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  • 1.
    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).

  • 2.
    Behailu Bekele, Haimanot
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Atypisk aktivering av komplementprotein C52019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 3.
    Carlsson, Stina K.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Effects of adenosine and acetylcholine on the lacrimal gland2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A balanced tear film is essential for a healthy ocular surface. Insufficient tear production may result in dry eye, a common disorder in the elderly population. Dry eye causes significant discomfort in the patients and may lead to visual impairment and ocular infections. The lacrimal gland secretes water, proteins and electrolytes to the aqueous layer of the tear film. Lacrimal gland secretion is tightly regulated by e.g. neuronally released acetylcholine. The effect of acetylcholine on lacrimal gland secretion was recently found to be potentiated by adenosine. Adenosine is an important signaling molecule acting upon the adenosine receptors: A1, A2A, A2B and A3.

    The aim of this thesis was to study effects of adenosine and acetylcholine on intracellular signaling pathways and lacrimal gland secretion. Cholinergic stimulation of secretion was shown to be regulated by the mitogen activated protein kinase p38, a protein previously not known to be involved in exocrine secretion. p38 was activated in response to cholinergic stimulation and inhibition of p38 significantly diminished cholinergic secretion.

    When investigating adenosine effects, potentiation of cholinergic secretion was observed by activation of the A2B receptor in addition to the previously studied A1 receptor. An A2 receptor agonist increased cholinergic rabbit lacrimal gland protein secretion at several concentrations. The increase was inhibited by antagonism of the A2B receptor, but not the A2A receptor. When investigating the intracellular signaling pathways following adenosine and acetylcholine receptor activation, adenosine was shown to increase of cAMP levels. An additional increase in cAMP levels was observed after parallel adenosine and cholinergic receptor activation. Inhibition of Ca2+ release from the endoplasmic reticulum had inhibitory effects of cholinergic stimulation of secretion. In addition, the expression of adenosine receptors in a mouse model of autoimmune dry eye was investigated. The results showed a lymphocyte dependent upregulation of A2A receptors in diseased mice compared to controls.

    In conclusion, the results in this thesis provide significant contributions in the search of dry eye therapeutics through studies of adenosine and acetylcholine receptor activation.

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  • 4.
    Christerson, Ulrika
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Keita, Åsa, V
    Linköping University, Sweden.
    Winberg, Martin E.
    Linköping University, Sweden.
    Söderholm, Johan D.
    Linköping University, Sweden;County Council Östergötland, Sweden.
    Gustafson-Svärd, Christina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Possible Involvement of Intracellular Calcium-Independent Phospholipase A(2) in the Release of Secretory Phospholipases from Mast Cells-Increased Expression in Ileal Mast Cells of Crohn's Disease2019In: Cells, E-ISSN 2073-4409, Vol. 8, no 7, p. 1-15, article id 672Article in journal (Refereed)
    Abstract [en]

    Increased activity of secretory phospholipases A(2) (sPLA(2)) type-II was previously observed in ileum of Crohn's disease (CD). Our aims were to explore the involvement of calcium-independent (i)PLA(2 beta) in the release of sPLA(2)s from the human mast cell (MC) line (HMC-1) and investigate expressions of cytosolic (c)PLA(2) alpha, iPLA(2)beta, sPLA(2)-IIA and sPLA(2)-V in MCs of CD ileum. The release of sPLA(2) was investigated in HMC-1 by immunocytochemistry and ELISA. The expression intensities of PLA(2)s in mucosal MCs, and the proportion of PLA(2)-positive MCs, were investigated in normal ileum and in ileum from patients with CD by immunohistochemistry. The calcium ionophore-stimulated release of sPLA(2)-IIA and sPLA(2)-V from HMC-1 was reduced by the iPLA(2)-inhibitor bromoenol lactone. All four PLA(2)s were detectable in mucosal MCs, both in normal ileum and in CD, but the proportion of iPLA(2)beta-containing mucosal MCs and the expression intensity of sPLA(2)-IIA was increased in CD. Results indicate that iPLA(2)beta is involved in the secretion of sPLA(2)s from HMC-1, and suggest that iPLA(2)beta-mediated release of sPLA(2) from intestinal MCs may contribute to CD pathophysiology. Ex vivo studies on isolated mucosal mast cells are however needed to clarify the precise role of MC PLA(2)s in the inflammatory processes of CD.

  • 5.
    Comasco, Erika
    et al.
    Uppsala University.
    Vumma, Ravi
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Toffoletto, Simone
    Uppsala University.
    Johansson, Jessica
    Örebro University.
    Flyckt, Lena
    Karolinska institutet.
    Lewander, Tommy
    Örebro university.
    Oreland, Lars
    Uppsala university.
    Bjerkenstedt, Lars
    Strömstad Academy, Strömstad, Sweden.
    Andreou, Dimitrios
    Karolinska institutet.
    Söderman, Erik
    Karolinska institutet.
    Terenius, Lars
    Karolinska institutet.
    Agartz, Ingrid
    Karolinska institutet ; University of Oslo, Norway ; Diakonhjemmet Hospital, Oslo, Norway.
    Jönsson, Erik G
    Karolinska institutet ; University of Oslo, Norway.
    Venizelos, Nikolaos
    Örebro university.
    Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia.2016In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 74, no 2, p. 96-103Article in journal (Refereed)
    Abstract [en]

    Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.

  • 6.
    Demirel, Isak
    et al.
    Univ Örebro, Dept Clin Med, Sch Hlth & Med Sci, Örebro, Sweden.
    Säve, Susanne
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kruse, Robert
    Univ Örebro, Dept Clin Med, Sch Hlth & Med Sci, Örebro, Sweden.
    Persson, Katarina
    Univ Örebro, Dept Clin Med, Sch Hlth & Med Sci, Örebro, Sweden.
    Expression of suppressor of cytokine signalling 3 (SOCS3) in human bladder epithelial cells infected with uropathogenic Escherichia coli2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 2, p. 158-167Article in journal (Refereed)
    Abstract [en]

    Suppressor of cytokine signalling (SOCS) proteins inhibit pro-inflammatory signalling mediated by Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathways. To evade the immune response some pathogens appear to modify the host SOCS proteins. Uropathogenic Escherichia coli (UPEC) are able to subvert the host response evoked by bladder epithelial cells, but the mechanisms are not fully understood. The objective of this study was to investigate whether UPEC can modify the host SOCS and STAT3 response. Real time RT-PCR studies demonstrated an increased SOCS1 and SOCS3 expression in the isolated human bladder epithelial cell lines (RT-4 and 5637) in response to cytokines. UPEC strain IA2 increased SOCS3, but not SOCS1, mRNA levels with a peak at 6h after infection. The increase of SOCS3 was confirmed at the protein level by Western blotting. The UPEC strain IA2 caused a time-dependent decrease in the phosphorylation of STAT3. This study demonstrates that UPEC are able to affect SOCS3 and STAT3 signalling in human uroepithelial cells. The finding that UPEC are able to induce mediators involved in suppression of host cytokine signalling may help to elucidate how UPEC may circumvent the host response during urinary tract infection.

  • 7.
    Edman, Maria
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Adenosine Receptors and Regulation of Rabbit Lacrimal Gland Secretion2007Doctoral thesis, monograph (Other academic)
  • 8.
    Englund Johansson, Ulrica
    et al.
    Lundbeck A/S, Denmark.
    Björklund, Anders
    Lund University, Sweden.
    In Vivo Properties of In Vitro-Propagated Neural Stem Cells After Transplantation to the Neonatal and Adult Rat Brain2004In: Stem Cells in the Nervous System: Functional and Clinical Implications. Research and Perspectives in Neurosciences / [ed] Fred H. Gage, Anders Björklund, Alain Prochiantz, Yves Christen, Springer, 2004Conference paper (Refereed)
    Abstract [en]

    The ability to isolate neural stem and precursor cells and expand them in culture has provided researchers a new tool, not only assisting studies of neural development but also providing a new source of defined and expandable cells for in vivo studies using transplantation. The purposes of this chapter are, first, to review available protocols for in vitro expansion of neural precursor cells, either epigenetically using growth factors or genetically by inserting immortalizing genes; and, second, to discuss the in vivo properties of in vitro-propagated neural stem and progenitor cells, as assessed by grafting to the developing or adult rodent brain. This discussion will focus on our own recent studies using growth factor-expanded neurosphere cells of mouse and human origin and a particularly interesting, conditionally immortalized neural cell line, RN33B.

  • 9.
    Englund Johansson, Ulrica
    et al.
    Lund University, Sweden.
    Netanyah, Eitan
    Lund University, Sweden.
    Johansson, Fredrik
    Lund University, Sweden.
    Tailor-Made Electrospun Culture Scaffolds Control Human Neural Progenitor Cell Behavior: Studies on Cellular Migration and Phenotypic Differentiation2017In: Journal of Biomaterials and Nanobiotechnology, ISSN 2158-7027, E-ISSN 2158-7043, Vol. 8, no 1, p. 1-21Article in journal (Refereed)
    Abstract [en]

    In neuroscience research, cell culture systems are essential experimental platforms. It is of great interest to explore in vivo-like culture substrates. We explored how basic properties of neural cells, nuclei polarization, phenotypic differentiation and distribution/migration, were affected by the culture at poly-L-lactic acid (PLLA) fibrous scaffolds, using a multipotent mitogen-expanded human neural progenitor cell (HNPC) line. HNPCs were seeded, at four different surfaces: two different electrospun PLLA (d = 1.2 - 1.3 μm) substrates (parallel or random aligned fibers), and planar PLL- and PLLA surfaces. Nuclei analysis demonstrated a non-directed cellular migration at planar surfaces and random fibers, different from cultures at aligned fibers where HNPCs were oriented parallel with the fibers. At aligned fibers, HNPCs displayed the same capacity for phenotypic differentiation as after culture on the planar surfaces. However, at random fibers, HNPCs showed a significant lower level of phenotypic differentiation compared with cultures at the planar surfaces. A clear trend towards greater neuronal formation at aligned fibers, compared to cultures at random fibers, was noted. We demonstrated that the topography of in vivo-resembling PLLA scaffolds significantly influences HNPC behavior, proven by different migration behavior, phenotypic differentiation potential and nuclei polarization. This knowledge is useful in future exploration of in vivo-resembling neural cell system using electrospun scaffolds.

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  • 10.
    Eriksson, Oskar
    et al.
    Uppsala University, Sweden.
    Hultström, Michael
    Uppsala University, Sweden.
    Persson, Barbro
    Uppsala University, Sweden.
    Lipcsey, Miklos
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Frithiof, Robert
    Uppsala University, Sweden.
    Mannose-Binding Lectin is Associated with Thrombosis and Coagulopathy in Critically Ill COVID-19 Patients2020In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, E-ISSN 2567-689X, Vol. 120, no 12, p. 1720-1724Article in journal (Refereed)
    Abstract [en]

    The ongoing COVID-19 pandemic has caused significant morbidity and mortality worldwide, as well as profound effects on society. COVID-19 patients have an increased risk of thromboembolic (TE) complications, which develop despite pharmacological thromboprophylaxis. The mechanism behind COVID-19-associated coagulopathy remains unclear. Mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, has been suggested as a potential amplifier of blood coagulation during thromboinflammation. Here we describe data from a cohort of critically ill COVID-19 patients ( n =65) treated at a tertiary hospital center intensive care unit (ICU). A subset of patients had strongly elevated MBL plasma levels, and activity upon ICU admission, and patients who developed symptomatic TE (14%) had significantly higher MBL levels than patients without TE. MBL was strongly correlated to plasma D-dimer levels, a marker of COVID-19 coagulopathy, but showed no relationship to degree of inflammation or other organ dysfunction. In conclusion, we have identified complement activation through the MBL pathway as a novel amplification mechanism that contributes to pathological thrombosis in critically ill COVID-19 patients. Pharmacological targeting of the MBL pathway could be a novel treatment option for thrombosis in COVID-19. Laboratory testing of MBL levels could be of value for identifying COVID-19 patients at risk for TE events.

  • 11.
    Ge, Li
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Health and Caring Sciences.
    Zhang, Suying
    The attached hospital of Fujian University of Traditional Chinese Medicine.
    Chen, Jinxiu
    Fujian University of Traditional Chinese Medicine.
    Xuemei, Yang
    Fujian University of Traditional Chinese Medicine.
    Xiaoyun, Zheng
    Fujian University of Traditional Chinese Medicine.
    Liqun, Yao
    Fujian University of Traditional Chinese Medicine.
    Albin, Björn
    Linnaeus University, Faculty of Health and Life Sciences, Department of Health and Caring Sciences.
    The Investigation and Analysis on Chinese Medicine Constitution Types of Pregnant Metaphase Women in Fuzhou2013In: Chinese General Practice, ISSN 1007-9572, Vol. 16, no 6A, p. 1920-1922Article in journal (Refereed)
    Abstract [en]

    AbstractObjective To investigate and analyze the Chinese medicine constitution types of pregnant metaphase women in Fuzhou of China. Methods Cross-sectional study and stratified sampling were used. A scale, <Classification and Determination of Constitution in TCM>, was as a tool for investigation. 1000 scale copies were handed out. 989 scale copies were got after excluding the scale copies with logic error. Constitution types were described by constituent ratio. Results In Fuzhou, the Chinese medicine constitution types of pregnant metaphase women were as following: Yang-deficiency type was 28.5%, damp-heat type was 25.5%, Yin-deficiency type was 25.2%, Qi-depression type and Qi-deficiency type were 23.1% respectively, gentleness type was 20.2%, stasis type was 19.1%, phlegm type was 10.9%, and special intrinsic type was 7.0%. The front three constitution types in different age groups: 20 years old~group: Qi-deficiency type was 29.4%, gentleness type was 24.8%, Yin-deficiency type and yang-deficiency type were 24.2% respectively; 25 years old~group:

    Yang-deficiency type was 27.6%, Yin-deficiency type and damp-heat type were 23.3% respectively; 30 years old~group: damp-heat type was 34.4%, Yang-deficiency type was 33.9%, Yin-deficiency type was 30.8%. The distribution of constitution types in different education background groups was similar as that of total constitution types of pregnant metaphase women. Conclusions The constitution type’s characteristics of pregnant metaphase women in Fuzhou were inclined to deficiency, heat and damp, and Qi-depression. Guided by the theory of “Preventive Treatment of Disease”, the staff working on antepartum care may provide targeted care according to different body constitution types of pregnant women.

  • 12.
    Jakobsson, Albin
    et al.
    Lund University Hospital, Sweden;Lund University, Sweden.
    Ottosson, Maximilian
    Lund University Hospital, Sweden;Lund University, Sweden.
    Zalis, Marina Castro
    Lund University Hospital, Sweden.
    O'Carroll, David
    Lund University, Sweden.
    Englund Johansson, Ulrica
    Lund University Hospital, Sweden.
    Johansson, Fredrik
    Lund University, Sweden.
    Three-dimensional functional human neuronal networks in uncompressed low-density electrospun fiber scaffolds2017In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 13, no 4, p. 1563-1573Article in journal (Refereed)
    Abstract [en]

    We demonstrate an artificial three-dimensional (3D) electrical active human neuronal network system, by the growth of brain neural progenitors in highly porous low density electrospun poly-ε-caprolactone (PCL) fiber scaffolds. In neuroscience research cell-based assays are important experimental instruments for studying neuronal function in health and disease. Traditional cell culture at 2D-surfaces induces abnormal cell–cell contacts and network formation. Hence, there is a tremendous need to explore in vivo-resembling 3D neural cell culture approaches. We present an improved electrospinning method for fabrication of scaffolds that promote neuronal differentiation into highly 3D integrated networks, formation of inhibitory and excitatory synapses and extensive neurite growth. Notably, in 3D scaffolds in vivo-resembling intermixed neuronal and glial cell network were formed, whereas in parallel 2D cultures a neuronal cell layer grew separated from an underlying glial cell layer. Hence, the use of the 3D cell assay presented will most likely provide more physiological relevant results.

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  • 13.
    Johansson, Ulrika
    et al.
    Swedish University of Agricultural Sciences ; Karolinska Institutet.
    Ria, Massimiliano
    Karolinska Institutet.
    Åvall, Karin
    Karolinska Institutet.
    Shalaly, Nancy Dekki
    KTH Royal Institute of Technology.
    Zaisev, Sergei V.
    Karolinska Institutet.
    Berggren, Per-Olof
    Karolinska Institutet.
    Hedhammar, My
    Karolinska Institutet.
    Pancreatic Islet Survival and Engraftment Is Promoted by Culture on Functionalized Spider Silk Matrices2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 19, no 10, p. 1-21Article in journal (Refereed)
    Abstract [en]

    Transplantation of pancreatic islets is one approach for treatment of diabetes, however, hampered by the low availability of viable islets. Islet isolation leads to disruption of the environment surrounding the endocrine cells, which contributes to eventual cell death. The reestablishment of this environment is vital, why we herein investigated the possibility of using recombinant spider silk to support islets in vitro after isolation. The spider silk protein 4RepCT was formulated into three different formats; 2D-film, fiber mesh and 3D-foam, in order to provide a matrix that can give the islets physical support in vitro. Moreover, cell-binding motifs from laminin were incorporated into the silk protein in order to create matrices that mimic the natural cell environment. Pancreatic mouse islets were thoroughly analyzed for adherence, necrosis and function after in vitro maintenance on the silk matrices. To investigate their suitability for transplantation, we utilized an eye model which allows in vivo imaging of engraftment. Interestingly, islets that had been maintained on silk foam during in vitro culture showed improved revascularization. This coincided with the observation of preserved islet architecture with endothelial cells present after in vitro culture on silk foam. Selected matrices were further evaluated for long-term preservation of human islets. Matrices with the cell-binding motif RGD improved human islet maintenance (from 36% to 79%) with preserved islets architecture and function for over 3 months in vitro. The islets established cell-matrix contacts and formed vessel-like structures along the silk. Moreover, RGD matrices promoted formation of new, insulin-positive islet-like clusters that were connected to the original islets via endothelial cells. On silk matrices with islets from younger donors (<35 year), the amount of newly formed islet-like clusters found after 1 month in culture were almost double compared to the initial number of islets added.

  • 14.
    Kroon, Martin
    Royal Institute of Technology KTH.
    A theoretical assessment of the influence of myosin filament dispersion on smooth muscle contraction2011In: Presented at ASME Summer Bioengineering Conference, 22-25 June, 2011, ASME Press, 2011, p. 145-146Conference paper (Refereed)
    Abstract [en]

    A new constitutive model for the biomechanical behavior of smooth muscle tissue is employed to investigate the influence of statistical dispersion in the orientation of myosin filaments. The number of activated cross-bridges between the actin and myosin filaments governs the contractile force generated by the muscle and also the contraction speed. A strain-energy function is used to describe the mechanical behavior of the smooth muscle tissue. The predictions from the constitutive model are compared to histological and isometric tensile test results for smooth muscle tissue from swine carotid artery. In order to be able to predict the active stress at different muscle lengths, a filament dispersion significantly larger than the one observed experimentally was required. Furthermore, a comparison of the predicted active stress for a case of uniaxially oriented myosin filaments and a case of filaments with a dispersion based on the experimental histological data shows that the difference in generated stress is noticeable but limited. Thus, the results suggest that myosin filament dispersion alone cannot explain the increase in active muscle stress with increasing muscle stretch.

  • 15. Kroon, Martin
    Dispersion Effects of Active Contractile Filaments in Smooth Muscle Cells2009In: Presented at 4th International Congress on Computational Bioengineering, 16-18 September, 2009, 2009Conference paper (Refereed)
  • 16.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Inferring time-dependent population growth rates in cell cultures undergoing adaptation2020In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 21, no 1, p. 1-13, article id 583Article in journal (Refereed)
    Abstract [en]

    Background: The population growth rate is an important characteristic of any cell culture. During sustained experiments, the growth rate may vary due to competition or adaptation. For instance, in presence of a toxin or a drug, an increasing growth rate indicates that the cells adapt and become resistant. Consequently, time-dependent growth rates are fundamental to follow on the adaptation of cells to a changing evolutionary landscape. However, as there are no tools to calculate the time-dependent growth rate directly by cell counting, it is common to use only end point measurements of growth rather than tracking the growth rate continuously. Results: We present a computer program for inferring the growth rate over time in suspension cells using nothing but cell counts, which can be measured non-destructively. The program was tested on simulated and experimental data. Changes were observed in the initial and absolute growth rates, betraying resistance and adaptation. Conclusions: For experiments where adaptation is expected to occur over a longer time, our method provides a means of tracking growth rates using data that is normally collected anyhow for monitoring purposes. The program and its documentation are freely available at under the permissive zlib license.

  • 17.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rotating between ponatiniband imatinib temporarily increasesthe efficacy of imatinib as shownin a chronic myeloid leukaemiamodel2022In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 5164Article in journal (Refereed)
    Abstract [en]

    Targeted therapies for chronic myeloid leukaemia (CML) are effective, but rarely curative. Patients typically require treatment indefinitely, which gives ample time for drug resistance to evolve. Drug resistance issues are one of the main causes of death owing to CML, thus any means of preventing resistance are of importance. Drug rotations, wherein treatment is switched periodically between different drugs are one such option, and have been theorized to delay the onset of resistance. In vitro testing of drug rotation therapy is a first step towards applying it in animal or human trials. We developed a method for testing drug rotation protocols in CML cell lines based around culturing cells with a moderate amount of inhibitors interspersed with washing procedures and drug swaps. Drug rotations of imatinib and ponatinib were evaluated in a CML specific cell line, KCL-22. The growth of KCL-22 cells was initially reduced by a drug rotation, but the cells eventually adapted to the protocol. Our results show that ponatinib in a drug rotation temporarily sensitizes the cells to imatinib, but the effect is short-lived and is eventually lost after a few treatment cycles. Possible explanations for this observation are discussed.

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  • 18. Moll, Guido
    et al.
    Rasmusson-Duprez, Ida
    von Bahr, Lena
    Conolly-Andersen, Ann-Marie
    Elgue, Graciela
    Funke, Lillemor
    Hamad, Osama
    Lönnies, Helena
    Magnusson, Peetra
    Sanchez, Javier
    Teramura, Yuji
    Nilsson Ekdahl, Kristina
    Uppsala University, Sweden.
    Ringden, Olof
    Korsgren, Olle
    Nilsson, Bo
    LeBlanc, Katarina
    Are therapeutic human mesenchymal stromal cells compatible with human blood?2012In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 30, no 7, p. 1565-1574Article in journal (Refereed)
    Abstract [en]

    Multipotent mesenchymal stromal cells (MSCs) are tested in numerous clinical trials. Questions have been raised concerning fate and function of these therapeutic cells after systemic infusion. We therefore asked whether culture-expanded human MSCs elicit an innate immune attack, termed instant blood-mediated inflammatory reaction (IBMIR), which has previously been shown to compromise the survival and function of systemically infused islet cells and hepatocytes. We found that MSCs expressed hemostatic regulators similar to those produced by endothelial cells but displayed higher amounts of prothrombotic tissue/stromal factors on their surface, which triggered the IBMIR after blood exposure, as characterized by formation of blood activation markers. This process was dependent on the cell dose, the choice of MSC donor, and particularly the cell-passage number. Short-term expanded MSCs triggered only weak blood responses in vitro, whereas extended culture and coculture with activated lymphocytes increased their prothrombotic properties. After systemic infusion to patients, we found increased formation of blood activation markers, but no formation of hyperfibrinolysis marker D-dimer or acute-phase reactants with the currently applied dose of 1.0–3.0 × 106 cells per kilogram. Culture-expanded MSCs trigger the IBMIR in vitro and in vivo. Induction of IBMIR is dose-dependent and increases after prolonged ex vivo expansion. Currently applied doses of low-passage clinical-grade MSCs elicit only minor systemic effects, but higher cell doses and particularly higher passage cells should be handled with care. This deleterious reaction can compromise the survival, engraftment, and function of these therapeutic cells.

  • 19.
    Mollick, Tanzina
    et al.
    Örebro University, Sweden.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Johansson, Kjell
    Örebro University, Sweden.
    Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina2016In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1646, p. 522-534Article in journal (Refereed)
    Abstract [en]

    Retinal neurodegenerative disorders like retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy and retinal detachment decrease retinal functionality leading to visual impairment. The pathological events are characterized by photoreceptor degeneration, synaptic disassembly, remodeling of postsynaptic neurons and activation of glial cells. Despite intense research, no effective treatment has been found for these disorders. The current study explores the potential of human neural progenitor cell (hNPC) derived factors to slow the degenerative processes in adult porcine retinal explants. Retinas were cultured for 3 days with or without hNPCs as a feeder layer and investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, western blot and quantitative real time-polymerase chain reaction (qRT-PCR) techniques. TUNEL showed that hNPCs had the capacity to limit photoreceptor cell death. Among cone photoreceptors, hNPC coculture resulted in better maintenance of cone outer segments and reduced opsin mislocalization. Additionally, maintained synaptic structural integrity and preservation of second order calbindin positive horizontal cells was also observed. However, Müller cell gliosis only seemed to be alleviated in terms of reduced Müller cell density. Our observations indicate that at 3 days of coculture, hNPC derived factors had the capacity to protect photoreceptors, maintain synaptic integrity and support horizontal cell survival. Human neural progenitor cell applied treatment modalities may be an effective strategy to help maintain retinal functionality in neurodegenerative pathologies. Whether hNPCs can independently hinder Müller cell gliosis by utilizing higher concentrations or by combination with other pharmacological agents still needs to be determined.

  • 20.
    Myring Jansson, Tove
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Folatbrist, ännu en biverkning av isotretinoin?: En litteraturstudie som undersöker om aknemedicinen isotretinoin har en negativ effekt på kroppens folatstatus.2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: Acne is one of the most common dermatological diseases generally affecting people going through puberty. The prevalence of adult acne is increasing and especially among women. Clinical symptoms of acne in moderate and severe cases are inflammatory lesions located in the face and upper body that can often cause scarring. Isotretinoin (Iso) is the most effective therapeutic drug against acne but has many side-effects. Iso appears to adversely affect the body's folate status according to two case presentations. Folate is an essential vitamin and has an important role in DNA synthesis and amino acid metabolism. Aim: The aim of the literature study was to examine if treatment with Iso has a negative effect on the body's folate status. Following questions were searched to be answered: Does Iso lower the body's folate status? Dose Iso increase plasma homocysteine levels? Does Iso lower the body's vitamin B12 status?Method: Eleven articles examining the effect of Iso treatment on folate status, homocysteine and B12 levels were collected from a literature search in Pubmed and Scopus during January and February 2021. Four different free text searches were carried out with isotretinoin as the consisting key word together with folic acid, folate, homocysteine ​​and vitamin B12. Results: The effect of Iso on the body's folate status was examined by ten studies and in six of these studies significantly reduced serum folate levels were observed. Homocysteine levels were examined in ten studies and in eight of these were increased homocysteine levels observed after treatment with Iso. Eight studies examined changes in the serum concentration of B12 and in three of these studies significantly decreased B12 levels were observed after treatment with Iso. Conclusion: The results give an indication that the turnover of folate and B12 may have increased with rising homocysteine plasma levels. Supplements of folic acid and B12 may be recommended for patients undergoing treatment with Iso if plasma homocysteine levels are rising during treatment. Studies with a longer treatment period with Iso need to be done to determine how a complete treatment with Iso affects folate and B12 status.

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  • 21.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Interactions between platelets and complement with implications for the regulation at surfaces2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Disturbances of host integrity have the potential to evoke activation of innate immunologic and hemostatic protection mechanisms in blood. Irrespective of whether the activating stimulus is typically immunogenic or thrombotic, it will generally affect both the complement system and platelets to a certain degree. The theme of this thesis is complement and platelet activity, which is intersected in all five included papers. The initial aim was to study the responses and mechanisms of the complement cascade in relation to platelet activation. The secondary aim was to use an applied approach to regulate platelets and complement on model biomaterial and cell surfaces.   

    Complement activation was found in the fluid phase in response to platelet activation in whole blood. The mechanism was traced to platelet release of stored chondroitin sulfate-A (CS-A) and classical pathway activation via C1q. C3 was detected at the platelet surface, though its binding was independent of complement activation. The inhibitors factor H and C4-binding protein (C4BP) were detected on activated platelets, and their binding was partly dependent on surface-exposed CS-A. Collectively, these results showed that platelet activation induces inflammatory complement activation in the fluid phase. CS-A was shown to be a central molecule in the complement-modulatory functions of platelets by its interaction with C1q, C4BP, and factor H.

    Platelet activation and surface adherence were successfully attenuated by conjugating an ADP-degrading apyrase on a model biomaterial. Only minor complement regulation was seen, and was therefore targeted specifically on surfaces and cells by co-immobilizing a factor H-binding peptide together with the apyrase. This combined approach led to a synchronized inhibition of both platelet and complement activation at the interface of biomaterials/xenogeneic cells and blood.

    In conclusion, here presents a novel crosstalk-mechanism for activation of complement when triggering platelets, which highlights the importance of regulating both complement and platelets to lower inflammatory events. In addition, a strategy to enhance the biocompatibility of biomaterials and cells by simultaneously targeting ADP-dependent platelet activation and the alternative complement C3-convertase is proposed.

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  • 22.
    Norrby, Marlene
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Evertsson, Kim
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Fjällström, Ann-Kristin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Svensson, Anna
    Tågerud, Sven
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle.2012In: Journal of Molecular Signaling, ISSN 1750-2187, E-ISSN 1750-2187, Vol. 7, no June, p. Article ID: 7-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: The present study examines the hypothesis that Akt (protein kinase B)/mTOR (mammalian target of rapamycin) signaling is increased in hypertrophic and decreased in atrophic denervated muscle. Protein expression and phosphorylation of Akt1, Akt2, glycogen synthase kinase-3beta (GSK-3beta), eukaryotic initiation factor 4E binding protein 1 (4EBP1), 70 kD ribosomal protein S6 kinase (p70S6K1) and ribosomal protein S6 (rpS6) were examined in six-days denervated mouse anterior tibial (atrophic) and hemidiaphragm (hypertrophic) muscles. RESULTS: In denervated hypertrophic muscle expression of total Akt1, Akt2, GSK-3beta, p70S6K1 and rpS6 proteins increased 2-10 fold whereas total 4EBP1 protein remained unaltered. In denervated atrophic muscle Akt1 and Akt2 total protein increased 2-16 fold. A small increase in expression of total rpS6 protein was also observed with no apparent changes in levels of total GSK-3beta, 4EBP1 or p70S6K1 proteins. The level of phosphorylated proteins increased 3-13 fold for all the proteins in hypertrophic denervated muscle. No significant changes in phosphorylated Akt1 or GSK-3beta were detected in atrophic denervated muscle. The phosphorylation levels of Akt2, 4EBP1, p70S6K1 and rpS6 were increased 2-18 fold in atrophic denervated muscle. CONCLUSIONS: The results are consistent with increased Akt/mTOR signaling in hypertrophic skeletal muscle. Decreased levels of phosphorylated Akt (S473/S474) were not observed in denervated atrophic muscle and results downstream of mTOR indicate increased protein synthesis in denervated atrophic anterior tibial muscle as well as in denervated hypertrophic hemidiaphragm muscle. Increased protein degradation, rather than decreased protein synthesis, is likely to be responsible for the loss of muscle mass in denervated atrophic muscles.

  • 23.
    Quach, Huy Quang
    et al.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Johnson, Christina
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Ekholt, Karin
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Islam, Rakibul
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Platelet-Depletion of Whole Blood Reveals That Platelets Potentiate the Release of IL-8 From Leukocytes Into Plasma in a Thrombin-Dependent Manner2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 865386Article in journal (Refereed)
    Abstract [en]

    ObjectiveIn a recent study, we found an elevated level of interleukin 8 (IL-8) in response to bacterial incubation in thrombin-sufficient human whole blood anticoagulated by the fibrin polymerization blocking peptide GPRP. Whether thrombin directly activated leukocytes or mediated the release via thrombin-dependent activation of platelets remains unresolved. Herein, we addressed the role of thrombin and platelets in IL-8 release. MethodsWe separated platelets from whole blood using a combination of 0.7% (w/v) citrate and GPRP for attenuating the hemostatic response during the separation of platelets. Cytokine responses were compared in whole blood and platelet-depleted blood upon Escherichia coli incubation. Cytokine responses were also profiled with and without reconstitution of either platelets or the supernatant from activated platelets. ResultsPlatelets were not activated during the separation process but responded to stimuli upon re-calcification. Plasma levels of IL-1 beta, IL-1Ra, IL-6, IL-8, IP-10, MIP-1 alpha, and MIP-1 beta were significantly reduced in platelet-depleted blood compared to whole blood, but recovered in the presence of platelets, or with the supernatant of activated platelets. The leukocyte fraction and platelets were each found to contribute to the elevation of IL-8 at around 5 ng/ml; however, if combined, the release of IL-8 increased to 26 ng/ml. This process was dependent on thrombin since the levels of IL-8 remained at 5 ng/ml in whole blood if thrombin was blocked. Intracellular staining revealed that monocytes were the main source for IL-8 expression. ConclusionOur findings suggest that the release of IL-8 is mediated by the leukocytes, mainly monocytes, but potentiated via thrombin-dependent activation of platelets.

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  • 24.
    Rangasami, Vignesh K.
    et al.
    Tampere Univ, Finland.
    Nawale, Ganesh
    Uppsala University, Sweden.
    Asawa, Kenta
    Univ Tokyo, Japan.
    Kadekar, Sandeep
    Uppsala University, Sweden.
    Samanta, Sumanta
    Tampere Univ, Finland.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Uppsala University, Sweden.
    Miettinen, Susanna
    Tampere Univ, Finland;Tampere Univ Hosp, Finland.
    Hilborn, Jons
    Uppsala University, Sweden.
    Teramura, Yuji
    Univ Tokyo, Japan;Uppsala University, Sweden.
    Varghese, Oommen P.
    Univ Tokyo, Japan.
    Oommen, Oommen P.
    Tampere Univ, Finland.
    Pluronic Micelle-Mediated Tissue Factor Silencing Enhances Hemocompatibility, Stemness, Differentiation Potential, and Paracrine Signaling of Mesenchymal Stem Cells2021In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 22, no 5, p. 1980-1989Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem/stromal cells (MSCs) evoke great excitement for treating different human diseases due to their ability to home inflamed tissues, suppress inflammation, and promote tissue regeneration. Despite great promises, clinical trial results are disappointing as allotransplantation of MSCs trigger thrombotic activity and are damaged by the complement system, compromising their survival and function. To overcome this, a new strategy is presented by the silencing of tissue factor (TF), a transmembrane protein that mediates procoagulant activity. Novel Pluronic-based micelles are designed with the pendant pyridyl disulfide group, which are used to conjugate TF-targeting siRNA by the thiol-exchange reaction. This nanocarrier design effectively delivered the payload to MSCs resulting in similar to 72% TF knockdown (KD) without significant cytotoxicity. Hematological evaluation of MSCs and TF-KD MSCs in an ex vivo human whole blood model revealed a significant reduction in an instant-blood-mediated-inflammatory reaction as evidenced by reduced platelet aggregation (93% of free platelets in the TF-KD group, compared to 22% in untreated bone marrow-derived MSCs) and thrombin- antithrombin complex formation. Effective TF silencing induced higher MSC differentiation in osteogenic and adipogenic media and showed stronger paracrine suppression of proinflammatory cytokines in macrophages and higher stimulation in the presence of endotoxins. Thus, TF silencing can produce functional cells with higher fidelity, efficacy, and functions.

  • 25.
    Shalaly, Nancy Dekki
    et al.
    KTH Royal Institute of Technology.
    Ria, Massimiliano
    Karolinska Institutet.
    Johansson, Ulrika
    KTH Royal Institute of Technology.
    Åvall, Karin
    Karolinska Institutet.
    Berggren, Per-Olof
    Karolinska Institutet.
    Hedhammar, My
    KTH Royal Institute of Technology ; Swedish University of Agricultural Sciences.
    Silk matrices promote formation of insulin-secreting islet-like clusters2016In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 90, p. 50-61Article in journal (Refereed)
    Abstract [en]

    Ex vivo expansion of endocrine cells constitutes an interesting alternative to be able to match the unmet need of transplantable pancreatic islets. However, endocrine cells become fragile once removed from their extracellular matrix (ECM) and typically become senescent and loose insulin expression during conventional 2D culture. Herein we develop a protocol where 3D silk matrices functionalized with ECM-derived motifs are used for generation of insulin-secreting islet-like clusters from mouse and human primary cells. The obtained clusters were shown to attain an islet-like spheroid shape and to maintain functional insulin release upon glucose stimulation in vitro. Furthermore, in vivo imaging of transplanted murine clusters showed engraftment with increasing vessel formation during time. There was no sign of cell death and the clusters maintained or increased in size throughout the period, thus suggesting a suitable cluster size for transplantation.

  • 26.
    Stening, Kent
    et al.
    Linnaeus University, Faculty of Health, Social Work and Behavioural Sciences, School of Health and Caring Sciences.
    Berg, Göran
    IKE, Linköpings universitet.
    Hammar, Mats
    IKE, Linköpings universitet.
    Voster, Helene
    IKE, Linköpings universitet.
    Eriksson, Olle
    IDA, Linköpngs universitet.
    Amandusson, Asa
    Avd. för Neurovetenskap, Uppsala universitet.
    Blomqvist, Anders
    IKE, Linköpings universitet.
    Influence of estrogen levels on thermal perception, pain thresholds, and pain tolerance: studies on women undergoing in vitro fertilization.2012In: Journal of Pain, ISSN 1526-5900, E-ISSN 1528-8447, Vol. 13, no 5, p. 459-466Article in journal (Refereed)
    Abstract [en]

    We examined the relationship between estrogen and pain in women undergoing in vitro fertilization (IVF). Quantitative sensory tests (QST) were performed twice during the IVF-regimen: once during hormonal down-regulation and once during hormonal up-regulation. A group of healthy men and a group of women using monophasic contraceptives were also examined, to control for session-to-session effects. Among the women undergoing IVF, serum 17β-estradiol levels differed strongly between treatments as expected, and increased from 65.7 (SD = 26) pmol/L during the down-regulation phase, to 5,188 (SD = 2,524) pmol/L during the up-regulation phase. Significant outcomes in the QST were only seen for temperature perception thresholds (1.7 °C versus 2.2 °C; P = .003) and cold pain threshold (11.5 °C versus 14.5 °C; P = .04). A similar change in cold pain threshold was also seen in the 2 control groups, however, and statistical analysis suggested that this change was due to a session-to-session effect rather than being the result of hormonal modulation. Heat pain thresholds, heat tolerance, pressure pain thresholds, and the cold pressor test showed no significant differences between sessions. These data demonstrate that pain perception and pain thresholds in healthy women show little, if any, changes even with major variations in serum estradiol levels. PERSPECTIVE: This study shows that pain perception and tolerance in women undergoing in vitro fertilization do not vary, despite the dramatic changes in 17β-estradiol levels induced by the treatment regimen. The result thus suggests that in humans, contrary to experimental animals, changes in estrogen levels have little influence on pain sensitivity.

  • 27.
    Svahn, Leo
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Bestämning och jämförelse av helblodspåsars leukocyt-innehåll: vid tre olika vilotider efter blodgivning, analyserat med flödescytometri2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    During blood donation, blood donors donate blood voluntarily. The blood can then be used in healthcare for, for example, blood transfusions, which requires blood products compatible with the patient. The presence of leukocytes in blood products increases the risk of febrile transfusion reactions in transfused patients. Therefore, leukocyte-reduction in blood products is necessary during production. Each blood center must perform quality control on produced blood products.

    With the analysis B-leukocyte particle concentration (LPK), the total number of leukocytes in whole blood can be calculated. Flow cytometry is a method that can analyze the optical and fluorescent properties of, for example, cells in a suspension, which can be used to quantify cell numbers. The BD Leucocount™-Kit (BD Biosciences) is intended for flow cytometric analysis of the number of leukocytes remaining in leukocyte-reduced blood products.

    When producing blood products, the whole blood bag should rest at room temperature for at least three hours after the donation. In Falun, either a day program is used where production takes place on the same day as the blood was donated, or an overnight program where production takes place the next day. Samples from 505 controlled erythrocyte units, collected in Falun, have shown a difference in leukocyte concentration depending on the program used.

    The reason why the leukocyte content of erythrocyte units differs is not known. The purpose of this study is therefore to investigate whether the resting period has any effect on the leukocyte concentration in whole blood bags.

    The LPK varied between the whole blood bags. An increasing leukocyte count was observed over time in most of the whole blood bags. However, hypothesis testing did not show statistical significance.

    The hypothesis that leukocyte counts increase goes against basic hematology. Based on the results of this study, the hypothesis cannot be proven. Further studies should be conducted.

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    Leo Svahn BMA-examensuppsats
  • 28.
    Widhe, Mona
    et al.
    Swedish University of Agricultural Sciences.
    Johansson, Ulrika
    Swedish University of Agricultural Sciences.
    Hillerdahl, Carl-Olof
    Swedish University of Agricultural Sciences.
    Hedhammar, My
    Swedish University of Agricultural Sciences.
    Recombinant spider silk with cell binding motifs for specific adherence of cells2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 33, p. 8223-8234Article in journal (Refereed)
    Abstract [en]

    Silk matrices have previously been shown to possess general properties governing cell viability. However, many cell types also require specific adhesion sites for successful in vitro culture. Herein, we have shown that cell binding motifs can be genetically fused to a partial spider silk protein, 4RepCT, without affecting its ability to self-assemble into stable matrices directly in a physiological-like buffer. The incorporated motifs were exposed in the formed matrices, and available for binding of integrins. Four different human primary cell types; fibroblasts, keratinocytes, endothelial cells and Schwann cells, were applied to the matrices and investigated under serum-free culture conditions. Silk matrices with cell binding motifs, especially RGD, were shown to promote early adherence of cells, which formed stress fibers and distinct focal adhesion points. Schwann cells acquired most spread-out morphology on silk matrices with IKVAV, where significantly more viable cells were found, also when compared to wells coated with laminin. This strategy is thus suitable for development of matrices that allow screening of various cell binding motifs and their effect on different cell types.

  • 29.
    Wojciechowski, Anita Blixt
    et al.
    Lund University Hospital, Sweden.
    Englund Johansson, Ulrica
    Lund University, Sweden.
    Lundberg, Cecilia
    Lund University, Sweden.
    Warfvinge, Karin
    Lund University Hospital, Sweden.
    Survival and Long Distance Migration of Brain‐Derived Precursor Cells Transplanted to Adult Rat Retina2004In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 22, no 1, p. 27-38Article in journal (Refereed)
    Abstract [en]

    Neural precursor cells transplanted to adult retina can integrate into the host. This is especially true when the neural precursor rat cell line RN33B is used. This cell line carries the reporter genes LacZ and green fluorescent protein (GFP). In grafted rat eyes, RN33B cells are localized from one eccentricity to the other of the host retina. In the present study, whole-mounted retinas were analyzed to obtain a more appropriate evaluation of the amount of transgene-expressing cells and the migratory capacity of these cells 3 and 8 weeks posttransplantation. Quantification was made of the number of β-galactosidase- and GFP-expressing cells with a semiautomatized stereological cell counting system. With the same system, delineation of the distribution area of the grafted cells was also performed. At 3 weeks, 68% of the grafted eyes contained marker-expressing cells, whereas at 8 weeks only 35% of the eyes contained such cells. Counting of marker-expressing cells demonstrated a lower number of transgene-expressing cells at 3 weeks compared with 8 weeks post-transplantation. The distribution pattern of marker gene-expressing cells revealed cells occupying up to 21% at 3 weeks and up to 68% at 8 weeks of the entire host retina postgrafting. The precursor cells survived well in the adult retina although the most striking feature of the RN33B cell line was its extraordinary migratory capacity. This capability could be useful if precursor cells are used to deliver necessary genes or gene products that need to be distributed over a large diseased area.

  • 30.
    Wojciechowski, Anita Blixt
    et al.
    Lund University Hospital, Sweden.
    Englund Johansson, Ulrica
    Lund University, Sweden.
    Lundberg, Cecilia
    Lund University, Sweden.
    Wictorin, Klas
    Lund University, Sweden.
    Warfvinge, Karin
    Lund University Hospital, Sweden.
    Subretinal Transplantation of Brain-derived Precursor Cells to Young RCS Rats Promotes Photoreceptor Cell Survival☆2002In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 75, no 1, p. 23-37Article in journal (Refereed)
    Abstract [en]

    The potential use of in vitro-expanded precursor cells or cell lines in brain repair includes transplantation of such cells for cell replacement purposes and the activation of host cells to provide 'self-repair'. Recently, it has been reported that the immortalized brain-derived cell line RN33B (derived from the embryonic rat medullary raphe) survive, integrate and differentiate after subretinal grafting to normal adult rats. Here, it is demonstrated that grafts of these cells survive for at least 6 weeks after implantation into postnatal days 21 and 35 retinas of normal and Royal College of Surgeons rats, a model of retinal degeneration. Implanted cells integrate into the retinal pigment epithelium and the inner retinal layers, and the anterior part of the optic nerve of both normal and Royal College of Surgeons rats. The RN33B cells migrate within the retina, occupying the whole retina from one eccentricity to the other. A significant number of the grafted cells differentiate into glial cells, as shown by the double labelling of the reporter genes LacZ or green fluorescent protein, with several glial markers, including oligodendrocytic markers. Many implanted cells in the host retina were in a proliferative stage judging from proliferative cell nuclear antigen and SV40 large T-antigen immunohistochemistry. Interestingly, there was a promotion of photoreceptor survival, extending over more than 2/3 of the superior hemisphere, in Royal College of Surgeons rats transplanted at postnatal day 21, but not at postnatal day 35. In addition, grafted cells were found in the surviving photoreceptor layer in these rats.

  • 31.
    Zalis, Marina C.
    et al.
    Lund University, Sweden .
    Johansson, Sebastian
    Lund University, Sweden .
    Englund Johansson, Ulrica
    Lund University, Sweden .
    Immunocytochemical Profiling of Cultured Mouse Primary Retinal Cells2017In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 65, no 4, p. 223-239Article in journal (Refereed)
    Abstract [en]

    Primary retinal cell cultures and immunocytochemistry are important experimental platforms in ophthalmic research. Translation of retinal cells from their native environment to the in vitro milieu leads to cellular stress, jeopardizing their in vivo phenotype features. Moreover, the specificity and stability of many retinal immunochemical markers are poorly evaluated in retinal cell cultures. Hence, we here evaluated the expression profile of 17 retinal markers, that is, recoverin, rhodopsin, arrestin, Chx10, PKC, DCX, CRALBP, GS, vimentin, TPRV4, RBPMS, Brn3a, β-tubulin III, NeuN, MAP2, GFAP, and synaptophysin. At 7 and 18 days of culture, the marker expression profiles of mouse postnatal retinal cells were compared with their age-matched in vivo retinas. We demonstrate stable in vitro expression of all markers, except for arrestin and CRALBP. Differences in cellular expression and location of some markers were observed, both over time in culture and compared with the age-matched retina. We hypothesize that these differences are likely culture condition dependent. Taken together, we suggest a thorough evaluation of the antibodies in specific culture settings, before extrapolating the in vitro results to an in vivo setting. Moreover, the identification of specific cell types may require a combination of different genes expressed or markers with structural information.

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  • 32.
    Zalis, Marina Castro
    et al.
    Lund University, Sweden.
    Johansson, Sebastian
    Lund University, Sweden.
    Johansson, Fredrik
    Lund University, Sweden.
    Englund Johansson, Ulrica
    Lund University, Sweden.
    Exploration of physical and chemical cues on retinal cell fate2016In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 75, p. 122-132Article in journal (Refereed)
    Abstract [en]

    Identification of the key components in the physical and chemical milieu directing donor cells into a desired phenotype is a requirement in the investigation of bioscaffolds for the advancement of cell-based therapies for retinal neurodegeneration.

    We explore the effect of electrospun poly-ε-caprolactone (PCL) fiber scaffold topography and functionalization and culture medium, on the behavior of mouse retinal cells. Dissociated mouse retinal post-natal cells were seeded on random or aligned oriented fibers, with or without laminin coating and cultured with either basic or neurotrophins enriched medium for 7 days.

    Addition of laminin in combination with neurotrophins clearly promoted cell– morphology, fate, and neurite extension. Nanotopography per se significantly affected cell morphology, with mainly bipolar profiles on aligned fibers and more multipolar profiles on random fibers. Laminin induced a remarkable 90° switch of neurite orientation. Herewith, we demonstrate that the chemical cue is stronger than the physical cue for the orientation of retinal neurites and describe the requirement of both neurotrophins and extracellular matrix proteins for extended neurite outgrowth and formation of complex retinal neuronal networks. Therefore, tailor-made PCL fiber mats, which can be physically and chemically modified, indeed influence cell behavior and hence motivate further retinal restorative studies using this system.

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