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  • 201.
    Bernacka Wojcik, Iwona
    et al.
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Huerta, Miriam
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Tybrandt, Klas
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Karady, Michal
    Swedish Univ Agr Sci, Sweden.
    Mulla, Yusuf
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Poxson, David
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Gabrielsson, Erik
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Ljung, Karin
    Swedish Univ Agr Sci, Sweden.
    Simon, Daniel
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Stavrinidou, Eleni
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Implantable Organic Electronic Ion Pump Enables ABA Hormone Delivery for Control of Stomata in an Intact Tobacco Plant2019In: Small, ISSN 1613-6810, E-ISSN 1613-6829, Vol. 15, no 43, article id 1902189Article in journal (Refereed)
    Abstract [en]

    Electronic control of biological processes with bioelectronic devices holds promise for sophisticated regulation of physiology, for gaining fundamental understanding of biological systems, providing new therapeutic solutions, and digitally mediating adaptations of organisms to external factors. The organic electronic ion pump (OEIP) provides a unique means for electronically-controlled, flow-free delivery of ions, and biomolecules at cellular scale. Here, a miniaturized OEIP device based on glass capillary fibers (c-OEIP) is implanted in a biological organism. The capillary form factor at the sub-100 mu m scale of the device enables it to be implanted in soft tissue, while its hyperbranched polyelectrolyte channel and addressing protocol allows efficient delivery of a large aromatic molecule. In the first example of an implantable bioelectronic device in plants, the c-OEIP readily penetrates the leaf of an intact tobacco plant with no significant wound response (evaluated up to 24 h) and effectively delivers the hormone abscisic acid (ABA) into the leaf apoplast. OEIP-mediated delivery of ABA, the phytohormone that regulates plants tolerance to stress, induces closure of stomata, the microscopic pores in leafs epidermis that play a vital role in photosynthesis and transpiration. Efficient and localized ABA delivery reveals previously unreported kinetics of ABA-induced signal propagation.

  • 202.
    Bernal, Victoria
    Linköping University, Department of Physics, Chemistry and Biology.
    DNA extraction comparisons between  fresh and boiled Atlantic Salmon (S. salar) tissues.2019Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    Barcode identification is a method that uses genetic information to differentiate species. Because of its general versatility it can be applied to contexts from archaeology to the food industry. Atlantic salmon (Salmo salar) is a fish species commonly hunted in modern times and has been found in archaeological settings. However, barcoding requires enough quality DNA for amplification and abiotic exposure tends to degrade it. High temperatures, such as when boiling, can diminish DNA quality. The extent of DNA degradation between fresh and boiled tissues and whether all tissues retain the same amount of DNA is unclear. In this study DNA was extracted from S. salar tissues fins, muscle, bones and scales without treatment and with boiling treatment. DNA concentrations between fresh and boiled bones were not significantly different, nor were comparisons between samples with the same treatments. Muscles had higher DNA concentrations when boiled and fins had higher when fresh. These findings show that regarding certain tissue types can be expected to better retain DNA concentrations after boiling. 

  • 203.
    Bettiga, Arianna
    et al.
    IRCCS Osped San Raffaele, Italy.
    Aureli, Massimo
    University of Milan, Italy.
    Colciago, Giorgia
    IRCCS Osped San Raffaele, Italy.
    Murdica, Valentina
    University of Milan, Italy.
    Moschini, Marco
    IRCCS Osped San Raffaele, Italy.
    Luciano, Roberta
    IRCCS Osped San Raffaele, Italy.
    Canals, Daniel
    SUNY Stony Brook, NY 11794 USA.
    Hannun, Yusuf
    SUNY Stony Brook, NY 11794 USA.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. IRCCS Osped San Raffaele, Italy.
    Lavorgna, Giovanni
    IRCCS Osped San Raffaele, Italy.
    Colombo, Renzo
    IRCCS Osped San Raffaele, Italy.
    Bassi, Rosaria
    University of Milan, Italy.
    Samarani, Maura
    University of Milan, Italy.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy; University of Vita Salute San Raffaele, Italy.
    Salonia, Andrea
    University of Vita Salute San Raffaele, Italy.
    Benigni, Fabio
    IRCCS Osped San Raffaele, Italy.
    Bladder cancer cell growth and motility implicate cannabinoid 2 receptor-mediated modifications of sphingolipids metabolism2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 42157Article in journal (Refereed)
    Abstract [en]

    The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour. Both cell lines expressed similar CB2. Exposure to CB2 agonists inhibited BC growth, down-modulated Akt, induced caspase 3-activation and modified SL metabolism. Baseline SL analysis in cell lines showed differences linked to unique migratory behaviours and cytoskeletal re-arrangements. CB2 activation changed the SL composition of more aggressive RT112 cells by reducing (p amp;lt; 0.01) Gb3 ganglioside (-50 +/- 3%) and sphingosine 1-phosphate (S1P, -40 +/- 4%), which ended up to reduction in cell motility (-46 +/- 5%) with inhibition of p-SRC. CB2-selective antagonists, gene silencing and an inhibitor of SL biosynthesis partially prevented CB2 agonist-induced effects on cell viability and motility. CB2 activation led to ceramide-mediated BC cell apoptosis independently of SL constitutive composition, which instead was modulated by CB2 agonists to reduce cell motility.

  • 204.
    Bialowas, Sonja
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Hagbom, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, Thommie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Sharma, Sumit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-­Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Intracellularly expressed rotavirus NSP4 stimulates release of serotonin (5-HT) from human enterochromaffin cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Rotavirus (RV) is associated with diarrhoea and vomiting, but the mechanisms behind these symptoms remain unresolved. While RV have been shown to infect and stimulate secretion of serotonin (5-hydroxytryptamine; 5-HT) from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice, it remains to identify which intracellularly expressed viral protein (VP) being responsible for this novel property.

    To address this issue, human EC cells were transfected with small interfering RNA (siRNA) targeting the structural (VP4, VP6 and VP7) and the non-structural protein 4 (NSP4) followed by infection with Rhesus rotavirus (RRV). siRNA specific to NSP4 (siRNANSP4) significantly attenuated secretion of 5-HT compared to siRNAVP4, siRNAVP6 , siRNAVP7 and non-targeting (Nt) siRNAnt. Intracellular calcium clamping with BABTA/AM showed that intracellularly expressed NSP4-stimulated secretion of 5-HT from EC cells was calcium-dependent. Furthermore RV down-regulated the 5-HT transporter (SERT) mRNA in ileum but not tryptophan hydroxylase 1 (TPH1) mRNA the rate-limiting enzyme for 5-HT synthesis. The unaffected expression of TPH1 mRNA in the intestinal segments suggests that release of 5- HT primarily originates from pre-made 5-HT rather than from newly synthesised 5-HT mRNA. Moreover, down-regulation of SERT mRNA in ileum presumably resulted in reduced re- uptake of 5-HT by SERT to EC cells and thus increased extracellular 5-HT in the small intestine. Moreover, 7/7 infant mice responded following intraperitoneal administration of 5-HT with rapid (<30 min) diarrhoea in dose-dependent manner. In the light of these results and the fact that both 5-HT and NSP4 can induce diarrhoea in mice, a disease mechanism to RV diarrhoea is proposed.

  • 205.
    Bianco, Giuseppe
    et al.
    Lund University, Sweden.
    Ilieva, Mihaela
    Lund University, Sweden; Bulgarian Academic Science, Bulgaria.
    Veibäck, Clas
    Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, Faculty of Science & Engineering.
    Öfjäll, Kristoffer
    Linköping University, Department of Electrical Engineering, Computer Vision. Linköping University, Faculty of Science & Engineering.
    Gadomska, Alicja
    Lund University, Sweden.
    Hendeby, Gustaf
    Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, Faculty of Science & Engineering.
    Felsberg, Michael
    Linköping University, Department of Electrical Engineering, Computer Vision. Linköping University, Faculty of Science & Engineering.
    Gustafsson, Fredrik
    Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, Faculty of Science & Engineering.
    Åkesson, Susanne
    Lund University, Sweden.
    Emlen funnel experiments revisited: methods update for studying compass orientation in songbirds2016In: Ecology and Evolution, ISSN 2045-7758, E-ISSN 2045-7758, Vol. 6, no 19, p. 6930-6942Article in journal (Refereed)
    Abstract [en]

    1 Migratory songbirds carry an inherited capacity to migrate several thousand kilometers each year crossing continental landmasses and barriers between distant breeding sites and wintering areas. How individual songbirds manage with extreme precision to find their way is still largely unknown. The functional characteristics of biological compasses used by songbird migrants has mainly been investigated by recording the birds directed migratory activity in circular cages, so-called Emlen funnels. This method is 50 years old and has not received major updates over the past decades. The aim of this work was to compare the results from newly developed digital methods with the established manual methods to evaluate songbird migratory activity and orientation in circular cages. 2 We performed orientation experiments using the European robin (Erithacus rubecula) using modified Emlen funnels equipped with thermal paper and simultaneously recorded the songbird movements from above. We evaluated and compared the results obtained with five different methods. Two methods have been commonly used in songbirds orientation experiments; the other three methods were developed for this study and were based either on evaluation of the thermal paper using automated image analysis, or on the analysis of videos recorded during the experiment. 3 The methods used to evaluate scratches produced by the claws of birds on the thermal papers presented some differences compared with the video analyses. These differences were caused mainly by differences in scatter, as any movement of the bird along the sloping walls of the funnel was recorded on the thermal paper, whereas video evaluations allowed us to detect single takeoff attempts by the birds and to consider only this behavior in the orientation analyses. Using computer vision, we were also able to identify and separately evaluate different behaviors that were impossible to record by the thermal paper. 4 The traditional Emlen funnel is still the most used method to investigate compass orientation in songbirds under controlled conditions. However, new numerical image analysis techniques provide a much higher level of detail of songbirds migratory behavior and will provide an increasing number of possibilities to evaluate and quantify specific behaviors as new algorithms will be developed.

  • 206.
    Bidleman, Terry
    et al.
    Umeå universitet, Sweden.
    Kucklick, John
    National Institute of Standards and Technology, South Carolina, USA.
    Letcher, Robert
    National Wildlife Research Centre, Canada.
    Jantunen, Liisa
    Environment and Climate Change, Canada.
    Wong, Fiona
    Environment and Climate Change, Canada.
    Kylin, Henrik
    Linköping University, Department of Thematic Studies, Tema Environmental Change. Linköping University, Faculty of Arts and Sciences.
    CONTAMINANTS OF EMERGING CONCERN IN THE ARCTIC: AN ASSESSMENT OF HALOGENATED NATURAL PRODUCTS2016In: Organohalogen Compounds, ISSN 1026-4892, Vol. 78, p. 193-196, article id 8.4010Article in journal (Refereed)
  • 207.
    Bilde, T.
    et al.
    Animal Ecology/Department of Ecology and Evolution, Evolutiona ry Biology Centre, University of Uppsala, Uppsala, Sweden / Department of Biological Sciences, Ecology and Genetics, University of Aarhus, Denmark.
    Friberg, Urban
    Animal Ecology/Department of Ecology and Evolution, Evolutiona ry Biology Centre, University of Uppsala, Uppsala Sweden / Department of Ecology, Evolution and Marine Biology, University of California, Santa Barbara, CaliforniaUSA.
    Maklakov, A. A.
    Animal Ecology/Department of Ecology and Evolution, Evolutionary Biology Centre, University of Uppsala, Uppsala, Sweden / School of Biological, Earth and Environmental Sciences, The University of New South Wales, Kensington, Australia.
    Fry, J. D.
    University of Rochester, Department of Biology, Rochester, New York, USA.
    Arnqvist, Göran
    Animal Ecology/Department of Ecology and Evolution, Evolutionary Biology Centre, University of Uppsala, Uppsala, Sweden.
    The genetic architecture of fitness in a seed beetle: assessing the potential for indirect genetic benefits of female choice2008In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 8, no 295, p. 95-Article in journal (Refereed)
    Abstract [en]

    Background

    Quantifying the amount of standing genetic variation in fitness represents an empirical challenge. Unfortunately, the shortage of detailed studies of the genetic architecture of fitness has hampered progress in several domains of evolutionary biology. One such area is the study of sexual selection. In particular, the evolution of adaptive female choice by indirect genetic benefits relies on the presence of genetic variation for fitness. Female choice by genetic benefits fall broadly into good genes (additive) models and compatibility (non-additive) models where the strength of selection is dictated by the genetic architecture of fitness. To characterize the genetic architecture of fitness, we employed a quantitative genetic design (the diallel cross) in a population of the seed beetle Callosobruchus maculatus, which is known to exhibit post-copulatory female choice. From reciprocal crosses of inbred lines, we assayed egg production, egg-to-adult survival, and lifetime offspring production of the outbred F1 daughters (F1 productivity).

    Results

    We used the bio model to estimate six components of genetic and environmental variance in fitness. We found sizeable additive and non-additive genetic variance in F1 productivity, but lower genetic variance in egg-to-adult survival, which was strongly influenced by maternal and paternal effects.

    Conclusion

    Our results show that, in order to gain a relevant understanding of the genetic architecture of fitness, measures of offspring fitness should be inclusive and should include quantifications of offspring reproductive success. We note that our estimate of additive genetic variance in F1 productivity (CV A = 14%) is sufficient to generate indirect selection on female choice. However, our results also show that the major determinant of offspring fitness is the genetic interaction between parental genomes, as indicated by large amounts of non-additive genetic variance (dominance and/or epistasis) for F1 productivity. We discuss the processes that may maintain additive and non-additive genetic variance for fitness and how these relate to indirect selection for female choice.

  • 208.
    Bilde, Trine
    et al.
    Animal Ecology/Department of Ecology and Evolution, Evolutionary Biol ogy Centre, Uppsala University , Uppsala Sweden / Department of Biological Sciences, Univer sity of Aarhus, Denmark.
    Maklakov, Alexei A
    Animal Ecology/Department of Ecology and Evolution, Evolutionary Biology Centre, Uppsala University, Uppsala Sweden / School of Biological, Earth an d Environmental Sciences, The University of New South Wales, Kensington, Sydney, Australia.
    Meisner, Katrine
    Department of Biological Sciences, University of Aarhus, Denmark.
    la Guardia, Lucia
    Department of Biological Sciences, University of Aarhus, Denmark.
    Friberg, Urban
    Animal Ecology/Department of Ecology and Evolution, Evolutionary Biology Centre, Uppsala University, Uppsala Sweden / Department of Ecology, Evolution and Marine Biology, University of California, Santa Barbara, California USA.
    Sex differences in the genetic architecture of lifespan in a seed beetle: extreme inbreeding extends male lifespan.2009In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 9, no 33Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sex differences in lifespan are ubiquitous throughout the animal kingdom but the causes underlying this phenomenon remain poorly understood. Several explanations based on asymmetrical inheritance patterns (sex chromosomes or mitochondrial DNA) have been proposed, but these ideas have rarely been tested experimentally. Alternatively, sexual dimorphism in lifespan could result from sex-specific selection, caused by fundamental differences in how males and females optimize their fitness by allocating resources into current and future reproduction.

    RESULTS: Here we used sex-specific responses to inbreeding to study the genetic architecture of lifespan and mortality rates in Callosobruchus maculatus, a seed beetle that shows sexual dimorphism in lifespan. Two independent assays revealed opposing sex-specific responses to inbreeding. The combined data set showed that inbred males live longer than outbred males, while females show the opposite pattern. Both sexes suffered reduced fitness measured as lifetime reproductive success as a result of inbreeding.

    CONCLUSION: No model based on asymmetrical inheritance can explain increased male lifespan in response to inbreeding. Our results are however compatible with models based on sex-specific selection on reproductive strategies. We therefore suggest that sex-specific differences in lifespan in this species primarily result from sexually divergent selection.

  • 209.
    Binzer, Amrei
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Biology. Linköping University, Faculty of Science & Engineering. University of Gottingen, Germany.
    Guill, Christian
    University of Gottingen, Germany; University of Potsdam, Germany; University of Amsterdam, Netherlands.
    Rall, Bjoern C.
    University of Gottingen, Germany; German Centre Integrat Biodivers Research iDiv, Germany; University of Jena, Germany.
    Brose, Ulrich
    University of Gottingen, Germany; German Centre Integrat Biodivers Research iDiv, Germany; University of Jena, Germany.
    Interactive effects of warming, eutrophication and size structure: impacts on biodiversity and food-web structure2016In: Global Change Biology, ISSN 1354-1013, E-ISSN 1365-2486, Vol. 22, no 1, p. 220-227Article in journal (Refereed)
    Abstract [en]

    Warming and eutrophication are two of the most important global change stressors for natural ecosystems, but their interaction is poorly understood. We used a dynamic model of complex, size-structured food webs to assess interactive effects on diversity and network structure. We found antagonistic impacts: Warming increases diversity in eutrophic systems and decreases it in oligotrophic systems. These effects interact with the community size structure: Communities of similarly sized species such as parasitoid-host systems are stabilized by warming and destabilized by eutrophication, whereas the diversity of size-structured predator-prey networks decreases strongly with warming, but decreases only weakly with eutrophication. Nonrandom extinction risks for generalists and specialists lead to higher connectance in networks without size structure and lower connectance in size-structured communities. Overall, our results unravel interactive impacts of warming and eutrophication and suggest that size structure may serve as an important proxy for predicting the community sensitivity to these global change stressors.

  • 210.
    Birgersson, Sabina
    Linköping University, Department of Physics, Chemistry and Biology.
    Personality assessment and interactions in eight captive bottlenose dolphins (Tursiops truncatus)2011Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    In recent years there has been an increased interest in measuring animal personality. It is argued that personality in animals is expressed through the behaviours they display. In this study personality has been investigated in a group of eight captive bottlenose dolphins (Tursiops truncatus). Data from focal samplings were analysed by using behavioural codings and the Five-factor model consisting of Openness to experience, Conscientiousness, Extraversion, Agreeableness and Neuroticism. The results revealed that the dolphins display both distinct personality differences as well as similarities in these factors. By calculating coefficients of association it was found that the dolphins also prefer the company of certain individuals over others. Knowledge of individual personality differences and its implications can be helpful in aspects such as management and reintroduction programs, evolution and genetics and in providing a complementary perspective to explain other behavioural and cognitive studies.

  • 211.
    Birznieks, Ingvars
    et al.
    UNSW Sydney, Australia; Neurosci Res Australia, Australia; Western Sydney Univ, Australia.
    Mcintyre, Sarah
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Neurosci Res Australia, Australia; Western Sydney Univ, Australia.
    Nilsson, Hanna Maria
    Linköping University. Sweden; Neurosci Res Australia, Australia.
    Nagi, Saad
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Western Sydney Univ, Australia.
    Macefield, Vaughan G.
    Neurosci Res Australia, Australia; Western Sydney Univ, Australia; Baker Heart and Diabet Inst, Australia.
    Mahns, David A.
    Western Sydney Univ, Australia.
    Vickery, Richard M.
    UNSW Sydney, Australia; Neurosci Res Australia, Australia.
    Tactile sensory channels over-ruled by frequency decoding system that utilizes spike pattern regardless of receptor type2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e46510Article in journal (Refereed)
    Abstract [en]

    The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies amp;lt; 60 Hz) and vibratory hum (frequencies amp;gt; 60 Hz), subserved by two distinct receptor types (Meissners and Pacinian corpuscle, respectively), which may engage different neural processing pathways or channels and fulfil quite different biological roles. In psychological and physiological literature, those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency, thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types.

  • 212.
    Bisson, Isabelle
    et al.
    Guys Hospital, England.
    Green, Emma
    Guys Hospital, England.
    Sharpe, Michaela
    Guys Hospital, England.
    Herbert, Chris
    Guys Hospital, England.
    Hyllner, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology. Guys Hospital, England.
    Mount, Natalie
    Guys Hospital, England.
    Landscape of current and emerging cell therapy clinical trials in the UK: current status, comparison to global trends and future perspectives2015In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 10, no 2, p. 169-179Article in journal (Refereed)
    Abstract [en]

    Cell Therapy Clinical Trial and Preclinical Research databases have been established by the Cell Therapy Catapult to document current and future cell therapy clinical trials in the UK. We identified 41 ongoing trials in April 2014, an increase of seven trials from April 2013. In addition, we identified 45 late-stage preclinical research projects. The majority of the clinical trials are early phase, primarily led by academic groups. The leading therapeutic areas are cancer, cardiology and neurology. The trends in the UK are also seen globally. As the field matures, more later phase and commercial studies will emerge and the challenges will likely evolve into how to manufacture sufficient cell quantities, manage complex logistics for multi-center trials and control cost.

  • 213.
    Bivall Persson, Petter
    et al.
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Cooper, Matthew
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering.
    Ynnerman, Anders
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology.
    Tibell, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Use of Chemical Force Feedback for Multisensory Insights into Ligand Docking2007In: VII European Symposium of The Protein Society: From Proteins to Proteome, 2007, p. 151-151Conference paper (Refereed)
  • 214.
    Bivall Persson, Petter
    et al.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering.
    Tibell, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Cooper, Matthew
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Ynnerman, Anders
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology.
    Evaluating the Effectiveness of Haptic Visualization in Biomolecular Education - Feeling Molecular Specificity in a Docking Task2006In: 12th IOSTE Symposium, Universiti Science Malaysia , 2006, p. 745-752Conference paper (Refereed)
    Abstract [en]

    Within the molecular life sciences extensive use is made of visual representations, ranging from sketches to advanced computer graphics, often used to convey abstract knowledge that is difficult for the student to grasp. This work evaluates a new visual and haptic (tactile/kinetic) tool for protein docking in an in situ learning situation by combining qualitative and quantitative methods, performing tests and interviews with students; all aiming at a proper inclusion of visualization tools into biomolecular education. Preliminary results indicate time gains, strong positive affective responses and learning gains from the tasks, however the influence of haptics needs further investigation.

  • 215.
    Bivall, Petter
    et al.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology.
    Ainsworth, Shaaron
    School of Psychology, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K..
    Tibell, Lena A. E.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology.
    Do Haptic Representations Help Complex Molecular Learning?2011In: Science Education, ISSN 0036-8326, E-ISSN 1098-237X, Vol. 95, no 4, p. 700-719Article in journal (Refereed)
    Abstract [en]

    This study explored whether adding a haptic interface (that provides users with somatosensory information about virtual objects by force and tactile feedback) to a three-dimensional (3D) chemical model enhanced students' understanding of complex molecular interactions. Two modes of the model were compared in a between-groups pre- and posttest design. In both modes, users could move and rotate virtual 3D representations of the chemical structures of the two molecules, a protein and a small ligand molecule. In addition, in a haptic mode users could feel the interactions (repulsive and attractive) between molecules as forces with a haptic device. Twenty postgraduate students (10 in each condition) took pretests about the process of protein--ligand recognition before exploring the model in ways suggested by structured worksheets and then completing a posttest. Analysis addressed quantitative learning outcomes and more qualitatively students' reasoning during the learning phase. Results showed that the haptic system helped students learn more about the process of protein–ligand recognition and changed the way they reasoned about molecules to include more force-based explanations. It may also have protected students from drawing erroneous conclusions about the process of protein–ligand recognition observed when students interacted with only the visual model.

  • 216.
    Bivik Stadler, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Genetic pathways controlling CNS development: The role of Notch signaling in regulating daughter cell proliferation in Drosophila2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The human central nervous system (CNS) displays the greatest cellular diversity of any organ system, consisting of billions of neurons, of numerous cell sub-types, interconnected in a vast network. Given this enormous complexity, decoding the genetic programs controlling the multistep process of CNS development remains a major challenge. While great progress has been made with respect to understanding sub-type specification, considerably less is known regarding how the generation of the precise number of each sub-type is controlled.

    The aim of this thesis was to gain deeper knowledge into the regulatory programs controlling cell specification and proliferation. To address these questions I have studied the Drosophila embryonic CNS as a model system, to thereby be able to investigate the genetic mechanisms at high resolution. Despite the different size and morphology between the Drosophila and the mammalian CNS, the lineages of their progenitors share similarity. Importantly for this thesis, both species progenitors show elaborate variations in their proliferation modes, either giving rise to daughters that can directly differentiate into neurons or glia (type 0), divide once (type I), or multiple times (type II).

    The studies launched off with a comprehensive chemical forward genetic screen, for the very last born cell in the well-studied lineage of progenitor NB5-6T: the Ap4 neuron, which expresses the neuropeptide FMRFa. NB5-6T is a powerful model to use, because it undergoes a programmed type I>0 daughter cell proliferation switch. An FMRF-eGFP transgenic reporter was utilized as readout for successful terminal differentiation of Ap4/FMRFa and thereby proper lineage progression of the ∼20 cells generated. The strongest mutants were mapped to genes with both known and novel essential functions e.g., spatial and temporal patterning, cell cycle control, cell specification and chromatin modification. Subsequently, we focused on some of the genes that showed a loss of function phenotype with an excess of lineage cells. We found that Notch is critical for the type I>0 daughter cell proliferation switch in the NB5-6T lineage and globally as well. When addressing the broader relevance of these findings, and to further decipher the Notch pathway, we discovered that selective groups of E(spl) genes is controlling the switch in a close interplay with four key cell cycle factors: Cyclin E, String, E2F and Dacapo, in most if not all embryonic progenitors. The Notch mediation of the switch is likely to be by direct transcriptional regulation. Furthermore, another gene identified in the screen, sequoia, was investigated. The analysis revealed that sequoia is also controlling the daughter cell switch in the CNS, and this partly through context dependent interactions with the Notch pathway.

    Taken together, the findings presented in this thesis demonstrate that daughter cell proliferation switches in Drosophila neural lineages are genetically programmed, and that Notch contributes to the triggering of these events. Given that early embryonic processes is frequently shown to be evolutionary conserved, you can speculate that changeable daughter proliferation programs could be applied to mammals, and contribute to a broader understanding of proliferation processes in humans as well.

     

    List of papers
    1. Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
    Open this publication in new window or tab >>Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
    Show others...
    2015 (English)In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 200, no 4, p. 1229-1244Article in journal (Refereed) Published
    Abstract [en]

    The expression of neuropeptides is often extremely restricted in the nervous system, making them powerful markers for addressing cell specification . In the developing Drosophila ventral nerve cord, only six cells, the Ap4 neurons, of some 10,000 neurons, express the neuropeptide FMRFamide (FMRFa). Each Ap4/FMRFa neuron is the last-born cell generated by an identifiable and well-studied progenitor cell, neuroblast 5-6 (NB5-6T). The restricted expression of FMRFa and the wealth of information regarding its gene regulation and Ap4 neuron specification makes FMRFa a valuable readout for addressing many aspects of neural development, i.e., spatial and temporal patterning cues, cell cycle control, cell specification, axon transport, and retrograde signaling. To this end, we have conducted a forward genetic screen utilizing an Ap4-specific FMRFa-eGFP transgenic reporter as our readout. A total of 9781 EMS-mutated chromosomes were screened for perturbations in FMRFa-eGFP expression, and 611 mutants were identified. Seventy-nine of the strongest mutants were mapped down to the affected gene by deficiency mapping or whole-genome sequencing. We isolated novel alleles for previously known FMRFa regulators, confirming the validity of the screen. In addition, we identified novel essential genes, including several with previously undefined functions in neural development. Our identification of genes affecting most major steps required for successful terminal differentiation of Ap4 neurons provides a comprehensive view of the genetic flow controlling the generation of highly unique neuronal cell types in the developing nervous system.

    Place, publisher, year, edition, pages
    Genetics Society of America, 2015
    Keywords
    Drosophila; CNS development; neural cell fate specification; forward genetic screening; FMRFamide
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-121318 (URN)10.1534/genetics.115.178483 (DOI)000359917000020 ()26092715 (PubMedID)
    Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2019-03-13Bibliographically approved
    2. Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
    Open this publication in new window or tab >>Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
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    2012 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 4, p. 678-689Article in journal (Refereed) Published
    Abstract [en]

    During neural lineage progression, differences in daughter cell proliferation can generate different lineage topologies. This is apparent in the Drosophila neuroblast 5-6 lineage (NB5-6T), which undergoes a daughter cell proliferation switch from generating daughter cells that divide once to generating neurons directly. Simultaneously, neural lineages, e.g. NB5-6T, undergo temporal changes in competence, as evidenced by the generation of different neural subtypes at distinct time points. When daughter proliferation is altered against a backdrop of temporal competence changes, it may create an integrative mechanism for simultaneously controlling cell fate and number. Here, we identify two independent pathways, Prospero and Notch, which act in concert to control the different daughter cell proliferation modes in NB5-6T. Altering daughter cell proliferation and temporal progression, individually and simultaneously, results in predictable changes in cell fate and number. This demonstrates that different daughter cell proliferation modes can be integrated with temporal competence changes, and suggests a novel mechanism for coordinately controlling neuronal subtype numbers.

    Place, publisher, year, edition, pages
    Company of Biologists, 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-74790 (URN)10.1242/dev.074500 (DOI)000300259800005 ()
    Note

    funding agencies|Swedish Research Council||Knut and Alice Wallenberg foundation||Swedish Cancer Foundation||

    Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2019-03-13
    3. Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
    Open this publication in new window or tab >>Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
    Show others...
    2016 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 4, article id e1005984Article in journal (Refereed) Published
    Abstract [en]

    The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2016
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-128759 (URN)10.1371/journal.pgen.1005984 (DOI)000375231900032 ()27070787 (PubMedID)
    Note

    Funding Agencies|Knut and Alice Wallenberg Foundation [KAW2012.0101]; Swedish Research Council [621-2010-5214]; Swedish Cancer Foundation [120531]

    Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2019-03-13
    4. sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
    Open this publication in new window or tab >>sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
    2016 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 143, no 20, p. 3774-3784Article in journal (Refereed) Published
    Abstract [en]

    Neural progenitors typically divide asymmetrically to renew themselves, while producing daughters with more limited potential. In the Drosophila embryonic ventral nerve cord, neuroblasts initially produce daughters that divide once to generate two neurons/glia (type I proliferation mode). Subsequently, many neuroblasts switch to generating daughters that differentiate directly (type 0). This programmed type I&gt;0 switch is controlled by Notch signaling, triggered at a distinct point of lineage progression in each neuroblast. However, how Notch signaling onset is gated was unclear. We recently identified Sequoia (Seq), a C2H2 zinc-finger transcription factor with homology to Drosophila Tramtrack (Ttk) and the positive regulatory domain (PRDM) family, as important for lineage progression. Here, we find that seq mutants fail to execute the type I&gt;0 daughter proliferation switch and also display increased neuroblast proliferation. Genetic interaction studies reveal that seq interacts with the Notch pathway, and seq furthermore affects expression of a Notch pathway reporter. These findings suggest that seq may act as a context-dependent regulator of Notch signaling, and underscore the growing connection between Seq, Ttk, the PRDM family and Notch signaling.

    Place, publisher, year, edition, pages
    The Company of Biologists Ltd, 2016
    Keywords
    Lineage tree, Cell cycle, Asymmetric division, Combinatorial control, Notch
    National Category
    Cell and Molecular Biology Biochemistry and Molecular Biology Cell Biology Medical Biotechnology
    Identifiers
    urn:nbn:se:liu:diva-132739 (URN)10.1242/dev.139998 (DOI)000393452500013 ()27578794 (PubMedID)
    Note

    Funding agencies: Swedish Research Council (Vetenskapsradet); Knut and Alice Wallenberg Foundation (Knut och Alice Wallenbergs Stiftelse); Swedish Cancer Foundation (Cancerfonden)

    Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2019-03-13Bibliographically approved
  • 217.
    Bivik Stadler, Caroline
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Arefin, Md Badrul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Queensland, Australia.
    PIP degron-stabilized Dacapo/p21(Cip)(1) and mutations in ago act in an anti- versus pro-proliferative manner, yet both trigger an increase in Cyclin E levels2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 13, article id UNSP dev175927Article in journal (Refereed)
    Abstract [en]

    During cell cycle progression, the activity of the CycE-Cdk2 complex gates S-phase entry. CycE-Cdk2 is inhibited by CDK inhibitors (CKIs) of the Cip/Kip family, which include the human p21(Cip)(1) and Drosophila Dacapo (Dap) proteins. Both the CycE and Cip/Kip family proteins are under elaborate control via protein degradation, mediated by the Cullin-RING ligase (CRL) family of ubiquitin ligase complexes. The CRL complex SCFFoxw7/Ago targets phosphorylated CycE, whereas p21(Cip)(1) and Dap are targeted by the CRLCdf2 complex, binding to the PIP degron. The role of CRL-mediated degradation of CycE and Cip/Kip proteins during CNS development is not well understood. Here, we analyse the role of ago (Fbxw7)-mediated CycE degradation, and of Dap and p21(Cip)(1) degradation during Drosophila CNS development. We find that ago mutants display over-proliferation, accompanied by elevated CycE expression levels. By contrast, expression of PIP degron mutant Dap and p21(Cip)(1) transgenes inhibit proliferation. However, surprisingly, this is also accompanied by elevated CycE levels. Hence, ago mutation and PIP degron Cip/Kip transgenic expression trigger opposite effects on proliferation, but similar effects on CycE levels.

  • 218.
    Bjällerhag, Nathalie
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Behaviours and experiences as indicators for the result in a behavioural test for dogs2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In 2005 Swedish Armed Forces (SAF) started a breeding program of military working dogs. The dogs leave SAF’s kennel at an age of 8 weeks and live with puppy raisers. To evaluate the suitability of dogs for military work the dogs conduct a behavioural test at an age of 15-18 months. An “Index value” is extracted from this behavioural test. The puppy raisers answered a modified version of Canine Behavioral Assessment and Research Questionnaire (C-BARQ) when the dogs were approximately 12 months old. Answered questionnaires and results from the behavioural test were obtained for 59 dogs. Dogs that had passed the behavioural test had tendency for higher scores for “Trainability” (p = 0.078) and “If lived with other animals” (p = 0.066). Failing dogs had significantly higher score for “Stranger Directed Fear” (p = 0.006), ”Non-Social Fear” (p = 0.005), “Dog Directed Fear” (p = 0.021), “Hours of daily activation” (p = 0.001), “Mounting objects” (p = 0.012), and a tendency for higher risk of “Urinating when home alone” (p = 0.058). In a regressions between the “Index value” and the values of the questions from C-BARQ, the “Index value” was negatively correlated to “Stranger Directed Fear” (p = 0.002), “Non-social Fear” (p = 0.003), and “Dog Directed Fear” (p = 0.006). The “Index value” was positively correlated to “Trainability” (p = 0.013), “Hours left home alone” (p=0.043), “Hyperactive” (p = 0.018), “Chases shadows/light spots” (p = 0.043), and a positive tendency for “Chewing on inappropriate objects” (p = 0.075). From a PCA at the categories in C-BARQ, 3 components were extracted. All three components had a correlation to the “Index value”. The results show that the use of C-BARQ can indicate whether the dog will pass the behavioural test or not.

  • 219.
    Björk, Kim
    Linköping University, Department of Physics, Chemistry and Biology.
    The effect of extra feed supply on stereotypic behaviour in Asian elephants (Elphas maximus)2011Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Stereotypes in captive elephants is a widespread issue. Ways to tackle this is with social and feedenrichment among others. The aim of this study was to investigate if extra feed supply wouldaffect stereotypic behaviour in Asian elephants held in captivity. Three elephant cows wereprovided with extra feed and recorded during the night and morning. The results showed asignificant decrease in stereotypic behavior for one of the elephants, from 31% to 9,5% (P =0,003). While the second elephant did not engage in stereotypic behaviour, the third elephantshowed the same frequency of stereotypic behavior, 9%, during both baseline and treatment. Thethird elephant did increase her foraging significantly, from 31% to 54% (P = 0,02). Waken timespent foraging increased for all three elephants to 64-80% which is in the same range as in wildAsian elephants. Additional enrichment in the form of extra feed supply can be used both todecrease stereotypic behaviours and to increase foraging.

  • 220.
    Björk Wilhelms, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Fever: Role of brain endothelial prostaglandins2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.

    Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.

    List of papers
    1. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
    Open this publication in new window or tab >>Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
    Show others...
    2013 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, p. 1973-1980Article in journal (Refereed) Published
    Abstract [en]

    Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

    Place, publisher, year, edition, pages
    Federation of American Society of Experimental Biology (FASEB), 2013
    Keywords
    lipopolysaccharide; methylcholanthrene-induced sarcoma; food intake; chimeric mice; Cre-LoxP; inducible cell-specific deletion
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-96147 (URN)10.1096/fj.12-225433 (DOI)000318226100017 ()
    Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2017-12-06
    2. Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2
    Open this publication in new window or tab >>Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2
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    2013 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 71, p. 124-129Article in journal (Refereed) Published
    Abstract [en]

    Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2.

    Place, publisher, year, edition, pages
    Elsevier, 2013
    Keywords
    Fever; Cyclooxygenase-2; Cyclooxygenase-1; Microsomal prostaglandin E synthase-1; Gene dosage; Hypothalamus
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-96170 (URN)10.1016/j.neuropharm.2013.03.012 (DOI)000320424200012 ()
    Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2017-12-06
    3. Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever
    Open this publication in new window or tab >>Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever
    Show others...
    2014 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 35, p. 11684-11690Article in journal (Refereed) Published
    Abstract [en]

    Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E-2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE(2) remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammation-induced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE(2) synthesis in brain endothelial cells is critical for inflammation-induced fever.

    Place, publisher, year, edition, pages
    Society for Neuroscience, 2014
    Keywords
    COX-2; endothelium; fever; mPGES-1; PGE(2); prostaglandin
    National Category
    Cell and Molecular Biology Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-111281 (URN)10.1523/JNEUROSCI.1838-14.2014 (DOI)000341314900017 ()25164664 (PubMedID)
    Note

    Funding Agencies|Swedish Medical Research Council; Swedish Cancer Foundation; European Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of stergotland; Wenner-Gren Fellowship

    Available from: 2014-10-14 Created: 2014-10-14 Last updated: 2018-01-11
    4. Cyclooxygenase isoform exchange blocks inflammatory symptoms
    Open this publication in new window or tab >>Cyclooxygenase isoform exchange blocks inflammatory symptoms
    2014 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Cyclooxygenase‐2 (COX‐2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. In contrast, COX‐1 is dispensable for most inflammatory symptoms. Global deletion of COX‐2 leads to a blockade of inflammation‐induced fever and appetite loss but also to high rates of fetal mortality. The latter is unfortunate since mice without COX‐2 are powerful tools in the study of inflammation and cardiovascular medicine. The differential functionality of the COX isoforms could be due to differences in regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, leading to distinct functional properties of the proteins. To study this in the context of inflammatory symptoms, we used mice in which the coding sequence of COX‐2 was replaced by the corresponding sequence of COX‐1. In these mice, COX‐1 mRNA was induced by inflammation but COX‐1 protein expression did not fully mimic inflammation‐induced COX‐2 expression. Just like mice globally lacking COX‐2, these mice showed a complete lack of fever and inflammation‐induced anorexia. However, as previously reported, they displayed close to normal survival rates. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate inflammatory symptoms, making the line an interesting alternative to COX‐2 knockouts for the study of inflammation. Our results also show that the functional differences between COX‐1 and COX‐2 in the context of inflammatory symptoms is not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels, which make hybrid genes less functional.

    National Category
    Cell Biology Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:liu:diva-111725 (URN)
    Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2015-11-06Bibliographically approved
  • 221.
    Björk Wilhelms, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cyclooxygenase isoform exchange blocks inflammatory symptoms2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Cyclooxygenase‐2 (COX‐2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. In contrast, COX‐1 is dispensable for most inflammatory symptoms. Global deletion of COX‐2 leads to a blockade of inflammation‐induced fever and appetite loss but also to high rates of fetal mortality. The latter is unfortunate since mice without COX‐2 are powerful tools in the study of inflammation and cardiovascular medicine. The differential functionality of the COX isoforms could be due to differences in regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, leading to distinct functional properties of the proteins. To study this in the context of inflammatory symptoms, we used mice in which the coding sequence of COX‐2 was replaced by the corresponding sequence of COX‐1. In these mice, COX‐1 mRNA was induced by inflammation but COX‐1 protein expression did not fully mimic inflammation‐induced COX‐2 expression. Just like mice globally lacking COX‐2, these mice showed a complete lack of fever and inflammation‐induced anorexia. However, as previously reported, they displayed close to normal survival rates. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate inflammatory symptoms, making the line an interesting alternative to COX‐2 knockouts for the study of inflammation. Our results also show that the functional differences between COX‐1 and COX‐2 in the context of inflammatory symptoms is not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels, which make hybrid genes less functional.

  • 222.
    Björklund Aksoy, Simon
    Linköping University, Department of Physics, Chemistry and Biology. 2015.
    Effects of serotonin on personality in field crickets (Gryllus bimaculatus)2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Animal personality can be defined as a set of physiological and behavioral characteristics that differ between individuals, but are consistent over time and across situations. The evolution of individual differences in behavior that are consistent over time and situations is still not clear. Our understanding of why animals have personality can be improved by investigating the underlying physiological mechanisms of animal behavior. Serotonin is a key monoamine that serves as a physiological modulator of animal behavior. Selective serotonin reuptake inhibitors are a group of chemicals that increase levels of serotonin in the brain. Fluoxetine is one such chemical and is used to treat depression in humans. In the field cricket (Gryllus bimaculatus), increased levels of serotonin have been linked to higher activity and boldness, which are both personality traits. In the current study, the effects of induced serotonin on activity, exploration, boldness and aggression was investigated. My results show that injecting fluoxetine causes substantial changes in behavioral traits used to describe personality in field crickets. This result is opposite to previous studies, as serotonin induced individuals were less active, less explorative, and won less fights, compared to control individuals. This could be due to serotonin existing naturally within the circulatory system of the field cricket, whereas fluoxetine is a manufactured chemical intended for human receptors, or that fluoxetine has a similar effect in modulating personality in field crickets as in humans. Since fluoxetine acts similarly in field crickets as in humans, an increased understanding of the effects of induced serotonin on different behaviors in field crickets could be beneficial for treating psychological illnesses.

  • 223.
    Björklund, Lars
    et al.
    Linköping University, Department of Social and Welfare Studies, Learning, Aesthetics, Natural science. Linköping University, Faculty of Educational Sciences.
    Stolpe, Karin
    Linköping University, Department of Social and Welfare Studies, Learning, Aesthetics, Natural science. Linköping University, Faculty of Educational Sciences.
    Being able to see the wood for the trees: Expert teachers' observational skills in complex environments explained by a neurocognirive model of learning2010Conference paper (Refereed)
  • 224.
    Björkroth, Jennie
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Effekter av naturvårdsgallring på förekomsten av lunglav på ädellövträd2015Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    Sun-exposed broad leaved deciduous trees have a great species diversity of epiphytic lichens. In Europe, these trees have decreased dramatically in number as wooded pastures have become overgrown with trees and bushes, and broad leaved deciduous stands have been replaced by planted coniferous trees. These are the main reasons for many lichens depending on deciduous trees being red-listed. Epiphytic lichens in overgrown areas could benefit from conservation thinning, but few studies have been performed on how this type of cutting affects the lichens. In a previous study, the presence of red-listed epiphytic lichens in a broad leaved deciduous forest was examined. After the study, thinning of trees and bushes was made. Here we study the effects of this thinning on Lobaria pulmonaria. We tested possible factors that may affect the growth of L. pulmonaria, and if there were any differences in incidence and vitality of the lichen between managed and unmanaged stands. Since Dutch elm disease and ash dieback are well spread in the area, we wanted to see if they also affected the growth of L. pulmonaria. There were no differences in incidence and growth between managed and unmanaged stands. The results were unexpected since other studies show that, for instance, increased sun exposure often has a great effect on the growth of lichens. Many elms and ashes were dead or dying and had a significant negative effect on the change of number of lobes and the lobe surface. The diseases of the trees can thus be assumed to be the greatest cause of why the lichens in the managed stand did not benefit from thinning.

  • 225.
    Blindow, Irmgard
    et al.
    Ernst Moritz Arndt University of Greifswald, Germany .
    Hargeby, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Hilt, Sabine
    Leibniz Institute Freshwater Ecol and Inland Fisheries, Germany .
    Facilitation of clear-water conditions in shallow lakes by macrophytes: differences between charophyte and angiosperm dominance2014In: Hydrobiologia, ISSN 0018-8158, E-ISSN 1573-5117, Vol. 737, no 1, p. 99-110Article in journal (Refereed)
    Abstract [en]

    A number of mechanisms result in a feedback between water clarity and macrophytes and, consequently, the occurrence of alternative stable states in shallow lakes. We hypothesize that bottom-up mechanisms and interactions within the benthic food web are more important in a charophyte-dominated clear-water state, while top-down mechanism and interactions in the planktonic food web prevail at angiosperm dominance. Charophytes, which dominate at lower nutrient concentrations and develop higher densities than most angiosperms, can have a higher influence on sedimentation, resuspension, and water column nutrients. During dominance of dense submerged vegetation like charophytes, zooplankton can be hampered by low food quality and quantity and by high predation pressure from juvenile fish, which in turn are favoured by the high refuge potential of this vegetation. Grazing pressure from zooplankton on phytoplankton can therefore be low in charophytes, but the main feedback in angiosperm-dominated ecosystems. Charophytes offer a higher surface than most angiosperms to periphyton, which favors benthic invertebrates. These support macrophytes by grazing periphyton and constitute a central link in a trophic cascade from fish to periphyton and macrophytes. To test these hypotheses, more experiments and field measurements comparing the effect of charophytes and angiosperms on water clarity are needed.

  • 226.
    Blissing, Annica
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thiopurine S-methyltransferase - characterization of variants and ligand binding2017Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Thiopurine S-methyltransferase (TPMT) belongs to the Class I S-adenosylmethionine-dependent methyltransferase (SAM-MT) super family of structurally related proteins. Common to the members of this large protein family is the catalysis of methylation reactions using S-adenosylmethionine (SAM) as a methyl group donor, although SAM-MTs act on a wide range of different substrates and carry out numerous biologically important functions. While the natural function of TPMT is unknown, this enzyme is involved in the metabolism of thiopurines, a class of pharmaceutical substances administered in treatment of immune-related disorders. Specifically, methylation by TPMT inactivates thiopurines and their metabolic intermediates, which reduces the efficacy of clinical treatment and increases the risk of adverse side effects. To further complicate matters, TPMT is a polymorphic enzyme with over 40 naturally occurring variants known to date, most of which exhibit lowered methylation activity towards thiopurines. Consequently, there are individual variations in TPMTmediated thiopurine inactivation, and the administered dose has to be adjusted prior to clinical treatment to avoid harmful side effects.

    Although the clinical relevance of TPMT is well established, few studies have investigated the molecular causes of the reduced methylation activity of variant proteins. In this thesis, the results of biophysical characterization of two variant proteins, TPMT*6 (Y180F) and TPMT*8 (R215H), are presented. While the properties of TPMT*8 were indistinguishable from those of the wild-type protein, TPMT*6 was found to be somewhat destabilized. Interestingly, the TPMT*6 amino acid substitution did not affect the functionality or folding pattern of the variant protein. Therefore, the decreased in vivo functionality reported for TPMT*6 is probably caused by increased proteolytic degradation in response to the reduced stability of this protein variant, rather than loss of function.

    Also presented herein are novel methodological approaches for studies of TPMT and its variants. Firstly, the advantages of using 8-anilinonaphthalene-1-sulfonic acid (ANS) to probe TPMT tertiary structure and active site integrity are presented. ANS binds exclusively to the native state of TPMT with high affinity (KD ~ 0.2 μm) and a 1:1 ratio. The stability of TPMT was dramatically increased by binding of ANS, which was shown to co-localize with the structurally similar adenine moiety of the cofactor SAM. Secondly, an enzyme activity assay based on isothermal titration calorimetry (ITC) is presented. Using this approach, the kinetics of 6-MP and 6-TG methylation by TPMT has been characterized.

  • 227.
    Blixt, Torbjörn
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    The behavioural response of mice to predator odours2012Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    The ability to detect and react to a predator odour is crucial for prey species. In the present study 10 mice (Mus musculus) were used to test the behavioural response of mice towards two predator odours (3-methyl-1-butanethiol and 3-mercapto-3-methyl-butan-1-ol) and one fruity odour (n-pentyl acetate). All three odours were tested against a near odourless blank stimulus (diethyl phthalate). The animals were individually placed in a test chamber of two equally sized compartments divided by a vertical Plexiglas wall with a semicircular opening. Their proximity to the odours, placed beneath the floor in petri dishes in each compartment, was measured continuously with stop watches. The mice spent less time in proximity to 3-methyl-1-butanethiol and n-pentyl acetate compared to diethyl phthalate (P<0,05). The mice did not prefer any specific compartment in the test with 3-mercapto-3-methyl-butan-1-ol compared to diethyl phthalate (P>0,05). The avoidance of 3-methyl-1-butanethiol and n-pentyl acetate can be explained either by neophobia, or in the case of 3-methyl-1-butanethiol that it contains sulphur. The lack of behavioural response towards 3-mercapto-3-methyl-butan-1-ol may be due to its loss of intensity over time. From this study it is not certain if mice have an innate fear of predator odours.

  • 228.
    Bohlin, Gustav
    et al.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology.
    Göransson, Andreas C.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology.
    Tibell, Lena A. E.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology.
    Diverse use of threshold concepts - A content analysis of online dynamic visualizations describing evolution.2015Conference paper (Refereed)
    Abstract [en]

    There is an abundance of dynamic visualizations (animations, videos and simulations) that claim to explain evolution available on the Internet. The present study explores what aspects of evolution that are represented in these potential learning tools. A criteria catalogue covering 40 operationalized variables was used as a content analysis grid in the analysis of 71 dynamic visualizations. The concepts, derived from research literature, were operationalized into variables sorted into four different categories: (a) content-specific concepts (such as limited resources or inherited variation), (b) threshold concepts (core concepts that transform and integrate understanding within a subject), (c) alternative conceptions (such as teleological explanations or anthropomorphism), and (d) model organism. The results indicate that some concepts are dominantly communicated while others are seldom or never included in online visualizations. Regarding the proposed threshold concepts, evolutionary events happening on small time- and spatial scales, such as subcellular processes, were seldom observed. Rather, the focus was on events happening at a population level in time scales spanning from years and longer. This echoes with an observed lack of explanations regarding randomly occurring mutations providing the basis for variation. Implications include that there are components of evolution that would benefit from being addressed with an increased focus in biology teaching and science education research. The results may also serve as a useful toolkit in the design of new educational material.

  • 229.
    Boij, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Aspects of inflammation, angiogenesis and coagulation in preeclampsia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).

    We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.

    A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18  (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.

    List of papers
    1. Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
    Open this publication in new window or tab >>Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
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    2010 (English)In: AMERICAN JOURNAL OF PATHOLOGY, ISSN 0002-9440, Vol. 177, no 5, p. 2387-2398Article in journal (Refereed) Published
    Abstract [en]

    Early diagnosis and treatment of preeclampsia would significantly reduce maternal and fetal morbidity and mortality. However, its etiology and prediction have remained elusive. Based on the hypothesis that sera from patients with preeclampsia could function as a "blueprint" of causative factors, we describe a serum-based pregnancy-specific mouse model that closely mirrors the human condition as well as an in vitro predictive assay. We show that a single administration of human preeclampsia serum in pregnant IL-10(-/-) mice induced the full spectrum of preeclampsia-like symptoms, caused hypoxic injury in uteroplacental tissues, and elevated soluble fins-like tyrosine kinase 1 and soluble endoglin, markers thought to be related to the disease. The same serum sample(s) induced a partial preeclampsia phenotype in wild-type mice. Importantly, preeclampsia serum disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity. Disruption of endovascular activity could be documented in serum samples as early as 12 to 14 weeks of gestation from patients who subsequently developed preeclampsia. These results indicate that preeclampsia patient sera can be used to understand the pregnancy-specific disease pathology in mice and can predict the disorder.

    Place, publisher, year, edition, pages
    American Society for Investigative Pathology (ASIP), 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-62755 (URN)10.2353/ajpath.2010.100475 (DOI)000284182900026 ()
    Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2016-11-11
    2. Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
    Open this publication in new window or tab >>Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
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    2012 (English)In: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, ISSN 1046-7408, Vol. 68, no 3, p. 258-270Article in journal (Refereed) Published
    Abstract [en]

    Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.

    Place, publisher, year, edition, pages
    John Wiley and Sons, 2012
    Keywords
    preeclampsia, coagulation, inflammation, angiogenesis, chemokines, cytokines and early onset preeclampsia
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81815 (URN)10.1111/j.1600-0897.2012.01158.x (DOI)000307440300012 ()
    Note

    Funding Agencies|FORSS (Medical Research Council of Southeast Sweden)||Futurum (the Research department of County of Jonkoping)||Swedish Research Council|2007-15809-48800-58|Linneaus University (Sweden)||

    Available from: 2012-09-26 Created: 2012-09-24 Last updated: 2016-11-11
    3. Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
    Open this publication in new window or tab >>Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
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    2015 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, no 4, p. 368-378Article in journal (Refereed) Published
    Abstract [en]

    Problem A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Objective Utilizing recent advances in flow cytometry phenotyping, we aimed to assess whether a deficiency of Treg subpopulations occurs in preeclampsia. Method of study Six-color flow cytometry was used for Treg phenotyping in 18 preeclamptic women (one early-onset, one severe and 16 both), 20 women with normal pregnancy, and 20 non-pregnant controls. Results No differences were found in major Treg populations including CD127(low)CD25(+)/CD127(ow)FOXP3(+), resting (FOXP3(dim)CD45RA(+)), and activated (FOXP3(bright)CD45RA(-)) Treg cells, whereas preeclamptic women showed increased CTLA-4(+) and CCR4(+) proportions within resting/activated Treg populations. Corticosteroid treatment prior to blood sampling (n = 10) affected the distribution of Treg populations. Conclusions Although we found no major alterations in circulating Treg frequencies, differences in CTLA-4(+) and CCR4(+) frequencies suggest a migratory defect of Treg cells in preeclampsia. Corticosteroid treatment should be taken into account when evaluating Treg cells.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 2015
    Keywords
    Early-onset preeclampsia; preeclampsia; pregnancy; regulatory T cells
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:liu:diva-122528 (URN)10.1111/aji.12410 (DOI)000362664200009 ()26118401 (PubMedID)
    Note

    Funding Agencies|FORSS (Medical Research Council of Southeast Sweden); Futurum, academy for Health and Care Jonkoping County Council, Sweden

    Available from: 2015-11-09 Created: 2015-11-06 Last updated: 2017-12-01
  • 230.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Studies on interfaces between primary and secondary hemostasis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Our conceptual understanding of hemostasis is still heavily influenced by outdated experimental models wherein the hemostatic activity of platelets and coagulation factors are understood and studied in isolation. Although perhaps convenient for researchers and clinicians, this reductionist view is negated by an ever increasing body of evidence pointing towards an intimate relationship between the two phases of hemostasis, marked by strong interdependence. In this thesis, I have focused on factual and proposed interfaces between primary and secondary hemostasis, and on how these interfaces can be studied.

    In my first project, we zoomed in on the mechanisms behind the well-known phenomenon of thrombin-induced platelet activation, an important event linking secondary to primary hemostasis. In our study, we examined how thrombin makes use of certain domains for high-affinity binding to substrates, called exosite I and II, to activate platelets via PAR4. We show that thrombin-induced platelet activation via PAR4 is critically dependent on exosite II, and that blockage of exosite II with different substances virtually eliminates PAR4 activation. Apart from providing new insights into the mechanisms by which thrombin activates PAR4, these results expand our knowledge of the antithrombotic actions of various endogenous proteins such as members of the serpin superfamily, which inhibit interactions with exosite II. Additionally, we show that inhibition of exosite II could be a feasible pharmacological strategy for achieving selective blockade of PAR4.

    In my second project, we examined the controversial issue of whether platelets can initiate the coagulation cascade by means of contact activation, a hypothesis which, if true, could provide a direct link between primary and secondary hemostasis. In contrast to previous results, our findings falsify this hypothesis, and show that some of the erroneous conclusions drawn from earlier studies can be explained by inappropriate experimental models unsuitable for the study of plateletcoagulation interfaces.

    My third project comprised an assessment of the methodological difficulties encountered when trying to measure the ability of platelets to initiate secondary hemostasis by the release of microparticles expressing tissue factor. Our study shows that the functional assays available for this purpose are highly susceptible to error caused by artificial contact activation. These results could help to improve the methodology of future research and thus pave the way for new insights into the roles of tissue factor-bearing microparticles in the pathophysiology of various thrombotic disorders.

    From a personal perspective, my PhD project has been a fascinating scientific odyssey into the largely unexplored interfaces between primary and secondary hemostasis. Looking forward, my ambition is to continue our work exploring platelet-coagulation interactions and to translate these insights into clinically meaningful information, which may someday improve the treatment of patients with bleeding and/or thrombosis.

    List of papers
    1. Thrombin-induced platelet activation via PAR4: pivotal role for exosite II
    Open this publication in new window or tab >>Thrombin-induced platelet activation via PAR4: pivotal role for exosite II
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    2014 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, no 3, p. 558-565Article in journal (Refereed) Published
    Abstract [en]

    Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Although the underlying mechanisms responsible for ensuring efficient PAR1 activation by thrombin have been extensively studied, the potential involvement of recognitions sites outside the active site of the protease in thrombin-induced PAR4 activation is largely unknown. In this study, we developed a new assay to assess the importance of exosite I and II for PAR4 activation with alpha- and gamma-thrombin. Surprisingly, we found that exosite II is critical for activation of PAR4. We also show that this dependency on exosite II likely represents a new mechanism, as it is unaffected by blockage of the previously known interaction between thrombin and glycoprotein Ib alpha.

    Place, publisher, year, edition, pages
    Schattauer Gmbh, 2014
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-111269 (URN)10.1160/TH13-12-1013 (DOI)000341547000015 ()24990072 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2010-65X-15060-07-3, K2013-65X-15060-10-3]; Swedish Heart and Lung Foundation [20100219, 20120263]

    Available from: 2014-10-15 Created: 2014-10-14 Last updated: 2017-12-05Bibliographically approved
    2. Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII
    Open this publication in new window or tab >>Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII
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    2013 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 23, p. 3818-3824Article in journal (Refereed) Published
    Abstract [en]

    The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Muller et al has been cited greater than100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of less than10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

    Place, publisher, year, edition, pages
    American Society of Hematology, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-104301 (URN)10.1182/blood-2013-05-499384 (DOI)000329735000021 ()
    Available from: 2014-02-17 Created: 2014-02-14 Last updated: 2017-12-06
    3. Response: platelets do not generate activated factor XII--how inappropriate experimental models have led to misleading conclusions
    Open this publication in new window or tab >>Response: platelets do not generate activated factor XII--how inappropriate experimental models have led to misleading conclusions
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    2014 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 10, p. 1692-1694Article in journal, Letter (Other academic) Published
    Place, publisher, year, edition, pages
    American Society of Hematology, 2014
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-111531 (URN)10.1182/blood-2014-04-566067 (DOI)000342762300027 ()25190755 (PubMedID)
    Available from: 2014-10-22 Created: 2014-10-22 Last updated: 2017-12-05Bibliographically approved
    4. Contact activation: important to consider when measuring the contribution of tissue factor-bearing microparticles to thrombin generation using phospholipid-containing reagents
    Open this publication in new window or tab >>Contact activation: important to consider when measuring the contribution of tissue factor-bearing microparticles to thrombin generation using phospholipid-containing reagents
    2014 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, no 4, p. 515-518Article in journal (Refereed) Published
    Abstract [en]

    Background A commercial MP reagent containing phospholipids is used for thrombin generation (TG) measurements to estimate the procoagulant activity of microparticles (MPs). Previous reports have shown that contact activation affects TG when TF levels are low, and that addition of phospholipids might augment this effect. Objectives To quantify the impact of contact activation on TG in the presence of phospholipids and low/no TF, as is the case using a commercially available MP-reagent. Methods Thrombin generation was analyzed using MP- or platelet-rich plasma (PRP)-reagent in the presence and absence of corn trypsin inhibitor and anti-TF antibodies, respectively. To quantify the impact of different experimental parameters on contact activation, microparticle-depleted plasma was analyzed in the presence of different concentrations of phospholipids, TF and/or contact activating agents (kaolin). Results Even with low contact activating blood collection tubes, substantial thrombin generation was observed with the MP-reagent, but this was completely inhibited by addition of corn trypsin inhibitor. Control experiments illustrate that the phospholipids in the reagent play a major role in enhancing TG initiated by FXIIa. Even with the PRP-reagent, which is recommended for determining the content of phospholipids from MPs, TG was partly dependent on contact activation. Conclusions Contact activation plays a major role in TG when using reagents/samples containing phospholipids but little or no tissue factor. This needs to be considered and accounted for in future clinical studies using TG to assess the procoagulant activity of MPs.

    Place, publisher, year, edition, pages
    Wiley, 2014
    Keywords
    cell-derived microparticles; thromboplastin; blood coagulation; thrombin; factor XII
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-106682 (URN)10.1111/jth.12503 (DOI)000334157000012 ()
    Available from: 2014-05-21 Created: 2014-05-19 Last updated: 2017-12-05
  • 231.
    Bolshakova, A.V.
    et al.
    Institute of Cytology RAS, St. Petersburg, Russian Federation.
    Petukhova, O.A.
    Institute of Cytology RAS, St. Petersburg, Russian Federation.
    Pinaev, G.P.
    Institute of Cytology RAS, St. Petersburg, Russian Federation.
    Magnusson, Karl-Erik
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    The comparative analysis of subcellular fractionation methods for revealing of a-actinin 1 and a-actinin 4 in A431 cells2009In: Tsitologiya, ISSN 0041-3771, Vol. 51, no 2, p. 122-129Article in journal (Refereed)
    Abstract [en]

    a-Actinin 1 and a-actinin 4 belong to a family of actin-binding proteins with shared structural function and regulation of several processes in a cell. Based on previous data on different distribution of these proteins in the nucleus and cytoplasm, we have explored in detail the distribution of a-actinin 1 and a-actinin 4 in subcellular fractions in A431 cells spread on fibronectin. Several methods of subcellular fractionation were used. Complex approach allowed resuming that revealing of a-actinin isoforms in fractions depended on the composition of lysis buffer and preliminary low-temperature freezing of the cells. We have drawn a conclusion that a-actinin 4 can be found in all cytoplasmic and nuclear subfractions, while a-actinin 1 is characterized by cytoplasmic and membrane localization with specificity of its distribution tightly to the nuclear membrane.

  • 232.
    Boman, Erik
    Linköping University, Department of Physics, Chemistry and Biology.
    Olfactory and cognitive abilities in two strains of Alzheimer`s disease model mice2009Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    The present study assessed olfactory and cognitive abilities in two strains of Alzheimer’s disease (AD) model mice and in healthy control mice over a four month time period. To this end an operant conditioning paradigm using an automated olfactometer and a spatial learning test with non-olfactory cues were employed and data on olfactory learning and memory, discrimination, and sensitivity as well as spatial learning and memory were collected. The mice were between 6 to 7 month old at the beginning of the study and 9 to 10 months old at the end of the data collection, that is, in the age range when the animals are supposed to display marked neuroanatomical changes typical of AD. The results demonstrate that there were no systematic differences in olfactory performance and spatial learning and memory abilities of AD model mice and the control mice up to the age they were tested. Further, there was no indication of an age-related decline in performance in any of the mouse strains across the testing period. Several reasons might account for the observed lack of difference in olfactory and cognitive performance between the mouse strains tested here: the AD model mice might not develop amyloid plaques and neurofibrillary tangles at all or they might develop them later than stated by the supplier. Alternatively, the AD model mice may have developed AD-typical neuroanatomical changes but these do not, or not yet, affect their olfactory performance and/or spatial learning and memory capabilities. Ongoing data collection will help to evaluate which of these explanations holds true.

  • 233.
    Booy, Evan P.
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Johar, Dina
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Maddika, Srilekha
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Pirzada, Hasan
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Sahib, Mickey M.
    Department of Oral Biology, University of Manitoba, Winnipeg, Canada .
    Gehrke, Iris
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Loewen, Shauna
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Louis, Sherif F.
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
    Kadkhoda, Kamran
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Mowat, Michael
    Manitoba Institute of Cell Biology,CancerCare Manitoba, University of Manitoba, ON6010-675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Monoclonal and bispecific antibodies as novel therapeutics2006In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 54, no 2, p. 85-101Article in journal (Refereed)
    Abstract [en]

    Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodies" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.

  • 234.
    Borg, Ann-Louise
    Linköping University, Department of Physics, Chemistry and Biology.
    Investigation of a Method for Determination of Anticomplementary Activity (ACA) in Octagam2009Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    This Master Thesis was conducted at Octapharma AB in Stockholm.

    Anticomplementary activity (ACA) is a measure of the product’s abilities to activate the complement system. IgG aggregates are mainly responsible for this activation. Two different performances of a method for determination of ACA in Octagam® are available. The two performances are based on the reference method for test of ACA in immunoglobulins in the European Pharmacopoeia Commission Guideline 6.0 (chapter 2.6.17). The method is carried out either in test tubes or on microtiter plates. The test tube method can be performed either in a manual manner or modified, being more automated. The latter performance has been applied in this study. The plate method is more automated than both of the tube methods. The plate method and the manual tube method have earlier seemed to result in different outcomes, which was the basis for this thesis.

    The plate method and the modified test tube method have been compared and robustness parameters have been studied in order to see which factors influence on the end result. The adequacy of using Human Biological Reference Preparation (human BRP) as a control for the ACA method in general has also been investigated. Samples of the product are outside the scope of this thesis and have not been investigated.

    According to this study, the plate method and the modified tube method are not comparable with regard to complement titration results and to ACA of the BRP control. A higher precision is gained with the plate method. This in combination with the higher degree of automation makes the plate method advantageous in several aspects. When it comes to the robustness of the ACA method in general, the sheep red blood cells (SRBC) used are critical. Haemolysin dilution and complement activity seem to be critical as well.

    Human BRP is, according to this study more adequate as a reference for the plate method than for the tube method. An In house control is believed to be more representative to the ACA method in general as it is of the same nature as the samples analysed, in contrast to the human BRP.

  • 235.
    Borgani, Riccardo
    et al.
    Royal Institute Technology, Sweden.
    Forchheimer, Daniel
    Royal Institute Technology, Sweden.
    Bergqvist, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Thoren, Per-Anders
    Royal Institute Technology, Sweden.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Haviland, David B.
    Royal Institute Technology, Sweden.
    Intermodulation electrostatic force microscopy for imaging surface photo-voltage2014In: Applied Physics Letters, ISSN 0003-6951, E-ISSN 1077-3118, Vol. 105, no 14, p. 143113-Article in journal (Refereed)
    Abstract [en]

    We demonstrate an alternative to Kelvin Probe Force Microscopy for imaging surface potential. The open-loop, single-pass technique applies a low-frequency AC voltage to the atomic force microscopy tip while driving the cantilever near its resonance frequency. Frequency mixing due to the nonlinear capacitance gives intermodulation products of the two drive frequencies near the cantilever resonance, where they are measured with high signal to noise ratio. Analysis of this intermodulation response allows for quantitative reconstruction of the contact potential difference. We derive the theory of the method, validate it with numerical simulation and a control experiment, and we demonstrate its utility for fast imaging of the surface photo-voltage on an organic photovoltaic material.

  • 236.
    Borglin, Johan
    et al.
    University of Gothenburg, Sweden.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Ericson, Marica B.
    University of Gothenburg, Sweden.
    Peptide Functionalized Gold Nanoparticles as a Stimuli Responsive Contrast Medium in Multiphoton Microscopy2017In: Nano letters (Print), ISSN 1530-6984, E-ISSN 1530-6992, Vol. 17, no 3, p. 2102-2108Article in journal (Refereed)
    Abstract [en]

    There is a need for biochemical contrast mediators with high signal-to-noise ratios enabling noninvasive biomedical sensing, for example, for neural sensing and protein protein interactions, in addition to cancer diagnostics. The translational challenge is to develop a biocompatible approach ensuring high biochemical contrast while avoiding a raise of the background signal. We here present a concept where gold nanoparticles (AuNPs) can be utilized as a stimuli responsive contrast medium by chemically triggering their ability to exhibit multiphoton-induced luminescence (MIL) when performing multiphoton laser scanning microscopy (MPM). Proof-of-principle is demonstrated using peptide-functionalized AuNPs sensitive to zinc ions (Zn2+). Dispersed particles are invisible in the MPM until addition of millimolar concentrations of Zn2+ upon which MIL is enabled through particle aggregation caused by specific peptide interactions and folding. The process can be reversed by removal of the Zn2+ using a chelator, thereby resuspending the AuNPs. In addition, the concept was demonstrated by exposing the particles to matrix metalloproteinase-7 (MMP-7) causing peptide digestion resulting in AuNP aggregation, significantly elevating the MIL signal from the background. The approach is based on the principle that aggregation shifts the plasmon resonance, elevating the absorption cross section in the near-infrared wavelength region enabling onset of MIL. This Letter demonstrates how biochemical sensing can be obtained in far-field MPM and should be further exploited as a future tool for noninvasive optical biosensing.

  • 237.
    Borgmastars, Emmy
    et al.
    Umea Univ, Sweden.
    de Weerd, Hendrik Arnold
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering. Univ Skovde, Sweden.
    Lubovac-Pilav, Zelmina
    Univ Skovde, Sweden.
    Sund, Malin
    Umea Univ, Sweden.
    miRFA: an automated pipeline for microRNA functional analysis with correlation support from TCGA and TCPA expression data in pancreatic cancer2019In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 20, article id 393Article in journal (Refereed)
    Abstract [en]

    BackgroundMicroRNAs (miRNAs) are small RNAs that regulate gene expression at a post-transcriptional level and are emerging as potentially important biomarkers for various disease states, including pancreatic cancer. In silico-based functional analysis of miRNAs usually consists of miRNA target prediction and functional enrichment analysis of miRNA targets. Since miRNA target prediction methods generate a large number of false positive target genes, further validation to narrow down interesting candidate miRNA targets is needed. One commonly used method correlates miRNA and mRNA expression to assess the regulatory effect of a particular miRNA.The aim of this study was to build a bioinformatics pipeline in R for miRNA functional analysis including correlation analyses between miRNA expression levels and its targets on mRNA and protein expression levels available from the cancer genome atlas (TCGA) and the cancer proteome atlas (TCPA). TCGA-derived expression data of specific mature miRNA isoforms from pancreatic cancer tissue was used.ResultsFifteen circulating miRNAs with significantly altered expression levels detected in pancreatic cancer patients were queried separately in the pipeline. The pipeline generated predicted miRNA target genes, enriched gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes (KEGG) pathways. Predicted miRNA targets were evaluated by correlation analyses between each miRNA and its predicted targets. MiRNA functional analysis in combination with Kaplan-Meier survival analysis suggest that hsa-miR-885-5p could act as a tumor suppressor and should be validated as a potential prognostic biomarker in pancreatic cancer.ConclusionsOur miRNA functional analysis (miRFA) pipeline can serve as a valuable tool in biomarker discovery involving mature miRNAs associated with pancreatic cancer and could be developed to cover additional cancer types. Results for all mature miRNAs in TCGA pancreatic adenocarcinoma dataset can be studied and downloaded through a shiny web application at https://emmbor.shinyapps.io/mirfa/.

  • 238.
    Bornefall, Karin
    Linköping University, The Department of Physics, Chemistry and Biology.
    Betydelsen av taggbuskar, ljus och hävd vid föryngring av ek (Quercus robur)2005Independent thesis Advanced level (degree of Magister), 10 points / 15 hpStudent thesis
    Abstract [en]

    Many species and hence biodiversity depend on old, large oaks (Quercus robur) with hollow trunks. The populations of oak-living organisms have to migrate to a nearby old oak in order to survive the death of the host. The oak district south of Linköping, Sweden, is unique in area and the number of old oaks. It is anyway doubtful whether regeneration of oak will secure future continuity. Oaks are light-demanding and thrive in open pastures. Grazers also pose a problem, eating acorns and seedlings not protected by e.g. thorny shrubs. This is a study of regeneration of young oaks in the oak district and the influence of management, light conditions and thorny shrubs. There were less grown-up oaks up to 40 cm diameter than between 40 and 80 cm in grazed areas. The occurrence of oak seedlings was very low in dark un-grazed areas. Seedlings were much more common under than outside of oak canopies regardless of management. Ground coverage was lower at seedlings than in random plots. In grazed areas the density of seedlings was 30 times higher in thorny shrub than outside, but few seedlings were higher than 80 cm. The study showed that thorny shrubs are vital for establishment and survival of oak seedlings in grazed areas. It also showed that there is a risk of gaps in oak age distribution in the oak district. Management should spare thorny shrub and help seedling establishment outside of oak canopies, were oak seedlings are more likely to become trees.

  • 239.
    Borrvall, Charlotte
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Biology . Linköping University, The Institute of Technology.
    Biodiversity and Species Extinctions in Model Food Webs2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many of the earth’s ecosystems are experiencing large species losses due to human impacts such as habitat destruction and fragmentation, climate change, species invasions, pollution, and overfishing. Due to the complex interactions between species in food webs the extinction of one species could lead to a cascade of further extinctions and hence cause dramatic changes in species composition and ecosystem processes. The complexity of ecological systems makes it difficult to study them empirically. The systems often consist of large species numbers with lots of interactions between species. Investigating ecological communities within a theoretical approach, using mathematical models and computer simulations, is an alternative or a complement to experimental studies. This thesis is a collection of theoretical studies. We use model food webs in order to explore how biodiversity (species number) affects the response of communities to species loss (Paper I-III) and to environmental variability (Paper IV).

    In paper I and II we investigate the risk of secondary extinctions following deletion of one species. It is shown that resistance against additional species extinctions increases with redundancy (number of species per functional group) (Paper I) in the absence of competition between basal species but decreases with redundancy in the presence of competition between basal species (Paper II). It is further shown that food webs with low redundancy run the risk of losing a greater proportion of species following a species deletion in a deterministic environment but when demographic stochasticity is included the benefits of redundancy are largely lost (Paper II). This finding implies that in the construction of nature reserves the advantages of redundancy for conservation of communities may be lost if the reserves are small in size. Additionally, food webs show higher risks of further extinctions after the loss of basal species and herbivores than after the loss of top predators (Paper I and II).

    Secondary extinctions caused by a primary extinction and mediated through direct and indirect effects, are likely to occur with a time delay since the manifestation of indirect effects can take long time to appear. In paper III we show that the loss of a top predator leads to a significantly earlier onset of secondary extinctions in model communities than does the loss of a species from other trophic levels. If local secondary extinctions occur early they are less likely to be balanced by immigration of species from local communities nearby implying that secondary extinctions caused by the loss of top predators are less likely to be balanced by dispersal than secondary extinctions caused by the loss of other species. As top predators are vulnerable to human-induced disturbances on ecosystems in the first place, our results suggest that conservation of top predators should be a priority. Moreover, in most cases time to secondary extinction is shown to increase with species richness indicating the decay of ecological communities to be slower in species-rich than in species-poor communities.

    Apart from the human-induced disturbances that often force species towards extinction the environment is also, to a smaller or larger extent, varying over time in a natural way. Such environmental stochasticity influences the dynamics of populations. In paper IV we compare the responses of food webs of different sizes to environmental stochasticity. Species-rich webs are found to be more sensitive to environmental stochasticity. Particularly, species-rich webs lose a greater proportion of species than species-poor webs and they also begin losing species faster than species-poor webs. However, once one species is lost time to final extinction is longer in species-rich webs than in species-poor webs. We also find that the results differ depending on whether species respond similarly to environmental fluctuations or whether they are totally uncorrelated in their response. For a given species richness, communities with uncorrelated species responses run a considerable higher risk of losing a fixed proportion of species compared with communities with correlated species responses.

    List of papers
    1. Biodiversity lessens the risk of cascading extinction in model food webs
    Open this publication in new window or tab >>Biodiversity lessens the risk of cascading extinction in model food webs
    2000 (English)In: Ecology Letters, ISSN 1461-023X , Vol. 3, no 2, p. 131-136Article in journal (Refereed) Published
    Abstract [en]

    Due to the complex interactions between species in food webs, the extinction of one species could lead to a cascade of further extinctions and hence cause dramatic changes in species composition and ecosystem processes. We found that the risk of additional species extinction, following the loss of one species in model food webs, decreases with the number of species per functional group. For a given number of species per functional group, the risk of further extinctions is highest when an autotroph is removed and lowest when a top predator is removed. In addition, stability decreases when the distribution of interaction strengths in the webs is changed from equal to skew (few strong and many weak links). We also found that omnivory appears to stabilize model food webs. Our results indicate that high biodiversity may serve as an insurance against radical ecosystem changes.

    Keywords
    Biodiversity, extinction • food webs, functional groups, redundancy, resistance, species deletion, stability
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-13855 (URN)10.1046/j.1461-0248.2000.00130.x (DOI)
    Available from: 2006-06-08 Created: 2006-06-08
    2. Community viability analysis: the response of ecological communities to species loss.
    Open this publication in new window or tab >>Community viability analysis: the response of ecological communities to species loss.
    2004 (English)In: Ecology, ISSN 0012-9658, Vol. 85, no 9, p. 2591-2600Article in journal (Refereed) Published
    Abstract [en]

    The loss of a species from an ecological community can set up a cascade of secondary extinctions that in the worst case could lead to the collapse of the community. Both deterministic and stochastic mechanisms may be involved in such secondary extinctions. To investigate the extent of secondary extinctions in ecological communities following the loss of a species, we here develop a community viability analysis. We introduce a measure called the “quasi-collapse risk” that is defined as the probability that the number of species in a community falls below some defined value within a fixed period of time following the loss of a species. We develop deterministic and stochastic methods for finding post-extinction communities. We use these methods to investigate the relationship between diversity (species richness) and quasi-collapse risks in model communities. It is shown that, in a deterministic context, communities with more species within trophic levels have a larger fraction of species remaining in post-extinction communities. This benefit of species richness is to a large extent lost in the presence of demographic stochasticity. The reason for this is a negative relationship between population density and species diversity. We also show that communities become increasingly triangular in shape as secondary extinctions take place, due to greater extinction risk of species at higher trophic levels. We argue that this new approach holds some promise for identifying fragile ecosystems and keystone species.

    Keywords
    collapse risk, community viability analysis, demographic stochasticity, individual-based models, permanence, redundancy, secondary extinctions, species diversity, species loss
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-13856 (URN)10.1890/03-8018 (DOI)
    Available from: 2006-06-08 Created: 2006-06-08 Last updated: 2009-05-08
    3. Early onset of secondary extinctions in ecological communities following the loss of top predators
    Open this publication in new window or tab >>Early onset of secondary extinctions in ecological communities following the loss of top predators
    2006 (English)In: Ecology Letters, ISSN 1461-023X, E-ISSN 1461-0248, Vol. 9, no 4, p. 435-442Article in journal (Refereed) Published
    Abstract [en]

    The large vulnerability of top predators to human-induced disturbances on ecosystems is a matter of growing concern. Because top predators often exert strong influence on their prey populations their extinction can have far-reaching consequences for the structure and functioning of ecosystems. It has, for example, been observed that the local loss of a predator can trigger a cascade of secondary extinctions. However, the time lags involved in such secondary extinctions remain unexplored. Here we show that the loss of a top predator leads to a significantly earlier onset of secondary extinctions in model communities than does the loss of a species from other trophic levels. Moreover, in most cases time to secondary extinction increases with increasing species richness. If local secondary extinctions occur early they are less likely to be balanced by immigration of species from local communities nearby. The implications of these results for community persistence and conservation priorities are discussed.

    Keywords
    Ecological community, food web, relaxation time, secondary extinction, species interactions, species loss, species richness, top predators, trophic level
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-13857 (URN)10.1111/j.1461-0248.2006.00893.x (DOI)
    Available from: 2006-06-08 Created: 2006-06-08 Last updated: 2017-12-13
    4. Biodiversity and persistence of ecological communities in a stochastic environment
    Open this publication in new window or tab >>Biodiversity and persistence of ecological communities in a stochastic environment
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13858 (URN)
    Available from: 2006-06-08 Created: 2006-06-08 Last updated: 2010-01-13
  • 240.
    Borutinskaite, Veronika Viktorija
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Characterization of proteins involved in differentiation and apoptosis of human leukemia and epithelial cancer cells2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today, cancer is understood as an epigenetic as well as a genetic disease. The main epigenetic hallmarks of the cancer cell are DNA methylation and histone modifications. The latter changes may be an optimal target for novel anticancer agents. The main goal of using histone deacetylase inhibitors (HDACIs) would be restoration of gene expression of those tumor-suppressor genes that have been transcriptionally silenced by promoter-associated histone deacetylation. However, HDACIs have pleiotropic effects that we are only just starting to understand. These may also be responsible for the induction of differentiation, cell-cycle arrest and pro-apoptotic effects.

    There are now so many HDACIs available, with such different chemical structures and biological and biochemical properties, that it is hopeful that at least some of them will succeed, probably in combination with other agents or therapies.

    In our studies we focussed ourselves on studies some new HDACIs, that can be useful for treating cancers, including leukemia and epithelial cancer. To do that, we used novel HDACIs, like BML-210, and their combination with the differentiation inducer all-trans retinoic acid (ATRA). Cell differentiation and proliferation in general, and specific gene expression require de novo protein synthesis and/or post-translational protein modifications. So, we tried to identify proteins in general and specifically the proteins that could be important for the cell differentiation process, and when and where in the cell the proteins appear.

    We delineated that HDACIs inhibited leukemia (NB4 and HL-60) cell growth in a time- and dose-dependent way. Moreover, BML-210 blocked HeLa cell growth and promoted apoptosis in a time-dependent way. Combining of BML-210 with ATRA induced a differentiation process in leukemia cell lines that lead to apoptosis. This correlated with cell cycle arrest in G0/G1 stage and changes in expression of cell cycle proteins (p21, p53), transcription factors (NF-κB, Sp1) and their binding activity to consensus or specific promoter sequences. We also assessed histone modifications, i.e. H3 phosphorylation and H4 hyperacetylation due to HDACI, leading to chromatin remodeling and changes in gene transcriptions.

    We have also studied changes in protein maps caused by HDACIs and differentiation agents, identifying differences for a few proteins due to growth inhibition and induction of differentiation in NB4 cells using BML-210 alone or in combination with ATRA. These proteins are involved in cell proliferation and signal transduction, like Rab, actin and calpain. One of them was alpha-dystrobrevin (α-DB). To further study possible roles of the latter, we determined changes of α-DB protein isoform expression that correlated with induction of differentiation. We thus identified a novel ensemble of α-DB interacting proteins in promyelocytic leukemia cells, including tropomyosin 3, actin, tubulin, RIBA, STAT and others, being important in cytoskeleton reorganization and signal transduction. Using confocal microscopy, we determined that α-DB co-localizes with HSP90 and F-actin in NB4 and HeLa cells. We also revealed that it changes sub-cellular compartment after treatment with ATRA and/or BML-210. α-DB silencing affected F-actin expression in HeLa cells, further supporting the idea that α-DB is involved in cytoskeleton reorganization in cells. Altogether, our results suggest that α−DB may work as a structural protein during proliferation and differentiation processes of human cancer cells.

    Based on our findings, we suggest that HDACIs, like BML-210, can be promising anticancer agents, especially in leukemia treatment, by inducing apoptosis and regulating proliferation and differentiation through the modulation of histone acetylations and gene expression.

    List of papers
    1. The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines
    Open this publication in new window or tab >>The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines
    Show others...
    2006 (English)In: European Journal of Pharmacology, ISSN 0014-2999, Vol. 549, no 1-3, p. 9-18Article in journal (Refereed) Published
    Abstract [en]

    Histone deacetylase inhibitors have a potent role in the strategy for the treatment of leukemias. BML-210 (N-(2-Aminophenyl)-N′ phenyloctanol diamine) is the novel histone deacetylase inhibitor, and its mechanism of action has not been characterized. In this study, we examined the in vitro effects of BML-210 on the human leukemia cell lines (NB4, HL-60, THP-1, and K562). We found that BML-210 inhibits the growth of all cell lines and promotes apoptosis in a dose- and time-dependent manner. BML-210 alone induces HL-60 and K562 cell differentiation (up to 30%) to granulocytes and erythrocytes, respectively, and in combination with differentiation agents — all-trans retinoic acid and hemin, markedly potentates it. Those treatments cause G1 arrest and histone H4 acetylation, affects transcription factor NF-κB and Sp1 binding activity to their consensus sequences, the p21 or the FasL promoters, and influences expression of Sp1, NF-κB, p21 and FasL. These findings suggest that BML-210 could be a promising antileukemic agent to induce apoptosis and to modulate differentiation through the modulation of histone acetylation and gene expression.

    Keywords
    Apoptosis; Differentiation; Histone deacetylase inhibitor; Leukemia; Transcription factors
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13262 (URN)10.1016/j.ejphar.2006.08.010 (DOI)
    Available from: 2008-05-30 Created: 2008-05-30
    2. Apoptotic effects of the novel histone deacetylase inhibitor BML-210 on HeLa cells
    Open this publication in new window or tab >>Apoptotic effects of the novel histone deacetylase inhibitor BML-210 on HeLa cells
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13263 (URN)
    Available from: 2008-05-30 Created: 2008-05-30 Last updated: 2010-01-13
    3. Effects of retinoic acid and histone deacetylase inhibitor Bml-210 on protein expression in NB4 cells
    Open this publication in new window or tab >>Effects of retinoic acid and histone deacetylase inhibitor Bml-210 on protein expression in NB4 cells
    2005 (English)In: Biologija, ISSN 1392-0146, Vol. 4, p. 88-93Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13264 (URN)
    Available from: 2008-05-30 Created: 2008-05-30
    4. Multiple roles of alpha-dystrobrevin in human cancer cells during proliferation and differentiation processes
    Open this publication in new window or tab >>Multiple roles of alpha-dystrobrevin in human cancer cells during proliferation and differentiation processes
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13265 (URN)
    Available from: 2008-05-30 Created: 2008-05-30 Last updated: 2010-01-13
    5. Retinoic acid and histone deacelytase inhibitor BML-210 inhibit proliferation of human cervical cancer HeLa cells
    Open this publication in new window or tab >>Retinoic acid and histone deacelytase inhibitor BML-210 inhibit proliferation of human cervical cancer HeLa cells
    2006 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, Vol. 1091, p. 346-355Article in journal (Refereed) Published
    Abstract [en]

    Human papillomavirus (HPV) infection is believed to be the central cause of cervical cancer. The viral proteins E6 and E7 from high-risk HPV types prevent cells from differentiating apoptosis and inducing hyperproliferative lesions. Human cervical carcinoma HeLa cells contain integrated human papillomavirus type 18 (HPV-18). Retinoic acid (RA) is a key regulator of epithelial cell differentiation and a growth inhibitor in vitro of HeLa cervical carcinoma cells. Cellular responses to RA are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors. On the other hand, histone deacetylase inhibitors have been shown to be chemopreventive agents for the treatment of cancer cells. In this article, we have examined the antiproliferative effect of RA and histone deacetylase inhibitor BML-210 on HeLa cells, and particularly the effects on protein expression that may be involved in the cell cycle control and apoptosis. Our data suggest that a combination of RA and BML-210 leads to cell growth inhibition with subsequent apoptosis in a treatment time-dependent manner. We confirm that BML-210 alone or in combination with RA causes a marked increase in the level of p21. The changes in the p53 level are under the influence of p38 phosphorylation. We also discovered that the histone deacetylase inhibitor BML-210 causes increased levels of anti-apoptotic protein Bcl-2 and phosphorylated p38 MAP Kinase; the latter link in cell cycle arrest with response to extracellular stimuli. Our results suggest that RA and BML-210 are involved in different signaling pathways that regulate cell cycle arrest and lead to apoptosis of HeLa cells.

    Keywords
    histone deacetylase inhibitor, proliferation, p53, p21
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13266 (URN)10.1196/annals.1378.079 (DOI)
    Available from: 2008-05-30 Created: 2008-05-30 Last updated: 2009-05-07
    6. The histone deacetylase inhibitor FK228 distinctly sensitizes the human leukemia cells to retinoic acid-induced differentiation
    Open this publication in new window or tab >>The histone deacetylase inhibitor FK228 distinctly sensitizes the human leukemia cells to retinoic acid-induced differentiation
    Show others...
    2006 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, Vol. 1091, p. 368-384Article in journal (Refereed) Published
    Abstract [en]

    FK228 (depsipeptide) is a novel histone deacetylase inhibitor (HDACI) that has shown therapeutical efficacy in clinical trials for malignant lymphoma. In this article, we examined in vitro effects of FK228 on human leukemia cell lines, NB4 and HL-60. FK228 alone (0.2–1 ng/mL) inhibited leukemia cell growth in a dose-dependent manner and induced death by apoptosis. FK228 had selective differentiating effects on two cell lines when used for 6 h before induction of granulocytic differentiation by retinoic acid (RA) or in combination with RA. These effects were accompanied by a time- and dose-dependent histone H4 hyper-acetylation or histone H3 dephosphorylation and alterations in DNA binding of NF-κB in association with cell death and differentiation. Pifithrin-α (PFT), an inhibitor of p53 transcriptional activity, protected only NB4 cells with functional p53 from FK228-induced apoptosis and did not interfere with antiproliferative activity in p53-negative HL-60 cells. In NB4 cells, PFT inhibited p53 binding to the p21 (Waf1/Cip1) promotor and induced DNA binding of NF-κB leading to enhanced cell survival. Thus, beneficial effects of FK228 on human promyelocytic leukemia may be exerted through the induction of differentiation or apoptosis via histone modification and selective involvement of transcription factors, such as NF-κB and p53.

    Keywords
    differentiation, histone deacetylase inhibitor, leukemia, NF-κB, p53
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13267 (URN)10.1196/annals.1378.081 (DOI)
    Available from: 2008-05-30 Created: 2008-05-30 Last updated: 2011-01-11
  • 241.
    Bosagna, Carlos Guerrero
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Developmental and Epigenetic Origins of Male Reproductive Pathologies2015In: The Epigenome and Developmental Origins of Health and Disease / [ed] Cheryl Rosenfeld, Elsevier, 2015, 1, p. 171-189Chapter in book (Refereed)
    Abstract [en]

    Transgenerational epigenetic inheritance has gained increased attention due to the possibility that exposure to environmental toxicants or other stressors can induce long-lasting changes in lineages of organisms. The mechanism involves exposure of pregnant females and induction of germline epigenetic alterations in their developing embryos. This early developmental exposure generates phenotypic alterations in the adults. The germline epigenomic changes produced are then transmitted to future generations and associate with disease phenotypes in the unexposed individuals of subsequent generations. Exposures to environmental toxicants such as fungicides, pesticides, or plastic compounds have been shown in rodents to produce abnormal reproductive or metabolic phenotypes that are transgenerationally transmitted. These include transgenerational increases in the incidence of obesity, polycystic ovary syndrome (PCOS)-like symptoms, pregnancy defects, or germ cell apoptosis. Importantly, the increased incidence of these transgenerationally transmitted diseases in response to environmental exposures in animal models is sometimes drastic. The current evidence on transgenerational epigenetic inheritance observed in animal models allows predicting that environmental exposures of today's inhabitants of the world may affect the incidence of noninfectious diseases in future generations, which would be correlated with long-lasting alterations in the epigenome. The present chapter summarizes the evidence to date for transgenerational epigenetic inheritance, in both humans and animal models.

  • 242.
    Bouwman, Henk
    et al.
    Nort-West University, South Africa.
    Krátká, M
    Masaryk University, Czech Republic.
    Choong Kwet Yive, Nee Sun
    University of Mauritius, Mauritius.
    Kylin, Henrik
    Linköping University, The Tema Institute, Department of Water and Environmental Studies. Linköping University, Faculty of Arts and Sciences.
    Klanova, Jana
    Masaryk University, Czech Republic.
    Do POPs Transfer from Plastic Marine Debris to Coral on Tropical Islands?2014In: Organohalogen Compounds, ISSN 1026-4892, Vol. 76, p. 1352-1355Article in journal (Refereed)
  • 243.
    Bouwman, Henk
    et al.
    North-West University, South Africa.
    Kylin, Henrik
    Linköping University, The Tema Institute, Department of Water and Environmental Studies. Linköping University, Faculty of Arts and Sciences.
    Louette, Michel
    Royal Museum for Central Africa, Belgium.
    Using ringing data to update the continental distributions of the subspecies of the Lesser Black-Backed Gull2012In: Afring News, ISSN 2222-341X, Vol. 41, p. 13-15Article in journal (Refereed)
  • 244.
    Bouwman, Hindrik
    et al.
    North West University, South Africa .
    Kylin, Henrik
    Linköping University, The Tema Institute, Department of Water and Environmental Studies. Linköping University, Faculty of Arts and Sciences.
    Sun Choong Kwet Yive, Nee
    Mauritian Wildlife Fdn, Mauritius .
    Loken, Katharina
    Norwegian School Vet Science, Norway .
    Utne Skaare, Janneche
    Norwegian School Vet Science, Norway .
    Polder, Anuschka
    Norwegian School Vet Science, Norway .
    First report of chlorinated and brominated hydrocarbon pollutants in marine bird eggs from an oceanic Indian Ocean island2012In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 118, p. 53-64Article in journal (Refereed)
    Abstract [en]

    We report for the first time levels of persistent organic pollutants in marine bird eggs from an oceanic island in the Indian Ocean, the worlds third largest ocean. Ten eggs each of the Common Noddy, also known as the Brown Noddy (Anous stolidus), and Sooty Tern (Sterna fuscata) were collected from Ile Cocos off the coast of the island of Rodrigues, located 560 km east of the island of Mauritius. Sigma PCBs had the highest levels (2.2 and 2.6 ng/g wm, wet mass; 20 and 19 ng/g lm, lipid mass) for common Noddy and Sooty Tern, respectively (and following), then Sigma DDT (1.9 and 3.1 ng/g wm; 17 and 23 ng/g lm), and mirex (0.96 and 0.69 ng/g wm; 8.7 and 5.0 ng/g lm). Sigma Chlordanes (0.094 and 0.15 ng/g wm; 0.48 and 0.73 ng/g lm) and Sigma toxaphenes (0.26 and 0.61 ng/g wm; 2.4 and 5.9 ng/g lm) are rare data for these compounds from this ocean. Brominated flame retardants were low (0.08 and 0.07 ng/g wm; 0.7 and 0.7 ng/g lm). Multivariate analyses indicated different contamination patterns in the prey items as Sooty Terns had significantly higher levels of mean Sigma chlordanes and Sigma toxaphenes, as well as CB105, -108 and -157. p,p-DDE had an association with thinner eggshells in the Sooty Tern. Although the contaminant levels were in all respects low, industrialisation, development on the periphery, commercial exploitation of the marine environment, and pollutants transferred over long distances by marine debris is likely to add to chemical pressure in this region. Monitoring changes in background levels of pollutants in remote regions will indicate such trends, and marine bird eggs from Rodrigues would be an excellent site.

  • 245.
    Bragde, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Jansson, Ulf
    Ryhov Cty Hosp, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Division of Forensic Genetics & Forensic Toxicology National Board of Forensic Medicine Linköping, Sweden.
    Söderman, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies2018In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 75, no 23, p. 4385-4401Article in journal (Refereed)
    Abstract [en]

    Establishing a celiac disease (CD) diagnosis can be difficult, such as when CD-specific antibody levels are just above cutoff or when small intestinal biopsies show low-grade injuries. To investigate the biological pathways involved in CD and select potential biomarkers to aid in CD diagnosis, RNA sequencing of duodenal biopsies from subjects with either confirmed Active CD (n=20) or without any signs of CD (n=20) was performed. Gene enrichment and pathway analysis highlighted contexts, such as immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. Twenty-nine potential CD biomarkers were selected based on differential expression and biological context. The biomarkers were validated by real-time polymerase chain reaction of eight RNA sequencing study subjects, and further investigated using an independent study group (n=43) consisting of subjects not affected by CD, with a clear diagnosis of CD on either a gluten-containing or a gluten-free diet, or with low-grade intestinal injury. Selected biomarkers were able to classify subjects with clear CD/non-CD status, and a subset of the biomarkers (CXCL10, GBP5, IFI27, IFNG, and UBD) showed differential expression in biopsies from subjects with no or low-grade intestinal injury that received a CD diagnosis based on biopsies taken at a later time point. A large number of pathways are involved in CD pathogenesis, and gene expression is affected in CD mucosa already in low-grade intestinal injuries. RNA sequencing of low-grade intestinal injuries might discover pathways and biomarkers involved in early stages of CD pathogenesis.

  • 246.
    Brandao, Wesley Nogueira
    et al.
    Univ Sao Paulo, Brazil.
    Andersen, Monica Levy
    Fed Univ Sao Paulo UNIFESP EPM, Brazil.
    Palermo-Neto, Joao
    Univ Sao Paulo, Brazil.
    Peron, Jean Pierre
    Univ Sao Paulo, Brazil.
    Zager, Adriano
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Univ Sao Paulo, Brazil.
    Therapeutic treatment with Modafinil decreases the severity of experimental autoimmune encephalomyelitis in mice2019In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 75, article id 105809Article in journal (Refereed)
    Abstract [en]

    The psychostimulant drug modafinil has been used for many years for the treatment of sleep disorders. Recent studies have indicated that modafinil has immunomodulatory properties in the central nervous system (CNS) and peripheral immune cells. Thus, our aim was to determine the effects of in vivo therapeutic treatment with modafinil on the severity of clinical symptoms and immune response during the acute phase of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis. Modafinil treatment, given after the onset of symptoms, resulted in an improvement of EAE symptoms and motor impairment, which was correlated with reduced cellular infiltrate and a decreased percentage of T helper (Th) 1 cells in the CNS. The spinal cord analysis revealed that modafinil treatment decreased interferon (IFN)-y and interleukin (IL)-6 protein levels and down regulated genes related to Th1 immunity, such as IFN-gamma and TBX21, without affecting Th17-related genes. Our research indicates that therapeutic modafinil treatment has anti-inflammatory properties in an EAE model by inhibiting brain Th1 response, and may be useful as adjuvant treatment for multiple sclerosis.

  • 247.
    Bravo, Gustavo A.
    et al.
    Harvard Univ, MA 02138 USA.
    Antonelli, Alexandre
    Harvard Univ, MA 02138 USA; Gothenburg Global Biodivers Ctr, Sweden; Univ Gothenburg, Sweden; Gothenburg Bot Garden, Sweden.
    Bacon, Christine D.
    Gothenburg Global Biodivers Ctr, Sweden; Univ Gothenburg, Sweden.
    Bartoszek, Krzysztof
    Linköping University, Department of Computer and Information Science, The Division of Statistics and Machine Learning. Linköping University, Faculty of Arts and Sciences.
    Blom, Mozes P. K.
    Swedish Museum Nat Hist, Sweden.
    Huynh, Stella
    Univ Neuchatel, Switzerland.
    Jones, Graham
    Univ Gothenburg, Sweden.
    Knowles, L. Lacey
    Univ Michigan, MI 48109 USA.
    Lamichhaney, Sangeet
    Harvard Univ, MA 02138 USA.
    Marcussen, Thomas
    Univ Oslo, Norway.
    Morlon, Helene
    Ecole Normale Super Paris, France.
    Nakhleh, Luay K.
    Rice Univ, TX USA.
    Oxelman, Bengt
    Gothenburg Global Biodivers Ctr, Sweden; Univ Gothenburg, Sweden.
    Pfeil, Bernard
    Univ Gothenburg, Sweden.
    Schliep, Alexander
    Chalmers Univ Technol, Sweden; Univ Gothenburg, Sweden.
    Wahlberg, Niklas
    Lund Univ, Sweden.
    Werneck, Fernanda P.
    Inst Nacl de Pesquisas da Amazonia, Brazil.
    Wiedenhoeft, John
    Chalmers Univ Technol, Sweden; Univ Gothenburg, Sweden; Rutgers State Univ, NJ USA.
    Willows-Munro, Sandi
    Univ Kwazulu Natal, South Africa.
    Edwards, Scott V
    Harvard Univ, MA 02138 USA; Univ Gothenburg, Sweden; Chalmers Univ Technol, Sweden.
    Embracing heterogeneity: coalescing the Tree of Life and the future of phylogenomics2019In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 7, article id e6399Article in journal (Refereed)
    Abstract [en]

    Building the Tree of Life (ToL) is a major challenge of modern biology, requiring advances in cyberinfrastructure, data collection, theory, and more. Here, we argue that phylogenomics stands to benefit by embracing the many heterogeneous genomic signals emerging from the first decade of large-scale phylogenetic analysis spawned by high-throughput sequencing (HTS). Such signals include those most commonly encountered in phylogenomic datasets, such as incomplete lineage sorting, but also those reticulate processes emerging with greater frequency, such as recombination and introgression. Here we focus specifically on how phylogenetic methods can accommodate the heterogeneity incurred by such population genetic processes; we do not discuss phylogenetic methods that ignore such processes, such as concatenation or supermatrix approaches or supertrees. We suggest that methods of data acquisition and the types of markers used in phylogenomics will remain restricted until a posteriori methods of marker choice are made possible with routine whole-genome sequencing of taxa of interest. We discuss limitations and potential extensions of a model supporting innovation in phylogenomics today, the multispecies coalescent model (MSC). Macroevolutionary models that use phylogenies, such as character mapping, often ignore the heterogeneity on which building phylogenies increasingly rely and suggest that assimilating such heterogeneity is an important goal moving forward. Finally, we argue that an integrative cyberinfrastructure linking all steps of the process of building the ToL, from specimen acquisition in the field to publication and tracking of phylogenomic data, as well as a culture that values contributors at each step, are essential for progress.

  • 248.
    Brengdahl, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Differentiation of dispersive traits under a fluctuating range distribution in Asellus aquaticus2014Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    Knowledge about dispersion is of utmost importance for understanding populations’ reaction to changes in the environment. Expansion of a population range brings with it both spatial sorting and over time, spatial selection. This means that dispersion rates increases over time at the expanding edge. Most studies have so far been performed on continuously expanding populations. This study aims to bring more knowledge about dispersal biology in dynamic systems. I studied dispersal traits in two permanent and two seasonal vegetation habitats of an isopod (Asellus aquaticus), for which differentiation between habitat types has previously been shown. I quantified differences in displacement (dispersal rate) and three morphological traits, head angle (body streamline) and leg of the third and seventh pair of legs. Isopods from the seasonal vegetation had higher displacement rates than animals from permanent vegetation. This inclines that mechanisms driving spatial selection in expanding population ranges also exist in dynamic systems. The more streamlined isopods found in seasonal sites further points towards spatial sorting by dispersion capability. Because no effect of permanence was found on leg length and there was no correlation between streamlining and displacement, the higher dispersion among animals from seasonal habitats most likely derives from behavioral differences.

  • 249.
    Brengdahl, Martin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Dispersive trait expression of Asellus aquaticus from a rare cave habitat2016Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    Dispersal influences several ecological and evolutionary processes, such as intraspecific competition, genetic drift and inbreeding. It can lead to phenotypic mismatch with the habitat when a locally adapted individual winds up in an environment with a divergent selection regime compared to the source habitat. The aim of this project was to compare dispersive traits in the freshwater isopod Asellus aquaticus from a cave habitat, with surface dwelling isopods collected upstream and downstream from the cave system. The subterranean stream (cave) represents a rare, geographically limited habitat which has a divergent selective pressure compared to the surrounding habitats. Experiments on dispersal were performed in the laboratory, in darkness with IR-equipment for visualization. Displacement was measured using one-dimensional test arenas. Compared to the surface phenotype, the cave phenotype was expected to have reduced fitness outside of the cave and unlikely to successfully disperse to new areas of similar suitable conditions. The results did not follow my main hypothesis that isopods from the cave would be less dispersive than individuals from the surface. The inconclusive results might derive from large variation in the data and divergent adaptations which yield similar expression of dispersal.

  • 250.
    Brengdahl, Martin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Kimber, Christopher
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Maguire-Baxter, Jack
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Friberg, Urban
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Sex differences in life span: Females homozygous for the X chromosome do not suffer the shorter life span predicted by the unguarded X hypothesis2018In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 72, no 3, p. 568-577Article in journal (Refereed)
    Abstract [en]

    Life span differs between the sexes in many species. Three hypotheses to explain this interesting pattern have been proposed, involving different drivers: sexual selection, asymmetrical inheritance of cytoplasmic genomes, and hemizygosity of the X(Z) chromosome (the unguarded X hypothesis). Of these, the unguarded X has received the least experimental attention. This hypothesis suggests that the heterogametic sex suffers a shortened life span because recessive deleterious alleles on its single X(Z) chromosome are expressed unconditionally. In Drosophila melanogaster, the X chromosome is unusually large (approximate to 20% of the genome), providing a powerful model for evaluating theories involving the X. Here, we test the unguarded X hypothesis by forcing D. melanogaster females from a laboratory population to express recessive X-linked alleles to the same degree as males, using females exclusively made homozygous for the X chromosome. We find no evidence for reduced life span or egg-to-adult viability due to X homozygozity. In contrast, males and females homozygous for an autosome both suffer similar, significant reductions in those traits. The logic of the unguarded X hypothesis is indisputable, but our results suggest that the degree to which recessive deleterious X-linked alleles depress performance in the heterogametic sex appears too small to explain general sex differences in life span.

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