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  • 1.
    Aabel, Peder
    et al.
    Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway;Akershus Univ Hosp, Ear Nose & Throat Dept, Div Surg, Lorenskog, Norway;Univ Oslo, Inst Clin Med, Div Surg, Oslo, Norway.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway;Univ Oslo, Inst Oral Biol, Fac Dent, Oslo, Norway.
    Olstad, Ole Kristoffer
    Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Dilley, Rodney James
    Ear Sci Inst Australia, Perth, WA, Australia;Univ Western Australia, Ear Sci Ctr, Nedlands, WA, Australia;Univ Western Australia, Ctr Cell Therapy & Regenerat Med, Nedlands, WA, Australia.
    von Unge, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Akershus Univ Hosp, Ear Nose & Throat Dept, Div Surg, Lorenskog, Norway;Univ Oslo, Inst Clin Med, Div Surg, Oslo, Norway.
    Transcription and microRNA Profiling of Cultured Human Tympanic Membrane Epidermal Keratinocytes2018In: Journal of the Association for Research in Otolaryngology, ISSN 1525-3961, E-ISSN 1438-7573, Vol. 19, no 3, p. 243-260Article in journal (Refereed)
    Abstract [en]

    The human tympanic membrane (TM) has a thin outer epidermal layer which plays an important role in TM homeostasis and ear health. The specialised cells of the TM epidermis have a different physiology compared to normal skin epidermal keratinocytes, displaying a dynamic and constitutive migration that maintains a clear TM surface and assists in regeneration. Here, we characterise and compare molecular phenotypes in keratinocyte cultures from TM and normal skin. TM keratinocytes were isolated by enzymatic digestion and cultured in vitro. We compared global mRNA and microRNA expression of the cultured cells with that of human epidermal keratinocyte cultures. Genes with either relatively higher or lower expression were analysed further using the biostatistical tools g:Profiler and Ingenuity Pathway Analysis. Approximately 500 genes were found differentially expressed. Gene ontology enrichment and Ingenuity analyses identified cellular migration and closely related biological processes to be the most significant functions of the genes highly expressed in the TM keratinocytes. The genes of low expression showed a marked difference in homeobox (HOX) genes of clusters A and C, giving the TM keratinocytes a strikingly low HOX gene expression profile. An in vitro scratch wound assay showed a more individualised cell movement in cells from the tympanic membrane than normal epidermal keratinocytes. We identified 10 microRNAs with differential expression, several of which can also be linked to regulation of cell migration and expression of HOX genes. Our data provides clues to understanding the specific physiological properties of TM keratinocytes, including candidate genes for constitutive migration, and may thus help focus further research.

  • 2. Aartsma-Rus, A.
    et al.
    Ferlini, A.
    McNally, E. M.
    Spitali, P.
    Sweeney, H. L.
    Al-Khalili Szigyarto, Cristina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Bello, L.
    Bronson, A.
    Brown, K.
    Buccella, F.
    Chadwick, J.
    Frank, D.
    Hoffman, E.
    Larkindale, J.
    McClorey, G.
    Munschauer, R.
    Muntoni, F.
    Owens, J.
    Schara, U.
    Straub, V.
    Tinsley, J.
    Versnel, J.
    Vroom, E.
    Welch, E.
    226th ENMC International Workshop:: Towards validated and qualified biomarkers for therapy development for Duchenne muscular dystrophy 20–22 January 2017, Heemskerk, The Netherlands2018In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 28, no 1, p. 77-86Article in journal (Refereed)
  • 3.
    Aasebo, Kristine
    et al.
    Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Mezheyeuski, Artur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Eide, Geir Egil
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Lifestyle Epidemiol Grp, Bergen, Norway;Haukeland Hosp, Clin Res Ctr, Bergen, Norway.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sorbye, Halfdan
    Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Oncol, Bergen, Norway.
    CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup2020In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 10, article id 8Article in journal (Refereed)
    Abstract [en]

    Background: Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential prognostic and predictive effect, but the importance in mCRC has not been fully investigated. Methods: Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC (n = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated. Results: Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if BRAF mutated (BRAFmut) and in 9% if KRAS mutated (KRASmut). CDX2 loss was associated with microsatellite instability, BRAFmut, and poor differentiation and inversely associated with KRASmut. Patients with CDX2 loss received less first-line (53 vs. 64%, p = 0.050) and second-line (23 vs. 39%, p = 0.006) chemotherapy and secondary surgery (1 vs. 9%, p = 0.019). Median progression-free survival and OS for patients given first-line combination chemotherapy was 4 and 10 months if CDX2 loss vs. 9 and 24 months if CDX2 expressed (p = 0.001, p < 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed (p = 0.003). Median OS in patients with BRAFmut or KRASmut and CDX2 expressed in tumor (both 21 months) was comparable to wild-type patients (27 months). However, if CDX2 loss, median OS was only 8 and 11 months in BRAFmut and KRASmut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, p = 0.027) and BRAFmut (hazard ratio: 1.62, p = 0.012) were independent poor prognostic markers for OS. Conclusion: In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of BRAFmut cases with a much better prognosis. Loss of CDX2 defines a small group of KRASmut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery.

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  • 4. Abbara, Aula
    et al.
    Al-Harbat, Nizar
    Karah, Nabil
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Abo-Yahya, Bashar
    El-Amin, Wael
    Hatcher, James
    Gabbar, Omar
    Antimicrobial Drug Resistance among Refugees from Syria, Jordan2017In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 23, no 5, p. 885-886Article in journal (Refereed)
  • 5.
    Abdelrazak Morsy, Mohammad Hamdy
    et al.
    Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Alexandria Univ, Med Res Inst, Dept Appl Med Chem, Alexandria, Egypt.;Karolinska Inst, Lab Med, Alfred Nobels Alle 8B, S-14152 Stockholm, Sweden..
    Lilienthal, Ingrid
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Solna, Sweden..
    Lord, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Merrien, Magali
    Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Wasik, Agata Magdalena
    Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Sureda-Gómez, Marta
    Inst Invest Biomed August Pi Sunyer, Barcelona, Spain..
    Amador, Virginia
    Inst Invest Biomed August Pi Sunyer, Barcelona, Spain.;Ctr Invest Biomed Red Canc, Madrid, Spain..
    Johansson, Henrik J.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Lehtiö, Janne
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Garcia-Torre, Beatriz
    Inst Invest Biomed August Pi Sunyer, Barcelona, Spain..
    Martin-Subero, Jose Ignacio
    Inst Invest Biomed August Pi Sunyer, Barcelona, Spain.;Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain..
    Tsesmetzis, Nikolaos
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Solna, Sweden..
    Tao, Sijia
    Emory Univ, Ctr Viro Sci & Cure, Sch Med, Dept Pediat, Atlanta, GA USA..
    Schinazi, Raymond F.
    Emory Univ, Ctr Viro Sci & Cure, Sch Med, Dept Pediat, Atlanta, GA USA..
    Kim, Baek
    Emory Univ, Ctr Viro Sci & Cure, Sch Med, Dept Pediat, Atlanta, GA USA..
    Sorteberg, Agnes L.
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Solna, Sweden..
    Wickström, Malin
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Solna, Sweden..
    Sheppard, Devon
    Francis Crick Inst, Macromol Struct Lab, London, England..
    Rassidakis, Georgios Z.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX USA..
    Taylor, Ian A.
    Francis Crick Inst, Macromol Struct Lab, London, England..
    Christensson, Birger
    Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Campo, Elias
    Inst Invest Biomed August Pi Sunyer, Barcelona, Spain.;Ctr Invest Biomed Red Canc, Madrid, Spain.;Univ Barcelona, Hosp Clin Barcelona, Dept Anat Pathol, Hematopathol Sect, Barcelona, Spain..
    Herold, Nikolas
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Solna, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Paediat Oncol, Stockholm, Sweden..
    Sander, Birgitta
    Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma2024In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 143, no 19, p. 1953-1964Article in journal (Refereed)
    Abstract [en]

    Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara -C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara -C ef fi cacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMGbox containing protein 11 (SOX11) as a novel direct binding partner and fi rst known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identi fi ed SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar af fi nity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara -C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identi fi ed SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its fi rst known endogenous inhibitor with potentially important implications for clinical therapy strati fi cation.

  • 6.
    Abdu, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Betydelsen av PDGF vid Trippelnegativ Bröstcancer2022Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Triple negative breast cancers (TNBC) are defined by the absence of estrogen andprogesterone receptors and the absence of HER2 protein overexpression. TNBC cancersrepresent a heterogeneous breast cancer subtype with poor prognosis. The heterogeneity of thedisease has limited the successful development of targeted therapy in unselected patientpopulations. Currently there are no approved targeted therapies for TNBC. However, intenseresearch is ongoing to identify specific targets and develop additional and better systemictreatment options. Recently researchers have found that the PDGF pathway plays a significantpart in communication between cancer cells and cells in the surrounding tissue. In thisliterature study evaluated if the PDGFR inhibition is a treatment strategy for triple negativebreast cancer. Method: literature original articles from database Pubmed was used in thisstudy. Results: results show that PDGF is more overexpressed in tissue cells than tumor cells.PDGF isoforms like PDGFRalfa and PDGF-C can increase the risk of distant recurrence tocentral nervsystem and early recurrence of primary breast cancer. The TNBC subtype (MES)is more likely to overexpress PDGF and inhibition with PDGF specific aptamer have shownsignificantly decreased tumor cell growth. Triple combination treatment with MEK1/2 and(JAK2) inhibitors resulted in significant reduction of cell growth and immunological inducedcell death through CD8+ t-cells. Single treatment with PDGFR inhibitors like Ponatinib andSunitinib reduced cell growth and cell migration in TNBC, but a combination treatment withDoxorubicin showed far greater inhibitor effect on cell growth and migration it also causedcell death. Chemotherapy Doxorubicin combination with a PDGFR- inhibitor resulted inbetter treatment compared to a single PDGFR- inhibitor to treat TNBC.Conclusion: It has been proven that PDGF isoforms have different significance in thedevelopment of TNBC. The PDGFC ligand is significantly more expressed in TNBCcompared to other PDGF isoforms. Ligand and receptor binding PDGFC-PDGFRα expressionis increased during breast cancer progression. PDGFRbeta signaling pathway plays a crucialrole in mediating vascular properties and therefore may be a good marker for reducing newvessel formation in endothelial cells. Combination therapy appears to be promising drugtreatment in TNBC. PDGFR inhibitors combined with cytostatic drugs or JAK & MEK1/2inhibitors can provide a pharmacological synergistic effect or activate the immune systemCD8+ T cells. Combination therapy reduces emergence of resistance mechanisms, howeverthere is a lack of studies on toxicity side effects. Nyckelord: Trippelnegativ bröstcan

  • 7.
    Abdul Rahman, Zozek
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Expression of FLAG-tagged argonautes in Dictyostelium discoideum2022Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Argonautes are conserved RNA-binding proteins that can regulate gene expression post transcriptionally through a process known as RNA interference (RNAi). This is done through the use of small RNAs, e.g. sRNAs that act as a guide for the argonautes, allowing for sequence-specific binding to the target site. This interaction has been studied in many organisms, one of which is the model organism Dictyostelium discoideum. D. discoideum is an amoeba that has been used extensively in genetic experiments due to its unique lifestyle, and ease of use. Being a eukaryotic, unicellular organism, it proves to be a great tool for the study of regulatory systems in eukaryotes, allowing us to study this argonaute-sRNA interaction in detail. By analysing which RNAs bind to the argonautes, we can better understand which genes these proteins regulate and what role RNAi has in the organisms as a whole. 

    In this study, I investigate three of the five argonautes found in D. discoideum, namely agnA, agnC and agnE. By transforming FLAG-tagged versions of these genes into the amoeba, I successfully express two of these modified proteins in D. discoideum and verified expression by using antibodies designed specifically to recognise the FLAG-tags. This opens up the possibility for the characterisation of the argonaute proteins to better understand their role and function in the regulation of genes. 

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  • 8.
    Abdulamir, Dalia
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Evaluation of the Role of Histidines Regarding the Self-assembly and Fibrillar Stability of Amyloid βeta2015Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 9.
    Abdullah Nasir, Ahmad
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Oncology Research Laboratory, NUS M31, Umeå, Sweden.
    Netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 8585Article in journal (Refereed)
    Abstract [en]

    Netrin-1 is a secreted protein that is well known for its involvement in axonal guidance during embryonic development and as an enhancer of cancer cell metastasis. Despite extensive efforts, the molecular mechanisms behind many of the physiological functions of netrin-1 have remained elusive. Here, we show that netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling in various cellular systems, including a mutually inhibitory interaction with the BMP-promoting function of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins. The BMP inhibitory function of netrin-1 in mouse embryonic fibroblasts was dependent on the netrin receptor neogenin, with the expression level regulated by both netrin-1 and LRIG proteins. Our results reveal a previously unrecognized function of netrin-1 that may help to explain several of the developmental, physiological, and cancer-promoting functions of netrins at the signal transduction level.

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  • 10.
    Abelius, Martina S
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping. Helsingborg Hospital, Helsingborg.
    Duchén, Karel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Nilsson, Lennart J
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    The Placental Immune Milieu is Characterized by a Th2- and Anti-Inflammatory Transcription Profile, Regardless of Maternal Allergy, and Associates with Neonatal Immunity2015In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 73, no 5, p. 445-459Article in journal (Refereed)
    Abstract [en]

    PROBLEM: How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear.

    METHOD OF STUDY: Expression of 40 genes was quantified by PCR arrays in placenta, peripheral blood mononuclear cells (PBMC), and cord blood mononuclear cells (CBMC) from 7 allergic and 12 non-allergic women and their offspring.

    RESULTS: Placental gene expression was dominated by a Th2-/anti-inflammatory profile, irrespectively of maternal allergy, as compared to gene expression in PBMC. p35 expression in placenta correlated with fetal Tbx21 (ρ = -0.88, P < 0.001) and IL-5 expression in PBMC with fetal galectin1 (ρ = 0.91, P < 0.001). Increased expression of Th2-associated CCL22 in CBMC preceded allergy development.

    CONCLUSIONS: Gene expression locally and systemically during pregnancy was partly associated with the offspring's gene expression, possibly indicating that the immunological milieu is important for fetal immune development. Maternal allergy was not associated with an enhanced Th2 immunity in placenta or PBMC, while a marked prenatal Th2 skewing, shown as increased CCL22 mRNA expression, might contribute to postnatal allergy development.

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  • 11.
    Abidine, Yara
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Liu, Lifeng
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Wallén, Oskar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Trybala, Edward
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Olofsson, Sigvard
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Bergström, Tomas
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Cellular Chondroitin Sulfate and the Mucin-like Domain of Viral Glycoprotein C Promote Diffusion of Herpes Simplex Virus 1 While Heparan Sulfate Restricts Mobility2022In: Viruses, E-ISSN 1999-4915, Vol. 14, no 8, article id 1836Article in journal (Refereed)
    Abstract [en]

    The diffusion of viruses at the cell membrane is essential to reach a suitable entry site and initiate subsequent internalization. Although many viruses take advantage of glycosaminoglycans (GAG) to bind to the cell surface, little is known about the dynamics of the virus–GAG interactions. Here, single-particle tracking of the initial interaction of individual herpes simplex virus 1 (HSV-1) virions reveals a heterogeneous diffusive behavior, regulated by cell-surface GAGs with two main diffusion types: confined and normal free. This study reports that different GAGs can have competing influences in mediating diffusion on the cells used here: chondroitin sulfate (CS) enhances free diffusion but hinders virus attachment to cell surfaces, while heparan sulfate (HS) promotes virus confinement and increases entry efficiency. In addition, the role that the viral mucin-like domains (MLD) of the HSV-1 glycoprotein C plays in facilitating the diffusion of the virus and accelerating virus penetration into cells is demonstrated. Together, our results shed new light on the mechanisms of GAG-regulated virus diffusion at the cell surface for optimal internalization. These findings may be extendable to other GAG-binding viruses.

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  • 12. Abraham, Nabil M.
    et al.
    Liu, Lei
    Jutras, Brandon Lyon
    Yadav, Akhilesh K.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Narasimhan, Sukanya
    Gopalakrishnan, Vissagan
    Ansari, Juliana M.
    Jefferson, Kimberly K.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Jacobs-Wagner, Christine
    Fikrig, Erol
    Pathogen-mediated manipulation of arthropod microbiota to promote infection2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 5, p. E781-E790Article in journal (Refereed)
    Abstract [en]

    Arthropods transmit diverse infectious agents; however, the ways microbes influence their vector to enhance colonization are poorly understood. Ixodes scapularis ticks harbor numerous human pathogens, including Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis. We now demonstrate that A. phagocytophilum modifies the I. scapularis microbiota to more efficiently infect the tick. A. phagocytophilum induces ticks to express Ixodes scapularis antifreeze glycoprotein (iafgp), which encodes a protein with several properties, including the ability to alter bacterial biofilm formation. IAFGP thereby perturbs the tick gut microbiota, which influences the integrity of the peritrophic matrix and gut barrier-critical obstacles for Anaplasma colonization. Mechanistically, IAFGP binds the terminal D-alanine residue of the pentapeptide chain of bacterial peptidoglycan, resulting in altered permeability and the capacity of bacteria to form biofilms. These data elucidate the molecular mechanisms by which a human pathogen appropriates an arthropod antibacterial protein to alter the gut microbiota and more effectively colonize the vector.

  • 13.
    Abrahamsson, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Jakobsson, H.E.
    Karolinska Institute, Stockholm, Sweden.
    Andersson, A.F.
    KTH Royal Institute of Technology, Stockholm, Sweden.
    Björksten, B.
    Karolinska Institute, Stockholm, Sweden; Örebro University, Sweden .
    Engstrand, L.
    Karolinska Institute, Stockholm, Sweden; KTH Royal Institute of Technology, Stockholm, Sweden.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Low gut microbiota diversity in early infancy precedes asthma at school age2014In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 44, no 6, p. 842-850Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Low total diversity of the gut microbiota during the first year of life is associated with allergic diseases in infancy, but little is known how early microbial diversity is related to allergic disease later in school age.

    OBJECTIVE:

    To assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to the prevalence of different allergic diseases in school age, such as asthma, allergic rhinoconjunctivitis (ARC) and eczema.

    METHODS:

    The microbial diversity and composition was analysed with barcoded 16S rDNA 454 pyrosequencing in stool samples at 1 week, 1 month and 12 months of age in 47 infants which were subsequently assessed for allergic disease and skin prick test reactivity at 7 years of age (ClinicalTrials.gov ID NCT01285830).

    RESULTS:

    Children developing asthma (n = 8) had a lower diversity of the total microbiota than non-asthmatic children at 1 week (P = 0.04) and 1 month (P = 0.003) of age, whereas allergic rhinoconjunctivitis (n = 13), eczema (n = 12) and positive skin prick reactivity (n = 14) at 7 years of age did not associate with the gut microbiota diversity. Neither was asthma associated with the microbiota composition later in infancy (at 12 months). Children having IgE-associated eczema in infancy and subsequently developing asthma had lower microbial diversity than those that did not. There were no significant differences, however, in relative abundance of bacterial phyla and genera between children with or without allergic disease.

    CONCLUSION AND CLINICAL RELEVANCE:

    Low total diversity of the gut microbiota during the first month of life was associated with asthma but not ARC in children at 7 years of age. Measures affecting microbial colonization of the infant during the first month of life may impact asthma development in childhood.

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  • 14.
    Abreu-Vieira, Gustavo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fischer, Alexander W.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Hamburg, Germany.
    Mattsson, Charlotte
    de Jong, Jasper M. A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ryden, Mikael
    Laurencikiene, Jurga
    Arner, Peter
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cidea improves the metabolic profile through expansion of adipose tissue2015In: Nature Communications, E-ISSN 2041-1723, Vol. 6, article id 7433Article in journal (Refereed)
    Abstract [en]

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

  • 15. Acevedo, Nathalie
    et al.
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Katayama, Shintaro
    Bruhn, Sören
    Andersson, Anna
    Wikberg, Gustav
    Lundeberg, Lena
    Lindvall, Jessica M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Greco, Dario
    Kere, Juha
    Söderhäll, Cilla
    Scheynius, Annika
    Epigenetic alterations in skin homing CD4(+)CLA(+) T cells of atopic dermatitis patients2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 18020Article in journal (Refereed)
    Abstract [en]

    T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations -(CD4(+), -CD4(+)CD45RA(+) naive, -CD4(+)CLA(+), and -CD8(+)) from adult AD patients and healthy controls (HC). Skin homing -CD4(+)CLA(+) T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in -CD4(+)CLA(+) T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in -CD4(+)CLA(+) T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing -CD4(+)CLA(+) T cells and uncover putative molecules participating in AD pathways.

  • 16. Acheva, Anna
    et al.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Caen Normandy, France.
    Sollazzo, Alice
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Launonen, Virpi
    Kamarainen, Meerit
    Presence of Stromal Cells Enhances Epithelial-to-Mesenchymal Transition (EMT) Induction in Lung Bronchial Epithelium after Protracted Exposure to Oxidative Stress of Gamma Radiation2019In: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, Vol. 2019, article id 4120379Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate the role of a microenvironment in the induction of epithelial-to-mesenchymal transition (EMT) as a sign of early stages of carcinogenesis in human lung epithelial cell lines after protracted low-dose rate gamma-radiation exposures. BEAS-2B and HBEC-3KT lung cell lines were irradiated with low-dose rate gamma-rays (Cs-137, 1.4 or 14 mGy/h) to 0.1 or 1 Gy with or without adding TGF-beta. TGF-beta-treated samples were applied as positive EMT controls and tested in parallel to find out if the radiation has a potentiating effect on the EMT induction. To evaluate the effect of the stromal component, the epithelial cells were irradiated in cocultures with stromal MRC-9 lung fibroblasts. On day 3 post treatment, the EMT markers: alpha-SMA, vimentin, fibronectin, and E-cadherin, were analyzed. The oxidative stress levels were evaluated by 8-oxo-dG analysis in both epithelial and fibroblast cells. The protracted exposure to low Linear Energy Transfer (LET) radiation at the total absorbed dose of 1 Gy was able to induce changes suggestive of EMT. The results show that the presence of the stromal component and its signaling (TGF-beta) in the cocultures enhances the EMT. Radiation had a minor cumulative effect on the TGF-beta-induced EMT with both doses. The oxidative stress levels were higher than the background in both epithelial and stromal cells post chronic irradiation (0.1 and 1 Gy); as for the BEAS-2B cell line, the increase was statistically significant. We suggest that the induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure and the presence of stromal component might enhance the effect through free radical production and accumulation.

  • 17.
    Achour, Cyrinne
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Long non-coding RNA and Polycomb: an intricate partnership in cancer biology2018In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 23, p. 2106-2132Article in journal (Refereed)
    Abstract [en]

    High-throughput analyses have revealed that the vast majority of the transcriptome does not code for proteins. These non-translated transcripts, when larger than 200 nucleotides, are termed long non-coding RNAs (lncRNAs), and play fundamental roles in diverse cellular processes. LncRNAs are subject to dynamic chemical modification, adding another layer of complexity to our understanding of the potential roles that lncRNAs play in health and disease. Many lncRNAs regulate transcriptional programs by influencing the epigenetic state through direct interactions with chromatin-modifying proteins. Among these proteins, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) have been shown to be recruited by lncRNAs to silence target genes. Aberrant expression, deficiency or mutation of both lncRNA and Polycomb have been associated with numerous human diseases, including cancer. In this review, we have highlighted recent findings regarding the concerted mechanism of action of Polycomb group proteins (PcG), acting together with some classically defined lncRNAs including X-inactive specific transcript (XIST), antisense non-coding RNA in the INK4 locus (ANRIL), metastasis associated lung adenocarcinoma transcript 1 (MALAT1), and HOX transcript antisense RNA (HOTAIR).

  • 18.
    Achour, Cyrinne
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Long Noncoding RNAs as Players in Breast Tumorigenesis2020In: The chemical biology of long noncoding RNAs / [ed] Stefan Jurga, Jan Barciszewski, Springer, 2020, , p. 19p. 385-403Chapter in book (Refereed)
    Abstract [en]

    Comprehensive analysis of the mammalian genome uncovered the discovery of pervasive transcription of large RNA transcripts that do not code for proteins, namely, long noncoding RNAs (lncRNAs). LncRNAs play important roles in the regulation of gene expression from integration of chromatin remodeling complexes to transcriptional and posttranscriptional regulation of protein-coding genes. Application of next-generation sequencing technologies to cancer transcriptomes has revealed that aberrant expression of lncRNAs is associated with tumor progression and metastasis. Although thousands of lncRNAs have been shown to be dysregulated in different cancer types, just few of them have been fully characterized. In this book chapter, we aim to highlight recent findings of the mechanistic function of lncRNAs in breast cancer and summarize key examples of lncRNAs that are misregulated during breast tumorigenesis. We have categorized breast cancer–associated lncRNA according to their contribution to tumor suppression or tumor progression based on recent studies. Because some of them are expressed in a specific molecular breast cancer subtype, we have outlined lncRNAs that can potentially serve as diagnostic and prognostic markers, in which expression is linked to chemotherapy resistance. Finally, we have discussed current limitations and perspectives on potential lncRNA targets for use in therapies against breast cancer.

  • 19.
    Acuña, Ulyana Muñoz
    et al.
    Ohio State University, USA.
    Curley, Robert W
    Ohio State University, USA.
    Fatima, Nighat
    Quaid-i-Azam University, Pakistan;University of Hawaii at Hilo, USA.
    Ahmed, Safia
    Quaid-i-Azam University, Pakistan.
    Chang, Leng Chee
    University of Hawaii at Hilo, USA.
    De Blanco, Esperanza J Carcache
    Ohio State University, USA.
    Differential Effect of Wortmannolone Derivatives on MDA-MB-231 Breast Cancer Cells.2017In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, no 4, p. 1617-1623Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIM: The survival rate of women diagnosed with triple-negative breast-cancer (TNBC) remains low. Hence, this study aimed at the chemical and biological optimization of furanosteroid derivatives for the treatment of this type of malignancy using TNBC cells.

    MATERIALS AND METHODS: Semi-synthetic analogs of wortmannolone (1-6) that negatively affected the aberrant pathways in tumor cells were evaluated in hormone-independent breast cancer cells using western blot and cell-cycle analysis.

    RESULTS: Wortmannolone derivatization generated NF-ĸB inhibitors as new lead structures for further development. Compound (3) was found to be the most significantly active lead.

    CONCLUSION: Structure-activity analysis in the present study showed that acetylation of the hydroxyl groups and substitution on C3 and C17 of wortmannolone enhanced biological activity. Alpha-substitution of the acetyl group in C3 on ring A (compound 3) resulted in ROS inducing effect; however, presence of an acetyl group in β-position of C3 displayed the highest NF-ĸB p65 inhibitory activity (0.60 μM).

  • 20.
    Ademovski, Emir
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV).
    In vitro effects of skincare ingredients on keratinocytes2023Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

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

  • 21.
    Adolfsson, Emma
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Friberg, Örjan
    Department of Cardiothoracic Surgery, Faculty of Health, Örebro University, Örebro, Sweden.
    Samano, Ninos
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Cardiothoracic Surgery.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology.
    Johansson, Karin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Bone marrow- and adipose tissue-derived mesenchymal stem cells from donors with coronary artery disease: growth, yield, gene expression and the effect of oxygen concentration2020In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 80, no 4, p. 318-326Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells (MSCs) for cardiovascular cell therapy are procured from different sources including bone marrow and adipose tissue. Differently located MSCs differ in growth potential, differentiation ability and gene expression when cultured in vitro, and studies show different healing abilities for different MSC subgroups. In this study, bone marrow derived MSCs (BMSCs) and adipose tissue derived MSCs (ADSCs) from six human donors with coronary artery disease were compared for growth potential and expression of target genes (Angpt1, LIF, HGF, TGF-β1 and VEGF-A) in response to exposure to 1% and 5% O2, for up to 48 h. We found greater growth of ADSCs compared to BMSCs. ADSCs expressed higher levels of Angpt1, LIF and TGF-β1 and equal levels of VEGF-A and HGF as BMSCs. In BMSCs, exposure to low oxygen resulted in upregulation of TGF-β1, whereas other target genes were unaffected. Upregulation was only present at 1% O2. In ADSCs, LIF was upregulated in both oxygen concentrations, whereas Angpt1 was upregulated only at 1% O2. Different response to reduced oxygen culture conditions is of relevance when expanding cells in vitro prior to administration. These findings indicate ADSCs as better suited for cardiovascular cell therapy compared to BMSCs.

  • 22.
    Adolfsson, Per I
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Bloth, Björn
    Department of Clinical Neuroscience, Laboratory of Translational Neuropharmacology, Center of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Futurum Academy for Health and Care, Jönköping County Council, Sweden.
    Svensson, Samuel P S
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Zinc Induces a Bell-shaped Proliferative Dose-response Effect in Cultured Smooth Muscle Cells From Benign Prostatic Hyperplasia.2015In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 85, no 3, p. 704.e15-704.e19Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the effects of zinc (Zn(2+)) concentrations on cultured benign prostatic hyperplasia (BPH) smooth muscle cell (SMC) proliferation.

    METHODS: The effects of Zn(2+) were studied in primary cultures of human BPH SMC, stimulated with either 10-μM lysophosphatidic acid (LPA) or LPA in combination with 100-nM testosterone. Deoxyribonucleic acid replication and protein synthesis using [(3)H]-thymidine and [(35)S]-methionine incorporation were measured. Furthermore, studies were performed to evaluate if Zn(2+) could potentiate the inhibitory effect of phosphodiesterase-5 blockers, on BPH SMC proliferation.

    RESULTS: Zn(2+) generated a bell-shaped concentration response, both regarding deoxyribonucleic acid replication and protein synthesis in cultured BPH SMC. Below a threshold value (approximately 200 μM), a significant mitogenic effect was seen, whereas higher concentrations inhibited SMC proliferation after stimulation with LPA. This effect was even more pronounced after stimulation of LPA in combination with testosterone. Moreover, phosphodiesterase-5 inhibitors, that is, sildenafil blocked LPA-stimulated BPH SMC proliferation. This antiproliferative effect, was significantly potentiated by coincubation with Zn(2+) in an additative manner.

    CONCLUSION: The bell-shaped concentration response of Zn(2+) on cultured BPH SMC proliferation suggests that changes in prostate Zn(2+) concentrations, during aging, diet, or inflammatory conditions, may be of importance in the pathogenesis of BPH.

  • 23.
    Adori, Csaba
    et al.
    Karolinska Inst, Sweden.
    Daraio, Teresa
    Karolinska Inst, Sweden.
    Kuiper, Raoul
    Karolinska Inst, Sweden.
    Barde, Swapnali
    Karolinska Inst, Sweden.
    Horvathova, Lubica
    Slovak Acad Sci, Slovakia.
    Yoshitake, Takashi
    Karolinska Inst, Sweden.
    Ihnatko, Robert
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Georg August Univ Gottingen, Germany.
    Valladolid-Acebes, Ismael
    Karolinska Inst, Sweden.
    Vercruysse, Pauline
    Karolinska Inst, Sweden.
    Wellendorf, Ashley M.
    Cincinnati Childrens Hosp Med Ctr, OH 45229 USA.
    Gramignoli, Roberto
    Karolinska Inst, Sweden.
    Bozoky, Bela
    Karolinska Univ Hosp, Sweden.
    Kehr, Jan
    Karolinska Inst, Sweden.
    Theodorsson, Elvar
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Cancelas, Jose A.
    Cincinnati Childrens Hosp Med Ctr, OH 45229 USA; Univ Cincinnati, OH 45267 USA.
    Mravec, Boris
    Slovak Acad Sci, Slovakia; Comenius Univ, Slovakia.
    Jorns, Carl
    Karolinska Univ Hosp Huddinge, Sweden.
    Ellis, Ewa
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Mulder, Jan
    Karolinska Inst, Sweden.
    Uhlen, Mathias
    Karolinska Inst, Sweden; Royal Inst Technol, Sweden.
    Bark, Christina
    Karolinska Inst, Sweden.
    Hökfelt, Tomas
    Karolinska Inst, Sweden.
    Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging2021In: Science Advances, E-ISSN 2375-2548, Vol. 7, no 30, article id eabg5733Article in journal (Refereed)
    Abstract [en]

    Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.

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  • 24. Adori, Monika
    et al.
    Bhat, Sadam
    Gramignoli, Roberto
    Valladolid-Acebes, Ismael
    Bengtsson, Tore
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Uhlèn, Mathias
    Adori, Csaba
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Karolinska Institutet, Sweden.
    Hepatic Innervations and Nonalcoholic Fatty Liver Disease2023In: Seminars in liver disease (Print), ISSN 0272-8087, E-ISSN 1098-8971, Vol. 43, no 02, p. 149-162Article, review/survey (Refereed)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.

  • 25.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts: Integrative Bioinformatic and Experimental Approaches2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology.

    In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM.

    In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted.

    In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.

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  • 26.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Österborg, Anders
    Department of Hematology, Karolinska University Hospital Solna.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancyManuscript (preprint) (Other academic)
    Abstract [en]

    Multiple myeloma (MM) is characterized by accumulation of post-germinal center, isotype switched, long-living plasma cells with retained proliferation capacity within the bone marrow. MM is highly heterogeneous and remains fatal. This heterogeneity has hampered identification of a common underlying mechanism for disease establishment and the development of targeted therapy. We recently provided proof-of-principle that gene silencing associated with H3K27me3 contributes to the malignancy of MM. Here we present the first epigenomic map of MM for H3K27me3 and H3K4me3 derived by ChIP- and RNA sequencing from freshly-isolated bone marrow plasma cells from four patients. We compile lists of targets common among the patients as well as unique to MM when compared with PBMCs. Indicating the clinical relevance of our findings, we find increased silencing of H3K27me3 targets with disease progression and in patients presenting with a poor prognosis. Bivalent genes further significantly correlated to under-expressed genes in MM and were unique to MM when compared to PBMCs. Furthermore, bivalent genes, unlike H3K27me3 targets, significantly associated with transcriptional activation upon Polycomb inhibition indicating a potential for drug targeting. Thus, we suggest that gene silencing by Polycomb plays an important role in the development of the malignant phenotype of the MM cell during tumor progression.

  • 27.
    Agelidis, Alex
    et al.
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Turturice, Benjamin A.
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Div Pulm Crit Care Sleep & Allergy, Dept Med, Chicago, IL 60612 USA..
    Suryawanshi, Rahul K.
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Yadavalli, Tejabhiram
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Jaishankar, Dinesh
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA.;Northwestern Univ, Dept Dermatol, Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA..
    Ames, Joshua
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Hopkins, James
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Koujah, Lulia
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Patil, Chandrashekhar D.
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Hadigal, Satvik R.
    Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Kyzar, Evan J.
    Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA..
    Campeau, Anaamika
    UCSD, Dept Pharmacol, La Jolla, CA USA.;UCSD, Skaggs Sch Pharm, La Jolla, CA USA..
    Wozniak, Jacob M.
    UCSD, Dept Pharmacol, La Jolla, CA USA.;UCSD, Skaggs Sch Pharm, La Jolla, CA USA..
    Gonzalez, David J.
    UCSD, Dept Pharmacol, La Jolla, CA USA.;UCSD, Skaggs Sch Pharm, La Jolla, CA USA..
    Vlodavsky, Israel
    Technion, Technion Integrated Canc Ctr TICC, Rappaport Fac Med, Haifa, Israel..
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Perkins, David L.
    Univ Illinois, Div Nephrol, Dept Med, Chicago, IL 60612 USA.;Univ Illinois, Dept Surg, Chicago, IL 60612 USA..
    Finn, Patricia W.
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Div Pulm Crit Care Sleep & Allergy, Dept Med, Chicago, IL 60612 USA..
    Shukla, Deepak
    Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA.;Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA..
    Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival2021In: JCI Insight, ISSN 2379-3708, Vol. 6, no 7, article id e144255Article in journal (Refereed)
    Abstract [en]

    The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we followed heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late-stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.

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  • 28.
    Aghanoori, Mohamad-Reza
    et al.
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Calgary, Cumming Sch Med, Dept Med Genet, 3330 Hosp Dr NW, Calgary, AB T2N 4N2, Canada..
    Agarwal, Prasoon
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Childrens Hosp Res Inst Manitoba, Winnipeg, MB, Canada..
    Gauvin, Evan
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada..
    Nagalingam, Raghu S.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Physiol & Pathophysiol, Winnipeg, MB, Canada.;St Boniface Gen Hosp, Inst Cardiovasc Sci, Albrechtsen Res Ctr, Winnipeg, MB, Canada..
    Bonomo, Raiza
    Loyola Univ, Cellular & Mol Dept, Stritch Sch Med, Chicago, IL 60611 USA..
    Yathindranath, Vinith
    Univ Manitoba, Kleysen Inst Adv Med, Winnipeg, MB, Canada..
    Smith, Darrell R.
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada..
    Hai, Yan
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Lee, Samantha
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Jolivalt, Corinne G.
    Univ Calif San Diego, Dept Pathol, San Diego, CA USA..
    Calcutt, Nigel A.
    Univ Calif San Diego, Dept Pathol, San Diego, CA USA..
    Jones, Meaghan J.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Czubryt, Michael P.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Physiol & Pathophysiol, Winnipeg, MB, Canada.;St Boniface Gen Hosp, Inst Cardiovasc Sci, Albrechtsen Res Ctr, Winnipeg, MB, Canada..
    Miller, Donald W.
    Univ Manitoba, Kleysen Inst Adv Med, Winnipeg, MB, Canada..
    Dolinsky, Vernon W.
    Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Childrens Hosp Res Inst Manitoba, Winnipeg, MB, Canada..
    Mansuy-Aubert, Virginie
    Loyola Univ, Cellular & Mol Dept, Stritch Sch Med, Chicago, IL 60611 USA..
    Fernyhough, Paul
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada..
    CEBP beta regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth2022In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 79, no 4, article id 193Article in journal (Refereed)
    Abstract [en]

    Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBP beta, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBP beta overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBP beta can be a promising therapeutic approach.

  • 29.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons2014In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 15, p. 2458-2468Article in journal (Refereed)
    Abstract [en]

    The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.

  • 30.
    Agnarsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Biomarker Discovery in Cutaneous Malignant Melanoma: A Study Based on Tissue Microarrays and Immunohistochemistry2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The incidence of cutaneous malignant melanoma has increased dramatically in Caucasians the last few decades, an increase that is partly explained by altered sun exposure habits. For the individual patient, with a localized disease, the tumor thickness of the excised lesion is the most important prognostic factor. However, there is a need to identify characteristics that can place patients in certain risk groups.

    In this study, the protein expression of multiple proteins in malignant melanoma tumors was studied, with the aim of identifying potential new candidate biomarkers. Representative samples from melanoma tissues were assembled in a tissue microarray format and protein expression was detected using immunohistochemistry. Multiple cohorts were used and for a subset of proteins the expression was also analyzed in melanocytes in normal skin and in benign nevi. The immunohistochemical staining was evaluated manually and for part of the proteins also with an automated algorithm.

    The protein expression of STX7 was described for the first time in tumors of the melanocytic lineage. Stronger expression of STX7 and SOX10 was seen in superficial spreading melanomas compared with nodular malignant melanomas. An inverse relationship between STX7 expression and T-stage was seen and between SOX10 expression and T-stage and Ki-67, respectively. In a population-based cohort the expression of MITF was analyzed and found to be associated with prognosis. Twenty-one potential biomarkers were analyzed using bioinformatics tools and a protein signature was identified which had a prognostic value independent of T-stage. The protein driving this signature was RBM3, a protein not previously described in malignant melanoma. Other markers included in the signature were MITF, SOX10 and Ki-67.

    In conclusion, the protein expression of numerous potential biomarkers was extensively studied and a new prognostic protein panel was identified which can be of value for risk stratification.

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    FULLTEXT01
  • 31.
    Agnarsdóttir, Margrét
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wagenius, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Mucci, Lorelei
    Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA, Department of Epidemiology, Harvard School of Public Health, Boston, USA .
    Magnusson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eaker-Fält, Sonja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    MITF as a Prognostic Marker in Cutaneous Malignant MelanomaManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Microphthalmia associated transcription factor (MITF) protein has a central role in the differentiation and survival of melanocytes. The aim of the study was to investigate whether MITF can be employed as a prognostic marker in patients operated on for cutaneous malignant melanoma.

    Methods: A cohort study design based on information collected from population-based registers. For included patients tissue microarrays and immunohistochemistry were employed to study the protein expression of MITF in the primary malignant melanoma tumors by estimating the fraction of positive tumor cells and the staining intensity.

    Results: The vast majority of tumors expressed MITF in >25% of the tumor cells with a strong staining intensity and looking at these factors individually these patients had a better prognosis. When cell fraction and intensity were combined a high-risk group dying of malignant melanoma was identified as those with 25% -75% of tumor cells staining with weak intensity and those with <25% of tumor cells staining with strong intensity. However, the majority of the deaths occurred in the lower risk groups.

    Conclusions: Although a high-risk group for death in malignant melanoma was identified we conclude that MITF is not useful as a prognostic marker because of the distribution of that particular expression in the population.

    Impact: Our results indicate a bi-phasic pattern of MITF expression and although not useful as a prognostic marker these results are in line with other experimental studies and are relevant to explore further.

     

  • 32.
    Agnarsdóttir, Margrét
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Rexhepaj, Elton
    UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
    Magnusson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Patil, Tushar
    Lab Surgpath, Mumbai, India.
    Johansson, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Jirström, Karin
    Center for Molecular Pathology, Department of Laboratory Medicine, Skåne University Hospital, Lund University, Malmö, Sweden .
    Uhlen, Mathias
    Department of Proteomics, School of Biotechnology, AlbaNova University Center, KTH-Royal Institute of Technology, SE-10691 Stockholm, Sweden .
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Gallagher, William
    UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland. .
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Protein Biomarkers in Malignant Melanoma: An Image Analysis-Based Study on Melanoma Markers of Potential Clinical RelevanceManuscript (preprint) (Other academic)
    Abstract [en]

    The thickness of a primary malignant melanoma tumor is the most important prognostic indicator for a patient with primary cutaneous malignant melanoma. To optimize the management and treatment of melanoma patients there is an unmet need to identify characteristics that can further stratify melanoma patients into high or low risk for progressive disease. Despite numerous studies no single marker has yet been shown to add significant prognostic information. An algorithmic approach, combining data from several markers provides an attractive model to identify patients of increased risk of dying from malignant melanoma. The primary aim of the present study was to analyze the correlation between clinical outcome and protein expression patterns of multiple proteins in malignant melanoma tumors using immunohistochemistry and tissue microarrays. Candidate proteins were identified based on a selective and differential expression pattern in melanoma tumors and tested in a cohort of 143 melanoma patients. Protein expression was analyzed using both manual scoring and automated image analysis-based algorithms. We found no single marker of prognosis that was independent of tumor thickness. When combining potential prognostic markers we could define a prognostic index, based on RBM3, MITF, SOX10 and Ki-67, that was independent of tumor thickness in multivariate analysis. Our findings suggest that a good prognosis signature can be identified in melanoma patients with tumors showing a low fraction of Ki-67 positive tumor cells and a high fraction of RBM3 positive tumor cells combined with low intensity levels of SOX10 and MITF.

     

  • 33. Agrawal, Ganesh Kumar
    et al.
    Sarkar, Abhijit
    Agrawal, Raj
    Ndimba, Bongani Kaiser
    Tanou, Georgia
    Dunn, Michael J
    Kieselbach, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cramer, Rainer
    Wienkoop, Stefanie
    Chen, Sixue
    Rafudeen, Mohammed Suhail
    Deswal, Renu
    Barkla, Bronwyn J
    Weckwerth, Wolfram
    Heazlewood, Joshua L
    Renaut, Jenny
    Job, Dominique
    Chakraborty, Niranjan
    Rakwal, Randeep
    Boosting the Globalization of Plant Proteomics through INPPO: Current Developments and Future Prospects2012In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 12, no 3, p. 359-368Article in journal (Refereed)
    Abstract [en]

    The International Plant Proteomics Organization (INPPO) is a non-profit-organization consisting of people who are involved or interested in plant proteomics. INPPO is constantly growing in volume and activity, which is mostly due to the realization among plant proteomics researchers worldwide for the need of such a global platform. Their active participation resulted in the rapid growth within the first year of INPPO's official launch in 2011 via its website (www.inppo.com) and publication of the 'Viewpoint paper' in a special issue of PROTEOMICS (May 2011). Here, we will be highlighting the progress achieved in the year 2011 and the future targets for the year 2012 and onwards. INPPO has achieved a successful administrative structure, the Core Committee (CC; composed of President, Vice-President, and General Secretaries), Executive Council (EC), and General Body (GB) to achieve INPPO objectives. Various committees and subcommittees are in the process of being functionalized via discussion amongst scientists around the globe. INPPO's primary aim to popularize the plant proteomics research in biological sciences has also been recognized by PROTEOMICS where a section dedicated to plant proteomics has been introduced starting January 2012, following the very first issue of this journal devoted to plant proteomics in May 2011. To disseminate organizational activities to the scientific community, INPPO has launched a biannual (in January and July) newsletter entitled 'INPPO Express: News & Views' with the first issue published in January 2012. INPPO is also planning to have several activities in 2012, including programs within the Education Outreach committee in different countries, and the development of research ideas and proposals with priority on crop and horticultural plants, while keeping tight interactions with proteomics programs on model plants such as Arabidopsis thaliana, rice, and Medicago truncatula. Altogether, the INPPO progress and upcoming activities are because of immense support, dedication, and hard work of all members of the INPPO community, and also due to the wide encouragement and support from the communities (scientific and non-scientific).

  • 34. Aguilo, Francesca
    et al.
    Avagyan, Serine
    Labar, Amy
    Sevilla, Ana
    Lee, Dung-Fang
    Kumar, Parameet
    Lemischka, Ihor R
    Zhou, Betty Y
    Snoeck, Hans-Willem
    Prdm16 is a physiologic regulator of hematopoietic stem cells.2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 19Article in journal (Refereed)
    Abstract [en]

    Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.

  • 35.
    Aguilo, Francesca
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Departments of Structural and Chemical Biology, Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Di Cecilia, Serena
    Walsh, Martin J
    Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease2016In: Long non-coding RNAs in human disease, Springer, 2016, Vol. 394, p. 29-39Chapter in book (Refereed)
    Abstract [en]

    The long non-coding RNA CDKN2B-AS1, commonly referred to as the Antisense Non-coding RNA in the INK4 Locus (ANRIL), is a 3.8-kb-long RNA transcribed from the short arm of human chromosome 9 on p21.3 that overlaps a critical region encompassing three major tumor suppressor loci juxtaposed to the INK4b-ARF-INK4a gene cluster and the methyl-thioadenosine phosphorylase (MTAP) gene. Genome-wide association studies have identified this region with a remarkable and growing number of disease-associated DNA alterations and single nucleotide polymorphisms, which corresponds to increased susceptibility to human disease. Recent attention has been devoted on whether these alterations in the ANRIL sequence affect its expression levels and/or its splicing transcript variation, and in consequence, global cellular homeostasis. Moreover, recent evidence postulates that ANRIL not only can regulate their immediate genomic neighbors in cis, but also has the capacity to regulate additional loci in trans. This action would further increase the complexity for mechanisms imposed through ANRIL and furthering the scope of this lncRNA in disease pathogenesis. In this chapter, we summarize the most recent findings on the investigation of ANRIL and provide a perspective on the biological and clinical significance of ANRIL as a putative biomarker, specifically, its potential role in directing cellular fates leading to cancer and cardiovascular disease.

  • 36.
    Aguilo, Francesca
    et al.
    Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Li, SiDe
    Balasubramaniyan, Natarajan
    Sancho, Ana
    Benko, Sabina
    Zhang, Fan
    Vashisht, Ajay
    Rengasamy, Madhumitha
    Andino, Blanca
    Chen, Chih-hung
    Zhou, Felix
    Qian, Chengmin
    Zhou, Ming-Ming
    Wohlschlegel, James A
    Zhang, Weijia
    Suchy, Frederick J
    Walsh, Martin J
    Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α2016In: Cell Reports, E-ISSN 2211-1247, Vol. 14, no 3, p. 479-492Article in journal (Refereed)
    Abstract [en]

    The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.

  • 37.
    Aguilo, Francesca
    et al.
    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Zakirova, Zuchra
    Nolan, Katie
    Wagner, Ryan
    Sharma, Rajal
    Hogan, Megan
    Wei, Chengguo
    Sun, Yifei
    Walsh, Martin J.
    Kelley, Kevin
    Zhang, Weijia
    Ozelius, Laurie J.
    Gonzalez-Alegre, Pedro
    Zwaka, Thomas P.
    Ehrlich, Michelle E.
    THAP1: role in mouse embryonic stem cell survival and differentiation2017In: Stem Cell Reports, ISSN 2213-6711, Vol. 9, no 1, p. 92-107Article in journal (Refereed)
    Abstract [en]

    THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression.

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  • 38. Aguilo, Francesca
    et al.
    Zhang, Fan
    Sancho, Ana
    Fidalgo, Miguel
    Di Cecilia, Serena
    Vashisht, Ajay
    Lee, Dung-Fang
    Chen, Chih-Hung
    Rengasamy, Madhumitha
    Andino, Blanca
    Jahouh, Farid
    Roman, Angel
    Krig, Sheryl R
    Wang, Rong
    Zhang, Weijia
    Wohlschlegel, James A
    Wang, Jianlong
    Walsh, Martin J
    Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming.2015In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 17, no 6, p. 689-704Article in journal (Refereed)
    Abstract [en]

    Epigenetic and epitranscriptomic networks have important functions in maintaining the pluripotency of embryonic stem cells (ESCs) and somatic cell reprogramming. However, the mechanisms integrating the actions of these distinct networks are only partially understood. Here we show that the chromatin-associated zinc finger protein 217 (ZFP217) coordinates epigenetic and epitranscriptomic regulation. ZFP217 interacts with several epigenetic regulators, activates the transcription of key pluripotency genes, and modulates N6-methyladenosine (m(6)A) deposition on their transcripts by sequestering the enzyme m(6)A methyltransferase-like 3 (METTL3). Consistently, Zfp217 depletion compromises ESC self-renewal and somatic cell reprogramming, globally increases m(6)A RNA levels, and enhances m(6)A modification of the Nanog, Sox2, Klf4, and c-Myc mRNAs, promoting their degradation. ZFP217 binds its own target gene mRNAs, which are also METTL3 associated, and is enriched at promoters of m(6)A-modified transcripts. Collectively, these findings shed light on how a transcription factor can tightly couple gene transcription to m(6)A RNA modification to ensure ESC identity.

  • 39. Aguilo, Francesca
    et al.
    Zhou, Ming-Ming
    Walsh, Martin J
    Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression.2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 16Article in journal (Refereed)
    Abstract [en]

    Polycomb group proteins (PcG) function as transcriptional repressors of gene expression. The important role of PcG in mediating repression of the INK4b-ARF-INK4a locus, by directly binding to the long noncoding RNA (lncRNA) transcript antisense noncoding RNA in the INK4 locus (ANRIL), was recently shown. INK4b-ARF-INK4a encodes 3 tumor-suppressor proteins, p15(INK4b), p14(ARF), and p16(INK4a), and its transcription is a key requirement for replicative or oncogene-induced senescence and constitutes an important barrier for tumor growth. ANRIL gene is transcribed in the antisense orientation of the INK4b-ARF-INK4a gene cluster, and different single-nucleotide polymorphisms are associated with increased susceptibility to several diseases. Although lncRNA-mediated regulation of INK4b-ARF-INK4a gene is not restricted to ANRIL, both polycomb repressive complex-1 (PRC1) and -2 (PRC2) interact with ANRIL to form heterochromatin surrounding the INK4b-ARF-INK4a locus, leading to its repression. This mechanism would provide an increased advantage for bypassing senescence, sustaining the requirements for the proliferation of stem and/or progenitor cell populations or inappropriately leading to oncogenesis through the aberrant saturation of the INK4b-ARF-INK4a locus by PcG complexes. In this review, we summarize recent findings on the underlying epigenetic mechanisms that link PcG function with ANRIL, which impose gene silencing to control cellular homeostasis as well as cancer development.

  • 40. Aguiló, Francesca
    et al.
    Camarero, Nuria
    Relat, Joana
    Marrero, Pedro F
    Haro, Diego
    Transcriptional regulation of the human acetoacetyl-CoA synthetase gene by PPARgamma.2010In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 427, no 2Article in journal (Refereed)
    Abstract [en]

    In the cytosol of lipogenic tissue, ketone bodies are activated by AACS (acetoacetyl-CoA synthetase) and incorporated into cholesterol and fatty acids. AACS gene expression is particularly abundant in white adipose tissue, as it is induced during adipocyte differentiation. In order to elucidate the mechanism controlling the gene expression of human AACS and to clarify its physiological role, we isolated the human promoter, characterized the elements required to initiate transcription and analysed the expression of the gene in response to PPARgamma (peroxisome-proliferator-activated receptor gamma), an inducer of adipogenesis. We show that the human AACS promoter is a PPARgamma target gene and that this nuclear receptor is recruited to the AACS promoter by direct interaction with Sp1 (stimulating protein-1).

  • 41.
    Agullo, Luis
    et al.
    Univ Vic Cent Univ Catalonia UVIC UCC, Dept Syst Biol, U Sci Tech, Sagrada Familia 7, Vic 08500, Spain..
    Buch, Ignasi
    Hosp Del Mar Med Res Inst IMIM, Computat Biophys Lab, Barcelona 08003, Spain..
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Garcia-Dorado, David
    Vall DHebron Res Inst VHIR, Cardiocirculatory Pathol Grp, Barcelona 08035, Spain..
    Villa-Freixa, Jordi
    Univ Vic Cent Univ Catalonia UVIC UCC, Dept Syst Biol, U Sci Tech, Sagrada Familia 7, Vic 08500, Spain..
    Computational exploration of the binding mode of heme-dependent stimulators into the active catalytic domain of soluble guanylate cyclase2016In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 84, no 10, p. 1534-1548Article in journal (Refereed)
    Abstract [en]

    Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction, and myocardial infarction. One of its agonists, BAY 41-2272 (Riociguat), has been recently approved for treatment of pulmonary arterial hypertension (PHA), while some others are in clinical phases of development. However, the location of the binding sites for the two known types of agonists, heme-dependent stimulators and heme-independent activators, is a matter of debate, particularly for the first group where both a location on the regulatory (H-NOX) and on the catalytic domain have been suggested by different authors. Here, we address its potential location on the catalytic domain, the unique well characterized at the structural level, by an in silico approach. Homology models of the catalytic domain of sGC in inactive or active conformations were constructed using the structure of previously described crystals of the catalytic domains of inactive sGCs (2WZ1, 3ET6) and of active adenylate cyclase (1CJU). Each model was submitted to six independent molecular dynamics simulations of about 1 s. Docking of YC-1, a classic heme-dependent stimulator, to all frames of representative trajectories of inactive and active conformations, followed by calculation of absolute binding free energies with the linear interaction energy (LIE) method, revealed a potential high-affinity binding site on the active structure. The site, located between the pseudo-symmetric and the catalytic site just over the loop (2)-(3), does not overlap with the forskolin binding site on adenylate cyclases.

  • 42.
    Ahlberg, Emelie
    et al.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Al-Kaabawi, Ahmed
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Thune, Rebecka
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Simpson, Melanie Rae
    Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Pedersen, Sindre Andre
    Library Section for Research Support, Data and Analysis, NTNU University Library, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Cione, Erika
    Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Cosenza, Italy.
    Jenmalm, Maria Christina
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Tingö, Lina
    Örebro University, School of Medical Sciences. Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Nutrition-Gut-Brain Interactions Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden; Food and Health Programme, Örebro University, Örebro, Sweden.
    Breast milk microRNAs: Potential players in oral tolerance development2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1154211Article, review/survey (Refereed)
    Abstract [en]

    Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex biological fluid contains numerous immunologically active factors such as microorganisms, immunoglobulins, cytokines and microRNAs (miRNAs). Here, we set out to predict the function of the top 10 expressed miRNAs in human breast milk, focusing on their relevance in oral tolerance development and allergy prevention in the infant. The top expressed miRNAs in human breast milk were identified on basis of previous peer-reviewed studies gathered from a recent systematic review and an updated literature search. The miRNAs with the highest expression levels in each study were used to identify the 10 most common miRNAs or miRNA families across studies and these were selected for subsequent target prediction. The predictions were performed using TargetScan in combination with the Database for Annotation, Visualization and Integrated Discovery. The ten top expressed miRNAs were: let-7-5p family, miR-148a-3p, miR-30-5p family, miR-200a-3p + miR-141-3p, miR-22-3p, miR-181-5p family, miR-146b-5p, miR-378a-3p, miR-29-3p family, miR-200b/c-3p and miR-429-3p. The target prediction identified 3,588 potential target genes and 127 Kyoto Encyclopedia of Genes and Genomes pathways; several connected to the immune system, including TGF-b and T cell receptor signaling and T-helper cell differentiation. This review highlights the role of breast milk miRNAs and their potential contribution to infant immune maturation. Indeed, breast milk miRNAs seem to be involved in several pathways that influence oral tolerance development.

  • 43.
    Ahlberg, Emelie
    et al.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Jenmalm, Maria C.
    Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Tingö, Lina
    Örebro University, School of Medical Sciences. Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Evaluation of five column-based isolation kits and their ability to extract miRNA from human milk2021In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 25, no 16, p. 7973-7979Article in journal (Refereed)
    Abstract [en]

    MicroRNA can be found in various body fluids, including breast milk. MicroRNA may be transferred from mother to infant via breast milk and potentially regulate the development of the infant's immune system on a post-transcriptional level. This study aimed to determine the microRNA extraction efficiency of five RNA extraction kits from human skim milk samples. Their efficiency was determined by comparing microRNA concentrations, total RNA yield and purity. Furthermore, hsa-miR-148a-3p expression and the recovery of an exogenous control, cel-miR-39-3p, were quantified using qPCR. Each kit extracted different amounts of microRNA and total RNA, with one kit tending to isolate the highest amount of both RNA species. Based on these results, the extraction kit ReliaPrep™ miRNA Cell and Tissue Miniprep System from Promega was found to be the most appropriate kit for microRNA extraction from human skim milk. Moreover, further research is needed to establish a standardized protocol for microRNA extraction from breast milk.

  • 44.
    Ahlford, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Applications of Four-Colour Fluorescent Primer Extension Technology for SNP Analysis and Discovery2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Studies on genetic variation can reveal effects on traits and disease, both in humans and in model organisms. Good technology for the analysis of DNA sequence variations is critical. Currently the development towards assays for large-scale and parallel DNA sequencing and genotyping is progressing rapidly. Single base primer extension (SBE) is a robust reaction principle based on four-colour fluorescent terminating nucleotides to interrogate all four DNA nucleotides in a single reaction. In this thesis, SBE methods were applied to the analysis and discovery of single nucleotide polymorphism (SNP) in the model organism Drosophila melanogaster and in humans.

    The tag-array minisequencing system in a microarray format is convenient for intermediate sized genotyping projects. The system is scalable and flexible to adapt to specialized and novel applications. In Study I of the thesis a tool was established to automate quality control of clustered genotype data. By calculating “Silhouette scores”, the SNP genotype assignment can be evaluated by a single numeric measure. Silhouette scores were then applied in Study I to compare the performance of four DNA polymerases and in Study III to evaluate freeze-dried reagents in the tag-array minisequencing system.

    The characteristics of the tag-array minisequencing system makes it suitable for inexpensive genome-wide gene mapping in the fruit fly. In Study II a high-resolution SNP map, and 293 genotyping assays, were established across the X, 2nd and 3rd chromosomes to distinguish commonly used Drosophila strains. A database of the SNP markers and a program for automatic allele calling and identification of map positions of mutants was also developed. The utility of the system was demonstrated by rapid mapping of 14 genes that disrupt embryonic muscle patterning.

    In Study III the tag-array minisequencing system was adapted to a lab-on-a-chip format for diagnostic testing for mutations in the TP53 gene. Freeze-drying was evaluated for storing reagents, including thermo-sensitive enzymes, on the microchip to reduce the complexity of the integrated test. Correct genotyping results were obtained using freeze-dried reagents in each reaction step of the genotyping protocol, both in test tubes and in single polymer test chambers. The results showed the potential of the approach to be implemented in fully integrated systems.

    The four-colour chemistry of SBE has been developed further to allow massively parallel sequencing (MPS) of short DNA fragments as in the Genome Analyzer system (Solexa/Illumina). In Study IV MPS was used to compare Nimblegen arrays and the SureSelect solution-based system for targeted enrichment of 56 continuous human candidate-gene regions totalling 3.1 Mb in size. Both methods detected known SNPs and discovered novel SNPs in the target regions, demonstrating the feasibility for complexity reduction of sequencing libraries by hybridization methods.

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  • 45.
    Ahlgren, Ulf
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gotthardt, Martin
    Department of Nuclear Medicine, Nijmegen, Netherlands.
    Approaches for imaging islets2010In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 654, p. 39-57Article in journal (Refereed)
    Abstract [en]

    The establishment of improved technologies for imaging of the pancreas is a key element in addressing several aspects of diabetes pathogenesis. In this respect, the development of a protocol that allows for non-invasive scoring of human islets, or islet beta-cells, is of particular importance. The development of such a technology would have profound impact on both clinical and experimental medicine, ranging from early diagnosis of diabetes to the evaluation of therapeutic regimes. Another important task is the development of modalities for high-resolution imaging of experimental animal models for diabetes. Rodent models for diabetes research have for decades been instrumental to the diabetes research community. The ability to image, and to accurately quantify, key players of diabetogenic processes with molecular specificity will be of great importance for elucidating mechanistic aspects of the disease. This chapter aims to overview current progress within these research areas.

  • 46.
    Ahlner, Alexandra
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Carlsson, Mats
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    PINT: a software for integration of peak volumes and extraction of relaxation rates2013In: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 56, no 3, p. 191-202Article in journal (Refereed)
    Abstract [en]

    We present the software Peak INTegration (PINT), designed to perform integration of peaks in NMR spectra. The program is very simple to run, yet powerful enough to handle complicated spectra. Peaks are integrated by fitting predefined line shapes to experimental data and the fitting can be customized to deal with, for instance, heavily overlapped peaks. The results can be inspected visually, which facilitates systematic optimization of the line shape fitting. Finally, integrated peak volumes can be used to extract parameters such as relaxation rates and information about low populated states. The utility of PINT is demonstrated by applications to the 59 residue SH3 domain of the yeast protein Abp1p and the 289 residue kinase domain of murine EphB2.

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  • 47.
    Ahmadian, Afshin
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Ren, Z P
    Williams, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Pontén, F
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Pontén, J
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Genetic instability in the 9q22.3 region is a late event in the development of squamous cell carcinoma.1998In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 17, no 14Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma (SCC) of the skin represents a group of neoplasms which is associated with exposure to UV light. Recently, we obtained data suggesting that invasive skin cancer and its precursors derive from one original neoplastic clone. Here, the analysis were extended by loss of heterozygosity (LOH) analysis in the chromosome 9q22.3 region. A total of 85 samples, taken from twenty-two sections of sun-exposed sites, corresponding to normal epidermis, morphological normal cells with positive immuno-staining for the p53 protein (p53 patches), dysplasias, cancer in situ (CIS) and squamous cell carcinomas (SCC) of the skin were analysed. Overall, about 70% of p53 patches had mutations in the p53 gene but not LOH in the p53 gene or 9q22.3 region. Approximately 70% of the dysplasias showed p53 mutations of which about 40% had LOH in the p53 region but not in the 9q22.3 region. In contrast, about 65% of SCC and CIS displayed LOH in the 9q22.3 region, as well as frequent (80%) mutations and/or LOH in the p53 gene. These findings strongly suggest that alterations in the p53 gene is an early event in the progression towards SCC, whereas malignant development involves LOH and alterations in at least one (or several) tumor suppressor genes located in chromosome 9q22.3.

  • 48.
    Ahmed, Heba A.
    et al.
    Department of Biological and Geological Sciences, University of Alexandria, Egypt.
    Ibrahim, Lidia L.
    Department of Biological and Geological Sciences, University of Alexandria, Egypt.
    El Mekkawy, Desouki A.
    Department of Zoology, University of Alexandria, Egypt.
    El Wakil, Abeer
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Biological and Geological Sciences, University of Alexandria, Egypt.
    Expression pattern of the orphan nuclear receptor, nurr1, in the developing mouse forelimb and its relationship to limb skeletogenesis and osteogenesis2015In: OnLine Journal of Biological Sciences, ISSN 1608-4217, Vol. 15, no 3, p. 162-169Article in journal (Refereed)
    Abstract [en]

    The NR4A orphan nuclear receptor, Nurr1, has been shown to regulate the expression of osteoblastic genes and osteoblastic differentiation. However, the expression profile of Nurr1 in the developing mouse forelimb and its relationship to skeletogenesis has not, to the best of our knowledge, been previously analyzed. In this study, the relationship between Nurr1 expression pattern, skeletogenesis and osteogenesis in the developing mouse forelimb was investigated. The expression level of Nurr1 during development was also quantified by real time-polymerase chain reaction. Our results revealed that Nurr1 is expressed in the mesenchyme cells that will form the skeleton. Nurr1 is aabundantly expressed in the primary ossification centers of the forelimb skeletal elements and its expression level is gradually increased during limb development, particularly, at the onset of ossification. Collectively, these data suggested that Nurr1 plays an important role in skeletogenesis and patterning of the developing mouse forelimb.

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  • 49.
    Ahmed, Meftun
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Oscillatory Ca2+ signaling in glucose-stimulated murine pancreatic β-cells: Modulation by amino acids, glucagon, caffeine and ryanodine2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Oscillations in cytoplasmic Ca2+ concentration ([Ca2+]i) is the key signal in glucose-stimulated β-cells governing pulsatile insulin release. The glucose response of mouse β-cells is often manifested as slow oscillations and rapid transients of [Ca2+] i. In the present study, microfluorometric technique was used to evaluate the role of amino acids, glucagon, ryanodine and caffeine on the generation and maintenance of [Ca2+] i oscillations and transients in individual murine β-cells and isolated mouse pancreatic islets. The amino acids glycine, alanine and arginine, at around their physiological concentrations, transformed the glucose-induced slow oscillations of [Ca2+] i in isolated mouse β-cells into sustained elevation. Increased Ca2+ entry promoted the reappearance of the slow [Ca2+] i oscillations. The [Ca2+] i oscillations were more resistant to amino acid transformation in intact islets, supporting the idea that cellular interactions are important for maintaining the oscillatory activity. Individual rat β-cells responded to glucose stimulation with slow [Ca2+] i oscillations due to periodic entry of Ca2+ as well as with transients evoked by mobilization of intracellular stores. The [Ca2+] i oscillations in rat β-cells had a slightly lower frequency than those in mouse β-cells and were more easily transformed into sustained elevation in the presence of glucagon or caffeine. The transients of [Ca2+] i were more common in rat than in mouse β-cells and often appeared in synchrony also in cells lacking physical contact. Depolarization enhanced the generation of [Ca2+] i transients. In accordance with the idea that β-cells have functionally active ryanodine receptors, it was found that ryanodine sometimes restored oscillatory activity abolished by caffeine. However, the IP3 receptors are the major Ca2+ release channels both in β-cells from rats and mice. Single β-cells from ob/ob mice did not differ from those of lean controls with regard to frequency, amplitudes and half-widths of the slow [Ca2+] i oscillations. Nevertheless, there was an excessive firing of [Ca2+] i transients in the β-cells from the ob/ob mice, which was suppressed by leptin at close to physiological concentrations. The enhanced firing of [Ca2+] i transients in ob/ob mouse β-cells may be due to the absence of leptin and mediated by activation of the phospholipase C signaling pathway.

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  • 50. Aho, Leena
    et al.
    Karkola, Kari
    Juusela, Jari
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Heavy alcohol consumption and neuropathological lesions: a post-mortem human study2009In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 87, no 12, p. 2786-2792Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies have indicated that excessive alcohol consumption leads to cognitive impairment, but the specific pathological mechanism involved remains unknown. The present study evaluated the association between heavy alcohol intake and the neuropathological hallmark lesions of the three most common neurodegenerative disorders, i.e., Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular cognitive impairment (VCI), in post-mortem human brains. The study cohort was sampled from the subjects who underwent a medicolegal autopsy during a 6-month period in 1999 and it included 54 heavy alcohol consumers and 54 age- and gender-matched control subjects. Immunohistochemical methodology was used to visualize the aggregation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein and the extent of infarcts. In the present study, no statistically significant influence was observed for alcohol consumption on the extent of neuropathological lesions encountered in the three most common degenerative disorders. Our results indicate that alcohol-related dementia differs from VCI, AD, and DLB; i.e., it has a different etiology and pathogenesis.

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