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  • 1.
    Abbey-Lee, Robin
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten. Max Planck Inst Ornithol, Germany.
    Araya-Ajoy, Yimen G.
    Norwegian Univ Sci and Technol, Norway.
    Mouchet, Alexia
    Max Planck Inst Ornithol, Germany.
    Moiron, Maria
    Max Planck Inst Ornithol, Germany.
    Stuber, Erica F.
    Univ Nebraska Lincoln, NE USA.
    Kempenaers, Bart
    Max Planck Inst Ornithol, Germany.
    Dingemanse, Niels J.
    Max Planck Inst Ornithol, Germany; Ludwig Maximilians Univ Munchen, Germany.
    Does perceived predation risk affect patterns of extra-pair paternity? A field experiment in a passerine bird2018Ingår i: Functional Ecology, ISSN 0269-8463, E-ISSN 1365-2435, Vol. 32, nr 4, s. 1001-1010Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Non-consumptive predator effects have been shown to influence a wide range of behavioural, life history and morphological traits. Extra-pair reproduction is widespread among socially monogamous birds and may incur predation costs. Consequently, altered rates of extra-pair reproduction are expected in circumstances characterized by increased adult perceived predation risk. In addition, extra-pair reproduction is expected to be most affected for birds with phenotypes that generally increase predation risk (such as more active individuals). In two consecutive years, perceived predation risk was manipulated for great tits Parus major breeding in 12 nest-box plots by broadcasting sounds of their main predator (European sparrowhawk Accipiter nisus; six plots). As a control treatment, sounds of a sympatric, avian non-predator species were broadcast (Eurasian blackbird Turdus merula; six plots). Levels of extra-pair paternity did not differ between plots with different predation risk treatments. Males that moved more in a novel environment (more active or faster exploring) tended to have offspring with fewer partners, but this effect did not vary with predation risk treatment. From an adaptive viewpoint, predation costs associated with extra-pair reproduction may be small and may not outweigh the benefits of extra-pair behaviour. Research on a broader range of taxa with different mating strategies is now needed to confirm the generality of our findings.

  • 2.
    Abbey-Lee, Robin
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten. Max Planck Inst Ornithol, Germany.
    Dingemanse, Niels J.
    Ludwig Maximilians Univ Munchen, Germany.
    Adaptive individual variation in phenological responses to perceived predation levels2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 1601Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The adaptive evolution of timing of breeding (a component of phenology) in response to environmental change requires individual variation in phenotypic plasticity for selection to act upon. A major question is what processes generate this variation. Here we apply multi-year manipulations of perceived predation levels (PPL) in an avian predator-prey system, identifying phenotypic plasticity in phenology as a key component of alternative behavioral strategies with equal fitness payoffs. We show that under low-PPL, faster (versus slower) exploring birds breed late (versus early); the pattern is reversed under high-PPL, with breeding synchrony decreasing in conjunction. Timing of breeding affects reproductive success, yet behavioral types have equal fitness. The existence of alternative behavioral strategies thus explains variation in phenology and plasticity in reproductive behavior, which has implications for evolution in response to anthropogenic change.

  • 3.
    Abbey-Lee, Robin N.
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Kreshchenko, Anastasia
    Mechanical and Aeronautical Engineering Division L5, Department of Mechanical, Aerospace & Civil Engineering, Dalton Nuclear Institute, FSE Research Institutes,The University of Manchester, UK.
    Fernandez Sala, Xavier
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten.
    Petkova, Irina
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten. School of Biological Sciences, Centre for Ecology,Evolution and Behaviour, Royal Holloway University of London, Egham UK.
    Løvlie, Hanne
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Effects of monoamine manipulations on the personality and gene expression of three-spined sticklebacks2019Ingår i: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 222, nr 20, artikel-id jeb211888Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Among-individual behavioral differences (i.e. animal personality) are commonly observed across taxa, although the underlying, causal mechanisms of such differences are poorly understood. Animal personality has been correlated with physiological functions as well as fitness-related traits. Variation in many aspects of monoamine systems, such as metabolite levels and gene polymorphisms, has been linked to behavioral variation. Therefore, here we experimentally investigated the potential role of monoamines in explaining individual variation in personality, using two common pharmaceuticals that respectively alter the levels of serotonin and dopamine in the brain: fluoxetine and ropinirole. We exposed three-spined sticklebacks, a species that shows animal personality, to either chemical alone or to a combination of the two chemicals, for 18 days. During the experiment, fish were assayed at four time points for the following personality traits: exploration, boldness, aggression and sociability. To quantify brain gene expression on short- and longer-term scales, fish were sampled at two time points. Our results show that monoamine manipulations influence fish behavior. Specifically, fish exposed to either fluoxetine or ropinirole were significantly bolder, and fish exposed to the two chemicals together tended to be bolder than control fish. Our monoamine manipulations did not alter the gene expression of monoamine or stress-associated neurotransmitter genes, but control, untreated fish showed covariation between gene expression and behavior. Specifically, exploration and boldness were predicted by genes in the dopaminergic, serotonergic and stress pathways, and sociability was predicted by genes in the dopaminergic and stress pathways. These results add further support to the links between monoaminergic systems and personality, and show that exposure to monoamines can causally alter animal personality.

  • 4.
    Abbey-Lee, Robin N.
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Kreshchenko, Anastasia
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Fernandez Sala, Xavier
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Petkova, Irina
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Løvlie, Hanne
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Effects of monoamine manipulations on the personality and gene expression of three-spined sticklebacks2019Dataset
    Abstract [en]

    Among-individual behavioral differences (i.e. animal personality) are commonly observed across taxa, although the underlying, causal mechanisms of such differences are poorly understood. Animal personality has been implicated in correlations with physiological functions as well as affecting fitness-related traits. Variation in many aspects of monoamine systems, such as metabolite levels and gene polymorphisms, has been linked to behavioral variation. Therefore, here we investigated the potential role of monoamines in explaining individual variation in personality, using two common pharmaceuticals that respectively alter the levels of serotonin and dopamine in the brain: fluoxetine and ropinirole. We exposed three- spined sticklebacks, a species that shows animal personality, to either chemical alone or to a combination of the two chemicals, for 18 days. During the experiment, fish were assayed at four time points for the following personality traits: exploration, boldness, aggression and sociability. To quantify brain gene expression on short- and longer-term scales, fish were sampled at two time points. Our results show that monoamine manipulations influence fish behavior. Specifically, fish exposed to either fluoxetine or ropinirole were significantly bolder, and fish exposed to the two chemicals together tended to be bolder than control fish. Our monoamine manipulations did not alter the gene expression of monoamine or stress-associated neurotransmitter genes, but control, untreated fish showed covariation between gene expression and behavior. Specifically, exploration and boldness were predicted by genes in the dopaminergic, serotonergic and stress pathways, and sociability was predicted by genes in the dopaminergic and stress pathways. These results add further support to the links between monoaminergic systems and personality, and show that exposure to monoamines can causally alter animal personality.

  • 5.
    Abbey-Lee, Robin N.
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Uhrig, Emily J.
    Department of Zoology, Stockholm University, 10691 Stockholm, Sweden.
    Zidar, Josefina
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Favati, Anna
    Department of Zoology, Stockholm University, 10691 Stockholm, Sweden.
    Almberg, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Dahlblom, Josefin
    Department of Neuroscience, Uppsala Biomedical Centre BMC, Uppsala University, Uppsala, Sweden.
    Winberg, Svante
    Department of Neuroscience, Uppsala Biomedical Centre BMC, Uppsala University, Uppsala, Sweden.
    Løvlie, Hanne
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    The influence of rearing on behavior, brain monoamines and gene expression in three-spined sticklebacks2018Dataset
    Abstract [en]
    1. The causes of individual variation in behavior are often not well understood, and potential underlying mechanisms include both intrinsic and extrinsic factors, such as early environmental, physiological, and genetic differences.
    2. In an exploratory laboratory study, we raised three-spined sticklebacks (Gasterosteus aculeatus) under 4 different environmental conditions (simulated predator environment, complex environment, variable social environment, and control). We investigated how these manipulations related to behavior, brain physiology and gene expression later in life, with focus on brain dopamine and serotonin levels, turnover rates, and gene expression.
    3. The different rearing environments influenced behavior and gene expression, but did not alter monoamine levels or metabolites. Specifically, compared to control fish, fish exposed to a simulated predator environment tended to be less aggressive, more exploratory, and more neophobic; and fish raised in both complex and variable social environments tended to be less neophobic. Exposure to a simulated predator environment tended to lower expression of dopamine receptor DRD4A, a complex environment increased expression of dopamine receptor DRD1B, while a variable social environment tended to increase serotonin receptor 5-HTR2B and increased serotonin transporter SLC6A4A expression. Despite both behavior and gene expression varying with early environment, there was no evidence that gene expression mediated the relationship between early environment and behavior.
    4. Our results confirm that environmental conditions early in life can affect phenotypic variation. However, the mechanistic pathway of the monoaminergic systems translating early environmental variation into observed behavioral responses was not detected.
  • 6.
    Abbey-Lee, Robin N.
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Uhrig, Emily
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Zidar, Josefina
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Favati, A.
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Almberg, J.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Dahlbom, J.
    Department of Neuroscience, Uppsala Biomedical Centre BMC, Uppsala University, Uppsala, Sweden.
    Winberg, S.
    Department of Neuroscience, Uppsala Biomedical Centre BMC, Uppsala University, Uppsala, Sweden.
    Løvlie, Hanne
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    The Influence of Rearing on Behavior, Brain Monoamines, and Gene Expression in Three-Spined Sticklebacks2018Ingår i: Brain, behavior, and evolution, ISSN 0006-8977, E-ISSN 1421-9743, Vol. 91, nr 4, s. 201-213Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The causes of individual variation in behavior are often not well understood, and potential underlying mechanisms include both intrinsic and extrinsic factors, such as early environmental, physiological, and genetic differences. In an exploratory laboratory study, we raised three-spined sticklebacks <i>(Gasterosteus aculeatus)</i> under 4 different environmental conditions (simulated predator environment, complex environment, variable social environment, and control). We investigated how these manipulations related to behavior, brain physiology, and gene expression later in life, with focus on brain dopamine and serotonin levels, turnover rates, and gene expression. The different rearing environments influenced behavior and gene expression, but did not alter monoamine levels or metabolites. Specifically, compared to control fish, fish exposed to a simulated predator environment tended to be less aggressive, more exploratory, and more neophobic; and fish raised in both complex and variable social environments tended to be less neophobic. Exposure to a simulated predator environment tended to lower expression of dopamine receptor DRD4A, a complex environment increased expression of dopamine receptor DRD1B, while a variable social environment tended to increase serotonin receptor 5-HTR2B and serotonin transporter SLC6A4A expression. Despite both behavior and gene expression varying with early environment, there was no evidence that gene expression mediated the relationship between early environment and behavior. Our results confirm that environmental conditions early in life can affect phenotypic variation. However, the mechanistic pathway of the monoaminergic systems translating early environmental variation into observed behavioral responses was not detected.

  • 7.
    Abbey-Lee, Robin
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Uhrig, Emily
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten. Southern Oregon Univ, OR 97520 USA.
    Garnham, Laura
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Lundgren, Kristoffer
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Child, Sarah
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten. Univ Manchester, England.
    Lovlie, Hanne
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Experimental manipulation of monoamine levels alters personality in crickets2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 16211Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Animal personality has been described in a range of species with ecological and evolutionary consequences. Factors shaping and maintaining variation in personality are not fully understood, but monoaminergic systems are consistently linked to personality variation. We experimentally explored how personality was influenced by alterations in two key monoamine systems: dopamine and serotonin. This was done using ropinirole and fluoxetine, two common human pharmaceuticals. Using the Mediterranean field cricket (Gryllus bimaculatus), we focused on the personality traits activity, exploration, and aggression, with confirmed repeatability in our study. Dopamine manipulations explained little variation in the personality traits investigated, while serotonin manipulation reduced both activity and aggression. Due to limited previous research, we created a dose-response curve for ropinirole, ranging from concentrations measured in surface waters to human therapeutic doses. No ropinirole dose level strongly influenced cricket personality, suggesting our results did not come from a dose mismatch. Our results indicate that the serotonergic system explains more variation in personality than manipulations of the dopaminergic system. Additionally, they suggest that monoamine systems differ across taxa, and confirm the importance of the mode of action of pharmaceuticals in determining their effects on behaviour.

  • 8.
    Abdelfattah, Ahmed
    et al.
    Univ Mediterranea Reggio Calabria, Italy.
    Malacrinò, Antonino
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Wisniewski, Michael
    USDA ARS, WV 25430 USA.
    Cacciola, Santa O.
    Univ Catania, Italy.
    Schena, Leonardo
    Univ Mediterranea Reggio Calabria, Italy.
    Metabarcoding: A powerful tool to investigate microbial communities and shape future plant protection strategies2018Ingår i: Biological control (Print), ISSN 1049-9644, E-ISSN 1090-2112, Vol. 120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microorganisms are the main drivers shaping the functioning and equilibrium of all ecosystems, contributing to nutrient cycling, primary production, litter decomposition, and multi-trophic interactions. Knowledge about the microbial assemblies in specific ecological niches is integral to understanding the assemblages interact and function the function, and becomes essential when the microbiota intersects with human activities, such as protecting crops against pests and diseases. Metabarcoding has proven to be a valuable tool and has been widely used for characterizing the microbial diversity of different environments and has been utilized in many research endeavors. Here we summarize the current status of metabarcoding technologies, the advantages and challenges in utilizing this technique, and how this pioneer approach is being applied to studying plant diseases and pests, with a focus on plant protection and biological control. Current and future developments in this technology will foster a more comprehensive understanding of microbial ecology, and the development of new, innovative pest control strategies.

  • 9.
    Abrahamsson, S.
    et al.
    SLU, Umeå, Sweden .
    Ahlinder, J.
    FOI, Umeå, Sweden .
    Waldmann, Patrik
    Linköpings universitet, Institutionen för datavetenskap, Statistik. Linköpings universitet, Tekniska högskolan.
    García-Gil, M. R.
    SLU, Umeå, Sweden .
    Maternal heterozygosity and progeny fitness association in an inbred Scots pine population2013Ingår i: Genetica, ISSN 0016-6707, E-ISSN 1573-6857, Vol. 141, nr 1-3, s. 41-50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Associations between heterozygosity and fitness traits have typically been investigated in populations characterized by low levels of inbreeding. We investigated the associations between standardized multilocus heterozygosity (stMLH) in mother trees (obtained from12 nuclear microsatellite markers) and five fitness traits measured in progenies from an inbred Scots pine population. The traits studied were proportion of sound seed, mean seed weight, germination rate, mean family height of one-year old seedlings under greenhouse conditions (GH) and mean family height of three-year old seedlings under field conditions (FH). The relatively high average inbreeding coefficient (F) in the population under study corresponds to a mixture of trees with different levels of co-ancestry, potentially resulting from a recent bottleneck. We used both frequentist and Bayesian methods of polynomial regression to investigate the presence of linear and non-linear relations between stMLH and each of the fitness traits. No significant associations were found for any of the traits except for GH, which displayed negative linear effect with stMLH. Negative HFC for GH could potentially be explained by the effect of heterosis caused by mating of two inbred mother trees (Lippman and Zamir 2006), or outbreeding depression at the most heterozygote trees and its negative impact on the fitness of the progeny, while their simultaneous action is also possible (Lynch. 1991). However,since this effect wasn’t detected for FH, we cannot either rule out that the greenhouse conditions introduce artificial effects that disappear under more realistic field conditions.

  • 10.
    Abrikossova, Natalia
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap. Linköpings universitet, Tekniska fakulteten.
    Investigation of nanoparticle-cell interactions for development of next generation of biocompatible MRI contrast agents2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Progress in synthesis technologies and advances in fundamental understanding of materials with low dimensionality has led to the birth of a new scientific field, nanoscience, and to strong expectations of multiple applications of nanomaterials. The physical properties of small particles are unique, bridging the gap between atoms and molecules, on one side, and bulk materials on the other side. The work presented in this thesis investigates the potential of using magnetic nanoparticles as the next generation of contrast agents for biomedical imaging. The focus is on gadolinium-based nanoparticles and cellular activity including the uptake, morphology and production of reactive oxygen species.

    Gd ion complexes, like Gd chelates, are used today in the clinic, world-wide. However, there is a need for novel agents, with improved contrast capabilities and increased biocompatibility. One avenue in their design is based on crystalline nanoparticles. It allows to reduce the total number of Gd ions needed for an examination. This can be done by nanotechnology, which allows one to improve and fine tune the physico- chemical properties on the nanomaterial in use, and to increase the number of Gd atoms at a specific site that interact with protons and thereby locally increase the signal. In the present work, synthesis, purification and surface modification of crystalline Gd2O3-based nanoparticles have been performed. The nanoparticles are selected on the basis of their physical properties, that is they show enhanced magnetic properties and therefore may be of high potential interest for applications as contrast agents.

    The main synthesis method of Gd2O3 nanoparticles in this work was the modified “polyol” route, followed by purification of as-synthesized DEG-Gd2O3 nanoparticles suspensions. In most cases the purification step involved dialysis of the nanoparticle samples. In this thesis, organosilane were chosen as an exchange agent for further functionalization. Moreover, several paths have been explored for modification of the nanoparticles, including Tb3+ doping and capping with sorbitol.

    Biocompatibility of the newly designed nanoparticles is a prerequisite for their use in medical applications. Its evaluation is a complex process involving a wide range of biological phenomena. A promising path adopted in this work is to study of nanoparticle interactions with isolated blood cells. In this way one could screen nanomaterial prior to animal studies.

    The primary cell type considered in the thesis are polymorphonuclear neutrophils (PMN) which represent a type of the cells of human blood belonging to the granulocyte family of leukocytes. PMNs act as the first defense of the immune system against invading pathogens, which makes them valuable for studies of biocompatibility of newly synthesized nanoparticles. In addition, an immortalized murine alveolar macrophage cell line (MH-S), THP-1 cell line, and Ba/F3 murine bone marrow-derived cell line were considered to investigate the optimization of the cell uptake and to examine the potential of new intracellular contrast agent for magnetic resonance imaging.

    In paper I, the nanoparticles were investigated in a cellular system, as potential probes for visualization and targeting intended for bioimaging applications. The production of reactive oxygen species (ROS) by means of luminol-dependent chemiluminescence from human neutrophils was studied in presence of Gd2O3 nanoparticles. In paper II, a new design of functionalized ultra-small rare earth-based nanoparticles was reported. The synthesis was done using polyol method followed by PEGylation, and dialysis. Supersmall gadolinium oxide (DEG-Gd2O3) nanoparticles, in the range of 3-5 nm were obtained and carefully characterized. Neutrophil activation after exposure to this nanomaterial was studied by means of fluorescence microscopy. In paper III, cell labeling with Gd2O3 nanoparticles in hematopoietic cells was monitored by magnetic resonance imaging (MRI). In paper IV, ultra-small gadolinium oxide nanoparticles doped with terbium ions were synthesized as a potentially bifunctional material with both fluorescent and magnetic contrast agent properties. Paramagnetic behavior was studied. MRI contrast enhancement was received, and the luminescent/ fluorescent property of the particles was attributable to the Tb3+ ion located on the crystal lattice of the Gd2O3 host. Fluorescent labeling of living cells was obtained. In manuscript V, neutrophil granulocytes were investigated with rapid cell signaling communicative processes in time frame of minutes, and their response to cerium-oxide based nanoparticles were monitored using capacitive sensors based on Lab-on-a-chip technology. This showed the potential of label free method used to measure oxidative stress of neutrophil granulocytes. In manuscript VI, investigations of cell-(DEGGd2O3) nanoparticle interactions were carried out. Plain (DEG-Gd2O3) nanoparticles, (DEG-Gd2O3) nanoparticles in presence of sorbitol and (DEG-Gd2O3) nanoparticles capped with sorbitol were studied. Relaxation studies and measurements of the reactive oxygen species production by neutrophils were based on chemiluminescence. Cell morphology was evaluated as a parameter of the nanoparticle induced inflammatory response by means of the fluorescence microscopy.

    The thesis demonstrates high potential of novel Gd2O3-based nanoparticles for development of the next generation contrast agents, that is to find biocompatible compounds with high relaxivity that can be detected at lower doses, and in the future enable targeting to provide great local contrast.

    Delarbeten
    1. Effects of gadolinium oxide nanoparticles on the oxidative burst from human neutrophil granulocytes
    Öppna denna publikation i ny flik eller fönster >>Effects of gadolinium oxide nanoparticles on the oxidative burst from human neutrophil granulocytes
    Visa övriga...
    2012 (Engelska)Ingår i: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 23, nr 27, s. 275101-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We have previously shown that gadolinium oxide (Gd2O3) nanoparticles are promising candidates to be used as contrast agents in magnetic resonance (MR) imaging applications. In this study, these nanoparticles were investigated in a cellular system, as possible probes for visualization and targeting intended for bioimaging applications. We evaluated the impact of the presence of Gd2O3 nanoparticles on the production of reactive oxygen species (ROS) from human neutrophils, by means of luminol-dependent chemiluminescence. Three sets of Gd2O3 nanoparticles were studied, i.e. as synthesized, dialyzed and both PEG-functionalized and dialyzed Gd2O3 nanoparticles. In addition, neutrophil morphology was evaluated by fluorescent staining of the actin cytoskeleton and fluorescence microscopy. We show that surface modification of these nanoparticles with polyethylene glycol (PEG) is essential in order to increase their biocompatibility. We observed that the as synthesized nanoparticles markedly decreased the ROS production from neutrophils challenged with prey (opsonized yeast particles) compared to controls without nanoparticles. After functionalization and dialysis, more moderate inhibitory effects were observed at a corresponding concentration of gadolinium. At lower gadolinium concentration the response was similar to that of the control cells. We suggest that the diethylene glycol (DEG) present in the as synthesized nanoparticle preparation is responsible for the inhibitory effects on the neutrophil oxidative burst. Indeed, in the present study we also show that even a low concentration of DEG, 0.3%, severely inhibits neutrophil function. In summary, the low cellular response upon PEG-functionalized Gd2O3 nanoparticle exposure indicates that these nanoparticles are promising candidates for MR-imaging purposes.

    Ort, förlag, år, upplaga, sidor
    Institute of Physics, 2012
    Nationell ämneskategori
    Teknik och teknologier
    Identifikatorer
    urn:nbn:se:liu:diva-79667 (URN)10.1088/0957-4484/23/27/275101 (DOI)000305802000001 ()
    Tillgänglig från: 2012-08-14 Skapad: 2012-08-13 Senast uppdaterad: 2018-11-12
    2. Synthesis and Characterization of PEGylated Gd2O3 Nanoparticles for MRI Contrast Enhancement
    Öppna denna publikation i ny flik eller fönster >>Synthesis and Characterization of PEGylated Gd2O3 Nanoparticles for MRI Contrast Enhancement
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    2010 (Engelska)Ingår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, nr 8, s. 5753-5762Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Recently, much attention has been given to the development of biofunctionalized nanoparticles with magnetic properties for novel biomedical imaging. Guided, smart, targeting nanoparticulate magnetic resonance imaging (MRI) contrast agents inducing high MRI signal will be valuable tools for future tissue specific imaging and investigation of molecular and cellular events. In this study, we report a new design of functionalized ultrasmall rare earth based nanoparticles to be used as a positive contrast agent in MRI. The relaxivity is compared to commercially available Gd based chelates. The synthesis, PEGylation, and dialysis of small (3−5 nm) gadolinium oxide (DEG-Gd2O3) nanoparticles are presented. The chemical and physical properties of the nanomaterial were investigated with Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, and dynamic light scattering. Neutrophil activation after exposure to this nanomaterial was studied by means of fluorescence microscopy. The proton relaxation times as a function of dialysis time and functionalization were measured at 1.5 T. A capping procedure introducing stabilizing properties was designed and verified, and the dialysis effects were evaluated. A higher proton relaxivity was obtained for as-synthesized diethylene glycol (DEG)-Gd2O3 nanoparticles compared to commercial Gd-DTPA. A slight decrease of the relaxivity for as-synthesized DEG-Gd2O3 nanoparticles as a function of dialysis time was observed. The results for functionalized nanoparticles showed a considerable relaxivity increase for particles dialyzed extensively with r1 and r2 values approximately 4 times the corresponding values for Gd-DTPA. The microscopy study showed that PEGylated nanoparticles do not activate neutrophils in contrast to uncapped Gd2O3. Finally, the nanoparticles are equipped with Rhodamine to show that our PEGylated nanoparticles are available for further coupling chemistry, and thus prepared for targeting purposes. The long term goal is to design a powerful, directed contrast agent for MRI examinations with specific targeting possibilities and with properties inducing local contrast, that is, an extremely high MR signal at the cellular and molecular level.

    Ort, förlag, år, upplaga, sidor
    American Chemical Society (ACS), 2010
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-54946 (URN)10.1021/la903566y (DOI)000276562300061 ()
    Tillgänglig från: 2010-04-23 Skapad: 2010-04-23 Senast uppdaterad: 2018-10-29Bibliografiskt granskad
    3. Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement
    Öppna denna publikation i ny flik eller fönster >>Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement
    Visa övriga...
    2011 (Engelska)Ingår i: International journal of nano medicine, ISSN 1178-2013, Vol. 6, s. 3233-3240Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd2O3) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd2O3 nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r1 and r2 at 1.5 T and 21°C, for Gd2O3 nanoparticles in different cell samples were 3.6–5.3 s-1 mM-1 and 9.6–17.2 s-1 mM-1, respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd2O3 nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed.

    Ort, förlag, år, upplaga, sidor
    Manchester, UK: Dove Medical Press Ltd, 2011
    Nyckelord
    gadolinium oxide, magnetic resonance imaging, contrast agent, cell labeling, Ba/F3 cells, THP-1 cells
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-72275 (URN)10.2147/IJN.S23940 (DOI)000298164300001 ()
    Anmärkning

    funding agencies|Swedish Research Council| 621-2007-3810 621-2009-5148 521-2009-3423 |VINNOVA| 2009-00194 |Center in Nanoscience and Technology at LiTH (CeNano)||

    Tillgänglig från: 2011-11-24 Skapad: 2011-11-24 Senast uppdaterad: 2018-10-29
    4. Synthesis and Characterization of Tb3+-Doped Gd2O3 Nanocrystals: A Bifunctional Material with Combined Fluorescent Labeling and MRI Contrast Agent Properties
    Öppna denna publikation i ny flik eller fönster >>Synthesis and Characterization of Tb3+-Doped Gd2O3 Nanocrystals: A Bifunctional Material with Combined Fluorescent Labeling and MRI Contrast Agent Properties
    Visa övriga...
    2009 (Engelska)Ingår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 113, nr 17, s. 6913-6920Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Ultrasmall gadolinium oxide nanoparticles doped with terbium ions were synthesized by the polyol route and characterized as a potentially bifunctional material with both fluorescent and magnetic contrast agent properties. The structural, optical, and magnetic properties of the organic-acid-capped and PEGylated Gd2O3:Tb3+ nanocrystals were studied by HR-TEM, XPS, EDX, IR, PL, and SQUID. The luminescent/fluorescent property of the particles is attributable to the Tb3+ ion located on the crystal lattice of the Gd2O3 host. The paramagnetic behavior of the particles is discussed. Pilot studies investigating the capability of the nanoparticles for fluorescent labeling of living cells and as a MRI contrast agent were also performed. Cells of two cell lines (THP-1 cells and fibroblasts) were incubated with the particles, and intracellular particle distribution was visualized by confocal microscopy. The MRI relaxivity of the PEGylated nanoparticles in water at low Gd concentration was assessed showing a higher T-1 relaxation rate compared to conventional Gd-DTPA chelates and comparable to that of undoped Gd2O3 nanoparticles.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12944 (URN)10.1021/jp808708m (DOI)000265529700009 ()
    Anmärkning

    On the day of the defence date the status of this article was Submitted

    Tillgänglig från: 2008-02-21 Skapad: 2008-02-21 Senast uppdaterad: 2018-10-29Bibliografiskt granskad
  • 11.
    Abrikossova, Natalia
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    In-vitro studier av inflammatorisk svar från helblod och neutrofila granulocyter vid aktivering med nanopartiklar2007Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats
    Abstract [sv]

    Syftet med detta arbete var att studera inflammatoriska effekter i mänskligt helblod och neutrofila granulocyter exponerade och stimulerade av nanopartiklar av gadoliniumoxid. Projektet utreder den toxiska potentialen hos nanopartiklar med olika kemiska och morfologiska egenskaper.

    I experimenten undersöktes cellresponsen hos blodceller exponerade med ofunktionaliserade och funktionaliserade nanopartiklarna. Effekterna av funktionaliserade och ofunktionaliserade nanopartiklarna på aggregation och syreradikalproduktion i helblod och hos neutrofila granulocyter studerades med hjälp av lumi-aggregometri.

    Studier har visat att varken ofunktionaliserade eller funktionaliserade nanopartiklarna ger aggregation i blodet. Syreradikalproduktionen ökar däremot. Resultaten av studier i helblod visar att stimulering med spädnings serier av funktionaliserade nanopartiklar ger mindre frisättning av syreradikaler än spädnings serier med ofunktionaliserade nanopartiklar. Detta bekräftas med studier av morfologiska skillnader i neutrofila granulocyter som var stimulerade med olika typer av nanopartiklar. Detta gjordes med hjälp av fluorescensmikroskopi. Resultaten från studierna tyder på att funktionaliserade nanopartiklar är mindre inflammatoriska än ofunktionaliserade nanopartiklar.

  • 12.
    Abrouk, Michael
    et al.
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Balcarkova, Barbora
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Simkova, Hana
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Kominkova, Eva
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Martis, Mihaela-Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Institute for Bioinformatics and Systems Biology, Helmholtz Center Munich, Neuherberg, Germany.
    Jakobson, Irena
    Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 19086, Estonia.
    Timofejeva, Ljudmilla
    Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 19086, Estonia.
    Rey, Elodie
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Vrana, Jan
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Kilian, Andrzej
    Diversity Arrays Technology Pty Ltd, Yarralumla, ACT2600, Australia.
    Järve, Kadri
    Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 19086, Estonia.
    Dolezel, Jaroslav
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Valarik, Miroslav
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    The in silico identification and characterization of a bread wheat/Triticum militinae introgression line: Characterization of alien introgression in wheat2017Ingår i: Plant Biotechnology Journal, ISSN 1467-7644, E-ISSN 1467-7652, Vol. 15, nr 2, s. 249-256Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The capacity of the bread wheat (Triticum aestivum) genome to tolerate introgression from related genomes can be exploited for wheat improvement. A resistance to powdery mildew expressed by a derivative of the cross bread wheat cv. Tähti ⨯ T. militinae (Tm) is known to be due to the incorporation of a Tm segment into the long arm of chromosome 4A. Here, a newly developed in silico method termed RICh (rearrangement identification and characterization) has been applied to characterize the introgression. A virtual gene order, assembled using the GenomeZipper approach, was obtained for the native copy of chromosome 4A; it incorporated 570 4A DArTseq markers to produce a zipper comprising 2,132 loci. A comparison between the native and introgressed forms of the 4AL chromosome arm showed that the introgressed region is located at the distal part of the arm. The Tm segment, derived from chromosome 7G, harbors 131 homoeologs out of the 357 genes present on the corresponding region of Chinese Spring 4AL. The estimated number of Tm genes transferred along with the disease resistance gene was 169. Characterizing the introgression's position, gene content and internal gene order should facilitate not only gene isolation, but may also be informative with respect to chromatin structure and behavior studies.

  • 13.
    Adams, David A.
    et al.
    Department of Biology, Middle Tennessee State University, USA.
    Walck, Jeffery L.
    Department of Biology, Middle Tennessee State University, USA.
    Howard, R. Stephen
    Department of Biology, Middle Tennessee State University, USA.
    Milberg, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Ekologi. Linköpings universitet, Tekniska högskolan.
    Forest Composition and Structure onGlade-forming Limestones in Middle Tennessee2012Ingår i: Castanea, ISSN 0008-7475, Vol. 77, nr 4, s. 335-347Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Within a successional context, the vegetation associated with the cedar gladeecosystem in middle Tennessee develops from bare limestone bedrock to subclimax redcedar,preclimax oak-hickory, and climax mixed hardwood forests. Studies on the composition andstructure of forests associated with cedar glade–forming limestones (Lebanon, Ridley) are rare.We sampled the canopy and understory of six forest stands in middle Tennessee on theselimestones. Observed number of canopy species was 14–24 across stands; estimated richnesswas greater by 1–3 species (bootstrap) or 3–6 species (first-order jackknife) than observedrichness. With the exception of Ailanthus altissima in one stand, all other canopy species werenative. Juniperus virginiana, Fraxinus americana, Carya ovata, and Quercus muehlenbergii wereprimary canopy components in 4 or 6 stands, and C. glabra, Q. shumardii, Ulmus alata, F.quadrangulata, Q. alba, and Q. velutina in 2–3 stands. When we included stands from apreviously published study (most on the non-glade Carters Limestone) with our data, aprincipal components analysis identified three groups with the axes approximating a moisturebedrockgradient and a time-successional gradient. An examination of regeneration in ourstands predicts that (1) mesophytes and/or fire-sensitive species (Acer saccharum, Fraxinus spp.,Celtis spp.) will increase and (2) xerophytes and/or fire-adapted species (Quercus spp., Caryaspp.) will decrease. Altogether, our results strongly suggest that the oak-hickory stage shown insuccessional outlines of vegetation development associated with the cedar glade ecosystem maynot occur in its current state in the future.

  • 14.
    Admassie, Shimelis
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska högskolan.
    Yang Nilsson, Ting
    University of Addis Ababa, Ethiopia.
    Inganas, Olle
    University of Addis Ababa, Ethiopia.
    Charge storage properties of biopolymer electrodes with (sub)tropical lignins2014Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 16, nr 45, s. 24681-24684Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The electrochemical and charge storage properties of different lignins inside biopolymer electrodes were studied and correlated with the chemical variations of the lignins as indicated from the nuclear magnetic resonance (NMR) spectroscopic data. The varying fractions of monolignols were found to correlate with charge storage properties. It was found that as the sinapyl to guaiacyl (S/G) ratio increased both the specific capacitance and charge capacity increased considerably. This indicates that quinones generated on S-units can contribute more to charge storage in the biopolymer electrodes.

  • 15.
    Agnvall, Beatrix
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Early domestication?: Phenotypic alterations of Red Junglefowl selected for divergent fear of humans2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Den här avhandlingen är ett resultat av ett projekt där vi avlat djur på tamhet för att undersöka egenskapens roll i den tidiga domesticeringen. De domesticerade djur som vi har i vår närhet har alla genomgått en process där de har anpassats för vår miljö. Det skulle kunna liknas vid en snabb evolution, där ett djurs utseende och beteende förändras under en relativt sett kort tid genom avel av människan. Domesticerade djur skiljer sig från sina vilda släktingar på många olika sätt, de kan vara både mindre och större är ursprunget, finnas i olika färgvariationer, ha ändrade kroppsproportioner och de skiljer sig även åt i tröskelvärden för beteende från de vilda djuren. Skillnaderna mellan domesticerade djur och ursprunget är förvånansvärt lika mellan djurarter och man brukar kalla detta för den domesticerade fenotypen.

    I det här projektet ville vi se om den domesticerade fenotypen egentligen är en biprodukt som uppkommer om man avlar djur på tamhet, på så sätt skulle rädslan för människor vara en nyckelegenskap för domesticeringen. För att undersöka detta använde vi det röda djungelhönset (RJF) som alla domesticerade höns härstammar ifrån. I sex generationer avlades RJF som antingen hade hög eller låg rädsla för människor. Eftersom vi bara har ett avelskriterium kan vi dra slutsatsen att om dessa djur kommer att skilja sig åt på fler sätt så beror det på korrelerade selektionseffekter. Det vill säga, man avlar på en egenskap och andra egenskaper följer med.

    I varje generation har vi utfört beteendetester på djuren som främst varit kopplade till rädsla, utforskande och sociala beteenden. Utöver beteendetesterna har vi undersökt djurens kroppsvikt, äggvikt, metabolism, födointag, fjäderdräkt och tagit blodprov för att mäta kortikosteron och serotonin. När djuren har avlivats har vi vägt hjärnan, hjärtat, levern, mjälten och testiklarna.

    Efter sex generationer av selekterad avel hade hönsen i projektet förändrats på olika sätt. Först och främst konstaterade vi att rädslan för människa är möjlig att avla på då den har en signifikant genetisk arvbarhet. De djuren som har en låg rädsla för människor har blivit större, socialt dominanta, lägger större ägg och får större avkomma. Metabolismen har påverkats så att de höns som har låg rädsla för människor har högre metabolism och omsätter även maten mer till tillväxt än de djuren med hög rädsla. Aveln har även påverkat djurens morfologi, de djuren som har hög rädsla för människor och alltså kan anses vara mer som ursprunget har större hjärna, hjärta, lever och mjälte. Många av dessa förändringar som uppkommit redan efter sex generationer korrelerar med de skillnader man ser mellan vilda och domesticerade djur vilket påvisar vikten av egenskapen för domesticeringsprocessen.

    Delarbeten
    1. Heritability and Genetic Correlations of Fear-Related Behaviour in Red Jungelfowl -Possible Implications for Early Domestication
    Öppna denna publikation i ny flik eller fönster >>Heritability and Genetic Correlations of Fear-Related Behaviour in Red Jungelfowl -Possible Implications for Early Domestication
    2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 4, s. e35162-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Domesticated species differ from their wild ancestors in a number of traits, generally referred to as the domesticated phenotype. Reduced fear of humans is assumed to have been an early prerequisite for the successful domestication of virtually all species. We hypothesized that fear of humans is linked to other domestication related traits. For three generations, we selected Red Junglefowl (ancestors of domestic chickens) solely on the reaction in a standardized Fear of Human-test. In this, the birds were exposed for a gradually approaching human, and their behaviour was continuously scored. This generated three groups of animals, high (H), low (L) and intermediate (I) fearful birds. The birds in each generation were additionally tested in a battery of behaviour tests, measuring aspects of fearfulness, exploration, and sociality. The results demonstrate that the variation in fear response of Red Junglefowl towards humans has a significant genetic component and is genetically correlated to behavioural responses in other contexts, of which some are associated with fearfulness and others with exploration. Hence, selection of Red Junglefowl on low fear for humans can be expected to lead to a correlated change of other behavioural traits over generations. It is therefore likely that domestication may have caused an initial suite of behavioural modifications, even without selection on anything besides tameness.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-76833 (URN)10.1371/journal.pone.0035162 (DOI)000305336200026 ()
    Tillgänglig från: 2012-04-20 Skapad: 2012-04-20 Senast uppdaterad: 2017-12-07
    2. Red Junglefowl (Gallus gallus) selected for low fear of humans are larger, more dominant and produce larger offspring
    Öppna denna publikation i ny flik eller fönster >>Red Junglefowl (Gallus gallus) selected for low fear of humans are larger, more dominant and produce larger offspring
    2014 (Engelska)Ingår i: animal, ISSN 1751-7311, Vol. 8, nr 9, s. 1498-1505Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Many traits associated with domestication are suggested to have developed as correlated responses to reduced fear of humans. Tameness may have reduced the stress of living in human proximity and improved welfare in captivity. We selected Red Junglefowl (ancestors of all domestic chickens) for four generations on high or low fear towards humans, mimicking an important aspect of the earliest period of domestication, and tested birds from the third and fourth generation in three different social tests. Growth and plumage condition, as well as size of eggs and offspring were also recorded, as indicators of some aspects of welfare. Birds selected for low fear had higher weight, laid larger eggs and generated larger offspring, and had a better plumage condition. In a social dominance test they also performed more aggressive behaviour and received less of the same, regardless of whether the restricted resource was feed or not. Hence, dominance appeared to increase as a consequence of reduced fear of humans. Furthermore, egg size and the weight of the offspring were larger in the less fearful birds, and plumage condition better, which could be interpreted as the less fearful animals being better adapted to the environment in which they were selected.

    Ort, förlag, år, upplaga, sidor
    Cambridge University Press, 2014
    Nyckelord
    Red Junglefowl, domestication, fearfulness, selection, social behaviour
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:liu:diva-109499 (URN)10.1017/S1751731114001426 (DOI)000342219000013 ()24910136 (PubMedID)
    Tillgänglig från: 2014-08-20 Skapad: 2014-08-20 Senast uppdaterad: 2016-11-17
    3. Is domestication driven by reduced fear of humans? Boldness, metabolism and serotonin levels in divergently selected red junglefowl (Gallus gallus)
    Öppna denna publikation i ny flik eller fönster >>Is domestication driven by reduced fear of humans? Boldness, metabolism and serotonin levels in divergently selected red junglefowl (Gallus gallus)
    2015 (Engelska)Ingår i: Biology Letters, ISSN 1744-9561, E-ISSN 1744-957X, Vol. 11, nr 9, artikel-id 20150509Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Domesticated animals tend to develop a coherent set of phenotypic traits. Tameness could be a central underlying factor driving this, and we therefore selected red junglefowl, ancestors of all domestic chickens, for high or low fear of humans during six generations. We measured basal metabolic rate (BMR), feed efficiency, boldness in a novel object (NO) test, corticosterone reactivity and basal serotonin levels (related to fearfulness) in birds from the fifth and sixth generation of the high- and low-fear lines, respectively (44-48 individuals). Corticosterone response to physical restraint did not differ between selection lines. However, BMR was higher in low-fear birds, as was feed efficiency. Low-fear males had higher plasma levels of serotonin and both low-fear males and females were bolder in an NO test. The results show that many aspects of the domesticated phenotype may have developed as correlated responses to reduced fear of humans, an essential trait for successful domestication.

    Ort, förlag, år, upplaga, sidor
    ROYAL SOC, 2015
    Nyckelord
    genetics; domestication; stress
    Nationell ämneskategori
    Zoologi Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-123162 (URN)10.1098/rsbl.2015.0509 (DOI)000364772300009 ()26382075 (PubMedID)
    Anmärkning

    Funding Agencies|research council Formas; ERC [322206]

    Tillgänglig från: 2015-12-07 Skapad: 2015-12-04 Senast uppdaterad: 2019-10-07Bibliografiskt granskad
    4. Effects of Divergent Selection for Fear of Humans on Behaviour in Red Junglefowl
    Öppna denna publikation i ny flik eller fönster >>Effects of Divergent Selection for Fear of Humans on Behaviour in Red Junglefowl
    2016 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 11, s. 1-12Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Domestication has caused a range of similar phenotypic changes across taxa, relating to physiology, morphology and behaviour. It has been suggested that this recurring domesticated phenotype may be a result of correlated responses to a central trait, namely increased tameness. We selected Red Junglefowl, the ancestors of domesticated chickens, during five generations for reduced fear of humans. This caused a marked and significant response in tameness, and previous studies have found correlated effects on growth, metabolism, reproduction, and some behaviour not directly selected for. Here, we report the results from a series of behavioural tests carried out on the initial parental generation (P0) and the fifth selected generation (S5), focusing on behaviour not functionally related to tameness, in order to study any correlated effects. Birds were tested for fear of humans, social reinstatement tendency, open field behaviour at two different ages, foraging/exploration, response to a simulated aerial predator attack and tonic immobility. In S5, there were no effects of selection on foraging/exploration or tonic immobility, while in the social reinstatement and open field tests there were significant interactions between selection and sex. In the aerial predator test, there were significant main effects of selection, indicating that fear of humans may represent a general wariness towards predators. In conclusion, we found only small correlated effects on behaviours not related to the tameness trait selected for, in spite of them showing high genetic correlations to fear of humans in a previous study on the same population. This suggests that species-specific behaviour is generally resilient to changes during domestication.

    Ort, förlag, år, upplaga, sidor
    PLOS, 2016
    Nationell ämneskategori
    Utvecklingsbiologi Genetik
    Identifikatorer
    urn:nbn:se:liu:diva-132742 (URN)10.1371/journal.pone.0166075 (DOI)000387909300035 ()27851792 (PubMedID)
    Anmärkning

    European Research Council [322206]; FORMAS [221-2007-838]; Vetenskapsradet [621-2008-5437]

    Tillgänglig från: 2016-11-22 Skapad: 2016-11-22 Senast uppdaterad: 2017-11-29Bibliografiskt granskad
  • 16.
    Agnvall, Beatrix
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Ali, A.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Olby, S.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi.
    Red Junglefowl (Gallus gallus) selected for low fear of humans are larger, more dominant and produce larger offspring2014Ingår i: animal, ISSN 1751-7311, Vol. 8, nr 9, s. 1498-1505Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many traits associated with domestication are suggested to have developed as correlated responses to reduced fear of humans. Tameness may have reduced the stress of living in human proximity and improved welfare in captivity. We selected Red Junglefowl (ancestors of all domestic chickens) for four generations on high or low fear towards humans, mimicking an important aspect of the earliest period of domestication, and tested birds from the third and fourth generation in three different social tests. Growth and plumage condition, as well as size of eggs and offspring were also recorded, as indicators of some aspects of welfare. Birds selected for low fear had higher weight, laid larger eggs and generated larger offspring, and had a better plumage condition. In a social dominance test they also performed more aggressive behaviour and received less of the same, regardless of whether the restricted resource was feed or not. Hence, dominance appeared to increase as a consequence of reduced fear of humans. Furthermore, egg size and the weight of the offspring were larger in the less fearful birds, and plumage condition better, which could be interpreted as the less fearful animals being better adapted to the environment in which they were selected.

  • 17.
    Agnvall, Beatrix
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Bélteky, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Brain size is reduced by selectionfor tameness in Red Junglefowl–correlated effects in vital organs2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 3306Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During domestication animals have undergone changes in size of brain and other vital organs. We hypothesize that this could be a correlated effect to increased tameness. Red Junglefowl (ancestors of domestic chickens) were selected for divergent levels of fear of humans for five generations. The parental (P0) and the fifth selected generation (S5) were culled when 48–54 weeks old and the brains were weighed before being divided into telencephalon, cerebellum, mid brain and optic lobes. Each single brain part as well as the liver, spleen, heart and testicles were also weighed. Brains of S5 birds with high fear scores (S5 high) were heavier both in absolute terms and when corrected for body weight. The relative weight of telencephalon (% of brain weight) was significantly higher in S5 high and relative weight of cerebellum was lower. Heart, liver, testes and spleen were all relatively heavier (% of body weight) in S5 high. Hence, selection for tameness has changed the size of the brain and other vital organs in this population and may have driven the domesticated phenotype as a correlated response.

  • 18.
    Agnvall, Beatrix
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Bélteky, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Katajamaa, Rebecca
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Is evolution of domestication driven by tameness? A selective review with focus on chickens2018Ingår i: Applied Animal Behaviour Science, ISSN 0168-1591, E-ISSN 1872-9045, Vol. 205, s. 227-233Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Domestication of animals offers unique possibilities to study evolutionary changes caused by similar selection pressures across a range of species. Animals from separate genera tend to develop a suite of phenotypic alterations referred to as "the domesticated phenotype". This involves changes in appearance, including loss of pigmentation, and alterations in body size and proportions. Furthermore, effects on reproduction and behaviour are typical. It is hypothesized that this recurring phenotype may be secondary effects of the increased tameness that is an inevitable first step in the domestication of any species. We first provide a general overview of observations and experiments from different species and then review in more detail a project attempting to recreate the initial domestication of chickens. Starting from an outbred population of Red Junglefowl, ancestors of all modem chickens, divergent lines were selected based on scores in a standardized fear-of-human test applied to all birds at 12 weeks of age. Up to the eighth selected generation, observations have been made on correlated effects of this selection on various phenotypes. The fear score had a significant heritability and was genetically correlated to several other behavioural traits. Furthermore, low-fear birds were larger at hatch, grew faster, laid larger eggs, had a modified metabolism and increased feed efficiency, had modified social behaviour and reduced brain size. Selection affected gene expression and DNA-methylation in the brains, but the genetic and epigenetic effects were not specifically associated with stress pathways. Further research should be focused on unraveling the genetic and epigenetic mechanisms underlying the correlated side-effects of reduced fear of humans.

  • 19.
    Agnvall, Beatrix
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Effects of Divergent Selection for Fear of Humans on Behaviour in Red Junglefowl2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 11, s. 1-12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Domestication has caused a range of similar phenotypic changes across taxa, relating to physiology, morphology and behaviour. It has been suggested that this recurring domesticated phenotype may be a result of correlated responses to a central trait, namely increased tameness. We selected Red Junglefowl, the ancestors of domesticated chickens, during five generations for reduced fear of humans. This caused a marked and significant response in tameness, and previous studies have found correlated effects on growth, metabolism, reproduction, and some behaviour not directly selected for. Here, we report the results from a series of behavioural tests carried out on the initial parental generation (P0) and the fifth selected generation (S5), focusing on behaviour not functionally related to tameness, in order to study any correlated effects. Birds were tested for fear of humans, social reinstatement tendency, open field behaviour at two different ages, foraging/exploration, response to a simulated aerial predator attack and tonic immobility. In S5, there were no effects of selection on foraging/exploration or tonic immobility, while in the social reinstatement and open field tests there were significant interactions between selection and sex. In the aerial predator test, there were significant main effects of selection, indicating that fear of humans may represent a general wariness towards predators. In conclusion, we found only small correlated effects on behaviours not related to the tameness trait selected for, in spite of them showing high genetic correlations to fear of humans in a previous study on the same population. This suggests that species-specific behaviour is generally resilient to changes during domestication.

  • 20.
    Agnvall, Beatrix
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Katajamaa, Rebecca
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi.
    Altimiras, Jordi
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Is domestication driven by reduced fear of humans? Boldness, metabolism and serotonin levels in divergently selected red junglefowl (Gallus gallus)2015Ingår i: Biology Letters, ISSN 1744-9561, E-ISSN 1744-957X, Vol. 11, nr 9, artikel-id 20150509Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Domesticated animals tend to develop a coherent set of phenotypic traits. Tameness could be a central underlying factor driving this, and we therefore selected red junglefowl, ancestors of all domestic chickens, for high or low fear of humans during six generations. We measured basal metabolic rate (BMR), feed efficiency, boldness in a novel object (NO) test, corticosterone reactivity and basal serotonin levels (related to fearfulness) in birds from the fifth and sixth generation of the high- and low-fear lines, respectively (44-48 individuals). Corticosterone response to physical restraint did not differ between selection lines. However, BMR was higher in low-fear birds, as was feed efficiency. Low-fear males had higher plasma levels of serotonin and both low-fear males and females were bolder in an NO test. The results show that many aspects of the domesticated phenotype may have developed as correlated responses to reduced fear of humans, an essential trait for successful domestication.

  • 21.
    Aguilar-Calvo, Patricia
    et al.
    University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA.
    Xiao, Xiangzhu
    Case Western Reserve University, OH 44116 USA.
    Bett, Cyrus
    University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA; US FDA, MD USA.
    Erana, Hasier
    CIC bioGUNE, Spain.
    Soldau, Katrin
    University of Calif San Diego, CA 92093 USA.
    Castilla, Joaquin
    University of Calif San Diego, CA 92093 USA; CIC bioGUNE, Spain; Ikerbasque, Spain.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Surewicz, Witold K.
    Case Western Reserve University, OH 44116 USA.
    Sigurdson, Christina J.
    University of Calif San Diego, CA 92093 USA; University of Calif San Diego, CA 92093 USA; University of Calif Davis, CA 95616 USA.
    Post-translational modifications in PrP expand the conformational diversity of prions in vivo2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 43295Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Misfolded prion protein aggregates (PrPSc) show remarkable structural diversity and are associated with highly variable disease phenotypes. Similarly, other proteins, including amyloid-beta, tau, alpha-synuclein, and serum amyloid A, misfold into distinct conformers linked to different clinical diseases through poorly understood mechanisms. Here we use mice expressing glycophosphatidylinositol (GPI)anchorless prion protein, PrPC, together with hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and a battery of biochemical and biophysical tools to investigate how posttranslational modifications impact the aggregated prion protein properties and disease phenotype. Four GPI-anchorless prion strains caused a nearly identical clinical and pathological disease phenotype, yet maintained their structural diversity in the anchorless state. HXMS studies revealed that GPIanchorless PrPSc is characterized by substantially higher protection against hydrogen/deuterium exchange in the C-terminal region near the N-glycan sites, suggesting this region had become more ordered in the anchorless state. For one strain, passage of GPI-anchorless prions into wild type mice led to the emergence of a novel strain with a unique biochemical and phenotypic signature. For the new strain, histidine hydrogen-deuterium mass spectrometry revealed altered packing arrangements of beta-sheets that encompass residues 139 and 186 of PrPSc. These findings show how variation in posttranslational modifications may explain the emergence of new protein conformations in vivo and also provide a basis for understanding how the misfolded protein structure impacts the disease.

  • 22.
    Ahlinder, Jon
    et al.
    Totalförsvarets Forskningsinstitut, FOI, Stockholm, Sweden.
    Nordgaard, Anders
    Linköpings universitet, Institutionen för datavetenskap, Statistik och maskininlärning. Linköpings universitet, Filosofiska fakulteten. Swedish National Forensic Centre (NFC), Linköping, Sweden.
    Wiklund Lindström, Susanne
    Totalförsvarets Forskningsinstitut, FOI, Stockholm, Sweden.
    Chemometrics comes to court: evidence evaluation of chem–bio threat agent attacks2015Ingår i: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 29, nr 5, s. 267-276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Forensic statistics is a well-established scientific field whose purpose is to statistically analyze evidence in order to support legal decisions. It traditionally relies on methods that assume small numbers of independent variables and multiple samples. Unfortunately, such methods are less applicable when dealing with highly correlated multivariate data sets such as those generated by emerging high throughput analytical technologies. Chemometrics is a field that has a wealth of methods for the analysis of such complex data sets, so it would be desirable to combine the two fields in order to identify best practices for forensic statistics in the future. This paper provides a brief introduction to forensic statistics and describes how chemometrics could be integrated with its established methods to improve the evaluation of evidence in court.

    The paper describes how statistics and chemometrics can be integrated, by analyzing a previous know forensic data set composed of bacterial communities from fingerprints. The presented strategy can be applied in cases where chemical and biological threat agents have been illegally disposed.

  • 23.
    Ahlrot, Ulrica
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi.
    Welfare in zoo kept felids: A study of resource usage2016Självständigt arbete på avancerad nivå (masterexamen), 40 poäng / 60 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Due to a large number of felid species being endangered they are subjects of conservation projects both in situ and ex situ. Keeping felids in zoos are problematic with stereotypic behaviours such as pacing and reproduction difficulties often occurring. The aim of this study was to review research and zoo husbandry knowledge about which resources are most important for the welfare of zoo kept felids, and in addition perform behavioural observations in seven felid species in four Swedish zoos to try to find an order of priority of resources. Observations were performed during opening hours in 36 sessions per species and zoo. The results showed that studies of felid resource usage are missing. Zoo husbandry practice is probably based mainly on traditions and anecdotal knowledge. The observations showed that except for minor differences felids behave similarly regardless of species but the use of resources varies. Small felid species seems to be hiding rather than pacing as a way of coping. Elevated resources and areas as well as numerous hiding places are important to felids but many factors might affect the choice of resting places. Therefore it is important to provide the felids with multiple choices. It is also important to evaluate both species and individuals when designing enclosures and providing resources. More multi-institutional studies with large number of individuals of all zoo kept felid species are needed to gather knowledge about felids needs and preferences of resources.

  • 24.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Bonnedahl, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten. Kalmar Cty Council, Sweden.
    Woksepp, Hanna
    Kalmar Cty Hosp, Sweden.
    Hernandez, Jorge
    Kalmar Cty Hosp, Sweden.
    Reed, John A.
    US Geol Survey, AK 99508 USA.
    Tibbitts, Lee
    US Geol Survey, AK 99508 USA.
    Olsen, Bjoern
    Uppsala Univ, Sweden.
    Douglas, David C.
    US Geol Survey, AK USA.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Satellite tracking of gulls and genomic characterization of faecal bacteria reveals environmentally mediated acquisition and dispersal of antimicrobial-resistant Escherichia coli on the Kenai Peninsula, Alaska2019Ingår i: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 28, nr 10, s. 2531-2545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gulls (Larus spp.) have frequently been reported to carry Escherichia coli exhibiting antimicrobial resistance (AMR E. coli); however, the pathways governing the acquisition and dispersal of such bacteria are not well described. We equipped 17 landfill-foraging gulls with satellite transmitters and collected gull faecal samples longitudinally from four locations on the Kenai Peninsula, Alaska to assess: (a) gull attendance and transitions between sites, (b) spatiotemporal prevalence of faecally shed AMR E. coli, and (c) genomic relatedness of AMR E. coli isolates among sites. We also sampled Pacific salmon (Oncorhynchus spp.) harvested as part of personal-use dipnet fisheries at two sites to assess potential contamination with AMR E. coli. Among our study sites, marked gulls most commonly occupied the lower Kenai River (61% of site locations) followed by the Soldotna landfill (11%), lower Kasilof River (5%) and upper Kenai River (amp;lt;1%). Gulls primarily moved between the Soldotna landfill and the lower Kenai River (94% of transitions among sites), which were also the two locations with the highest prevalence of AMR E. coli. There was relatively high spatial and temporal variability in AMR E. coli prevalence in gull faeces and there was no evidence of contamination on salmon harvested in personal-use fisheries. We identified E. coli sequence types and AMR genes of clinical importance, with some isolates possessing genes associated with resistance to as many as eight antibiotic classes. Our findings suggest that gulls acquire AMR E. coli at habitats with anthropogenic inputs and subsequent movements may represent pathways through which AMR is dispersed.

  • 25.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Woksepp, Hanna
    Kalmar Council, Sweden.
    Bonnedahl, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten. Kalmar Council, Sweden.
    Early emergence of mcr-1-positive Enterobacteriaceae in gulls from Spain and Portugal2019Ingår i: Environmental Microbiology Reports, ISSN 1758-2229, E-ISSN 1758-2229Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We tested extended-spectrum beta-lactamase producing bacteria from wild gulls (Larus spp.) sampled in 2009 for the presence of mcr-1. We report the detection of mcr-1 and describe genome characteristics of four Escherichia coli and one Klebsiella pneumoniae isolate from Spain and Portugal that also exhibited colistin resistance. Results represent the earliest evidence for colistin-resistant bacteria in European wildlife.

  • 26.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Woksepp, Hanna
    Dept Dev and Publ and Hlth, Sweden.
    Bonnedahl, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi, infektion och inflammation. Linköpings universitet, Medicinska fakulteten. Dept Infect Dis, Sweden.
    Repeated Detection of Carbapenemase-Producing Escherichia coil in Gulls Inhabiting Alaska2019Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, nr 8, artikel-id e00758-19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Here, we report the first detection of carbapenemase-producing Escherichia coli in Alaska and in wildlife in the United States. Wild bird (gull) feces sampled at three locations in Southcentral Alaska yielded isolates that harbored plasmidencoded bla(kpc-2), or chromosomally encoded bla(OXA-48) and genes associated with antimicrobial resistance to up to eight antibiotic classes.

  • 27.
    Ahlsén, Hanna
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi.
    The Effects of Abiotic Stress on Alternative Splicing in Non-specific Lipid Transfer Proteins in Marchantia polymorpha2018Självständigt arbete på grundnivå (kandidatexamen), 10,5 poäng / 16 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Due to global warming, our planet will experience more extreme weather conditions. Plants can protect themselves against these abiotic stress conditions with their stress response, which includes alternative splicing of certain genes. Alternative splicing is a post-transcriptional process where a single gene gives rise to different mRNAs, which in turn produces different proteins. In plants, this is usually done by intron retention. One type of protein that may be involved in this stress response are the non-specific lipid transfer proteins (LTPs). Indeed, evidence of intron retention has been found in the LTP genes in the liverwort Marchantia polymorpha, called MpLTPd. To investigate whether this alternative splicing is caused by abiotic stress or not, I subjected the moss to two different types of stress trials, drought and cold, and compared the general expression of the intron in MpLTPd2 and MpLTPd3 from the stressed samples to samples from a moss grown under normal conditions. I found that the expression of the intron did change in the stressed moss, but none of the differences were significant. This suggests that alterative splicing in MpLTPd2 and MpLTPd3 is not caused by cold and drought and that the intron-containing protein plays no role in the protection of M. polymorpha against abiotic stress.

  • 28.
    Ahmad, Fareed
    et al.
    Hannover Medical Sch, Germany.
    Shankar, Esaki M.
    University of Malaya, Malaysia; University of Malaya, Malaysia; School Basic Appl Science, India.
    Yong, Yean K.
    University of Malaya, Malaysia.
    Tan, Hong Y.
    University of Malaya, Malaysia.
    Ahrenstorf, Gerrit
    Hannover Medical Sch, Germany.
    Jacobs, Roland
    Hannover Medical Sch, Germany.
    Larsson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Schmidt, Reinhold E.
    Hannover Medical Sch, Germany.
    Kamarulzaman, Adeeba
    University of Malaya, Malaysia; University of Malaya, Malaysia.
    Ansari, Abdul W.
    University of Malaya, Malaysia; University of Malaya, Malaysia.
    Negative Checkpoint Regulatory Molecule 2B4 (CD244) Upregulation Is Associated with Invariant Natural Killer T Cell Alterations and Human Immunodeficiency Virus Disease Progression2017Ingår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, artikel-id 338Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The CD1d-restricted invariant natural killer T (iNKT) cells are implicated in innate immune responses against human immunodeficiency virus (HIV). However, the determinants of cellular dysfunction across the iNKT cells subsets are seldom defined in HIV disease. Herein, we provide evidence for the involvement of the negative checkpoint regulator (NCR) 2B4 in iNKT cell alteration in a well-defined cohort of HIV-seropositive anti-retroviral therapy (ART) naive, ART-treated, and elite controllers (ECs). We report on exaggerated 2B4 expression on iNKT cells of HIV-infected treatment-naive individuals. In sharp contrast to CD4-iNKT cells, 2B4 expression was significantly higher on CD4+ iNKT cell subset. Notably, an increased level of 2B4 on iNKT cells was strongly correlated with parameters associated with HIV disease progression. Further, iNKT cells from ARTnaive individuals were defective in their ability to produce intracellular IFN-gamma Together, our results suggest that the levels of 2B4 expression and the downstream co-inhibitory signaling events may contribute to impaired iNKT cell responses.

  • 29.
    Aineslahti, Emmi
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi.
    Training of spider monkeys in a food-rewarded two-choice olfactory discrimination paradigm and assessment of olfactory learning and memory performance2019Självständigt arbete på avancerad nivå (masterexamen), 40 poäng / 60 hpStudentuppsats (Examensarbete)
    Abstract [en]

    There is little knowledge about olfactory learning in primates, even though primates are known to use olfaction in several behaviors including food selection and territorial defense. Therefore I assessed the olfactory learning and memory performance in five adult spider monkeys (Ateles geoffroyi) using a food-rewarded two-choice olfactory discrimination paradigm. The spider monkeys acquired the initial odor discrimination in 530-1102 trials and in a series of intramodal transfer tasks they needed 30-510 trials to reach the learning criterion. There was a significant negative correlation between the number of trials needed to reach the learning criterion and the number of transfer tasks completed. Thus, as a group, the animals displayed olfactory learning set formation. The number of trials that the spider monkeys needed in initial olfactory learning was comparable to that of other primate species tested previously but higher compared to that of other mammals such as dogs and rats. The learning speed of the spider monkeys in intramodal transfer tasks was similar to that of other mammals tested, suggesting that primates are less prepared to use olfactory cues in the initial solving of a problem but that once they learn the concept, their learning speed with novel odor discrimination problems is not generally slower than that of non-primate mammals. All spider monkeys tested reached the learning criterion in the memory tasks straight on the first testing day, that is: within 30 trials, suggesting similar long-term odor memory capabilities in spider monkeys and other mammals such as dogs, mice and rats.

  • 30.
    Aira, Naomi
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Lactate Dehydrogenase and Citrate Synthase activity in cardiac and skeletal muscle of lowland and highland tinamous2013Självständigt arbete på grundnivå (kandidatexamen), 10,5 poäng / 16 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Tinamous (Tinamidae) have the smallest heart in relation to body mass compared to any other flying bird today (Bishop 1997). This means that heart size is likely to restrict aerobic metabolism. Tinamous inhabit areas from sea level to 4800 m a.s.l., which means that the high altitude living species, Nothoprocta ornata (NO), is exposed to hypoxia. In this study the activity of the two metabolic enzymes Lactate Dehydrogenase (LDH) and Citrate Synthase (CS) was measured and the ratio between the enzyme activities calculated to examine if the small heart of the tinamous affects their aerobic/anaerobic metabolism. The activity of the two enzymes was measured in the heart and the gastrocnemius muscle in the three species Nothoprocta ornata (NO), Nothoprocta perdicaria (NP) and Gallus gallus (GG). CS activity was significantly higher in the heart compared to the skeletal muscle and LDH activity was significant higher in the skeletal muscle than in the heart in all three species. The LDH/CS ratio was significantly higher in NO’s skeletal muscle than in chickens but there was no significant difference between species in the heart. The higher ratio in NO´s muscle could be a sign of a higher anaerobic metabolism that is used in the muscles to compensate for the small heart NO have. In conclusion, the Tinamous

  • 31.
    Ajjan, Fátima
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska fakulteten.
    Casado, N.
    University of Basque Country, Spain.
    Rebis, Tomasz
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska fakulteten.
    Elfwing, Anders
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska fakulteten.
    Solin, Niclas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska fakulteten.
    Mecerreyes, D.
    University of Basque Country, Spain; Ikerbasque, Spain.
    Inganäs, Olle
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biomolekylär och Organisk Elektronik. Linköpings universitet, Tekniska fakulteten.
    High performance PEDOT/lignin biopolymer composites for electrochemical supercapacitors2016Ingår i: Journal of Materials Chemistry A, ISSN 2050-7488, Vol. 4, nr 5, s. 1838-1847Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Developing sustainable organic electrode materials for energy storage applications is an urgent task. We present a promising candidate based on the use of lignin, the second most abundant biopolymer in nature. This polymer is combined with a conducting polymer, where lignin as a polyanion can behave both as a dopant and surfactant. The synthesis of PEDOT/Lig biocomposites by both oxidative chemical and electrochemical polymerization of EDOT in the presence of lignin sulfonate is presented. The characterization of PEDOT/Lig was performed by UV-Vis-NIR spectroscopy, FTIR infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, cyclic voltammetry and galvanostatic charge-discharge. PEDOT doped with lignin doubles the specific capacitance (170.4 F g(-1)) compared to reference PEDOT electrodes (80.4 F g(-1)). The enhanced energy storage performance is a consequence of the additional pseudocapacitance generated by the quinone moieties in lignin, which give rise to faradaic reactions. Furthermore PEDOT/Lig is a highly stable biocomposite, retaining about 83% of its electroactivity after 1000 charge/discharge cycles. These results illustrate that the redox doping strategy is a facile and straightforward approach to improve the electroactive performance of PEDOT.

  • 32.
    Akoto, Brenda
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Is spring burning a viable management tool for species-rich grasslands?2012Självständigt arbete på avancerad nivå (masterexamen), 80 poäng / 120 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Semi- natural grasslands are species-rich and also one of the most threatened biotopes in Europe. The area of these grasslands has declined and grassland vegetation is threatened as a result of lack of management and land use change. Appropriate management is therefore required to maintain the conservation values and high species richness of semi- natural grasslands. Traditional management, that is, grazing or annual mowing is expensive, which motivates evaluation of alternative cheaper methods of management. Burning is less costly and therefore I evaluated burning along with the conventional methods. The study addressed the main question: is burning an option to mowing and grazing? I searched the literature for available studies suitable for metaanalysis, but located only detailed reports from a series of eleven Swedish long-term field trials. In addition, I collected data in the only one of these trials still running. To facilitate metaanalysis, l used different indicator systems of classification of grassland plants then calculating the odds for a random record being an indicator after one, eight, fourteen, twenty-eight and thirty-nine spring burns. The results show an increasing proportion of grassland indicators of good management in the mowed and grazed plots compared with the burnt plots, indicating a general negative effect of burning on grassland plants compared with mowing and grazing. Hence, burning is not an appropriate long-term management method if the aim is to maintain vegetation diversity in semi-natural grassland.

  • 33.
    Alberti, Esteban
    et al.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Garcia, Rocio
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Fraga, JL
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Serrano, T.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Hernandez, E.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Klonisch, Thomas
    Department of Human Anatomy and Cell Sciences, and Manitoba Institute of Child Health, Winnipeg, Canada.
    Macías, R.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Martinez, L.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    Castillo, L.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba..
    de la Cuétara, K.
    Department of Neurobiology, International Center of Neurological Restoration, CIREN, Havana, Cuba.
    Prolonged Survival and expression of neural markers by bone marrow-derived stem cells transplanted into brain lesions2009Ingår i: Medical Science Monitor, ISSN 1234-1010, E-ISSN 1643-3750, Vol. 15, nr 2, s. BR47-BR54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Bone marrow-derived stem cell transplantation is a potentially viable therapeutic option for the treatment of neurodegenerative disease. MATERIAL/METHODS: We have isolated bone marrow stem cells by standard method. We then evaluated the survival of rats' bone marrow mononuclear cells implanted in rats' brain. The cells were extracted from rats' femurs, and marked for monitoring purposes by adenoviral transduction with Green Fluorescent Protein (GFP). Labeled cells were implanted within the area of rats' striatum lesions that were induced a month earlier employing quinolinic acid-based method. The implants were phenotyped by monitoring CD34; CD38; CD45 and CD90 expression. Bone marrow stromal cells were extracted from rats' femurs and cultivated until monolayer bone marrow stromal cells were obtained. The ability of bone marrow stromal cells to express NGF and GDNF was evaluated by RT-PCR. RESULTS: Implanted cells survived for at least one month after transplantation and dispersed from the area of injection towards corpus callosum and brain cortex. Interestingly, passaged rat bone marrow stromal cells expressed NGF and GDNF mRNA. CONCLUSIONS: The bone marrow cells could be successfully transplanted to the brain either for the purpose of trans-differentiation, or for the expression of desired growth factors.

  • 34.
    Albouy, Camille
    et al.
    IFREMER, France.
    Archambault, Philippe
    Univ Laval, Canada.
    Appeltans, Ward
    UNESCO, Belgium.
    Araujo, Miguel B.
    CSIC, Spain; Univ Evora, Portugal; Univ Copenhagen, Denmark.
    Beauchesne, David
    Univ Quebec Rimouski, Canada.
    Cazelles, Kevin
    Univ Guelph, Canada.
    Cirtwill, Alyssa
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk Biologi. Linköpings universitet, Tekniska fakulteten. Univ Canterbury, New Zealand.
    Fortin, Marie-Josee
    Univ Toronto, Canada.
    Galiana, Nuria
    CNRS, France.
    Leroux, Shawn J.
    Mem Univ, Canada.
    Pellissier, Loik
    Swiss Fed Inst Technol, Switzerland; Swiss Fed Res Inst WSL, Switzerland.
    Poisot, Timothee
    Univ Montreal, Canada; McGill Univ, Canada.
    Stouffer, Daniel B.
    Univ Canterbury, New Zealand.
    Wood, Spencer A.
    Univ Washington, WA 98195 USA.
    Gravel, Dominique
    Univ Montreal, Canada; Univ Sherbrooke, Canada.
    The marine fish food web is globally connected2019Ingår i: Nature Ecology & Evolution, E-ISSN 2397-334X, Vol. 3, nr 8, s. 1153-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The productivity of marine ecosystems and the services they provide to humans are largely dependent on complex interactions between prey and predators. These are embedded in a diverse network of trophic interactions, resulting in a cascade of events following perturbations such as species extinction. The sheer scale of oceans, however, precludes the characterization of marine feeding networks through de novo sampling. This effort ought instead to rely on a combination of extensive data and inference. Here we investigate how the distribution of trophic interactions at the global scale shapes the marine fish food web structure. We hypothesize that the heterogeneous distribution of species ranges in biogeographic regions should concentrate interactions in the warmest areas and within species groups. We find that the inferred global metaweb of marine fish-that is, all possible potential feeding links between co-occurring species-is highly connected geographically with a low degree of spatial modularity. Metrics of network structure correlate with sea surface temperature and tend to peak towards the tropics. In contrast to open-water communities, coastal food webs have greater interaction redundancy, which may confer robustness to species extinction. Our results suggest that marine ecosystems are connected yet display some resistance to perturbations because of high robustness at most locations.

  • 35.
    Aleckovic, Ehlimana
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Andersson, Linnea
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Chamoun, Sherley
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Einarsson, Ellen
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Ekstedt, Ebba
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Eriksen, Emma
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Madan-Andersson, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Method Development for Determining the Stability of Heat Stable Proteins Combined with Biophysical Characterization of Human Calmodulin and the Disease Associated Variant D130G2016Självständigt arbete på grundnivå (kandidatexamen), 10,5 poäng / 16 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Calmodulin is a highly conserved calcium ion binding protein expressed in all eukaryotic species. The 149 amino acid residues in the primary structure are organized in seven α helices with the highly flexible central α helix connecting the two non-cooperative domains of calmodulin. Each domain contains two EF-hand motifs to which calcium ions bind in a cooperative manner, hence the binding of four calcium ions saturate one calmodulin molecule. In the cardiovascular area calmodulin is involved in the activation of cardiac muscle contraction, and mutations that arise in the genetic sequence of the protein often have severe consequences. One such consequential mutation that can arise brings about the replacement of the highly conserved aspartic acid with glycine at position 130 in the amino acid sequence. In this research, the thermal and chemical stability within the C domain of the D130G variant of human calmodulin was investigated using a new method only requiring circular dichroism spectroscopic measurements. Affinity studies within the C domain of the D130G variant of human calmodulin were performed using fluorescence spectroscopy, and the ligands chosen for this purpose were trifluoperazine and p- HTMI. All analytical experiments were performed with the C domain of wild type human calmodulin as a reference. From the new method, it was concluded that the C domain of the D130G variant of human calmodulin has a slightly decreased stability in terms of Tm and Cm values compared to the C domain of wild type human calmodulin. The affinity analyses indicated that neither trifluoperazine nor p-HTMI discriminates between the C domain of the D130G variant of human calmodulin and the C domain of wild type human calmodulin in terms of dissociation constants. The pivotal outcome from this research is that the new method is applicable for determination of the stability parameters Tm and Cm of heat stable proteins. 

  • 36.
    Alexander, Helen K.
    et al.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Booy, Evan P.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Xiao, Wenyan
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba,.
    Ezzati, Peyman
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba,.
    Baust, Heinrich
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba,.
    Los, Marek Jan
    Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.
    Selected technologies to control genes and their products for experimental and clinical purposes2007Ingår i: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, Vol. 55, nr 3, s. 139-149Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    "On-demand" regulation of gene expression is a powerful tool to elucidate the functions of proteins and biologically-active RNAs. We describe here three different approaches to the regulation of expression or activity of genes or proteins. Promoter-based regulation of gene expression was among the most rapidly developing techniques in the 1980s and 1990s. Here we provide basic information and also some characteristics of the metallothionein-promoter-based system, the tet-off system, Muristerone-A-regulated expression through the ecdysone response element, RheoSwitch (R), coumermycin/novobiocin-regulated gene expression, chemical dimerizer-based promoter activation systems, the "Dual Drug Control" system, "constitutive androstane receptor"-based regulation of gene expression, and RU486/mifepristone-driven regulation of promoter activity. A large part of the review concentrates on the principles and usage of various RNA interference techniques (RNAi: siRNA, shRNA, and miRNA-based methods). Finally, the last part of the review deals with historically the oldest, but still widely used, methods of temperature-dependent regulation of enzymatic activity or protein stability (temperature-sensitive mutants). Due to space limitations we do not describe in detail but just mention the tet-regulated systems and also fusion-protein-based regulation of protein activity, such as estrogen-receptor fusion proteins. The information provided below is aimed to assist researchers in choosing the most appropriate method for the planned development of experimental systems with regulated expression or activity of studied proteins.

  • 37.
    Alexander, Helen K.
    et al.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Booy, Evan P.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Xiao, Wenyan
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Ezzati, Peyman
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Baust, Heinrich
    Department of Radiooncology, University of Erlangen, Erlangen, Germany .
    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, .
    Selected technologies to control genes and their products for experimental and clinical purposes2007Ingår i: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 55, nr 3, s. 139-149Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    "On-demand" regulation of gene expression is a powerful tool to elucidate the functions of proteins and biologically-active RNAs. We describe here three different approaches to the regulation of expression or activity of genes or proteins. Promoter-based regulation of gene expression was among the most rapidly developing techniques in the 1980s and 1990s. Here we provide basic information and also some characteristics of the metallothionein-promoter-based system, the tet-off system, Muristerone-A-regulated expression through the ecdysone response element, RheoSwitch (R), coumermycin/novobiocin-regulated gene expression, chemical dimerizer-based promoter activation systems, the "Dual Drug Control" system, "constitutive androstane receptor"-based regulation of gene expression, and RU486/mifepristone-driven regulation of promoter activity. A large part of the review concentrates on the principles and usage of various RNA interference techniques (RNAi: siRNA, shRNA, and miRNA-based methods). Finally, the last part of the review deals with historically the oldest, but still widely used, methods of temperature-dependent regulation of enzymatic activity or protein stability (temperature-sensitive mutants). Due to space limitations we do not describe in detail but just mention the tet-regulated systems and also fusion-protein-based regulation of protein activity, such as estrogen-receptor fusion proteins. The information provided below is aimed to assist researchers in choosing the most appropriate method for the planned development of experimental systems with regulated expression or activity of studied proteins.

  • 38.
    Alexandre, Campos
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Apraiz, Itzaso
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    da Fonseca, Rute R
    The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Shotgun analysis of the marine mussel Mytilus edulis hemolymph proteome and mapping the innate immunity elements.2015Ingår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 15, nr 23-24, s. 4021-4029Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The marine mussel innate immunity provides protection to pathogen invasion and inflammation.In this regard, the mussel hemolymph takes a main role in the animal innate response.Despite the importance of this body fluid in determining the physiological condition of theanimal, little is known about the molecular mechanisms underlying the cellular and humoralresponses. In this work, we have applied aMS (nano-LC-MS/MS) strategy integrating genomicand transcriptomic data with the aim to: (i) identify the main protein functional groups thatcharacterize hemolymph and (ii) to map the elements of innate immunity in the marine musselMytilus edulis hemolymph proteome. After sample analysis and first protein identificationbased onMS/MS data comparison, proteins with unknown functions were annotated with blastusing public database (nrNCBI) information. Overall 595 hemolymph proteins were identifiedwith high confidence and annotated. These proteins encompass primary cellular metabolicprocesses: energy production and metabolism of biomolecules, as well as processes related tooxidative stress defence, xenobiotic detoxification, drug metabolism, and immune response.A group of proteins was identified with putative immune effector, receptor, and signalingfunctions in M. edulis. Data are available via ProteomeXchange with identifier PXD001951(http://proteomecentral.proteomexchange.org/dataset/PXD001951).

  • 39.
    Alexsson, Andrei
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Unsupervised hidden Markov model for automatic analysis of expressed sequence tags2011Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    This thesis provides an in-depth analyze of expressed sequence tags (EST) that represent pieces of eukaryotic mRNA by using unsupervised hidden Markov model (HMM). ESTs are short nucleotide sequences that are used primarily for rapid identificationof new genes with potential coding regions (CDS). ESTs are made by sequencing on double-stranded cDNA and the synthesizedESTs are stored in digital form, usually in FASTA format. Since sequencing is often randomized and that parts of mRNA contain non-coding regions, some ESTs will not represent CDS.It is desired to remove these unwanted ESTs if the purpose is to identifygenes associated with CDS. Application of stochastic HMM allow identification of region contents in a EST. Softwares like ESTScanuse HMM in which a training of the HMM is done by supervised learning with annotated data. However, because there are not always annotated data at hand this thesis focus on the ability to train an HMM with unsupervised learning on data containing ESTs, both with and without CDS. But the data used for training is not annotated, i.e. the regions that an EST consists of are unknown. In this thesis a new HMM is introduced where the parameters of the HMM are in focus so that they are reasonablyconsistent with biologically important regionsof an mRNA such as the Kozak sequence, poly(A)-signals and poly(A)-tails to guide the training and decoding correctly with ESTs to proper statesin the HMM. Transition probabilities in the HMMhas been adapted so that it represents the mean length and distribution of the different regions in mRNA. Testing of the HMM's specificity and sensitivityhave been performed via BLAST by blasting each EST and compare the BLAST results with the HMM prediction results.A regression analysis test shows that the length of ESTs used when training the HMM is significantly important, the longer the better. The final resultsshows that it is possible to train an HMM with unsupervised machine learning but to be comparable to supervised machine learning as ESTScan, further expansion of the HMM is necessary such as frame-shift correction of ESTs byimproving the HMM's ability to choose correctly positioned start codons or nucleotides. Usually the false positive results are because of incorrectly positioned start codons leadingto too short CDS lengths. Since no frame-shift correction is implemented, short predicted CDS lengths are not acceptable and is hence not counted as coding regionsduring prediction. However, when there is a lack of supervised models then unsupervised HMM is a potential replacement with stable performance and able to be adapted forany eukaryotic organism.

  • 40.
    Alfirevic, Ana
    et al.
    University of Liverpool, UK.
    Gonzalez-Galarza, Faviel
    University of Liverpool, UK.
    Bell, Catherine
    University of Liverpool, UK.
    Martinsson, Klara
    University of Liverpool, UK.
    Platt, Vivien
    University of Liverpool, UK.
    Bretland, Giovanna
    University of Liverpool, UK.
    Evely, Jane
    University of Liverpool, UK.
    Lichtenfels, Maike
    University of Liverpool, UK.
    Cederbrant, Karin
    Safety Assessment, AstraZeneca, Gartuna, Södertälje, Sweden.
    French, Neil
    University of Liverpool, UK.
    Naisbitt, Dean
    University of Liverpool, UK.
    Park, B Kevin
    University of Liverpool, UK.
    Jones, Andrew R
    University of Liverpool, UK.
    Pirmohamed, Munir
    University of Liverpool, UK.
    In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers2012Ingår i: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 4, nr 6, artikel-id 51Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood.

    METHODS: To study these mechanisms, we established an HLA-typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView.

    RESULTS: We demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity.

    CONCLUSIONS: Our bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with next-generation sequencing techniques, will be needed to define the causal alleles associated with DILI.

  • 41.
    Alizadeh, Javad
    et al.
    University of Manitoba, Canada.
    Zeki, Amir A.
    Centre Comparat Resp Biol and Med, CA USA.
    Mirzaei, Nima
    University of Manitoba, Canada.
    Tewary, Sandipan
    University of Manitoba, Canada.
    Rezaei Moghadam, Adel
    University of Manitoba, Canada; University of Manitoba, Canada.
    Glogowska, Aleksandra
    University of Manitoba, Canada.
    Nagakannan, Pandian
    University of Manitoba, Canada.
    Eftekharpour, Eftekhar
    University of Manitoba, Canada.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Logopedi, Audiologi och Otorhinolaryngologi. Linköpings universitet, Medicinska fakulteten.
    Gordon, Joseph W.
    University of Manitoba, Canada; University of Manitoba, Canada; University of Manitoba, Canada.
    Xu, Fred. Y.
    University of Manitoba, Canada; University of Manitoba, Canada.
    Field, Jared T.
    University of Manitoba, Canada.
    Yoneda, Ken Y.
    Centre Comparat Resp Biol and Med, CA USA.
    Kenyon, Nicholas J.
    Centre Comparat Resp Biol and Med, CA USA.
    Hashemi, Mohammad
    Zehedan University of Medical Science, Iran.
    Hatch, Grant M.
    University of Manitoba, Canada; University of Manitoba, Canada.
    Hombach-Klonisch, Sabine
    University of Manitoba, Canada.
    Klonisch, Thomas
    University of Manitoba, Canada.
    Ghavami, Saeid
    University of Manitoba, Canada; University of Manitoba, Canada; Shiraz University of Medical Science, Iran.
    Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 44841Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP-and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB231( breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.

  • 42.
    Alkaissi, Hammoudi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    BACKGROUND: Autoimmune diseases require the involvement and activation of immune cells and occur when the body builds up an immune response against its own tissues. This process takes place due to the inability to distinguish self-antigen from foreign antigen. Systemic autoimmunity represents an important cause of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Genome wide association study (GWAS) is a powerful method, used to identify genetic risk factors in numerous diseases, such as systemic autoimmune diseases. The goal of GWAS is to identify these genetic risk factors in order to make predictions about who is at risk and investigate the biological process of disease susceptibility. There are several valuable mouse models to investigate the underlying mechanisms causing systemic autoimmune diseases in which mercury induced autoimmunity (HgIA) is a well- established and relevant model. HgIA in mice includes development of autoantibodies, immune complex glomerulonephritis, lymphocyte proliferation, hypergammaglobulinemia and polyclonal B cell activation. In humans, mercury exposure accumulates with considerable concentrations in kidney, liver, and brain. Toxicokinetics of Hg has been studied extensively but the key for inter-individual variation in humans are largely unclear. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg.

    OBJECTIVES: To find loci and candidate genes associated with phenotypes involved in the development of autoimmunity and find candidate genes involved in the regulation of renal Hg excretion.

    METHODS: MHC II (H-2s) mice were paired (A.SW x B10.S) to obtain F2 offspring exposed to 2.0 or 4.0 mg Hg in drinking water for 6 weeks. Mercury induced autoimmune phenotypes were studied with immunofluorescence (anti-nucleolar antibodies (ANoA)), ELISA anti-DNP/anti-ssDNA (polyclonal B cell activation), anti-chromatin antibodies (ACA) (4.0 mg Hg), and serum IgG1 concentrations. Mercury accumulation in kidney was performed previously and data was included as phenotype. F2 mice exposed to 2.0 mg Hg were genotyped with microsatellites for genome-wide scan with Ion Pair Reverse Phase High Performance Liquid Chromatography (IP RP HPLC). F2 mice exposed to 4.0 mg Hg were genotyped with single nucleotide polymorphisms for genomewide scan with SNP&SEQ technology platform. Quantitative trait loci (QTL) was established with R/QTL. Denaturing HPLC, next generation sequencing, conserved region analysis and genetic mouse strain comparison were used for haplotyping and fine mapping on QTLs associated with Hg concentration in kidney, development of ANoA and serum IgG1 hypergammaglobulinemia. Candidate genes (Pprc1, Bank1 and Nfkb1) verified by additional QTL were further investigated by real time polymerase chain reaction. Genes involved in the intracellular signaling together with candidate genes were included for gene expression analysis.

    RESULTS: F2 mice exposed to 2.0 mg Hg had low or no development of autoantibodies and showed no significant difference in polyclonal B cell activation in the B10.S and F2 strains. F2 mice exposed to 4.0 mg Hg developed autoantibodies and significantly increased IgG1 concentration and polyclonal B cell activation (anti-DNP). QTL analysis showed a logarithm of odds ratio (LOD) score between 2.9 – 4.36 on all serological phenotypes exposed to 4.0 mg Hg, and a LOD score of 5.78 on renal Hg concentration. Haplotyping and fine mapping associated the development of ANoA with Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkb1 (nuclear factor kappa B subunit 1). The serum IgG1 concentration was associated with a locus on chromosome 3, in which Rxfp4 (Relaxin Family Peptide/INSL5 Receptor 4) is a potential candidate gene. The renal Hg concentration was associated with Pprc1 (Peroxisome Proliferator-Activated Receptor Gamma, Co-activator-Related). Gene expression analysis revealed that the more susceptible A.SW strain expresses significantly higher levels of Nfkb1, Il6 and Tnf than the less susceptible B10.S strain. The A.SW strain expresses significantly lower levels of Pprc1 and cascade proteins than the B10.S strain. Development of ACA was associated with chromosomes 3, 6, 7 and 16 (LOD 3.1, 3.2, 3.4 and 6.8 respectively). Polyclonal B cell activation was associated with chromosome 2 with a LOD score of 2.9.

    CONCLUSIONS: By implementing a GWAS on HgIA in mice, several QTLs were discovered to be associated with the development of autoantibodies, polyclonal B cell activation and hypergammaglobulinemia. This thesis plausibly supports Bank1 and Nfkb1 as key regulators for ANoA development and HgIA seems to be initiated by B cells rather than T cells. GWAS on renal mercury excretion plausibly supports Pprc1 as key regulator and it seems that this gene has a protective role against Hg.

    Delarbeten
    1. Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
    Öppna denna publikation i ny flik eller fönster >>Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
    Visa övriga...
    2016 (Engelska)Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, nr 7, s. 920-926Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A. SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S.

    OBJECTIVES: We aimed to find candidate genes associated with regulation of renal Hg concentrations.

    METHODS: A. SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis.

    RESULTS: Renal Hg concentrations differed significantly between A. SW and B10. S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A. SW strain than in the B10. S strain.

    CONCLUSIONS: This study supports Pprc1 as a key regulator for renal Hg excretion.

    Ort, förlag, år, upplaga, sidor
    U.S. Department of Health and Human Services * National Institute of Environmental Health Sciences, 2016
    Nationell ämneskategori
    Annan biologi
    Identifikatorer
    urn:nbn:se:liu:diva-131584 (URN)10.1289/ehp.1409284 (DOI)000380749300012 ()26942574 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council Branch of Medicine; County Council of Ostergotland; Linkoping University

    Tillgänglig från: 2016-09-27 Skapad: 2016-09-27 Senast uppdaterad: 2018-10-24Bibliografiskt granskad
    2. Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
    Öppna denna publikation i ny flik eller fönster >>Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
    Visa övriga...
    2018 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 7, artikel-id e0199979Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.

    Ort, förlag, år, upplaga, sidor
    PUBLIC LIBRARY SCIENCE, 2018
    Nationell ämneskategori
    Genetik
    Identifikatorer
    urn:nbn:se:liu:diva-150265 (URN)10.1371/journal.pone.0199979 (DOI)000438866600014 ()30016332 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council Branch of Medicine; County Council of Ostergotland; Linkoping University

    Tillgänglig från: 2018-08-17 Skapad: 2018-08-17 Senast uppdaterad: 2019-04-24
  • 43.
    Alkaissi, Hammoudi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Ekstrand, Jimmy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Jawad, Aksa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Nielsen, Jesper Bo
    University of Southern Denmark, Denmark.
    Havarinasab, Said
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice2016Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, nr 7, s. 920-926Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A. SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S.

    OBJECTIVES: We aimed to find candidate genes associated with regulation of renal Hg concentrations.

    METHODS: A. SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis.

    RESULTS: Renal Hg concentrations differed significantly between A. SW and B10. S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A. SW strain than in the B10. S strain.

    CONCLUSIONS: This study supports Pprc1 as a key regulator for renal Hg excretion.

  • 44.
    Alkaissi, Hammoudi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Havarinasab, Said
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Nielsen, Jesper Bo
    Univ Southern Denmark, Denmark.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 7, artikel-id e0199979Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.

  • 45.
    Allan, Douglas W
    et al.
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115 USA.
    St Pierre, Susan E
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115 USA.
    Miguel-Aliaga, Irene
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115 USA.
    Thor, Stefan
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115 USA.
    Specification of Neuropeptide Cell Identity by the Integration of Retrograde BMP Signaling and a Combinatorial Transcription Factor Code2003Ingår i: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 113, nr 1, s. 73-86Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Individual neurons express only one or a few of the many identified neurotransmitters and neuropeptides, but the molecular mechanisms controlling their selection are poorly understood. In the Drosophila ventral nerve cord, the six Tv neurons express the neuropeptide gene FMRFamide. Each Tv neuron resides within a neuronal cell group specified by the LIM-homeodomain gene apterous. We find that the zinc-finger gene squeeze acts in Tv cells to promote their unique axon pathfinding to a peripheral target. There, the BMP ligand Glass bottom boat activates the Wishful thinking receptor, initiating a retrograde BMP signal in the Tv neuron. This signal acts together with apterous and squeeze to activate FMRFamide expression. Reconstituting this "code," by combined BMP activation and apterous/squeeze misexpression, triggers ectopic FMRFamide expression in peptidergic neurons. Thus, an intrinsic transcription factor code integrates with an extrinsic retrograde signal to select a specific neuropeptide identity within peptidergic cells.

  • 46.
    Almberg, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Variation in proactive - reactive personality types in the red junglefowl2013Självständigt arbete på grundnivå (kandidatexamen), 10,5 poäng / 16 hpStudentuppsats (Examensarbete)
    Abstract [en]

    It has been shown in many species that individuals exhibit consistent differences in behaviour over time and/or across situations. These differences in behaviour are called personality. One way to categorise personality types typically used for rodents, is along a proactive-reactive gradient, which describes how individuals cope with stressful challenges. Proactive individuals pay less attention to their environment, form routines easily and take longer to adapt when routines are broken compared to reactive individuals. Avian species have to date rarely been described along this gradient, thus the generality of this description across species is unclear. The present study has investigated variation in proactivity-reactivity in red junglefowl chicks (Gallus gallus). To observe the chicks’ coping styles, a proactive-reactive test was conducted where the chicks were trained to form a routine, which was then broken. Their behavioural response to this was recorded and used as a measure for proactivity-reactivity. The behavioural response was then linked to individual behavioural variation in additional personality assays. Individuals that were more vigilant in the proactive-reactive test often uttered stress calls and took longer to complete the test. In contrast, individuals that walked more and did not utter stress calls had a shorter time to complete the test. These findings can be used to describe proactive red junglefowl chicks; those that are more stressed when routines are broken, compared to calmer reactive individuals. I found no difference in routine formation between proactive and reactive red junglefowl chicks, suggesting that what describes proactive and reactive individuals may vary across species.

  • 47.
    Almstedt, Karin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Protein Misfolding in Human Diseases2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    There are several diseases well known that are due to aberrant protein folding. These types of diseases can be divided into three main categories:

    1. Loss-of-function diseases
    2. Gain-of-toxic-function diseases
    3. Infectious misfolding diseases

     

    Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to inherited mutations. The rare disease marble brain disease (MBD) also known as carbonic anhydrase II deficiency syndrome (CADS) can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. We have over the past 10-15 years studied the folding, misfolding and aggregation of the enzyme human carbonic anhydrase II. In summary our HCA II folding studies have shown that the protein folds via an intermediate of molten-globule type, which lacks enzyme activity and the molten globule state of HCA II is prone to aggregation. One mutation associated with MBD entails the His107Tyr (H107Y) substitution. We have demonstrated that the H107Y mutation is a remarkably destabilizing mutation influencing the folding behavior of HCA II. A mutational survey of position H107 and a neighboring conserved position E117 has been performed entailing the mutants H107A, H107F, H107N, E117A and the double mutants H107A/E117A and H107N/E117A. All mutants were severely destabilized versus GuHCl and heat denaturation. Thermal denaturation and GuHCl phase diagram and ANS analyses showed that the mutants shifted HCA II towards populating ensembles of intermediates of molten globule type under physiological conditions. The enormously destabilizing effects of the H107Y mutation is not due to loss of specific interactions of H107 with residue E117, instead it is caused by long range sterical destabilizing effects of the bulky tyrosine residue. We also showed that the folding equilibrium can be shifted towards the native state by binding of the small-molecule drug acetazolamide, and we present a small molecule inhibitor assessment with select sulfonamide inhibitors of varying potency to investigate the effectiveness of these molecules to inhibit the misfolding of HCA II H107Y. We also demonstrate that high concentration of the activator compound L-His increases the enzyme activity of the mutant but without stabilizing the folded protein.

     

    The infectious misfolding diseases is the smallest group of misfolding diseases. The only protein known to have the ability to be infectious is the prion protein. The human prion diseases Kuru, Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob are characterized by depositions of amyloid plaque from misfolded prion protein (HuPrP) in various regions of the brain depending on disease. Amyloidogenesis of HuPrP is hence strongly correlated with prion disease.

    Our results show that amyloid formation of recHuPrP90-231 can be achieved starting from the native protein under gentle conditions without addition of denaturant or altered pH. The process is efficiently catalyzed by addition of preformed recHuPrP90-231 amyloid seeds. It is plausible that amyloid seeding reflect the mechanism of transmissibility of prion diseases. Elucidating the mechanism of PrP amyloidogenesis is therefore of interest for strategic prevention of prion infection.

    Delarbeten
    1. Unfolding a folding disease: folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II
    Öppna denna publikation i ny flik eller fönster >>Unfolding a folding disease: folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II
    Visa övriga...
    2004 (Engelska)Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 342, nr 2, s. 619-633Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to mutations. The disease marble brain syndrome (MBS), known also as carbonic anhydrase II deficiency syndrome (CADS), can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. One mutation associated with MBS entails the His107Tyr substitution. Here, we demonstrate that this mutation is a remarkably destabilizing folding mutation. The loss-of-function is clearly a folding defect, since the mutant shows 64% of CO2 hydration activity compared to that of the wild-type at low temperature where the mutant is folded. On the contrary, its stability towards thermal and guanidine hydrochloride (GuHCl) denaturation is highly compromised. Using activity assays, CD, fluorescence, NMR, cross-linking, aggregation measurements and molecular modeling, we have mapped the properties of this remarkable mutant. Loss of enzymatic activity had a midpoint temperature of denaturation (Tm) of 16 °C for the mutant compared to 55 °C for the wild-type protein. GuHCl-denaturation (at 4 °C) showed that the native state of the mutant was destabilized by 9.2 kcal/mol. The mutant unfolds through at least two equilibrium intermediates; one novel intermediate that we have termed the molten globule light state and, after further denaturation, the classical molten globule state is populated. Under physiological conditions (neutral pH; 37 °C), the His107Tyr mutant will populate the molten globule light state, likely due to novel interactions between Tyr107 and the surroundings of the critical residue Ser29 that destabilize the native conformation. This intermediate binds the hydrophobic dye 8-anilino-1-naphthalene sulfonic acid (ANS) but not as strong as the molten globule state, and near-UV CD reveals the presence of significant tertiary structure. Notably, this intermediate is not as prone to aggregation as the classical molten globule. As a proof of concept for an intervention strategy with small molecules, we showed that binding of the CA inhibitor acetazolamide increases the stability of the native state of the mutant by 2.9 kcal/mol in accordance with its strong affinity. Acetazolamide shifts the Tm to 34 °C that protects from misfolding and will enable a substantial fraction of the enzyme pool to survive physiological conditions.

    Ort, förlag, år, upplaga, sidor
    Oxford: Elsevier, 2004
    Nyckelord
    Misfolding, loss-of-function, aggregation, molten globule, misfolding inhibitor
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-21072 (URN)10.1016/j.jmb.2004.07.024 (DOI)
    Tillgänglig från: 2009-09-28 Skapad: 2009-09-28 Senast uppdaterad: 2018-04-25Bibliografiskt granskad
    2. Thermodynamic interrogation of a folding disease. Mutant mapping of position 107 in human carbonic anhydrase II linked to marble brain disease.
    Öppna denna publikation i ny flik eller fönster >>Thermodynamic interrogation of a folding disease. Mutant mapping of position 107 in human carbonic anhydrase II linked to marble brain disease.
    2008 (Engelska)Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 47, nr 5, s. 1288-1298Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Marble brain disease (MBD) also known as Guibaud−Vainsel syndrome is caused by autosomal recessive mutations in the human carbonic anhydrase II (HCA II) gene. HCA II is a 259 amino acid single domain enzyme and is dominated by a 10-stranded β-sheet. One mutation associated with MBD entails the H107Y substitution where H107 is a highly conserved residue in the carbonic anhydrase protein family. We have previously demonstrated that the H107Y mutation is a remarkably destabilizing folding mutation [Almstedt et al. (2004) J. Mol. Biol. 342, 619−633]. Here, the exceptional destabilization by the H107Y mutation has been further investigated. A mutational survey of position H107 and a neighboring conserved position E117 has been performed entailing the mutants H107A, H107F, H107N, E117A and the double mutants H107A/E117A and H107N/E117A. All mutants were severely destabilized versus GuHCl and heat denaturation. Thermal denaturation and GuHCl phase diagram and ANS analyses showed that the mutants shifted HCA II toward populating ensembles of intermediates of molten globule type under physiological conditions. The native state stability of the mutants was in the following order:  wt > H107N > E117A > H107A > H107F > H107Y > H107N/E117A > H107A/E117A. In conclusion:  (i) H107N is least destabilizing likely due to compensatory H-bonding ability of the introduced Asn residue. (ii) Double mutant cycles surprisingly reveal additive destabilization of H107N and E117A showing that H107 and E117 are independently stabilizing the folded protein. (iii) H107Y and H107F are exceptionally destabilizing due to bulkiness of the side chains whereas H107A is more accommodating, indicating long-range destabilizing effects of the natural pathogenic H107Y mutation.

    Ort, förlag, år, upplaga, sidor
    Washington: ACS, 2008
    Nyckelord
    mutant mapping, carbonic anhydrase, misfolding, loss-of-function, molten globule
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-21056 (URN)10.1021/bi701720p (DOI)
    Tillgänglig från: 2009-09-28 Skapad: 2009-09-28 Senast uppdaterad: 2018-04-25Bibliografiskt granskad
    3. Small-Molecule Suppression of Misfolding of Mutated Human Carbonic Anhydrase II Linked to Marble Brain Disease
    Öppna denna publikation i ny flik eller fönster >>Small-Molecule Suppression of Misfolding of Mutated Human Carbonic Anhydrase II Linked to Marble Brain Disease
    Visa övriga...
    2009 (Engelska)Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, nr 23, s. 5358-5364Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Carbonic anhydrase II deficiency syndrome or Marble brain disease (MBD) is caused by autosomal recessive mutations in the human carbonic anhydrase II (HCA II) gene. Here we report a small-molecule stabilization study of the exceptionally destabilized HCA II mutant H107Y employing inhibitors based on p-aminobenzoyisulfonamide compounds and 1,3,4-thiadiazolylsulfonamides as well as amino acid activators. Protein stability assays showed a significant stabilization by the aromatic sulfonamide inhibitors when present at 10 mu M concentration, providing shifts of the midpoint of thermal denaturation between 10 degrees C and 16 degrees C and increasing the free energies of denaturation 0.5-3.0 kcal/mol as deduced from GuHCl denaturation. This study could be used as a starting point for the design of small-molecule folding modulators and possibly autoactivatable molecules for suppression of misfolding of destabilized HCA II mutants.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-19548 (URN)10.1021/bi900128e (DOI)
    Anmärkning
    On the day of the defence date tha status of this articel was In Manuscript.Tillgänglig från: 2009-06-29 Skapad: 2009-06-26 Senast uppdaterad: 2018-04-25Bibliografiskt granskad
    4. Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates
    Öppna denna publikation i ny flik eller fönster >>Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates
    2009 (Engelska)Ingår i: Prion, ISSN 1933-6896, Vol. 3, nr 4, s. 224-235Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Propagation and infectivity of prions in human prionopathies are likely associated with conversion of the mainly α-helical human prion protein, HuPrP, into an aggregated form with amyloid-like properties. Previous reports on efficient conversion of recombinant HuPrP have used mild to harsh denaturing conditions to generate amyloid fibrils in vitro. Herein we report on the in vitro conversion of four forms of truncated HuPrP (sequences 90-231 and 121-231 with and without an N-terminal hexa histidine tag) into amyloid-like fibrils within a few hours by using a protocol (phosphate buffered saline solutions at neutral pH with intense agitation) close to physiological conditions. The conversion process monitored by thioflavin T, ThT, revealed a three stage process with lag, growth and equilibrium phases. Seeding with preformed fibrils shortened the lag phase demonstrating the classic nucleated polymerization mechanism for the reaction. Interestingly, comparing thioflavin T kinetics with solubility and turbidity kinetics it was found that the protein initially formed non-thioflavionophilic, morphologically disordered aggregates that over time matured into amyloid fibrils. By transmission electron microscopy and by fluorescence microscopy of aggregates stained with luminescent conjugated polythiophenes (LCPs); we demonstrated that HuPrP undergoes a conformational conversion where spun and woven fibrils protruded from morphologically disordered aggregates. The initial aggregation functioned as a kinetic trap that decelerated nucleation into a fibrillation competent nucleus, but at the same time without aggregation there was no onset of amyloid fibril formation. The agitation, which was necessary for fibril formation to be induced, transiently exposes the protein to the air-water interface suggests a hitherto largely unexplored denaturing environment for prion conversion.

    Ort, förlag, år, upplaga, sidor
    Austin: Landes Bioscience Journals, 2009
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-21064 (URN)10.4161/pri.3.4.10112 (DOI)000280061100009 ()
    Tillgänglig från: 2009-09-28 Skapad: 2009-09-28 Senast uppdaterad: 2019-11-08
  • 48.
    Almstedt, Karin
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Lundqvist, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Carlsson, Jonas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Jonsson, Bengt-Harald
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska högskolan.
    Carlsson, Uno
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Unfolding a folding disease: folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II2004Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 342, nr 2, s. 619-633Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to mutations. The disease marble brain syndrome (MBS), known also as carbonic anhydrase II deficiency syndrome (CADS), can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. One mutation associated with MBS entails the His107Tyr substitution. Here, we demonstrate that this mutation is a remarkably destabilizing folding mutation. The loss-of-function is clearly a folding defect, since the mutant shows 64% of CO2 hydration activity compared to that of the wild-type at low temperature where the mutant is folded. On the contrary, its stability towards thermal and guanidine hydrochloride (GuHCl) denaturation is highly compromised. Using activity assays, CD, fluorescence, NMR, cross-linking, aggregation measurements and molecular modeling, we have mapped the properties of this remarkable mutant. Loss of enzymatic activity had a midpoint temperature of denaturation (Tm) of 16 °C for the mutant compared to 55 °C for the wild-type protein. GuHCl-denaturation (at 4 °C) showed that the native state of the mutant was destabilized by 9.2 kcal/mol. The mutant unfolds through at least two equilibrium intermediates; one novel intermediate that we have termed the molten globule light state and, after further denaturation, the classical molten globule state is populated. Under physiological conditions (neutral pH; 37 °C), the His107Tyr mutant will populate the molten globule light state, likely due to novel interactions between Tyr107 and the surroundings of the critical residue Ser29 that destabilize the native conformation. This intermediate binds the hydrophobic dye 8-anilino-1-naphthalene sulfonic acid (ANS) but not as strong as the molten globule state, and near-UV CD reveals the presence of significant tertiary structure. Notably, this intermediate is not as prone to aggregation as the classical molten globule. As a proof of concept for an intervention strategy with small molecules, we showed that binding of the CA inhibitor acetazolamide increases the stability of the native state of the mutant by 2.9 kcal/mol in accordance with its strong affinity. Acetazolamide shifts the Tm to 34 °C that protects from misfolding and will enable a substantial fraction of the enzyme pool to survive physiological conditions.

  • 49.
    Almstedt, Karin
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Carlsson, Uno
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Thermodynamic interrogation of a folding disease. Mutant mapping of position 107 in human carbonic anhydrase II linked to marble brain disease.2008Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 47, nr 5, s. 1288-1298Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Marble brain disease (MBD) also known as Guibaud−Vainsel syndrome is caused by autosomal recessive mutations in the human carbonic anhydrase II (HCA II) gene. HCA II is a 259 amino acid single domain enzyme and is dominated by a 10-stranded β-sheet. One mutation associated with MBD entails the H107Y substitution where H107 is a highly conserved residue in the carbonic anhydrase protein family. We have previously demonstrated that the H107Y mutation is a remarkably destabilizing folding mutation [Almstedt et al. (2004) J. Mol. Biol. 342, 619−633]. Here, the exceptional destabilization by the H107Y mutation has been further investigated. A mutational survey of position H107 and a neighboring conserved position E117 has been performed entailing the mutants H107A, H107F, H107N, E117A and the double mutants H107A/E117A and H107N/E117A. All mutants were severely destabilized versus GuHCl and heat denaturation. Thermal denaturation and GuHCl phase diagram and ANS analyses showed that the mutants shifted HCA II toward populating ensembles of intermediates of molten globule type under physiological conditions. The native state stability of the mutants was in the following order:  wt > H107N > E117A > H107A > H107F > H107Y > H107N/E117A > H107A/E117A. In conclusion:  (i) H107N is least destabilizing likely due to compensatory H-bonding ability of the introduced Asn residue. (ii) Double mutant cycles surprisingly reveal additive destabilization of H107N and E117A showing that H107 and E117 are independently stabilizing the folded protein. (iii) H107Y and H107F are exceptionally destabilizing due to bulkiness of the side chains whereas H107A is more accommodating, indicating long-range destabilizing effects of the natural pathogenic H107Y mutation.

  • 50.
    Alonso-Magdalena, Paloma
    et al.
    Departamento de Biología Aplicada, Universidad Miguel Hernández.
    Rivera, Fransisco J.
    Laboratory of Stem Cells and Neurogeneration, Institute of Anatomy, Histology and Pathology, Facultu of Medicine and Center for INterdiciplinary Studies on the Nervous System (CISNe), Universitad Austral de Chile; Institute for Molecular Regenerative MEdicine and Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus University, Salzburg, Austira.
    Guerrero Bosagna, Carlos
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Bisphenol-A and metabolic diseases: epigenetic developmental and transgenerational basis2016Ingår i: Environmental Epigenetics, ISSN 2058-5888, Vol. 2, nr 3, s. 1-10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exposure to environmental toxicants is now accepted as a factor contributing to the increasing incidence of obesity and metabolic diseases around the world. Such environmental compounds are known as ‘obesogens’. Among them, bisphenol-A (BPA) is the most widespread and ubiquitous compound affecting humans and animals. Laboratory animal work has provided conclusive evidence that early-life exposure to BPA is particularly effective in predisposing individuals to weight gain. Embryonic exposure to BPA is reported to generate metabolic disturbances later in life, such as obesity and diabetes. When BPA administration is combined with a high-fat diet, there is an exacerbation in the development of metabolic disorders. Remarkably, upon BPA exposure of gestating females, metabolic disturbances have been found both in the offspring and later in life in the mothers themselves. When considering the metabolic effects generated by an early developmental exposure to BPA, one of the questions that arises is the role of precursor cells in the etiology of metabolic disorders. Current evidence shows that BPA and other endocrine disruptors have the ability to alter fat tissue development and growth by affecting the capacity to generate functional adipocytes, as well as their rate of differentiation to specific cell types. Epigenetic mechanisms seem to be involved in the BPA-induced effects related to obesity, as they have been described in both in vitro and in vivo models. Moreover, recent reports also show that developmental exposure to BPA generates abnormalities that can be transmitted to future generations, in a process called as transgenerational epigenetic inheritance.

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