 23. Edqvist, Per-Henrik D.
    et al.
    Fagerberg, Linn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hallström, Bjorn M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Danielsson, Angelika
    Edlund, Karolina
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Expression of Human Skin-Specific Genes Defined by Transcriptomics and Antibody-Based Profiling2015In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 63, no 2, 129-141 p.Article in journal (Refereed)
    Abstract [en]

    To increase our understanding of skin, it is important to define the molecular constituents of the cell types and epidermal layers that signify normal skin. We have combined a genome-wide transcriptomics analysis, using deep sequencing of mRNA from skin biopsies, with immunohistochemistry-based protein profiling to characterize the landscape of gene and protein expression in normal human skin. The transcriptomics and protein expression data of skin were compared to 26 (RNA) and 44 (protein) other normal tissue types. All 20,050 putative protein-coding genes were classified into categories based on patterns of expression. We found that 417 genes showed elevated expression in skin, with 106 genes expressed at least five-fold higher than that in other tissues. The 106 genes categorized as skin enriched encoded for well-known proteins involved in epidermal differentiation and proteins with unknown functions and expression patterns in skin, including the C1orf68 protein, which showed the highest relative enrichment in skin. In conclusion, we have applied a genome-wide analysis to identify the human skin-specific proteome and map the precise localization of the corresponding proteins in different compartments of the skin, to facilitate further functional studies to explore the molecular repertoire of normal skin and to identify biomarkers related to various skin diseases.

  • 24. Eklund, D. Magnus
    et al.
    Staldal, Veronika
    Valsecchi, Isabel
    Cierlik, Izabela
    Eriksson, Caitriona
    Hiratsu, Keiichiro
    Ohme-Takagi, Masaru
    Sundstrom, Jens F.
    Thelander, Mattias
    Ezcurra, Ines
    KTH, School of Biotechnology (BIO), Glycoscience.
    Sundberg, Eva
    The Arabidopsis thaliana STYLISH1 Protein Acts as a Transcriptional Activator Regulating Auxin Biosynthesis2010In: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 22, no 2, 349-363 p.Article in journal (Refereed)
    Abstract [en]

    The establishment and maintenance of auxin maxima in vascular plants is regulated by auxin biosynthesis and polar intercellular auxin flow. The disruption of normal auxin biosynthesis in mouse-ear cress ( Arabidopsis thaliana) leads to severe abnormalities, suggesting that spatiotemporal regulation of auxin biosynthesis is fundamental for normal growth and development. We have shown previously that the induction of the SHORT-INTERNODES/STYLISH (SHI/STY) family member STY1 results in increased transcript levels of the YUCCA (YUC) family member YUC4 and also higher auxin levels and auxin biosynthesis rates in Arabidopsis seedlings. We have also shown previously that SHI/STY family members redundantly affect development of flowers and leaves. Here, we further examine the function of STY1 by analyzing its DNA and protein binding properties. Our results suggest that STY1, and most likely other SHI/STY members, are DNA binding transcriptional activators that target genes encoding proteins mediating auxin biosynthesis. This suggests that the SHI/STY family members are essential regulators of auxin-mediated leaf and flower development. Furthermore, the lack of a shoot apical meristem in seedlings carrying a fusion construct between STY1 and a repressor domain, SRDX, suggests that STY1, and other SHI/STY members, has a role in the formation and/or maintenance of the shoot apical meristem, possibly by regulating auxin levels in the embryo.

  • 25. Facey, Jody-Ann
    et al.
    Venner, Laura
    Hyde, Michael
    Pouya, Iman
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
    Howard, Rebecca
    Polar substitutions in the ion-conducting pore of GLIC alter gating and alcohol modulation2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, 1061.9- p.Article in journal (Other academic)
  • 26. Fenton, Robert A.
    et al.
    Moeller, Hanne B.
    Zelenina, Marina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Snaebjornsson, Marteinn T.
    Holen, Torgeir
    MacAulay, Nanna
    Differential water permeability and regulation of three aquaporin 4 isoforms2010In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 67, no 5, 829-840 p.Article in journal (Refereed)
    Abstract [en]

    Aquaporin 4 (AQP4) is expressed in the perivascular glial endfeet and is an important pathway for water during formation and resolution of brain edema. In this study, we examined the functional properties and relative unit water permeability of three functional isoforms of AQP4 expressed in the brain (M1, M23, Mz). The M23 isoform gave rise to square arrays when expressed in Xenopus laevis oocytes. The relative unit water permeability differed significantly between the isoforms in the order of M1 > Mz > M23. None of the three isoforms were permeable to small osmolytes nor were they affected by changes in external K+ concentration. Upon protein kinase C (PKC) activation, oocytes expressing the three isoforms demonstrated rapid reduction of water permeability, which correlated with AQP4 internalization. The M23 isoform was more sensitive to PKC regulation than the longer isoforms and was internalized significantly faster. Our results suggest a specific role for square array formation.

  • 27.
    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)
  • 28.
    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, 8615-8629 p.Article 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.

  • 29. 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, 19-19 p.Article in journal (Other academic)
  • 30.
    Frisk, Thomas
    et al.
    KTH, School of Electrical Engineering (EES), Microsystem Technology.
    Rydholm, Susanna
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Nano Biotechnology.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Stemme, Göran
    KTH, School of Electrical Engineering (EES), Microsystem Technology.
    Three dimensional asymmetric microenvironment for cell biologigal studies2005In: Proceedings Micro Total Analysis Systems (muTAS) 2005, 2005Conference paper (Refereed)
  • 31. Fusco, Ludovico
    et al.
    Lefort, Riwal
    Smith, Kevin
    École Polytechnique Fédérale de Lausanne.
    Benmansour, Fethallah
    Gonzalez, German
    Barillari, C
    Rinn, Bernd
    Fleuret, Francois
    Fua, Pascal
    Pertz, Olivier
    Computer vision profiling of neurite outgrowth dynamics reveals spatio-temporal modularity of Rho GTPase signaling2016In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 212, no 1, 91-111 p.Article in journal (Refereed)
    Abstract [en]

    Rho guanosine triphosphatases (GTPases) control the cytoskeletal dynamics that power neurite outgrowth. This process consists of dynamic neuriteinitiation, elongation, retraction, and branching cycles that are likely to be regulated by specific spatiotemporal signaling networks, which cannot be resolved with static, steady-state assays. We present Neurite-Tracker, a computer-vision approach to automatically segment and track neuronal morphodynamics in time-lapse datasets. Feature extraction then quantifies dynamic neurite outgrowth phenotypes. We identify a set of stereotypic neurite outgrowth morphodynamic behaviors in a cultured neuronal cell system. Systematic RNA interference perturbation of a Rho GTPase interactome consisting of 219 proteins reveals a limited set of morphodynamic phenotypes. As proof of concept, we show that loss of function of two distinct RhoA-specific GTPase-activating proteins (GAPs) leads to opposite neurite outgrowth phenotypes. Imaging of RhoA activation dynamics indicates that both GAPs regulate different spatiotemporal Rho GTPase pools, with distinct functions. Our results provide a starting point to dissect spatiotemporal Rho GTPase signaling networks that regulate neurite outgrowth.

  • 32. Gerttula, S.
    et al.
    Zinkgraf, M.
    Muday, G. K.
    Lewis, D. R.
    Ibatullin, Farid M.
    KTH, School of Biotechnology (BIO), Glycoscience. National Research Center Kurchatov Institute, Russian Federation.
    Brumer, Harry
    KTH, School of Biotechnology (BIO), Glycoscience. University of British Columbia, Canada.
    Hart, F.
    Mansfield, S. D.
    Filkov, V.
    Groover, A.
    Transcriptional and hormonal regulation of gravitropism of woody stems in populus2015In: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 27, no 10, 2800-2813 p.Article in journal (Refereed)
    Abstract [en]

    Angiosperm trees reorient their woody stems by asymmetrically producing a specialized xylem tissue, tension wood, which exerts a strong contractile force resulting in negative gravitropism of the stem. Here, we show, in Populus trees, that initial gravity perception and response occurs in specialized cells through sedimentation of starch-filled amyloplasts and relocalization of the auxin transport protein, PIN3. Gibberellic acid treatment stimulates the rate of tension wood formation and gravibending and enhances tissue-specific expression of an auxin-responsive reporter. Gravibending, maturation of contractile fibers, and gibberellic acid (GA) stimulation of tension wood formation are all sensitive to transcript levels of the Class I KNOX homeodomain transcription factor-encoding gene ARBORKNOX2 (ARK2). We generated genome-wide transcriptomes for trees in which gene expression was perturbed by gravistimulation, GA treatment, and modulation of ARK2 expression. These data were employed in computational analyses to model the transcriptional networks underlying wood formation, including identification and dissection of gene coexpression modules associated with wood phenotypes, GA response, and ARK2 binding to genes within modules. We propose a model for gravitropism in the woody stem in which the peripheral location of PIN3-expressing cells relative to the cambium results in auxin transport toward the cambium in the top of the stem, triggering tension wood formation, while transport away from the cambium in the bottom of the stem triggers opposite wood formation.

  • 33. Gilbert, P. M.
    et al.
    Havenstrite, K. L.
    Magnusson, Klas E. G.
    KTH, School of Electrical Engineering (EES), Signal Processing.
    Sacco, A.
    Leonardi, N. A.
    Kraft, P.
    Nguyen, N. K.
    Thrun, S.
    Lutolf, M. P.
    Blau, H. M.
    Substrate Elasticity Regulates Skeletal Muscle Stem Cell Self-Renewal in Culture2010In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 329, no 5995, 1078-1081 p.Article in journal (Refereed)
    Abstract [en]

    Stem cells that naturally reside in adult tissues, such as muscle stem cells (MuSCs), exhibit robust regenerative capacity in vivo that is rapidly lost in culture. Using a bioengineered substrate to recapitulate key biophysical and biochemical niche features in conjunction with a highly automated single-cell tracking algorithm, we show that substrate elasticity is a potent regulator of MuSC fate in culture. Unlike MuSCs on rigid plastic dishes (similar to 10(6) kilopascals), MuSCs cultured on soft hydrogel substrates that mimic the elasticity of muscle (12 kilopascals) self-renew in vitro and contribute extensively to muscle regeneration when subsequently transplanted into mice and assayed histologically and quantitatively by noninvasive bioluminescence imaging. Our studies provide novel evidence that by recapitulating physiological tissue rigidity, propagation of adult muscle stem cells is possible, enabling future cell-based therapies for muscle-wasting diseases.

  • 34. Gilbert, Penney M.
    et al.
    Corbel, Stephane
    Doyonnas, Regis
    Havenstrite, Karen
    Magnusson, Klas E. G.
    KTH, School of Electrical Engineering (EES), Signal Processing. KTH, School of Electrical Engineering (EES), Centres, ACCESS Linnaeus Centre.
    Blau, Helen M.
    A single cell bioengineering approach to elucidate mechanisms of adult stem cell self-renewal2012In: Integrative Biology, ISSN 1757-9694, E-ISSN 1757-9708, Vol. 4, no 4, 360-367 p.Article in journal (Refereed)
    Abstract [en]

    The goal of regenerative medicine is to restore form and function to damaged and aging tissues. Adult stem cells, present in tissues such as skeletal muscle, comprise a reservoir of cells with a remarkable capacity to proliferate and repair tissue damage. Muscle stem cells, known as satellite cells, reside in a quiescent state in an anatomically distinct compartment, or niche, ensheathed between the membrane of the myofiber and the basal lamina. Recently, procedures for isolating satellite cells were developed and experiments testing their function upon transplantation into muscles revealed an extraordinary potential to contribute to muscle fibers and access and replenish the satellite cell compartment. However, these properties are rapidly lost once satellite cells are plated in culture. Accordingly, elucidating the role of extrinsic factors in controlling muscle stem cell fate, in particular self-renewal, is critical. Through careful design of bioengineered culture platforms, analysis of specific proteins presented to stem cells is possible. Critical to the success of the approach is single cell analysis, as more rapidly proliferating progenitors may mask the behavior of stem cells that proliferate slowly. Bioengineering approaches provide a potent means of gaining insight into the role of extrinsic factors in the stem cell microenvironment on stem cell function and the mechanisms that control their diverse fates. Ultimately, the multidisciplinary approach presented here will lead to novel therapeutic strategies for degenerative diseases.

  • 35. Gremel, Gabriela
    et al.
    Bergman, Julia
    Djureinovic, Dijana
    Edqvist, Per-Henrik
    Maindad, Vikas
    Bharambe, Bhavana M.
    Khan, Wasif Ali Z. A.
    Navani, Sanjay
    Elebro, Jacob
    Jirström, Karin
    Hellberg, Dan
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Micke, Patrick
    Pontén, Fredrik
    A systematic analysis of commonly used antibodies in cancer diagnostics2014In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 64, no 2, 293-305 p.Article in journal (Refereed)
    Abstract [en]

    AimsImmunohistochemistry plays a pivotal role in cancer differential diagnostics. To identify the primary tumour from a metastasis specimen remains a significant challenge, despite the availability of an increasing number of antibodies. The aim of the present study was to provide evidence-based data on the diagnostic power of antibodies used frequently for clinical differential diagnostics. Methods and resultsA tissue microarray cohort comprising 940 tumour samples, of which 502 were metastatic lesions, representing tumours from 18 different organs and four non-localized cancer types, was analysed using immunohistochemistry with 27 well-established antibodies used in clinical differential diagnostics. Few antibodies, e.g. prostate-specific antigen and thyroglobulin, showed a cancer type-related sensitivity and specificity of more than 95%. A majority of the antibodies showed a low degree of sensitivity and specificity for defined cancer types. Combinations of antibodies provided limited added value for differential diagnostics of cancer types. ConclusionsThe results from analysing 27 diagnostic antibodies on consecutive sections of 940 defined tumours provide a unique repository of data that can empower a more optimal use of clinical immunohistochemistry. Our results highlight the benefit of immunohistochemistry and the unmet need for novel markers to improve differential diagnostics of cancer.

  • 36.
    Guldevall, Karolin
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Frisk, Thomas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Vanherberghen, Bruno
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Khorsidi, Mohammed Ali
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Manneberg, Otto
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Christakou, Athanasia
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Imaging immune surveillance by individual Natural Killer cells isolated in arrays of nanoliter wells2010Conference paper (Refereed)
  • 37. Gunnarson, E.
    et al.
    Axehult, G.
    Baturina, G.
    Zelenin, S.
    Zelenina, Marina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Aperia, A.
    Lead induces increased water permeability in astrocytes expressing aquaporin 42005In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 136, no 1, 105-114 p.Article in journal (Refereed)
    Abstract [en]

    The water channel aquaporin 4 (AQP4) is abundantly expressed in astrocytes. There is now compelling evidence that AQP4 may contribute to an unfavorable course in brain edema. Acute lead intoxication is a condition that causes brain damage preceded by brain edema. Here we report that lead increases AQP4 water permeability (P-f) in astrocytes. A rat astrocyte cell line that does not express aquaporin 4 was transiently transfected with aquaporin 4 tagged with green fluorescent protein (GFP). Using confocal laser scanning microscopy we measured water permeability in these cells and in AQP4-negative cells located on the same plate. AQP4-expressing astrocytes had a three-fold higher water permeability than astrocytes not expressing AQP4. Lead exposure induced a significant, 40%, increase in water permeability in astrocytes expressing AQP4, but had no effect on Pf in astrocytes not expressing AQP4. The increase in water permeability persisted after lead washout, while treatment with a lead chelator, meso-2,3-dimercaptosuccinic acid, abolished the lead-induced increase in Pf. The effect of lead was attenuated in the presence of a calcium (Ca2+)/ calmodulin-dependent protein kinase 11 (CaMKII) inhibitor, but not in the presence of a protein kinase C inhibitor. In cells expressing AQP4 where the consensus site for CaMKII phosphorylation was mutated, lead failed to increase water permeability. Lead exposure also increased Pf in rat astroglial cells in primary culture, which express endogenous AQP4. Lead had no effect on Pf in astrocytes transfected with aquaporin 3. In situ hybridization studies on rat brain after oral lead intake for three days showed no change in distribution of AQP4 mRNA. It is suggested that lead-triggered stimulation of water transport in AQP4-expressing astrocytes may contribute to the pathology of acute lead intoxication.

  • 38.
    Gunnarson, E
    et al.
    Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Zelenina, Marina
    Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Aperia, Anita
    Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Regulation of brain aquaporins2004In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 129, no 4, 947-955 p.Article in journal (Refereed)
    Abstract [en]

    Emerging evidence suggests that brain aquaporins (AQP) play important roles for the dynamic regulation of brain water homeostasis and for the regulation of cerebrospinal fluid production. This review deals with the short- and long-term regulation of AQP4 and AQP9, both expressed in astrocytes, and of AQP1, expressed in the choroid plexus. AQP1 and 4 have in other cell types been shown to be regulated by phosphorylation. Phosphorylation affects the gating of AQP4 and the trafficking and insertion into membrane of AQP1. Mercury inhibits the water permeability of AQP1 and AQP9, but not AQP4. The permeability of AQP4 is increased by lead. AQP4 is also regulated by protein-protein interaction. The assembly between AQP4 and syntrophin is required for the proper localization of AQP4 in the astrocyte plasma membrane that faces capillaries. There is evidence from studies on peripheral tissues that steroid hormones regulate the expression of AQP1, AQP4 and AQP9. There is also evidence that the expression of AQP1 can be regulated by ubiquitination, and that osmolality can regulate the expression of AQP1, AQP4 and AQP9. Further insight into the mechanisms by which brain AQPs are regulated will be of utmost clinical importance, since perturbed water flow via brain AQPs has been implicated in many neurological diseases and since, in brain edema, water flow via AQP4 may have a harmful effect.

  • 39. Gunnarson, E.
    et al.
    Zelenina, Marina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Song, Yutong
    Illarionova, N.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Andersson, Ulf
    Zelenin, S.
    Aperia, Anita
    Effect of the brain protecting agent erythropoietin on astrocyte function2009Conference paper (Refereed)
  • 40. Gunnarson, Eli
    et al.
    Song, Yutong
    Kowalewski, Jacob M
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brines, Michael
    Cerami, Anthony
    Andersson, Ulf
    Zelenina, Marina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Aperia, Anita
    Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection.2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 1091-6490, Vol. 106, no 5, 1602-7 p.Article in journal (Refereed)
    Abstract [en]

    Disturbed brain water homeostasis with swelling of astroglial cells is a common complication in stroke, trauma, and meningitis and is considered to be a major cause of permanent brain damage. Astroglial cells possess the water channel aquaporin 4 (AQP4). Recent studies from our laboratory have shown that glutamate, acting on group I metabotropic glutamate receptors (mGluRs), increases the permeability of astrocyte AQP4, which, in situations of hypoxia-ischemia, will increase astrocyte water uptake. Here we report that erythropoietin (EPO), which in recent years has emerged as a potent neuro-protective agent, antagonizes the effect of a group I mGluR agonist on astrocyte water permeability. Activation of group I mGluRs triggers fast and highly regular intracellular calcium oscillations and we show that EPO interferes with this signaling event by altering the frequency of the oscillations. These effects of EPO are immediate, in contrast to the neuroprotective effects of EPO that are known to depend upon gene activation. Our findings indicate that EPO may directly reduce the risk of astrocyte swelling in stroke and other brain insults. In support of this conclusion we found that EPO reduced the neurological symptoms in a mouse model of primary brain edema known to depend upon AQP4 water transport.

  • 41. Gunnarson, Eli
    et al.
    Zelenina, Marina
    Axehult, Gustav
    Song, Yutong
    Bondar, Alexander
    Krieger, Patrik
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Zelenin, Sergey
    Aperia, Anita
    Identification of a molecular target for glutamate regulation of astrocyte water permeability2008In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 56, no 6, 587-596 p.Article in journal (Refereed)
    Abstract [en]

    Astrocytes play a key role for maintenance of brain water homeostasis, but little is known about mechanisms of short-term regulation of astrocyte water permeability. Here, we report that glutamate increases astrocyte water permeability and that the molecular target for this effect is the aquaporin-4 (AQP4) serine 111 residue, which is in a strategic position for control of the water channel gating. The glutamate effect involves activation of group I metabotropic glutamate receptors (mGluR), intracellular calcium release, and activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and nitric oxide synthase (NOS). The physiological impact of our results is underlined by the finding that mGluR activation increases the rate of hypoosmotic tissue swelling in acute rat hippocampal slices. Cerebral ischemia is associated with an excessive release of glutamate, and in postischemic cerebral edema ablation of AQP4 attenuates the degree of damage. Thus, we have identified AQP4 as the molecular target for drugs that may attenuate the development of brain edema.

  • 42. Haylock, Anna-Karin
    et al.
    Nilvebrant, Johan
    KTH, School of Biotechnology (BIO), Protein Technology.
    Mortensen, Anja
    Velikyan, Irina
    Nestor, Marika
    Falk, Ronny
    Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 39, 65152-65170 p.Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this study was to generate and characterize scFv antibodies directed to human CD44v6, as well as to radiolabel and evaluate top candidates in vitro and in vivo for their potential use in CD44v6-targeted molecular imaging in cancer patients. Materials and methods: Phage display selections were used to isolate CD44v6-specific scFvs. A chain shuffling strategy was employed for affinity maturation based on a set of CD44v6-specific first-generation clones. Two second-generation scFv clones were then chosen for labeling with 111In or 125I and assessed for CD44v6-specific binding on cultured tumor cells. In vivo uptake and distribution was evaluated in tumor-bearing mice using a dual tumor model. Finally, a proof-of-concept small animal PET-CT study was performed on one of the candidates labeled with 124I. Results: Two affinity-matured clones, CD44v6-scFv-A11 and CD44v6-scFv-H12, displayed promising binding kinetics. Seven out of eight radiolabeled conjugates demonstrated CD44v6-specific binding. In vivo studies on selected candidates demonstrated very advantageous tumor-to-organ ratios, in particular for iodinated conjugates, where 125I-labeled scFvs exhibited favorable kinetics and tumor-to-blood ratios above five already at 24 hours p. i.. The small animal PET-CT study using 124I-labeled CD44v6-scFv-H12 was in line with the biodistribution data, clearly visualizing the high CD44v6-expressing tumor. Conclusion: The single chain fragments, CD44v6-scFv-A11 and CD44v6-scFv-H12 specifically bind to CD44v6, and the radiolabeled counterparts provide high tumor-to-blood ratios and fast clearance from organs and blood. We conclude that radioiodinated CD44v6-scFv-A11 and CD44v6-scFv-H12 possess features highly suitable for stringent molecular imaging.

  • 43. Hsu, Hsiang-Ting
    et al.
    Mace, Emily M.
    Carisey, Alexandre F.
    Viswanath, Dixita I.
    Christakou, Athanasia
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Önfelt, Bjorn
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Orange, Jordan S.
    NK cells converge lytic granules to promote cytotoxicity and prevent bystander killing2016In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 215, no 6, 875-889 p.Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cell activation triggers sequential cellular events leading to destruction of diseased cells. We previously identified lytic granule convergence, a dynein-and integrin signal-dependent movement of lysosome-related organelles to the microtubule-organizing center, as an early step in the cell biological process underlying NK cell cytotoxicity. Why lytic granules converge during NK cell cytotoxicity, however, remains unclear. We experimentally controlled the availability of human ligands to regulate NK cell signaling and promote granule convergence with either directed or nondirected degranulation. By the use of acoustic trap microscopy, we generated specific effector-target cell arrangements to define the impact of the two modes of degranulation. NK cells with converged granules had greater targeted and less nonspecific "bystander" killing. Additionally, NK cells in which dynein was inhibited or integrin blocked under physiological conditions demonstrated increased nondirected degranulation and bystander killing. Thus, NK cells converge lytic granules and thereby improve the efficiency of targeted killing and prevent collateral damage to neighboring healthy cells.

  • 44. Ivanova, L N
    et al.
    Solyenov, E I
    Zelenina, M N
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Khegay, I I
    Decrease in the response to ADH of the rat kidney as a result of early postnatal treatment with cortisol.1987In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 408, no 4, 328-32 p.Article in journal (Refereed)
    Abstract [en]

    Wistar rats were injected just once, intraperitoneally with cortisol (1 microgram/g) or saline at the age of 5 days. The cortisol-treated rats did not differ significantly in the (U/P)osm ratio from the saline-treated controls before 15 days of life. Their response to ADH was distinct but weaker than in the saline controls aged 30 days. This reduced response persisted to 60 days of life. In the collecting tubule fragments, (3H)AVP specific binding was lower in the cortisol-treated rats than in the controls at the age of 20 and 60 days. There was no (3H)AVP specific binding in the proximal convoluted tubules in the cortisol- and saline-injected rats of both ages. The ontogenetic patterns of cAMP specific binding in the papillary cytosolic fraction were different: the early increase in cAMP binding was protracted in the cortisol-treated rats, and no peak appeared at the age of 25 days. Cytosolic protein kinase activity was lower, no peak appeared at 30 days, no activation of protein kinase occurred to the end of weaning in the cortisol-treated rats. The difference between the cortisol and saline groups was abolished by day 30. The interference of cortisol with the ontogenetic changes in AVP binding capacity and cAMP-dependent protein kinase appears to be a plausible cause of the altered development of the response to ADH.

  • 45. Ivanova, L N
    et al.
    Zelenina, M N
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Logvinenko, N S
    Svitasheva, N G
    Solenov, E I
    [Age-related changes in the molecular mechanisms of the hormonal regulation of kidney function].1990In: Zhurnal evoliutsionnoĭ biokhimii i fiziologii, ISSN 0044-4529, Vol. 26, no 4, 482-9 p.Article in journal (Refereed)
  • 46. Ivanova, L N
    et al.
    Zelenina, M N
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Melidi, N N
    Solenov, E I
    Khegaĭ, I I
    [Vasopressin: the ontogeny of antidiuretic action at the cellular level].1989In: Fiziologicheskiĭ zhurnal SSSR imeni I. M. Sechenova, ISSN 0015-329X, Vol. 75, no 7, 970-9 p.Article in journal (Refereed)
    Abstract [ru]

    The data on the development of molecular mechanism of the antidiuretic effect of vasopressin and the molecular structure of the AVP receptor, cytosolic cAMP-dependent protein-kinases and renal response to AVP, are discussed. The experiments were performed in normal rats and mice, nephrogenic diabetes insipidus mutants and rats treated with cortisol in early postnatal period. The development of the kidney sensitivity to AVP seems to be closely connected with the development of the molecular structure of the AVP receptor, age-related increase of the AVP-activated adenylate cyclase, and the maturation of cAMP-dependent protein kinases.

  • 47.
    Jahn, Michael
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Vorpahl, Carsten
    Huebschmann, Thomas
    Harms, Hauke
    Mueller, Susann
    Copy number variability of expression plasmids determined by cell sorting and Droplet Digital PCR2016In: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 15, 211Article in journal (Refereed)
    Abstract [en]

    Background: Plasmids are widely used for molecular cloning or production of proteins in laboratory and industrial settings. Constant modification has brought forth countless plasmid vectors whose characteristics in terms of average plasmid copy number (PCN) and stability are rarely known. The crucial factor determining the PCN is the replication system; most replication systems in use today belong to a small number of different classes and are available through repositories like the Standard European Vector Architecture (SEVA). Results: In this study, the PCN was determined in a set of seven SEVA-based expression plasmids only differing in the replication system. The average PCN for all constructs was determined by Droplet Digital PCR and ranged between 2 and 40 per chromosome in the host organism Escherichia coli. Furthermore, a plasmid-encoded EGFP reporter protein served as a means to assess variability in reporter gene expression on the single cell level. Only cells with one type of plasmid (RSF1010 replication system) showed a high degree of heterogeneity with a clear bimodal distribution of EGFP intensity while the others showed a normal distribution. The heterogeneous RSF1010-carrying cell population and one normally distributed population (ColE1 replication system) were further analyzed by sorting cells of sub-populations selected according to EGFP intensity. For both plasmids, low and highly fluorescent sub-populations showed a remarkable difference in PCN, ranging from 9.2 to 123.4 for ColE1 and from 0.5 to 11.8 for RSF1010, respectively. Conclusions: The average PCN determined here for a set of standardized plasmids was generally at the lower end of previously reported ranges and not related to the degree of heterogeneity. Further characterization of a heterogeneous and a homogeneous population demonstrated considerable differences in the PCN of sub-populations. We therefore present direct molecular evidence that the average PCN does not represent the true number of plasmid molecules in individual cells.

  • 48. Jonsson, L.
    et al.
    Fridberg, M.
    Wangefjord, S.
    Nodin, B.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Eberhard, J.
    Jirström, K.
    High expression of RBM3 in colorectal cancer is a predictor of improved response to oxaliplatin treatment2012In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 61, 82-83 p.Article in journal (Other academic)
  • 49. Kampf, C.
    et al.
    Andersson, A. -C
    Wester, K.
    Björling, E.
    Uhlen, Mathias
    KTH, Superseded Departments, Biotechnology.
    Ponten, F.
    Antibody-based tissue profiling as a tool for clinical proteomics2004In: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 1, no 3-4, 285-299 p.Article in journal (Refereed)
    Abstract [en]

    Here, we show a strategy for high-throughput antibody-based tissue profiling with the aim to create an atlas of protein expression patterns in normal human tissues and cancer tissues representing the 20 most prevalent cancer types. A set of standardized tissue microarrays (TMAs) was produced to allow for rapid screening of a multitude of different cells and tissues using immunohistochemistry. Eight TMA blocks were produced containing 48 different normal human tissues in triplicate and cancer tissue from 216 individually different tumors in duplicate. Sections from these blocks were immunohistochemically stained using five commercial and five in-house generated antibodies. Digital images for annotation of expression profiles were generated using a semiautomated approach. Five hundred seventy-six images and annotation data corresponding to a total of 30 Gbytes of data were collected for each antibody. The data presented here suggest that antibody-based profiling of protein expression in tissues can be used as a valuable tool in clinical proteomics.

  • 50. Kampf, Caroline
    et al.
    Mardinoglu, Adil
    Fagerberg, Linn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hallström, Björn M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Edlund, Karolina
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Nielsen, Jens
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    The human liver-specific proteome defined by transcriptomics and antibody-based profiling2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 7, 2901-2914 p.Article in journal (Refereed)
    Abstract [en]

    Human liver physiology and the genetic etiology of the liver diseases can potentially be elucidated through the identification of proteins with enriched expression in the liver. Here, we combined data from RNA sequencing (RNA-Seq) and antibody-based immunohistochemistry across all major human tissues to explore the human liver proteome with enriched expression, as well as the cell type-enriched expression in hepatocyte and bile duct cells. We identified in total 477 protein-coding genes with elevated expression in the liver: 179 genes have higher expression as compared to all the other analyzed tissues; 164 genes have elevated transcript levels in the liver shared with at least one other tissue type; and an additional 134 genes have a mild level of increased expression in the liver. We identified the precise localization of these proteins through antibody-based protein profiling and the subcellular localization of these proteins through immunofluorescent-based profiling. We also identified the biological processes and metabolic functions associated with these proteins, investigated their contribution in the occurrence of liver diseases, and identified potential targets for their treatment. Our study demonstrates the use of RNA-Seq and antibody-based immunohistochemistry for characterizing the human liver proteome, as well as the use of tissue-specific proteins in identification of novel drug targets and discovery of biomarkers.

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