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  • Public defence: 2016-12-07 09:00 Berzeliussalen, Linköping
    Atikuzzaman, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Atikuzzaman, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Seminal Influence on the Oviduct: Mating and/or semen components induce gene expression changes in the pre-ovulatory functional sperm reservoir in poultry and pigs2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Internal fertilization occurs in birds and eutherian mammals. Foetal development, however, is either extra- respectively intra-corpore (egg vs uterus). In these animal classes, the female genital tract stores ejaculated spermatozoa into a restricted oviductal segment; the functional pre-ovulatory sperm reservoir, where they survive until ovulation/s occur. Paradoxically, this immunologically foreign sperm suspension in seminal fluid/plasma, often microbiologically contaminated, ought to be promptly eliminated by the female local immune defence which, instead, tolerates its presence. The female immune tolerance is presumably signalled via a biochemical interplay of spermatozoa, as well as the peptides and proteins of the extracellular seminal fluid, with female epithelial and immune cells. Such interplay can result in gene expression shifts in the sperm reservoir in relation to variations in fertility. To further aid our understanding of the underlying mechanisms, this thesis studied the proteome of the seminal fluid (using 2D SDS-PAGE and mass spectrometry) including cytokine content (using Luminex and/or ELISA) of healthy, sexually mature and fertile boars and cocks. As well, gene expression changes (using cDNA microarray) in the oviductal sperm reservoirs of sexually-mature females, mated or artificially infused with homologous sperm-free seminal fluid/plasma were studied. Pigs were of commercial, fertility-selected modern breeds (Landrace), while chicken belonged to the ancestor Red Junglefowl (RJF, low egg laying-capacity), a selected egg-layer White Leghorn (WL) and of their Advanced Intercross Line (AIL). Ejaculates were manually collected as single sample in cocks or as the sperm-rich fraction [SRF] and the post- SRF fraction in boars to harvest seminal fluid/plasma for proteome/cytokine and infusion-studies. Oviducts were retrieved for gene-expression analyses via microarray immediately post-mortem (chicken) or at surgery (pig), 24 h after mating or genital infusion. In pigs, the protein-rich seminal plasma showed the highest amounts of cytokines [interferon-γ, interferon gamma-induced protein 10 (IP-10/CXCL10), macrophage derived chemokine (MDC/CCL22), growth-regulated oncogene (GRO/CXCL1), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemo-attractant protein-1 (MCP-1/ CCL2), interleukin (IL)-6, IL-8/CXCL8, IL-10, IL-15, IL-17 and transforming growth factor (TGF)-β1-3) in the larger, protein-rich and sperm-poor post-SRF, indicating its main immune signalling influence. Chicken showed also a plethora of seminal fluid proteins with serum albumin and ovotransferrin being conserved through selection/evolution. However, they showed fewer cytokines than pigs, as the anti-inflammatory/immune-modulatory TGF-β2 or the pro-inflammatory CXCL10. The RJF contained fewer immune system process proteins and lacked TGF-β2 compared to WL and AIL, suggesting selection for increased fertility could be associated with higher expression of immune-regulating peptides/proteins. The oviductal sperm reservoir reacted in vivo to semen exposure. In chicken, mating significantly changed the expression of immune-modulatory and pH-regulatory genes in AIL. Moreover, modern fertile pigs (Landrace) and chicken (WL), albeit being taxonomically distant, shared gene functions for preservation of viable sperm in the oviduct. Mating or SP/SF-infusion were able to change the expression of comparable genes involved in pH-regulation (SLC16A2, SLC4A9, SLC13A1, SLC35F1, ATP8B3, ATP13A3) or immune-modulation (IFIT5, IFI16, MMP27, ADAMTS3, MMP3, MMP12). The results of the thesis demonstrate that both mating and components of the sperm-free seminal fluid/plasma elicit gene expression changes in the pre-ovulatory female sperm reservoir of chickens and pigs, some conserved over domestication and fertility-selection.

    List of papers
    1. The Seminal Plasma of the Boar is Rich in Cytokines, with Significant Individual and Intra-Ejaculate Variation
    Open this publication in new window or tab >>The Seminal Plasma of the Boar is Rich in Cytokines, with Significant Individual and Intra-Ejaculate Variation
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    2015 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, no 6, 523-532 p.Article in journal (Refereed) Published
    Abstract [en]

    Problem The boar, as human, sequentially ejaculates sperm-rich and sperm-poor fractions. Seminal plasma (SP) spermadhesins (PSP-I/PSP-II) induce a primary endometrial inflammatory response in female sows, similar to that elicited by semen deposition in other species, including human. However, the SP is also known to mitigate such response, making it transient to allow for embryo entry to a cleansed endometrium. Although cytokine involvement has been claimed, the exploration of cytokines in different SP fractions is scarce. This study determines Th1, Th2, Th17 and Th3 cytokine profiles in specific ejaculate SP fractions from boars of proven fertility. Methods SP samples from the sperm-rich fraction (SRF) and the sperm-poor post-SRF fraction (post-SRF) of manually collected ejaculates from eight boars (four ejaculates per boar) were analysed by commercial multiplex bead assay kits (Milliplex MAP, Millipore, USA) for interferon-gamma, interferon gamma-induced protein 10, macrophage-derived chemokine, growth-regulated oncogene, granulocyte-macrophage colony-stimulating factor, monocyte chemo-attractant protein-1, interleukins (IL)-6, IL-8, IL-10, IL-15, IL-17 and transforming growth factor (TGF)-beta 1-beta 3. Results Cytokine concentrations differed between the ejaculate fractions among boars, being highest in the post-SRF. Conclusion Boar SP is rich in Th1, Th2, Th17 and Th3 cytokines, with lowest concentrations in the sperm-peak-containing fraction, indicating its main immune influence might reside in the larger, protein-rich sperm-poor post-SRF.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 2015
    Keyword
    Ejaculate fractions; immunomodulatory molecules; pig; seminal plasma peptides
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-124497 (URN)10.1111/aji.12432 (DOI)000367669300006 ()26412440 (PubMedID)
    Note

    Funding Agencies|MINECO Madrid (Spain) [AGL2012-39903]; FEDER funds (EU); Formas (Stockholm, Sweden); MECD (Madrid, Spain); Seneca Foundation (Murcia, Spain)

    Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2016-11-17
    2. Selection for higher fertility reflects in the seminal fluid proteome of modern domestic chicken
    Open this publication in new window or tab >>Selection for higher fertility reflects in the seminal fluid proteome of modern domestic chicken
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    2017 (English)In: Comparative Biochemistry and Physiology - Part D: Genomics and Proteomics, ISSN 1744-117X, E-ISSN 1878-0407, Vol. 21, 27-40 p.Article in journal (Refereed) Published
    Abstract [en]

    The high egg-laying capacity of the modern domestic chicken (i.e. White Leghorn, WL) has arisen from the low egg-laying ancestor Red Junglefowl (RJF) via continuous trait selection and breeding. To investigate whether this long-term selection impacted the seminal fluid (SF)-proteome, 2DE electrophoresis-based proteomic analyses and immunoassays were conducted to map SF-proteins/cytokines in RJF, WL and a 9th generation Advanced Intercross Line (AIL) of RJF/WL-L13, including individual SF (n = 4, from each RJF, WL and AIL groups) and pools of the SF from 15 males of each group, analyzed by 2DE to determine their degree of intra-group (AIL, WL, and RJF) variability using Principal Component Analysis (PCA); respectively an inter-breed comparative analysis of intergroup fold change of specific SF protein spots intensity between breeds. The PCA clearly highlighted a clear intra-group similarity among individual roosters as well as a clear inter-group variability (e.g. between RJF, WL and AIL) validating the use of pools to minimize confounding individual variation. Protein expression varied considerably for processes related to sperm motility, nutrition, transport and survival in the female, including signaling towards immunomodulation. The major conserved SF-proteins were serum albumin and ovotransferrin. Aspartate aminotransferase, annexin A5, arginosuccinate synthase, glutathione S-transferase 2 and l-lactate dehydrogenase-A were RJF-specific. Glyceraldehyde-3-phosphate dehydrogenase appeared specific to the WL-SF while angiotensin-converting enzyme, γ-enolase, coagulation factor IX, fibrinogen α-chain, hemoglobin subunit α-D, lysozyme C, phosphoglycerate kinase, Src-substrate protein p85, tubulins and thioredoxin were AIL-specific. The RJF-SF contained fewer immune system process proteins and lower amounts of the anti-inflammatory/immunomodulatory TGF-β2 compared to WL and AIL, which had low levels- or lacked pro-inflammatory CXCL10 compared to RJF. The seminal fluid proteome differs between ancestor and modern chicken, with a clear enrichment of proteins and peptides related to immune-modulation for sperm survival in the female and fertility.

    Place, publisher, year, edition, pages
    Elsevier, 2017
    Keyword
    Rooster seminal fluid proteome, Cytokines, Egg-laying capacity, Red Junglefowl, White Leghorn, Advanced intercross line, Chicken
    National Category
    Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Genetics and Breeding
    Identifiers
    urn:nbn:se:liu:diva-132624 (URN)10.1016/j.cbd.2016.10.006 (DOI)27852008 (PubMedID)
    Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2016-11-22Bibliographically approved
    3. Mating induces the expression of immune- and pH-regulatory genes in the utero-vaginal junction containing mucosal sperm-storage tubuli of hens
    Open this publication in new window or tab >>Mating induces the expression of immune- and pH-regulatory genes in the utero-vaginal junction containing mucosal sperm-storage tubuli of hens
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    2015 (English)In: Reproduction (Cambridge, England), ISSN 1741-7899, Vol. 150, no 6, 473-483 p.Article in journal (Refereed) Published
    Abstract [en]

    The female chicken, as with other species with internal fertilization, can tolerate the presence of spermatozoa within specialized sperm-storage tubuli (SST) located in the mucosa of the utero-vaginal junction (UVJ) for days or weeks, without eliciting an immune response. To determine if the oviduct alters its gene expression in response to sperm entry, segments from the oviduct (UVJ, uterus, isthmus, magnum and infundibulum) of mated and unmated (control) hens, derived from an advanced inter-cross line between Red Junglefowl and White Leghorn, were explored 24 h after mating using cDNA microarray analysis. Mating shifted the expression of fifteen genes in the UVJ (53.33% immune-modulatory and 20.00% pH-regulatory) and seven genes in the uterus, none of the genes in the latter segment overlapping the former (with the differentially expressed genes themselves being less related to immune-modulatory function). The other oviductal segments did not show any significant changes. These findings suggest sperm deposition causes a shift in expression in the UVJ (containing mucosal SST) and the uterus for genes involved in immune-modulatory and pH-regulatory functions, both relevant for sperm survival in the hen's oviduct.

    National Category
    Genetics
    Identifiers
    urn:nbn:se:liu:diva-122573 (URN)10.1530/REP-15-0253 (DOI)000365344400004 ()26370241 (PubMedID)
    Note

    Funding agencies: Research Council FORMAS, Stockholm [221-2011-512]; FORMAS [221-2012-667]; VR [621-2011-4802]

    Available from: 2015-11-09 Created: 2015-11-09 Last updated: 2016-11-17
  • Public defence: 2016-12-07 09:15 Planck, Fysikhuset, Linköping
    Agnvall, Beatrix
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Agnvall, Beatrix
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Early domestication?: Phenotypic alterations of Red Junglefowl selected for divergent fear of humans2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Domestication is the process through which animals adapt to conditions provided by humans. The domesticated phenotype differs from wild ancestors in a number of traits relating to physiology, morphology and behaviour. One of the most striking differences is the animals’ fear response towards humans, and reduced fear of humans is assumed to have been an early prerequisite for the success of domestication. The early alterations seen in the domesticated phenotype may be traits developed as a correlated selection response due to tameness rather than selected upon one by one.

    This thesis summarizes a project where Red Junglefowl were selected for divergent fear of humans during six generations. In every generation, fear response to human was assessed in a standardized test and, according to fear score, the animals were bred for either high fear of humans (H) or low fear of humans (L). The animals were, above that of the standardized selection test, behaviourally phenotyped in different tests in each generation mainly focusing on fear, exploration and social behaviour. In addition to behaviour, the animals were phenotyped for body weight, egg weight, metabolism, feed intake, plumage condition, blood plasma corticosterone and peripheral serotonin. After culling, vital organs and brains were harvested and weighed.

    In paper I, we demonstrated that the selection trait has a significant genetic heritability and is genetically correlated with other behavioural responses associated with fearfulness and exploration. In paper II, we concluded that animals from the L strain had better plumage condition, higher weight, laid larger eggs and also generated larger offspring. Furthermore, when tested in a social dominance test with a limited resource, they received less and performed more aggression regardless of whether the restricted source was edible or not. In paper III, we revealed that animals from the L strain had higher basal metabolic rate as chicks, gained more weight in relation to feed intake and were bolder in a Novel Object test. Furthermore, the L males had higher plasma levels of peripheral serotonin, but the corticosterone after a restraint stress test did not differ. In paper IV and V, we concluded the project by comparing brain and organ weights as well as behaviour of the parental generation (P0) with the fifth selected generation (S5). The absolute brain weight as well as the weight specific brain weight were larger in the animals selected on H than in the L-animals. The relative weight of telencephalon was significantly higher in H whereas relative weight of cerebellum was significantly lower. Heart, liver, spleen and testes were all relatively heavier in H animals than in L. Interestingly, the behaviours assessed in P0 and S5 seemed to be rather resilient to the selection with only small differences in S5.

    To summarize, the selection on divergent tameness in Red Junglefowl has affected several phenotypic traits associated with the domesticated phenotype. The results of this project indicate that tameness in Red Junglefowl could be an underlying factor driving trait modifications towards the domesticated phenotype.

    List of papers
    1. Heritability and Genetic Correlations of Fear-Related Behaviour in Red Jungelfowl -Possible Implications for Early Domestication
    Open this publication in new window or tab >>Heritability and Genetic Correlations of Fear-Related Behaviour in Red Jungelfowl -Possible Implications for Early Domestication
    2012 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 4, e35162- p.Article in journal (Refereed) 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.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-76833 (URN)10.1371/journal.pone.0035162 (DOI)000305336200026 ()
    Available from: 2012-04-20 Created: 2012-04-20 Last updated: 2016-11-17
    2. Red Junglefowl (Gallus gallus) selected for low fear of humans are larger, more dominant and produce larger offspring
    Open this publication in new window or tab >>Red Junglefowl (Gallus gallus) selected for low fear of humans are larger, more dominant and produce larger offspring
    2014 (English)In: animal, ISSN 1751-7311, Vol. 8, no 9, 1498-1505 p.Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    Cambridge University Press, 2014
    Keyword
    Red Junglefowl, domestication, fearfulness, selection, social behaviour
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-109499 (URN)10.1017/S1751731114001426 (DOI)000342219000013 ()24910136 (PubMedID)
    Available from: 2014-08-20 Created: 2014-08-20 Last updated: 2016-11-17
    3. Is domestication driven by reduced fear of humans? Boldness, metabolism and serotonin levels in divergently selected red junglefowl (Gallus gallus)
    Open this publication in new window or tab >>Is domestication driven by reduced fear of humans? Boldness, metabolism and serotonin levels in divergently selected red junglefowl (Gallus gallus)
    2015 (English)In: Biology Letters, ISSN 1744-9561, E-ISSN 1744-957X, Vol. 11, no 9, 20150509Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    ROYAL SOC, 2015
    Keyword
    genetics; domestication; stress
    National Category
    Zoology Evolutionary Biology
    Identifiers
    urn:nbn:se:liu:diva-123162 (URN)10.1098/rsbl.2015.0509 (DOI)000364772300009 ()26382075 (PubMedID)
    Note

    Funding Agencies|research council Formas; ERC [322206]

    Available from: 2015-12-07 Created: 2015-12-04 Last updated: 2016-11-17
    4. Effects of Divergent Selection for Fear of Humans on Behaviour in Red Junglefowl
    Open this publication in new window or tab >>Effects of Divergent Selection for Fear of Humans on Behaviour in Red Junglefowl
    2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, 1-12 p.Article in journal (Refereed) 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.

    Place, publisher, year, edition, pages
    PLOS, 2016
    National Category
    Developmental Biology Genetics
    Identifiers
    urn:nbn:se:liu:diva-132742 (URN)10.1371/journal.pone.0166075 (DOI)27851792 (PubMedID)
    Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2016-11-28Bibliographically approved
  • Public defence: 2016-12-08 09:00 Berzeliussalen, Linköping
    Aho, Nikolas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Aho, Nikolas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Victimization, Prevalence, Health and Peritraumatic Reactions in Swedish Adolescents2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis was to expand the knowledge of victimization in children and youth in Sweden. Victimization, prevalence, health and peritraumatic reactions were explored in a cross sectional, representative sample of 5,960 second grade high school students in Sweden. A computerized survey was developed and administered in class room setting.

    Lifetime victimization was found in 84.1% of the sample (m=83.0%, f=85.2%), and, in relation to the five domains, 66.4% had experienced conventional crime, 24% child maltreatment, 54.4% peer and sibling victimization, 21.8% sexual victimization, and 54% had experienced witness victimization. Females experienced significantly more child maltreatment, peer and sibling victimization, sexual victimization, and witnessed victimization, males more conventional crime (p<0.001). Using logistic regression risk factors for victimization were confirmed by a significant increase OR regarding gender, environment and lack of both parents.

    Symptoms (TSCC), were clearly associated with both victimizations per se and the number of victimizations. The results indicated a relatively linear increase in symptoms with an increase in number of events experienced. Mental health of the polyvictimized group was significantly worse than that of the non-polyvictimized group, with significantly elevated TSCC scores (t<0.001). Hierarchical regression analysis resulted in beta value reduction when polyvictimization was introduced supporting the independent effect on symptoms. Social anxiety was found in 10.2 % (n = 605) of the total group (n = 5,960). A significant gender difference emerged, with more females than males reporting social anxiety. Elevated PTSS was found in 14.8 % (n=883). Binary logistic regression revealed the highest OR for having had contact with child and adolescent psychiatry was found for the combined group with social anxiety and elevated PTSS (OR = 4.88, 95 % CI = 3.53–6.73, p<001). Significant associations were also found between use of child and adolescent psychiatry and female gender (OR = 2.05, 95 % CI = 1.70–2.45), Swedish birth origin (OR = 1.68, 95 % CI = 1.16–2.42) and living in a small municipality (OR = 1.33, 95 % CI = 1.02–1.73).

    Mediation models used peritraumatic reactions (PT): total, physiological arousal (PA), peritraumatic dissociation (PD), and intervention thoughts (IT) and JVQ and TSCC. Of the n=5,332 cases, a total of n=4,483 (84.1%) reported at least one victimizing event (m = 83.0%, f = 85.2%). Of these, 74.9% (n=3,360) also experienced a PT reaction of some kind. The effect mediated by PT tot was b= 0.479, BCa CI [0.342 – 0.640], representing a relatively small effect of 7.6%, κ2=0.076, 95% BCa CI [0.054- 0.101]. The mediating effect of JVQ on TSCC was mediated by PD more for males (b=0.394 BCa CI [0.170-0.636]) than for females (b=0.247, BCa CI [0.021-0.469]). The indirect effect of the JVQ on the TSCC tot mediated by the different PT reactions was significant for PD (b=0.355, BCa CI [0.199- 0.523]. In males a mediating effect of PD could be seen in the different models, while females had a more mixed result. IT did not show any indirect effect in males, but had a mixed effect for females.

    The empirical findings in this thesis lead to the conclusion that victimization is highly prevalent in children and youth and is related to health issues. The association of victimization on symptoms was mediated by peritraumatic reactions. Using a comprehensive instrument such as the JVQ provides the researcher or clinician the opportunity to acquire more complete measurement and also makes it possible to identify polyvictimization, a high-level category of events with severe impact on health.  

    List of papers
    1. The Prevalence of Potentially Victimizing Events, Poly-Victimization, and Its Association to Sociodemographic Factors: A Swedish Youth Survey
    Open this publication in new window or tab >>The Prevalence of Potentially Victimizing Events, Poly-Victimization, and Its Association to Sociodemographic Factors: A Swedish Youth Survey
    2016 (English)In: Journal of Interpersonal Violence, ISSN 0886-2605, E-ISSN 1552-6518, Vol. 31, no 4, 620-651 p.Article in journal (Refereed) Published
    Abstract [en]

    Studying the extent to which children are exposed to victimizing events is important to fully understand the effect of such exposure in shaping them as adults. The aim of this study was to use self-report by adolescents to measure the prevalence of victimizing events and of poly-victimization. A representative sample of 5,960 students (aged 17) from high schools in Sweden was given the self-administrated version of the Juvenile Victimization Questionnaire (JVQ) along with questions concerning gender, birthplace, parents birthplace and employment, residence, educational program, and municipality size. The results show that 84.1% (83.0% young men and 85.2% young women) of the students had experienced victimization during their lifetime, and 10.3% were categorized as poly-victims (8.1% young men and 12.5% young women; OR = 1.62, 95% confidence interval [CI] = [1.35, 1.94]). Adolescents living with both parents were at lower risk of any form of victimization for both genders, while females were at higher risk of maltreatment, peer victimization, and, most significantly, sexual victimization. In conclusion, the vast majority of young people have been victimized during their lifetime. A greater awareness of the impact of these victimizing events on children and adolescents is important as a basis for providing a safer milieu and establishing better interventions, especially for those that have been victimized on multiple occasions. The high-exposure group was determined by using 10 events as a cutoff. Findings on this group corresponded with findings in other international studies regarding distribution, elevated risk for females, and the possibility of limiting the effects of victimization by modifying living conditions.

    Place, publisher, year, edition, pages
    SAGE PUBLICATIONS INC, 2016
    Keyword
    JVQ; victim; youth; poly-victimization; sociodemographics
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:liu:diva-124456 (URN)10.1177/0886260514556105 (DOI)000367838200004 ()25392393 (PubMedID)
    Note

    Funding Agencies|Crime Victim Compensation and Support Authority in Sweden; Medical Research Council of Southeast Sweden

    Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2016-11-17
    2. Victimization, polyvictimization , and health in Swedish adolescents
    Open this publication in new window or tab >>Victimization, polyvictimization , and health in Swedish adolescents
    2016 (English)In: Adolescent Health, Medicine and Therapeutics, ISSN 1179-318X, Vol. 7, 89-99 p.Article in journal (Refereed) Published
    Abstract [en]

    The main objective of this article was to study the relationship between the different areas of victimization (eg, sexual victimization) and psychological symptoms, taking into account the full range of victimization domains. The final aim was to contribute further evidence regarding the bias that studies that focus on just one area of victimization may be introduced into our psychological knowledge. The sample included 5,960 second-year high school students in Sweden with a mean age of 17.3 years (range =16–20 years, standard deviation =0.652), of which 49.6% were females and 50.4% males. The Juvenile Victimization Questionnaire and the Trauma Symptom Checklist for Children were used to assess victimization and psychological problems separately. The results show that a majority of adolescents have been victimized, females reported more total events and more sexual victimization and childhood maltreatment, and males were more often victims of conventional crime. The majority of victimization domains as well as the sheer number of events (polyvictimization [PV]) proved to be harmful to adolescent health, affecting females more than males. PV explained part of the health effect and had an impact on its own and in relation to each domain. This suggests the possibility that PV to a large degree explains trauma symptoms. In order to understand the psychological effects of trauma, clinicians and researchers should take into account the whole range of possible types of victimization.

    Place, publisher, year, edition, pages
    Dovepress, 2016
    Keyword
    victimization, childhood trauma, psychological symptoms, JVQ, TSCC
    National Category
    Clinical Medicine Public Health, Global Health, Social Medicine and Epidemiology Psychiatry Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-132626 (URN)10.2147/AHMT.S109587 (DOI)27616895 (PubMedID)
    Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2016-11-22Bibliographically approved
    3. Posttraumatic stress symptoms and mental health services utilization in adolescents with social anxiety disorder and experiences of victimization
    Open this publication in new window or tab >>Posttraumatic stress symptoms and mental health services utilization in adolescents with social anxiety disorder and experiences of victimization
    Show others...
    2013 (English)In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 22, no 3, 177-184 p.Article in journal (Refereed) Published
    Abstract [en]

    Recent findings from studies on adults show similarities between social anxiety disorder (SAD) and posttraumatic stress in the form of recurrent memories and intrusive and distressing images of earlier aversive events. Further, treatment models for SAD in adults have been successfully developed by using transdiagnostic knowledge on posttraumatic stress symptoms (PTSS). Studies on adolescents are though missing. The present study aimed at exploring the association between PTSS and SAD in Swedish adolescents. A second aim was to study mental health services utilization in relation to these conditions. A total of 5,960 high-school students participated and reported on SAD, life time victimization, PTSS and mental health service utilization. Socially anxious adolescents reported significantly higher levels of PTSS than adolescents not reporting SAD and this difference was seen in victimized as well as non-victimized subjects. Contact with a school counselor was the most common mental health service utilization in subjects with SAD and those with elevated PTSS. In the prediction of contact with a CAP-clinic, significant odds ratios were found for a condition of SAD and elevated PTSS (OR = 4.88, 95 % CI = 3.53–6.73) but not for SAD only. Screening of PTSS in adolescents with SAD is recommended. The service of school counselors is important in detecting and helping young people with SAD and elevated PTSS. Clinical studies on SAD and PTSS in adolescents could aid in modifying treatment models for SAD.

    Place, publisher, year, edition, pages
    Springer, 2013
    Keyword
    Social anxiety disorder, victimization, mental health service utilization, adolescents
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-89939 (URN)10.1007/s00787-012-0336-z (DOI)000315736200005 ()
    Available from: 2013-03-11 Created: 2013-03-11 Last updated: 2016-11-17
  • Public defence: 2016-12-08 10:15 Planck, Fysikhuset, Linköping
    del Río, Lía Fernández
    Linköping University, Department of Physics, Chemistry and Biology, Applied Optics . Linköping University, Faculty of Science & Engineering.
    del Río, Lía Fernández
    Linköping University, Department of Physics, Chemistry and Biology, Applied Optics . Linköping University, Faculty of Science & Engineering.
    Optical and Structural Characterization of Natural Nanostructures2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The spectacular biodiversity of our planet is the result of millions of years of evolution. Over this time animals and plants have evolved and adapted to different environments, developing specific behavioral and physical adaptations to increase their chances of survival. During the last centuries human's curiosity has pushed us to study and understand the phenomena and mechanisms of the nature that surrounds us. This understanding has even led to the fields of biomimetics where we seek solutions to human challenges by emulating nature.

    Scarab beetles (from the insect family Scarabaeidae) have fascinated humans for centuries due to the brilliant metallic shine of their chitin-rich exoskeletons and more recently for their ability to polarize reflected light. This doctoral thesis focuses on the optical characterization of the polarized reflected light from beetles in the Chrysina genus, although beetles from other genera also have been investigated. All the Chrysina beetles studied here share one characteristic, they all reflect left-handed near-circular polarized light. In some cases we also detect right-handed polarized light.

    We have observed two different main behaviors among the studied Chrysina beetles. Those which are green-colored scatter the reflected polarized light, whereas those with metallic appearance are broadband specular reflectors. We present a detailed analysis of the optical properties with Mueller-matrix spectroscopic ellipsometry combined with optical- and electron-microscopy studies of the exoskeletons. This allow us to create a model that reproduces the optical properties of these structures. The model consists of a chiral (helicoidal) multilayer structure with a gradual change of the pitch and a constant rotation of the optic axis of the layers.

    Beetles are not alone to have polarizing structures in nature and it is known that many birds and insects have the ability to detect linearly polarized light. This raises the question of whether the polarization properties of the beetles are the direct or indirect results of evolution or just pure coincidence. In order to get a better understanding of the possible reasons of this particular ability, we present a simulation study of different possible scenarios in nature where incoming light could be polarized or unpolarized, and where we consider detectors (eyes) sensitive to different states of polarized light. If the beetles are able to use this characteristic for camouflage, to confuse predators or for intraspecific communication is,

    however, still unknown and requires further investigation.

    My research results provide deeper understanding of the properties of light reflected on the beetle's exoskeleton and the nanostructures responsible for the polarization of the reflected light. The developed model could be used as bioinspiration for the fabrication of novel nano-optical devices. My results can also complement biological behavioral experiments aiming to understand the purposes of this specific optical characteristics in nature.

    List of papers
    1. Polarizing properties and structure of the cuticle of scarab beetles from the Chrysina genus
    Open this publication in new window or tab >>Polarizing properties and structure of the cuticle of scarab beetles from the Chrysina genus
    2016 (English)In: PHYSICAL REVIEW E, ISSN 2470-0045, Vol. 94, no 1, 012409- p.Article in journal (Refereed) Published
    Abstract [en]

    The optical properties of several scarab beetles have been previously studied but few attempts have been made to compare beetles in the same genus. To determine whether there is any relation between specimens of the same genus, we have studied and classified seven species from the Chrysina genus. The polarization properties were analyzed with Mueller-matrix spectroscopic ellipsometry and the structural characteristics with optical microscopy and scanning electron microscopy. Most of the Chrysina beetles are green colored or have a metallic look (gold or silver). The results show that the green-colored beetles polarize reflected light mainly at off-specular angles. The gold-colored beetles polarize light left-handed near circular at specular reflection. The structure of the exoskeleton is a stack of layers that form a cusplike structure in the green beetles whereas the layers are parallel to the surface in the case of the gold-colored beetles. The beetle C. gloriosa is green with gold-colored stripes along the elytras and exhibits both types of effects. The results indicate that Chrysina beetles can be classified according to these two major polarization properties.

    Place, publisher, year, edition, pages
    AMER PHYSICAL SOC, 2016
    National Category
    Mathematical Analysis
    Identifiers
    urn:nbn:se:liu:diva-130835 (URN)10.1103/PhysRevE.94.012409 (DOI)000380116500010 ()
    External cooperation:
    Note

    Funding Agencies|Knut and Alice Wallenberg foundation; Swedish Research Council; Centre in Nano Science and Nano Technology (CeNano) at Linkoping University

    Available from: 2016-08-26 Created: 2016-08-26 Last updated: 2016-11-16
    2. Polarizing properties and structural characteristics of the cuticle of the scarab Beetle Chrysina gloriosa
    Open this publication in new window or tab >>Polarizing properties and structural characteristics of the cuticle of the scarab Beetle Chrysina gloriosa
    2014 (English)In: Thin Solid Films, ISSN 0040-6090, E-ISSN 1879-2731, Vol. 571, no 3, 410-415 p.Article in journal (Refereed) Published
    Abstract [en]

    The scarab beetle Chrysina gloriosa is green with gold-colored stripes along its elytras. The properties of light reflected on these areas are investigated using Mueller-matrix spectroscopic ellipsometry. Both areas reflect light with high degree of left-handed polarization but this effect occurs for specular reflection for the gold-colored areas and for off-specular angles for the green areas. The colors and polarization phenomena originate from reflection of light in the cuticle and a structural analysis is presented to facilitate understanding of the different behaviors of these two areas. Scanning electron microscopy (SEM) images of the cross section of beetle cuticles show a multilayered structure. On the gold-colored areas the layers are parallel to the surface whereas on the green-colored areas they form cusp-like structures. Optical microscopy images show a rather flat surface in the gold-colored areas compared to the green-colored areas which display a net of polygonal cells with star-shaped cavities in the center. Each of the polygons corresponds to one of the cusps observed in the SEM images. Atomic force microscopy images of the star-shaped cavities are also provided. The roughness of the surface and the cusp-like structure of the green-colored areas are considered to cause scattering on this area.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    Keyword
    Scarab beetle; Near-circular polarization; Mueller-matrix spectroscopic ellipsometry
    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:liu:diva-112885 (URN)10.1016/j.tsf.2013.11.149 (DOI)000346055200013 ()
    Conference
    ICSE-VI International Conference on Spectroscopic Ellipsometry May 2013
    Funder
    Swedish Research CouncilKnut and Alice Wallenberg Foundation
    Available from: 2014-12-18 Created: 2014-12-18 Last updated: 2016-11-16Bibliographically approved
    3. Polarization of light reflected from Chrysina gloriosa under various illuminations
    Open this publication in new window or tab >>Polarization of light reflected from Chrysina gloriosa under various illuminations
    2014 (English)In: Materials Today: Proceedings, Elsevier Ltd , 2014, Vol. 1, 172-176 p.Conference paper (Refereed)
    Abstract [en]

    When illuminated with unpolarized light, the scarab beetle Chrysina gloriosa, reflects left-handed near-circularly polarized light for a broad range of angles of incidence and wavelengths in the visible. It is, however, known that light scattered from the sky, reflected on water or transmitted through leaves often is linearly polarized. In this study we have analysed the polarization of light reflected on this beetle when illuminated with different polarization states of light. We have also analysed how the response would be with a polarization-sensitive detector. The reflected irradiance is shown to be highest when the incident light is s-polarized or left-handed polarized and the detector is unpolarized (or vice versa). In the case in which both, the source and the detector, are polarized, the irradiance is highest when both are s-polarized. On the contrary the visibility is low when the source is s-polarized and the detector is p-polarized.

    Place, publisher, year, edition, pages
    Elsevier Ltd, 2014
    Series
    , Materials Today: Proceedings, ISSN 2214-7853
    Keyword
    Mueller-matrix spectroscopic ellipsometry; Near-circular polarization; Scarab beetle
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-116444 (URN)10.1016/j.matpr.2014.09.020 (DOI)2-s2.0-84923048023 (ScopusID)
    Conference
    Living Light: Uniting biology and photonics - A memorial meeting in honour of Prof Jean-Pol Vigneron
    Available from: 2015-03-27 Created: 2015-03-26 Last updated: 2016-11-16
    4. Comparison and analysis of Mueller-matrix spectra from exoskeletons of blue, green and red Cetonia aurata
    Open this publication in new window or tab >>Comparison and analysis of Mueller-matrix spectra from exoskeletons of blue, green and red Cetonia aurata
    2014 (English)In: Thin Solid Films, ISSN 0040-6090, E-ISSN 1879-2731, Vol. 571, 739-743 p.Article in journal (Refereed) Published
    Abstract [en]

    The exoskeleton, also called the cuticle, of specimens of the scarab beetle Cetonia aurata is a narrow-band reflector which exhibits metallic shine. Most specimens of C. aurata have a reflectance maximum in the green part of the spectrum but variations from blue–green to red–green are also found. A few specimens are also more distinct blue or red. Furthermore, the reflected light is highly polarized and at near-normal incidence near-circular left-handed polarization is observed. The polarization and color phenomena are caused by a nanostructure in the cuticle. This nanostructure can be modeled as a multilayered twisted biaxial layer from which reflection properties can be calculated. Specifically we calculate the cuticle Mueller matrix which then is fitted to Mueller matrices determined by dual-rotating compensator ellipsometry in the spectral range 400–800 nm at multiple angles of incidence. This non-linear regression analysis provides structural parameters like pitch of the chiral structure as well as layer refractive index data for the different layers in the cuticle. The objective here is to compare spectra measured on C. aurata with different colors and develop a generic structural model. Generally the degree of polarization is large in the spectral region corresponding to the color of the cuticle which for the blue specimen is 400–600 nm whereas for the red specimen it is 530–730 nm. In these spectral ranges, the Mueller-matrix element m41 is non-zero and negative, in particular for small angles of incidence, implicating that the reflected light becomes near-circularly polarizedwith an ellipticity angle in the range 20°–45°.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    Keyword
    Mueller-matrix ellipsometry; Scarab beetles; Chiral structures; Circular polarization; Natural photonic structures
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:liu:diva-112685 (URN)10.1016/j.tsf.2014.02.012 (DOI)000346055200076 ()
    Conference
    6th International Conference on Spectroscopic Ellipsometry (ICSE-VI), May 26–31, 2013, Kyoto, Japan
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research Council
    Available from: 2014-12-08 Created: 2014-12-08 Last updated: 2016-11-16Bibliographically approved
  • Public defence: 2016-12-08 10:15 ACAS, A-huset, Linköping
    Staack, Ingo
    Linköping University, Department of Management and Engineering, Fluid and Mechatronic Systems. Linköping University, Faculty of Science & Engineering.
    Staack, Ingo
    Linköping University, Department of Management and Engineering, Fluid and Mechatronic Systems. Linköping University, Faculty of Science & Engineering.
    Aircraft Systems Conceptual Design: An object-oriented approach from <element> to <aircraft>2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Aircraft Conceptual Design (ACD) is facing new challenges on the way to enhanced fidelity level required of the nowadays complex system design. Namely the integration of models and simulations of different fidelity levels to enhance the analysis capability while maintaining a streamlined, transparent, and low cost working process is required.

    In this thesis, the use of object-oriented Knowledge-Based Engineering (KBE) methods to enable an early integration of simulation models within the ACD phase are presented. Careful investigations of modelling and simulation approaches of multi-domain systems are carried out before, and their use in the ACD phase is examined regarding the efficiency between spend effort and result in accuracy. Enabling the named topics, a central, parametric information model approach is presented. By the extended use of XML, XSD and XSLT, domain-specific models can be translated from this dataset, supporting a direct CAD and automated simulations integration.

    Modelling systems as graph networks is a simple approach for unified modelling within the conceptual design stage. Based on this theory, the similarity of different modelling approaches like Dependency Structure Matrix (DSM), MDDSM, or Channel-Agency Networks is shown. Using object-oriented programming, all these and more aspects such as e.g. Fault Tree Analysis (FTA) can be globally handled as one graph set.

    Based on the outcomes of the theoretical part, the development of a ACD framework is described. Backed by a central XML-based namespace, this framework integrates a complete CAD environment to ensure an appropriate environment for the geometric domain modelling. Furthermore, the use of KBE for automated simulation model integration is exemplified by a whole aircraft simulation including the hydraulic aircraft flight control system (FCS).

  • Public defence: 2016-12-09 09:00 Berzeliussalen, Linköping
    Sundell, Anna Lena
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit. The Institute for Postgraduate Dental Education, Department of Paediatric Dentistry, Jönköping, Sweden.
    Sundell, Anna Lena
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit. The Institute for Postgraduate Dental Education, Department of Paediatric Dentistry, Jönköping, Sweden.
    Children with orofacial clefts: dental caries and health-related quality of life2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background. The current understanding on caries and enamel developmental defects prevalence and frequency, caries risk, health-related quality life (HRQoL) and stress response in young children with cleft lip and/or palate (CL/P) are sparse. In this thesis these aspects were investigated in 5- and 10- year-old children with CL/P in comparison to non-cleft children in the same ages.

    Design. The studies in this thesis have a cross-sectional case-control design. Participants. The study group consisted of 139 children with CL/P (80 children aged 5 years and 59 aged 10 years) and 313 non-cleft controls (144 children aged 5 years and 169 aged 10 years).

    Method. Caries was scored according to International Caries Detection and Assessment System (ICDAS II) and developmental enamel defects were measured as presence and frequency of hypoplasia and hypomineralization. Oral hygiene was assessed using Quigley-Hein plaque index. Stimulated saliva samples were analyzed for mutans streptococci, lactobacilli, buffering capacity and secretion rates. Information regarding children’s oral hygiene routines, dietary habits and fluoride exposure were collected with questionnaires. Caries risk was evaluated with algorithm-based software, Cariogram while HRQoL was perceived with KIDSCREEN-52. Stress response was analyzed with cortisol concentration in saliva at three different time points using a commercial competitive radioimmunoassay.

    Results. Caries prevalence (36% versus 18%) and caries frequency (1.2 dmfs versus 0.9 dmfs) was significantly higher in 5-year-old children with CL/P in comparison to non-cleft controls. In 10-yearolds no significant difference was found between children with CL/P and non-cleft controls in caries prevalence (47% versus 38%) or in caries frequency (0.7 DMFS versus 0.5 DMFS). Children with CL/P had significantly higher prevalence of enamel defects, higher counts of salivary lactobacilli and less good oral hygiene. The odds of being categorized with high caries risk were elevated in children with CL/P. Children with CL/P had similar HRQoL and salivary cortisol concentrations as non-cleft controls. However, 10-year-old boys with CL/P had significantly higher cortisol concentrations in the evening than non-cleft boys.

    Conclusions. Preschool children with CL/P seem to have more caries in the primary dentition than non-cleft controls. Children with CL/P had increased odds of being categorized as high caries risk individuals compared to controls. Some of the contributing factors seem to be higher prevalence of enamel defects, impaired oral hygiene and elevated salivary lactobacilli. Furthermore, as measured with the help of cortisol concentrations in saliva, children with CL/P were not more stressed than noncleft controls and their HRQoL was comparable to a European norm population. It appears that regular comprehensive preventive oral care in children with CL/P is effective in preventing caries development in permanent teeth. However, children with CL/P are at risk of caries development and preventive oral care should be implemented and started earlier than today.

    List of papers
    1. Caries prevalence and enamel defects in 5-and 10-year-old children with cleft lip and/or palate: A case-control study
    Open this publication in new window or tab >>Caries prevalence and enamel defects in 5-and 10-year-old children with cleft lip and/or palate: A case-control study
    Show others...
    2016 (English)In: Acta Odontologica Scandinavica, ISSN 0001-6357, E-ISSN 1502-3850, Vol. 74, no 2, 90-95 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective. To determine the prevalence of dental caries and enamel defects in 5- and 10-year-old Swedish children with cleft lip and/or palate (CL(P)) in comparison to non-cleft controls. Materials and methods. The study group consisted of 139 children with CL(P) (80 subjects aged 5 years and 59 aged 10 years) and 313 age-matched non-cleft controls. All children were examined by one of two calibrated examiners. Caries was scored according to the International Caries Detection and Assessment System (ICDAS-II) and enamel defects as presence and frequency of hypoplasia and hypomineralization. Results. The caries prevalence among the 5-year-old CL(P) children and the non-cleft controls was 36% and 18%, respectively (p &lt; 0.05). The CL(P) children had higher caries frequency (initial and cavitated lesions) in the primary dentition than their controls (1.2 vs 0.9; p &lt; 0.05). A significantly higher prevalence of enamel defects was found in CL(P) children of both age groups and anterior permanent teeth were most commonly affected. Conclusions. Preschool children with cleft lip and/or palate seem to have more caries in the primary dentition than age-matched non-cleft controls. Enamel defects were more common in CL(P) children in both age groups.

    Place, publisher, year, edition, pages
    TAYLOR & FRANCIS LTD, 2016
    Keyword
    Cleft palate; cleft lip and palate; dental caries; hypomineralization; hypoplasia
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-124077 (URN)10.3109/00016357.2015.1044562 (DOI)000366811600002 ()25972142 (PubMedID)
    Note

    Funding Agencies|FORSS Medical Research Council of Southeast Sweden; Futurum Academy of Health and Care Jonkoping County Council; Swedish Dental Association; Swedish Society of Paediatric Dentistry

    Available from: 2016-01-25 Created: 2016-01-19 Last updated: 2016-11-17
    2. Comparing caries risk profiles between 5-and 10-year-old children with cleft lip and/or palate and non-cleft controls
    Open this publication in new window or tab >>Comparing caries risk profiles between 5-and 10-year-old children with cleft lip and/or palate and non-cleft controls
    2015 (English)In: BMC Oral Health, ISSN 1472-6831, Vol. 15, no 85Article in journal (Refereed) Published
    Abstract [en]

    Background: Previous studies have suggested that children with oral clefts may have higher caries prevalence in comparison with non-cleft controls but the relative importance of the potential risk factors is not clear. The aim of this study was to compare the caries risk profiles in a group of cleft lip and/or palate (CL(P)) children with non-cleft controls in the same age using a computerized caries risk assessment model. Methods: The study group consisted of 133 children with CL(P) (77 subjects aged 5 years and 56 aged 10 years) and 297 non-cleft controls (133 aged 5 years and 164 aged 10 years). A questionnaire was used to collect data concerning the childs oral hygiene routines, dietary habits and fluoride exposure. Oral hygiene was assessed using Quigley-Hein plaque Index and the caries prevalence and frequency was scored according to the International Caries Detection and Assessment System. Whole saliva samples were analyzed for mutans streptococci, lactobacilli, buffering capacity and secretion rate. The risk factors and risk profiles were compared between the groups with aid of Cariogram and the estimated risk for future caries was categorized as "high" or "low". Results: Children with CL(P) (the entire study group) had significantly higher counts of salivary lactobacilli (p less than 0.05) and displayed less good oral hygiene (p less than 0.05). More 10-year-old children in the CL(P) group had low secretion rate but this difference was not significant. The average chance to avoid caries ranged from 59 to 67 % but there were no significant differences between the groups. The odds of being categorized with high caries risk in the CL(P) group was significantly elevated (OR = 1.89; 95 % CI = 1.25-2.86). In both groups, children in the high risk category had a higher caries experience than those with low risk. Conclusion: Children with CL(P) displayed increased odds of being categorized at high caries risk with impaired oral hygiene and elevated salivary lactobacilli counts as most influential factors. The results suggest that a caries risk assessment model should be applied in the routine CL(P) care as a basis for the clinical decision-making and implementation of primary and secondary caries prevention.

    Place, publisher, year, edition, pages
    BioMed Central, 2015
    Keyword
    Cleft lip; Cleft palate; Cleft lip and/or palate; Caries risk; Cariogram; Children
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-120739 (URN)10.1186/s12903-015-0067-x (DOI)000358428000002 ()26208495 (PubMedID)
    Note

    Funding Agencies|FORSS - Medical Research Council of Southeast Sweden, Futurum, - Academy of Health and Care Jonkoping County Council; Swedish Dental Association; Swedish Society of Paediatric Dentistry

    Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2016-11-17
    3. A comparison of health-related quality of life in 5- and 10-year-old Swedish children with and without cleft lip and/or palate
    Open this publication in new window or tab >>A comparison of health-related quality of life in 5- and 10-year-old Swedish children with and without cleft lip and/or palate
    2016 (English)In: International Journal of Paediatric Dentistry, ISSN 0960-7439, E-ISSN 1365-263XArticle in journal (Refereed) Epub ahead of print
    Abstract [en]

    Background The current understanding on health-related quality of life (HRQoL) in young Swedish children with cleft lip and/or palate (CL/P) is sparse, and therefore, research on impact of CL/P on HRQoL in children is needed.

    Aims To investigate HRQoL in 5- and 10-year-old Swedish children with CL/P in comparison with non-cleft controls. Also to analyse whether there were any differences in HRQoL between children with cleft lip (with or without cleft palate, CL ± P) and cleft palate only (CP) and/or gender differences. Design A total of 137 children with CL/P and 305 non-cleft controls participated. HRQoL was measured with KIDSCREEN-52.

    Results All children in the study exhibited HRQoL within or above the age-matched reference interval of the method with similar results in both groups; however, in the dimension ‘social support and peers’, the 10-year-old children with CL/P perceived lower HRQoL than the non-cleft controls, but it did not reach statistical significance. Type of cleft or gender did not influence HRQoL.

    Conclusions Both 5- and 10-year-old Swedish children with CL/P had HRQoL in the normal reference interval. Their general life situations were well adjusted to their clefts, but the older children with CL/P felt more excluded and less supported by peers.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2016
    National Category
    Surgery Dentistry
    Identifiers
    urn:nbn:se:liu:diva-132622 (URN)10.1111/ipd.12253 (DOI)27464906 (PubMedID)
    Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2016-11-22Bibliographically approved
  • Public defence: 2016-12-09 10:15 Key 1, House K, Linköping
    Sadowski, Helga
    Linköping University, Department of Thematic Studies, The Department of Gender Studies. Linköping University, Faculty of Arts and Sciences.
    Sadowski, Helga
    Linköping University, Department of Thematic Studies, The Department of Gender Studies. Linköping University, Faculty of Arts and Sciences.
    Digital Intimacies: Doing Digital Media Differently2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Digital media have become an integral part of many people’s everyday lives and constitute an intimate presence therein. Utilizing the concept of digital intimacy to focus on these recent developments, this doctoral dissertation takes the perspectives of feminist cultural studies and affect theory to analyze how digital media are becoming more intimate and how in turn intimacy is remediated within digital cultures.

    This research brings together three different strategic examples of digital intimacy. The first is chosen from the context of online hate and harassment, and works to counteract digital forms of intimidation. The second is from the world of software development training initiatives tailored for women and designed to make them digitally intimate. The third investigates the digital subculture around ASMR (‘autonomous sensory meridian response’), which is an intimate multi-sensory stimulation induced by such things as online video clips.

    It is argued that these three initiatives are good illustrations of contemporary gender relations in digital cultures, and also do digital media differently. This  means that they develop and apply sometimes straightforward, sometimes rather playful strategies to counteract gender-based inimicalities (such as forms of discrimination or exclusion, or objectification) within digital cultures. The thesis argues that such digitally intimate strategies can be utilized analytically in order to contribute to contemporary feminist internet politics.

  • Public defence: 2016-12-09 13:00 Berzeliussalen, Linköping
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Mechanisms Behind Illness-Induced Anorexia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Loss of appetite is together with fever and malaise hallmarks of infection. Loosing appetite during an acute infection such as influenza does not result in any longlasting effects, but loosing appetite during chronic diseases such as cancer or AIDS constitutes a risk factor for mortality. Food intake regulation during inflammation is orchestrated by the brain in response to peripheral inflammatory signals. It is known that expression of the prostaglandin synthesizing enzyme cyclooxygenase 2 (COX-2) is crucial for the mechanisms underlying inflammation-induced anorexia, and that prostaglandin E2 (PGE2) is involved in anorexia induced by interleukin-1 beta (IL-1β). In this thesis I examined the prostaglandin-pathways proposed to be involved in anorexia. We show that acute anorexia is dependent on COX-2 expression, while cancer-induced anorexia is mediated by cyclooxygenase 1 (COX-1), at least in the initial stages, suggesting that the signaling pathways for chronic- and acute anorexia are distinct. We were able to demonstrate that the pathway underlying acute anorexia is distinct from that of fever, and that taste aversion is prostaglandin independent. We could also show that both acute and chronic anorexia-cachexia is dependent on expression of myeloid differentiation primary response gene (MyD88) in hematopoietic/myeloid cells.

    In summary, the findings presented in this thesis suggest that anorexia is a result of many different signaling pathways, as opposed to what is the case for several other inflammatory symptoms such as fever and malaise, where the pathways have been shown to be very exclusive. This provides new insight into the diversity of the pathways underlying inflammatory symptoms, which is fundamental for the ability to present potential, symptom-specific drug targets.

    List of papers
    1. Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1
    Open this publication in new window or tab >>Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1
    Show others...
    2013 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 29, 124-135 p.Article in journal (Refereed) Published
    Abstract [en]

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia–cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia–cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE2 levels in plasma – a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE2-levels in the cerebrospinal fluid. Neutralization of plasma PGE2 with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP4 receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE2 and neuronal EP4 signaling.

    Place, publisher, year, edition, pages
    Elsevier, 2013
    Keyword
    Cancer anorexia-cachexia, Cyclooxygenase, Microsomal prostaglandin E synthase-1, Prostaglandin E2
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-90188 (URN)10.1016/j.bbi.2012.12.020 (DOI)000315365400013 ()
    Note

    Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||Swedish Brain Foundation||

    Available from: 2013-04-04 Created: 2013-03-21 Last updated: 2016-11-18Bibliographically approved
    2. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
    Open this publication in new window or tab >>Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
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    2013 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, 1973-1980 p.Article in journal (Refereed) Published
    Abstract [en]

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

    Place, publisher, year, edition, pages
    Federation of American Society of Experimental Biology (FASEB), 2013
    Keyword
    lipopolysaccharide; methylcholanthrene-induced sarcoma; food intake; chimeric mice; Cre-LoxP; inducible cell-specific deletion
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-96147 (URN)10.1096/fj.12-225433 (DOI)000318226100017 ()
    Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2016-11-18
    3. The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent
    Open this publication in new window or tab >>The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent
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    2016 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139Article in journal (Refereed) In press
    Abstract [en]

    From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1–4) that was critical for the anorexic response to peripherally injected interleukin-1β (IL-1β). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1β induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1β evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1β in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1β; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1β evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.

    Keyword
    Anorexia, Prostaglandin E2, EP receptors, Interleukin-1, Cyclooxygenase-2, Mice
    National Category
    Immunology Cell Biology Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-132639 (URN)10.1016/j.bbi.2016.06.014 (DOI)27375005 (PubMedID)
    Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2016-11-23Bibliographically approved
  • Public defence: 2016-12-09 13:15 TEMCAS, TEMA-huset, Linköping
    Mehrabi, Tara
    Linköping University, Department of Thematic Studies, The Department of Gender Studies. Linköping University, Faculty of Arts and Sciences.
    Mehrabi, Tara
    Linköping University, Department of Thematic Studies, The Department of Gender Studies. Linköping University, Faculty of Arts and Sciences.
    Making Death Matter: A Feminist Technoscience Study of Alzheimer's Sciences in the Laboratory2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis is a contribution to feminist laboratory studies and a critical engagement with the natural sciences, or more precisely research on the biochemical workings and deadly relations of Alzheimer’s disease emanating from a year of field work in a Drosophila fly lab. The natural sciences have been a point of fascination within the field of gender studies for decades. Such sciences produce knowledge on what gets to count as nature and natural, healthy or sick, normal or not, and they have done it with great societal authority and impact throughout European modernity. However, feminist technoscience scholars argue that science and knowledge is socially produced, and political too. Concepts such as nature, animal, human, body, sex, and life itself are not simply given natural realities but phenomena processed through the naturecultures of the laboratory. Situated within such theoretical and methodological approaches, this thesis wonders how scientific facts about Alzheimer’s disease are made in the lab today. What kinds of realities, bodies and ethico-political concerns are enacted? Who gets to live and who gets to die in everyday laboratory practices? Theoretically, the thesis is grounded, particularly, within Karen Barad’s agential realism and posthumanist performativity, and as such it accounts for human and nonhuman entanglements through which AD is performed in the lab in relational ways. In other words, the thesis explores how AD is enacted in the bodies of transgenic fruit flies (Drosophila melanogaster), as these flies embody the disease, live and die with it. Last but not least, the thesis explores the materialities of death, dying, embodiment and biological waste in a biochemistry lab as constitutive parts of the produced knowledge about AD.

  • Public defence: 2016-12-13 13:15 Visionen, Hus B, Linköping
    O'Reilly, Ossian
    Linköping University, Department of Mathematics, Computational Mathematics. Linköping University, Faculty of Science & Engineering.
    O'Reilly, Ossian
    Linköping University, Department of Mathematics, Computational Mathematics. Linköping University, Faculty of Science & Engineering.
    Numerical methods for wave propagation in solids containing faults and fluid-filled fractures2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis develops numerical methods for the simulation of wave propagation in solids containing faults and fluid-filled fractures. These techniques have applications in earthquake hazard analysis, seismic imaging of reservoirs, and volcano seismology. A central component of this work is the coupling of mechanical systems. This aspect involves the coupling of both ordinary differential equations (ODE)(s) and partial differential equations (PDE)(s) along curved interfaces.  All of these problems satisfy a mechanical energy balance. This mechanical energy balance is mimicked by the numerical scheme using high-order accurate difference approximations that satisfy the principle of summation by parts, and by weakly enforcing the coupling conditions. 

    The first part of the thesis considers the simulation of dynamic earthquake ruptures along non-planar fault geometries and the simulation of seismic wave radiation from earthquakes, when the earthquakes are idealized as point moment tensor sources. The dynamic earthquake rupture process is simulated by coupling the elastic wave equation at a fault interface to nonlinear ODEs that describe the fault mechanics. The fault geometry is complex and treated by combining structured and unstructured grid techniques. In other applications, when the earthquake source dimension is smaller than wavelengths of interest, the earthquake can be accurately described by a point moment tensor source localized at a single point. The numerical challenge is to discretize the point source with high-order accuracy and without producing spurious oscillations.

    The second part of the thesis presents a numerical method for wave propagation in and around fluid-filled fractures. This problem requires the coupling of the elastic wave equation to a fluid inside curved and branching fractures in the solid. The fluid model is a lubrication approximation that incorporates fluid inertia, compressibility, and viscosity. The fracture geometry can have local irregularities such as constrictions and tapered tips. The numerical method discretizes the fracture geometry by using curvilinear multiblock grids and applies implicit-explicit time stepping to isolate and overcome stiffness arising in the semi-discrete equations from viscous diffusion terms, fluid compressibility, and the particular enforcement of the fluid-solid coupling conditions. This numerical method is applied to study the interaction of waves in a fracture-conduit system. A methodology to constrain fracture geometry for oil and gas (hydraulic fracturing) and volcano seismology applications is proposed.

    The third part of the thesis extends the summation-by-parts methodology to staggered grids. This extension reduces numerical dispersion and enables the formulation of stable and high-order accurate multiblock discretizations for wave equations in first order form on staggered grids. Finally, the summation-by-parts methodology on staggered grids is further extended to second derivatives and used for the treatment of coordinate singularities in axisymmetric wave propagation.

    List of papers
    1. Simulation of Earthquake Rupture Dynamics in Complex Geometries Using Coupled Finite Difference and Finite Volume Methods
    Open this publication in new window or tab >>Simulation of Earthquake Rupture Dynamics in Complex Geometries Using Coupled Finite Difference and Finite Volume Methods
    2015 (English)In: Communications in Computational Physics, ISSN 1815-2406, E-ISSN 1991-7120, Vol. 17, no 2, 337-370 p.Article in journal (Refereed) Published
    Abstract [en]

    We couple a node-centered finite volume method to a high order finite difference method to simulate dynamic earthquake ruptures along nonplanar faults in two dimensions. The finite volume method is implemented on an unstructured mesh, providing the ability to handle complex geometries. The geometric complexities are limited to a small portion of the overall domain and elsewhere the high order finite difference method is used, enhancing efficiency. Both the finite volume and finite difference methods are in summation-by-parts form. Interface conditions coupling the numerical solution across physical interfaces like faults, and computational ones between structured and unstructured meshes, are enforced weakly using the simultaneousapproximation-term technique. The fault interface condition, or friction law, provides a nonlinear relation between fields on the two sides of the fault, and allows for the particle velocity field to be discontinuous across it. Stability is proved by deriving energy estimates; stability, accuracy, and efficiency of the hybrid method are confirmed with several computational experiments. The capabilities of the method are demonstrated by simulating an earthquake rupture propagating along the margins of a volcanic plug.

    Place, publisher, year, edition, pages
    Global Science Press, 2015
    Keyword
    elastic waves, earthquake, high order finite difference finite volume, summation-by-parts, simultaneous approximation term, nonlinear boundary conditions
    National Category
    Computational Mathematics Mathematics
    Identifiers
    urn:nbn:se:liu:diva-113745 (URN)10.4208/cicp.111013.120914a (DOI)000353693400002 ()
    Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2016-11-17
    2. Discretizing singular point sources in hyperbolic wave propagation problems
    Open this publication in new window or tab >>Discretizing singular point sources in hyperbolic wave propagation problems
    2016 (English)In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 321, 532-555 p.Article in journal (Refereed) Published
    Abstract [en]

    We develop high order accurate source discretizations for hyperbolic wave propagation problems in first order formulation that are discretized by finite difference schemes. By studying the Fourier series expansions of the source discretization and the finite difference operator, we derive sufficient conditions for achieving design accuracy in the numerical solution. Only half of the conditions in Fourier space can be satisfied through moment conditions on the source discretization, and we develop smoothness conditions for satisfying the remaining accuracy conditions. The resulting source discretization has compact support in physical space, and is spread over as many grid points as the number of moment and smoothness conditions. In numerical experiments we demonstrate high order of accuracy in the numerical solution of the 1-D advection equation (both in the interior and near a boundary), the 3-D elastic wave equation, and the 3-D linearized Euler equations.

    Keyword
    Singular sources, Hyperbolic wave propagation, Moment conditions, Smoothness conditions, Summation by parts
    National Category
    Computational Mathematics Mathematical Analysis
    Identifiers
    urn:nbn:se:liu:diva-132630 (URN)10.1016/j.jcp.2016.05.060 (DOI)
    Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2016-11-17
  • Public defence: 2016-12-14 09:15 Planck, Fysikhuset, Linköping
    Bélteky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Bélteky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Chicken domestication: Effects of tameness on brain gene expression and DNA methylation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Domestication greatly increases phenotypic variation in a short time span, with selection for a single phenotype and a plethora of associated phenotypic changes as an outcome of the process. The domestication process influences the underlying genomic architecture of a species, and the success and speed of the process is likely influenced by it. The main aims of my thesis was to study how domestication affects the brain of chickens: specifically changes in morphology, gene expression, and DNA methylation. Differences in gene expression and DNA methylation between White Leghorn and Red Junglefowl chickens were mapped, and inheritance of these patterns were quantified, indicating a faithful transmission of breed-specific epigenetic markers. Selection on the behavioral trait fearfulness, generated high and low fearful lines of Red Junglefowl. Both the parental population and the fifth selected generation were used for the analyses in this thesis. One experiment studied morphological changes in the brain and other vital organs, and found that relative total brain size increased in high fearful birds, as a consequence of an increase in cerebral hemisphere size in high fearful birds and not in low fearful birds. Also, the relative heart, liver, spleen and testis size increased in high fearful birds, indicating correlated morphological changes with selection for fearfulness. Two additional experiments examined differential gene expression in the hypothalamus and the anterior cerebral hemisphere. The hypothalamus differed in expression of genes with reproductive and immunological functions, whilst the cerebral hemisphere differed in expression of genes related to social behaviors and neurological functions especially those upregulated in low fearful birds.  These results indicate the occurrence of tissue- and species-specific changes in gene expression as overlap with other domestication events were nearly nonexistent. A fourth experiment sought to associate the change in fear levels and gene expression differences with DNA methylation. Chromosomal regions with differential DNA methylation between high and low fearful birds were identified, and genes in these regions had annotated functions relevant to phenotypic differences between the selection lines. This thesis is the first to study the genetic alterations of domestication using the wild ancestor of an already domesticated species to repeat the domestication process selecting against fear of humans. The findings corroborate results from previous comparisons of wild and domestic animals, and further support the theory that rigorous selection for a behavioral trait can cause a cascade of genetic and epigenetic changes facilitating the domestication of a population.

    List of papers
    1. Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
    Open this publication in new window or tab >>Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
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    2012 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, no 59Article in journal (Refereed) Published
    Abstract [en]

    Variations in gene expression, mediated by epigenetic mechanisms, may cause broad phenotypic effects in animals. However, it has been debated to what extent expression variation and epigenetic modifications, such as patterns of DNA methylation, are transferred across generations, and therefore it is uncertain what role epigenetic variation may play in adaptation. Here, we show that in Red Junglefowl, ancestor of domestic chickens, gene expression and methylation profiles in thalamus/hypothalamus differ substantially from that of a domesticated egg laying breed. Expression as well as methylation differences are largely maintained in the offspring, demonstrating reliable inheritance of epigenetic variation. Some of the inherited methylation differences are tissue-specific, and the differential methylation at specific loci are little changed after eight generations of intercrossing between Red Junglefowl and domesticated laying hens. There was an over-representation of differentially expressed and methylated genes in selective sweep regions associated with chicken domestication. Hence, our results show that epigenetic variation is inherited in chickens, and we suggest that selection of favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation states which are inherited independently of sequence differences, may have been an important aspect of chicken domestication.

    Place, publisher, year, edition, pages
    BioMed Central, 2012
    Keyword
    Domestication, gene expression, tiling array, behaviour, methylation
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-70159 (URN)10.1186/1471-2164-13-59 (DOI)000301440800001 ()
    Note

    funding agencies|Swedish Research Council| 2008-14496-59340-36 |Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning| 221 2007 838 |

    Available from: 2011-08-22 Created: 2011-08-22 Last updated: 2016-11-30Bibliographically approved
    2. Domestication and tameness: brain geneexpression in red junglefowl selected for less fear of humans suggests effects on reproduction and immunology
    Open this publication in new window or tab >>Domestication and tameness: brain geneexpression in red junglefowl selected for less fear of humans suggests effects on reproduction and immunology
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    2016 (English)In: Royal Society Open Science, ISSN 2052-3068, E-ISSN 2046-2069, no 3, 160033Article in journal (Refereed) Published
    Abstract [en]

    The domestication of animals has generated a set of phenotypicmodifications, affecting behaviour, appearance, physiologyand reproduction, which are consistent across a range ofspecies. We hypothesized that some of these phenotypes couldhave evolved because of genetic correlation to tameness,an essential trait for successful domestication. Starting froman outbred population of red junglefowl, ancestor of alldomestic chickens, we selected birds for either high or lowfear of humans for five generations. Birds from the fifthselected generation (S5) showed a divergent pattern of growthand reproduction, where low fear chickens grew larger andproduced larger offspring. To examine underlying geneticmechanisms, we used microarrays to study gene expressionin thalamus/hypothalamus, a brain region involved in fearand stress, in both the parental generation and the S5. Whileparents of the selection lines did not show any differentiallyexpressed genes, there were a total of 33 genes with adjustedp-values below 0.1 in S5. These were mainly related to spermfunction,immunological functions, with only a few known tobe relevant to behaviour. Hence, five generations of divergentselection for fear of humans produced changes in hypothalamicgene expression profiles related to pathways associated withmale reproduction and to immunology. This may be linked to the effects seen on growth and size of offspring. These results support the hypothesis thatdomesticated phenotypes may evolve because of correlated effects related to reduced fear of humans.

    Place, publisher, year, edition, pages
    Royal Society Publishing, 2016
    Keyword
    artificial selection, gene expression, microarray, chicken, fearfulness
    National Category
    Ecology
    Identifiers
    urn:nbn:se:liu:diva-130501 (URN)10.1098/rsos.160033 (DOI)000384411000002 ()
    Note

    Funding agencies:  Research council Formas; Vetenskapsradet; ERC [322206]

    Available from: 2016-08-11 Created: 2016-08-11 Last updated: 2016-11-30
  • Public defence: 2016-12-15 09:00 Hasselqvistsalen, Växthuset, Linköping
    Loftås, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping.
    Loftås, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping.
    Response to neoadjuvant treatment in rectal cancer surgery2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.

    Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.

    Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.

    Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.

    Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.

    List of papers
    1. EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY
    Open this publication in new window or tab >>EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY
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    2009 (English)In: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, ISSN 0360-3016, Vol. 75, no 1, 137-142 p.Article in journal (Refereed) Published
    Abstract [en]

    Purpose: FXYD-3 (MAT-8) is overexpressed in several types of cancers; however, its clinical relevance in rectal cancers has not been studied. Therefore, we examined FXYD-3 expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative radiotherapy (RT) to determine whether FXYD-3 was overexpressed in rectal cancers and correlated with RT, survival, and other clinicopathologic variables. Methods and Materials: The study included 140 rectal cancer patients who participated in a clinical trial of preoperative RT, 65 with and 75 without RT before surgery. FXYD-3 expression was immumohistochemically examined in distant (n = 70) and adjacent (n = 101) normal mucosa, primary tumors (n = 140), and lymph node metastasis (n = 36). Results: In the whole cohort, strong FXYD-3 expression was correlated with infiltrative tumor growth (p = 0.02). In the RT group, strong FXYD-3 expression alone (p = 0.02) or combined with phosphatase of regenerating liver was associated with an unfavorable prognosis (p = 0.02), independent of both TNM stage and tumor differentiation. In tumors with strong FXYD-3 expression, there was less tumor necrosis (p = 0.02) and a trend toward increased incidence of distant metastasis (p = 0.08) after RT. None of these effects was seen in the non-RT group. FXYD-3 expression in the primary tumors tended to he increased compared with normal mucosa regardless of RT. Conclusion: FXYD-3 expression was a prognostic factor independent of tumor stage and differentiation in patients receiving preoperative RT for rectal cancer.

    Keyword
    FXYD-3, Rectal cancer, Radiotherapy, Prognosis, Immunohistochemistry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20598 (URN)10.1016/j.ijrobp.2008.10.076 (DOI)
    Available from: 2009-09-16 Created: 2009-09-15 Last updated: 2016-11-24
    2. FXYD-3 expression in relation to local recurrence of rectal cancer
    Open this publication in new window or tab >>FXYD-3 expression in relation to local recurrence of rectal cancer
    Show others...
    2016 (English)In: Radiation Oncology Journal, ISSN 2234-1900 (print), 2234-3156 (online), Vol. 34, no 1, 52-58 p.Article in journal (Refereed) Published
    Abstract [en]

    Purpose: In a previous study, the transmembrane protein FXYD-3 was suggested as a biomarker for a lower survival rate and reduced radiosensitivity in rectal cancer patients receiving preoperative radiotherapy. The purpose of preoperative irradiation in rectal cancer is to reduce local recurrence. The aim of this study was to investigate the potential role of FXYD-3 as a biomarker for increased risk for local recurrence of rectal cancer.

    Materials and Methods: FXYD-3 expression was immunohistochemically examined in surgical specimens from a cohort of patients with rectal cancer who developed local recurrence (n = 48). The cohort was compared to a matched control group without recurrence (n = 81).

    Results: Weak FXYD-3 expression was found in 106/129 (82%) of the rectal tumors and strong expression in 23/129 (18%). There was no difference in the expression of FXYD-3 between the patients with local recurrence and the control group. Furthermore there was no difference in FXYD-3 expression and time to diagnosis of local recurrence between patients who received preoperative radiotherapy and those without.

    Conclusion: Previous findings indicated that FXYD-3 expression may be used as a marker of decreased sensitivity to radiotherapy or even overall survival. We were unable to confirm this in a cohort of rectal cancer patients who developed local recurrence.

    Place, publisher, year, edition, pages
    Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, 2016
    Keyword
    Rectal cancer, Human FXYD3 protein, Local recurrence
    National Category
    Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-132758 (URN)10.3857/roj.2016.34.1.52 (DOI)27104167 (PubMedID)
    Available from: 2016-11-23 Created: 2016-11-23 Last updated: 2016-11-29Bibliographically approved
    3. Nodal involvement in luminal complete response after neoadjuvant treatment for rectal cancer
    Open this publication in new window or tab >>Nodal involvement in luminal complete response after neoadjuvant treatment for rectal cancer
    2016 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 42, no 6, 801-807 p.Article in journal (Refereed) Published
    Abstract [en]

    Background: Pathological complete response (pCR) after neoadjuvant therapy in rectal cancer is correlated with improved survival. There is limited knowledge on the incidence of pCR at a national level with uniform guidelines. The aim of this prospective register-based study was to investigate the incidence and outcome of pCR in relation to neoadjuvant therapy in a national cohort. Method: All patients abdominally operated for rectal cancer between 2007 and 2012 (n = 7885) were selected from The Swedish Colorectal Cancer Register. Twenty-six per cent (n = 2063) had neoadjuvant therapy with either long or short course radiotherapy with amp;gt;4 weeks delay with the potential to achieve pCR. The primary endpoints were pCR and survival in relation to neoadjuvant therapy. Results: Complete eradication of the luminal tumor, ypTO was found in 161 patients (8%). In 83% of the ypTO the regional lymph nodes were tumor negative (ypTONO), 12% had 1-3 positive lymph nodes (ypTON1) and 4% had more than three positive lymph nodes (ypTON2). There was significantly greater survival with ypTO compared to ypT+ (hazard ratio 0.38 (C.I 0.25-0.58)) and survival was significantly greater in patients with ypTONO compared to ypT0N1-2 (hazard ratio 0.36 (C.I 0.15-0.86)). In ypTO, cT3-4 tumors had the greater risk of node-positivity. The added use of chemotherapy resulted in 10% ypTO compared to 5.1% in the group without chemotherapy (p amp;lt; 0.00004). Conclusion: Luminal pathological complete response occurred in 8%, 16% of them had tumor positive nodes. The survival benefit of luminal complete response is dependent upon nodal involvement status. (C) 2016 Elsevier Ltd. All rights reserved.

    Place, publisher, year, edition, pages
    ELSEVIER SCI LTD, 2016
    Keyword
    Rectal cancer; Complete response; Lymph nodes; Neoadjuvant treatment
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-130432 (URN)10.1016/j.ejso.2016.03.013 (DOI)000379559300007 ()27146960 (PubMedID)
    Available from: 2016-08-07 Created: 2016-08-05 Last updated: 2016-11-24
  • Public defence: 2016-12-15 10:15 Plank, Fysikhuset, Linköping
    Zeglio, Erica
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Zeglio, Erica
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Self-doped Conjugated Polyelectrolytes for Bioelectronics Applications2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Self-doped conjugated polyelectrolytes (CPEs) are a class of conducting polymers constituted of a π-conjugated backbone and charged side groups. The ionic groups provide the counterions needed to balance the charged species formed in the CPEs backbones upon oxidation. As a result, addition of external counterions is not required, and the CPEs can be defined as selfdoped. The combination of their unique optical and electrical properties render them the perfect candidates for optoelectronic applications. Additionally, their “soft” nature provide for the mechanical compatibility necessary to interface with biological systems, rendering them promising materials for bioelectronics applications. CPEs solubility, aggregation state, and optoelectronic properties can be easily tuned by different means, such as blending or interaction with oppositely charged species (such as surfactants), in order to produce materials with the desired properties. In this thesis both the strategies have been explored to produce new functional materials that can be deposited to form a thin film and,  therefore, used as an active layer in organic electrochemical transistors (OECTs). Microstructure formation of the films as well as influence on devices operation and performance have been investigated. We also show that these methods can be exploited to produce materials whose uniquecombination of self-doping ability and hydrophobicity allows incorporation into the phospholipid double layer of biomembranes, while retaining their properties. As a result, self-doped CPEs can be used both as sensing elements to probe the physical state of biomembranes, and as functional ones providing them with new functionalities, such as electrical conductivity. Integration of conductive electronic biomembranes into OECTs devices has brought us one step forward on the interface of manmade technologies with biological systems.

    List of papers
    1. Conjugated Polyelectrolyte Blends for Electrochromic and Electrochemical Transistor Devices
    Open this publication in new window or tab >>Conjugated Polyelectrolyte Blends for Electrochromic and Electrochemical Transistor Devices
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    2015 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 27, no 18, 6385-6393 p.Article in journal (Refereed) Published
    Abstract [en]

    Two self-doped conjugated polyelectrolytes, having semiconducting and metallic behaviors, respectively, have been blended from aqueous solutions in order to produce materials with enhanced optical and electrical properties. The intimate blend of two anionic conjugated polyelectrolytes combine the electrical and optical properties of these, and can be tuned by blend stoichiometry. In situ conductance measurements have been done during doping of the blends, while UV vis and EPR spectroelectrochemistry allowed the study of the nature of the involved redox species. We have constructed an accumulation/depletion mode organic electrochemical transistor whose characteristics can be tuned by balancing the stoichiometry of the active material.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2015
    National Category
    Materials Chemistry Condensed Matter Physics
    Identifiers
    urn:nbn:se:liu:diva-122212 (URN)10.1021/acs.chemmater.5b02501 (DOI)000361935000028 ()
    Note

    Funding Agencies|Marie Curie network "Renaissance"; Knut and Alice Wallenberg foundation through Wallenberg Scholar grant; Swedish Research Council [VR-2014-3079, D0556101]; Carl Trygger Foundation [CTS 12:206]

    Available from: 2015-10-26 Created: 2015-10-23 Last updated: 2016-11-21
    2. Electronic polymers in lipid membranes
    Open this publication in new window or tab >>Electronic polymers in lipid membranes
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    2015 (English)In: Scientific Reports, ISSN 2045-2322, Vol. 5, no 11242Article in journal (Refereed) Published
    Abstract [en]

    Electrical interfaces between biological cells and man-made electrical devices exist in many forms, but it remains a challenge to bridge the different mechanical and chemical environments of electronic conductors (metals, semiconductors) and biosystems. Here we demonstrate soft electrical interfaces, by integrating the metallic polymer PEDOT-S into lipid membranes. By preparing complexes between alkyl-ammonium salts and PEDOT-S we were able to integrate PEDOT-S into both liposomes and in lipid bilayers on solid surfaces. This is a step towards efficient electronic conduction within lipid membranes. We also demonstrate that the PEDOT-S@alkyl-ammonium: lipid hybrid structures created in this work affect ion channels in the membrane of Xenopus oocytes, which shows the possibility to access and control cell membrane structures with conductive polyelectrolytes.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2015
    National Category
    Biophysics
    Identifiers
    urn:nbn:se:liu:diva-120045 (URN)10.1038/srep11242 (DOI)000356090400002 ()26059023 (PubMedID)
    Note

    Funding Agencies|Knut and Alice Wallenberg Foundation; Swedish Research Council

    Available from: 2015-07-06 Created: 2015-07-06 Last updated: 2016-11-21
    3. Conjugated Polyelectrolyte Blend as Photonic Probe of Biomembrane Organization
    Open this publication in new window or tab >>Conjugated Polyelectrolyte Blend as Photonic Probe of Biomembrane Organization
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    2016 (English)In: ChemistrySelect, ISSN 2365-6549, Vol. 1, no 14, 4340-4344 p.Article in journal (Refereed) Published
    Abstract [en]

    In the following report, a conjugated polyelectrolyte (CPE) blend has been introduced for the first time as a fluorescent probe of membrane organization. Insertion of the blend into the lipid double layer has been rendered possible through formation of a hydrophobic complex by counterion exchange. Changes in membrane physical state from liquid-disordered (Ldis) to liquid-ordered (Lord), and to solid-ordered (Sord) result in red shifts of blend excitation (up to Δλex=+90 nm) and emission (up to Δλnm=+37 nm) maxima attributable to backbone planarization of CPEs. We found that blend stoichiometry can be adjusted to attain the best interplay among single polyelectrolytes properties, such as sensitivity and luminescence. The resulting probes therefore allow a bimodal detection of membrane physical state: changes in absorption permit a direct visualization of membrane organization, while variations in emission spectra demonstrate that CPE-blends are a promising probes that can be used for imaging applications.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2016
    Keyword
    Conjugated Polyelectrolytes, Fluorescent Probes, Liposomes, Membrane Probes, Polyelectrolytes blend
    National Category
    Biomaterials Science Condensed Matter Physics
    Identifiers
    urn:nbn:se:liu:diva-132729 (URN)10.1002/slct.201600920 (DOI)
    Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2016-11-21Bibliographically approved
  • Public defence: 2016-12-15 13:00 VAL, Hus Vallfarten, Linköping
    Månsson, Kristoffer N. T.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Månsson, Kristoffer N. T.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Restructuring the socially anxious brain: Using magnetic resonance imaging to advance our understanding of effective cognitive behaviour therapy for social anxiety disorder2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Social anxiety disorder (SAD) is a common psychiatric disorder associated with considerable suffering. Cognitive behaviour therapy (CBT) has been shown to be effective but a significant proportion does not respond or relapses, stressing the need of augmenting treatment. Using neuroimaging could elucidate the psychological and neurobiological interaction and may help to improve current therapeutics. To address this issue, functional and structural magnetic resonance imaging (MRI) were repeatedly conducted on individuals with SAD randomised to receive CBT or an active control condition. MRI was performed pre-, and post-treatment, as well as at one-year follow-up. Matched healthy controls were also scanned to be able to evaluate disorder-specific neural responsivity and structural morphology. This thesis aimed at answering three major questions. I) Does the brain’s fear circuitry (e.g., the amygdala) change, with regard to neural response and structural morphology, immediately after CBT? II) Are the immediate changes in the brain still present at long-term follow-up? III) Can neural responsivity in the fear circuitry predict long-term treatment outcome at the level of the individual? Thus, different analytic methods were performed. Firstly, multimodal neuroimaging addressed questions on concomitant changes in neural response and grey matter volume. Secondly, two different experimental functional MRI tasks captured both neural response to emotional faces and self-referential criticism. Thirdly, support vector machine learning (SVM) was used to evaluate neural predictors at the level of the individual.

    Amygdala responsivity to self-referential criticism was found to be elevated in individuals with SAD, as compared to matched healthy controls, and the neural response was attenuated after effective CBT. In individuals with SAD, amygdala grey matter volume was positively correlated with symptoms of anticipatory speech anxiety, and CBT-induced symptom reduction was associated with decreased grey matter volume of the amygdala. Also, CBT-induced reduction of amygdala grey matter volume was evident both at short- and long-term follow-up. In contrast, the amygdala neural response was weakened immediately after treatment, but not at one-year follow-up. In extension to treatment effects on the brain, pre-treatment connectivity between the amygdala and the dorsal anterior cingulate cortex (dACC) was stronger in long-term CBT non-responders, as compared to long-term CBT responders. Importantly, by use of an SVM algorithm, pre-treatment neural response to self-referential criticism in the dACC accurately predicted (>90%) the clinical response to CBT.

    In conclusion, modifying the amygdala is a likely mechanism of action in CBT, underlying the anxiolytic effects of this treatment, and the brain’s neural activity during self-referential criticism may be an accurate and clinically relevant predictor of the long-term response to CBT. Along these lines, neuroimaging is a vital tool in clinical psychiatry that could potentially improve clinical decision-making based on an individual’s neural characteristics.

    List of papers
    1. Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder
    Open this publication in new window or tab >>Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder
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    2013 (English)In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 214, no 3, 229-237 p.Article in journal (Refereed) Published
    Abstract [en]

    Randomized controlled trials have yielded promising results for internet-delivered cognitive behavior therapy (iCBT) for patients with social anxiety disorder (SAD). The present study investigated anxiety-related neural changes after iCBT for SAD. The amygdala is a critical hub in the neural fear network, receptive to change using emotion regulation strategies and a putative target for iCBT. Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3T assessing neural changes during an affective face processing task. Treatment outcome was assessed using social anxiety self-reports and the Clinical Global Impression-Improvement (CGI-I) scale. ICBT yielded better outcome than ABM (66% vs. 25% CGI-I responders). A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT. Changes in the amygdala were related to a behavioral measure of social anxiety. Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral (dlPFC) cortices. Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general.

    Place, publisher, year, edition, pages
    Elsevier, 2013
    Keyword
    Amygdala, Cognitive behavior therapy, dlPFC, fMRI, mOFC, vlPFC
    National Category
    Psychology
    Identifiers
    urn:nbn:se:liu:diva-102160 (URN)10.1016/j.pscychresns.2013.08.012 (DOI)000327531600008 ()24064198 (PubMedID)
    Available from: 2013-12-01 Created: 2013-12-01 Last updated: 2016-11-18Bibliographically approved
    2. Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder
    Open this publication in new window or tab >>Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder
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    2016 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, no e727Article in journal (Refereed) Published
    Abstract [en]

    Patients with anxiety disorders exhibit excessive neural reactivity in the amygdala, which can be normalized by effective treatment like cognitive behavior therapy (CBT). Mechanisms underlying the brains adaptation to anxiolytic treatments are likely related both to structural plasticity and functional response alterations, but multimodal neuroimaging studies addressing structure-function interactions are currently missing. Here, we examined treatment-related changes in brain structure (gray matter (GM) volume) and function (blood-oxygen level dependent, BOLD response to self-referential criticism) in 26 participants with social anxiety disorder randomly assigned either to CBT or an attention bias modification control treatment. Also, 26 matched healthy controls were included. Significant time x treatment interactions were found in the amygdala with decreases both in GM volume (family-wise error (FWE) corrected P-FWE = 0.02) and BOLD responsivity (P-FWE = 0.01) after successful CBT. Before treatment, amygdala GM volume correlated positively with anticipatory speech anxiety (P-FWE = 0.04), and CBT-induced reduction of amygdala GM volume (pre-post) correlated positively with reduced anticipatory anxiety after treatment (P-FWE &lt;= 0.05). In addition, we observed greater amygdala neural responsivity to self-referential criticism in socially anxious participants, as compared with controls (P-FWE = 0.029), before but not after CBT. Further analysis indicated that diminished amygdala GM volume mediated the relationship between decreased neural responsivity and reduced social anxiety after treatment (P = 0.007). Thus, our results suggest that improvement-related structural plasticity impacts neural responsiveness within the amygdala, which could be essential for achieving anxiety reduction with CBT.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2016
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-127755 (URN)10.1038/tp.2015.218 (DOI)000373892200004 ()26836415 (PubMedID)
    Note

    Funding Agencies|Linkoping University; Swedish Research Council; Swedish Council for Working Life and Social Research; LJ Boethius Foundation; PRIMA Psychiatry Research Foundation

    Available from: 2016-05-12 Created: 2016-05-12 Last updated: 2016-11-18
    3. Structural but not functional neuroplasticity one year after effective cognitive behaviour therapy for social anxiety disorder
    Open this publication in new window or tab >>Structural but not functional neuroplasticity one year after effective cognitive behaviour therapy for social anxiety disorder
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    2017 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 318, 45-51 p.Article in journal (Refereed) Published
    Abstract [en]

    Abstract Effective psychiatric treatments ameliorate excessive anxiety and induce neuroplasticity immediately after the intervention, indicating that emotional components in the human brain are rapidly adaptable. Still, the interplay between structural and functional neuroplasticity is poorly understood, and studies of treatment-induced long-term neuroplasticity are rare. Functional and structural magnetic resonance imaging (using 3 T MRI) was performed in 13 subjects with social anxiety disorder on 3 occasions over 1 year. All subjects underwent 9 weeks of Internet-delivered cognitive behaviour therapy in a randomized cross-over design and independent assessors used the Clinically Global Impression-Improvement (CGI-I) scale to determine treatment response. Gray matter (GM) volume, assessed with voxel-based morphometry, and functional blood-oxygen level-dependent (BOLD) responsivity to self-referential criticism were compared between treatment responders and non-responders using 2 × 2 (group × time; pretreatment to follow-up) ANOVA. At 1-year follow-up, 7 (54%) subjects were classified as CGI-I responders. Left amygdala GM volume was more reduced in responders relative to non-responders from pretreatment to 1-year follow-up (Z = 3.67, Family-Wise Error corrected p = 0.02). In contrast to previous short-term effects, altered BOLD activations to self-referential criticism did not separate responder groups at follow-up. The structure and function of the amygdala changes immediately after effective psychological treatment of social anxiety disorder, but only reduced amygdala GM volume, and not functional activity, is associated with a clinical response 1 year after CBT.

    Place, publisher, year, edition, pages
    Elsevier, 2017
    Keyword
    Amygdala, Neuroplasticity, Long-term, Social anxiety disorder, Cognitive behavior therapy
    National Category
    Psychology
    Identifiers
    urn:nbn:se:liu:diva-132638 (URN)10.1016/j.bbr.2016.11.018 (DOI)27838341 (PubMedID)
    Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2016-11-23Bibliographically approved
    4. Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning.
    Open this publication in new window or tab >>Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning.
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    2015 (English)In: Translational psychiatry, ISSN 2158-3188, Vol. 5, e530- p.Article in journal (Refereed) Published
    Abstract [en]

    Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2-97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale-Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC-amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC-amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual.

    National Category
    Applied Psychology
    Identifiers
    urn:nbn:se:liu:diva-117119 (URN)10.1038/tp.2015.22 (DOI)000367654700004 ()25781229 (PubMedID)
    Note

    Funding agencies: Swedish Research Council; Linkoping University; Swedish Research Council for Health, Working Life and Welfare; PRIMA Psychiatry Research Foundation; Kings College London Centre of Excellence in Medical Engineering - Wellcome Trust; Engineering and Physica

    Available from: 2015-04-16 Created: 2015-04-16 Last updated: 2016-11-18
  • Public defence: 2016-12-15 13:00 Berzeliussalen, Linköping
    Bivik Stadler, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Bivik Stadler, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Genetic pathways controlling CNS development: The role of Notch signaling in regulating daughter cell proliferation in Drosophila2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

    Place, publisher, year, edition, pages
    Genetics Society of America, 2015
    Keyword
    Drosophila; CNS development; neural cell fate specification; forward genetic screening; FMRFamide
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-121318 (URN)10.1534/genetics.115.178483 (DOI)000359917000020 ()26092715 (PubMedID)
    Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2016-11-30Bibliographically approved
    2. Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
    Open this publication in new window or tab >>Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
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    2012 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 4, 678-689 p.Article in journal (Refereed) Published
    Abstract [en]

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

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-74790 (URN)10.1242/dev.074500 (DOI)000300259800005 ()
    Note

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

    Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2016-11-30
    3. Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
    Open this publication in new window or tab >>Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
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    2016 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 4, e1005984Article in journal (Refereed) Published
    Abstract [en]

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

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

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

    Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2016-11-30
    4. sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
    Open this publication in new window or tab >>sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
    2016 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 143, no 20, 3774-3784 p.Article in journal (Refereed) Published
    Abstract [en]

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

    Place, publisher, year, edition, pages
    The Company of Biologists Ltd, 2016
    Keyword
    Lineage tree, Cell cycle, Asymmetric division, Combinatorial control, Notch
    National Category
    Cell and Molecular Biology Biochemistry and Molecular Biology Cell Biology Medical Biotechnology
    Identifiers
    urn:nbn:se:liu:diva-132739 (URN)10.1242/dev.139998 (DOI)27578794 (PubMedID)
    Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2016-11-28Bibliographically approved
  • Public defence: 2016-12-15 13:15 Schrödinger (E324), Fysikhuset, Linköping
    Oruganti, Baswanth
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Oruganti, Baswanth
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Computational Design of Molecular Motors and Excited-State Studies of Organic Chromophores2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis presents computational quantum chemical studies of molecular motors and excited electronic states of organic chromophores.

    The first and major part of the thesis is concerned with the design of light-driven rotary molecular motors. These are molecules that absorb light energy and convert it into 360° unidirectional rotary motion around a double bond connecting two molecular halves. In order to facilitate potential applications of molecular motors in nanotechnology, such as in molecular transport or in development of materials with photo-controllable properties, it is critical to optimize the rates and efficiencies of the chemical reactions that produce the rotary motion. To this end, computational methods are in this thesis used to study two different classes of molecular motors.

    The first class encompasses the sterically overcrowded alkenes developed by Ben Feringa, co-recipient of the 2016 Nobel Prize in Chemistry. The rotary cycles of these motors involve two photoisomerization and two thermal isomerization steps, where the latter are the ones that limit the attainable rotational frequencies. In the thesis, several new motors of this type are proposed by identifying steric, electronic and conformational approaches to accelerate the thermal isomerizations. The second class contains motors that incorporate a protonated Schiff base and are capable to achieve higher photoisomerization rates than overcrowded alkene-based motors. In the thesis, a new motor of this type is proposed that produces unidirectional rotary motion by means of two photochemical steps alone. Also, this motor lacks both a stereocenter and helical motifs, which are key features of almost all synthetic rotary motors developed to date.

    The second part of the thesis focuses on the design and assessment of composite computational procedures for modeling excited electronic states of organic chromophores. In particular, emphasis is put on developing procedures that facilitate the calculations of accurate 0−0 excitation energies of such compounds in a cost-effective way by combining quantum chemical methods with different accuracies.

    List of papers
    1. Computational study of the working mechanism and rate acceleration of overcrowded alkene-based light-driven rotary molecular motors
    Open this publication in new window or tab >>Computational study of the working mechanism and rate acceleration of overcrowded alkene-based light-driven rotary molecular motors
    2014 (English)In: RSC Advances, ISSN 2046-2069, Vol. 4, no 20, 10240-10251 p.Article in journal (Refereed) Published
    Abstract [en]

    In recent years, much progress has been made in the design, synthesis and operation of light-driven rotary molecular motors based on chiral overcrowded alkenes. Through consecutive cistrans photoisomerization and thermal helix inversion steps, where the latter dictate the overall rate of rotation, these motors achieve a full 360° unidirectional rotation around the carbon–carbon double bond connecting the two (rotator and stator) alkene halves. In this work, we report quantum chemical calculations indicating that a particularly fast-rotating overcrowded alkene-based motor capable of reaching the MHz regime, can be made to rotate even faster by the substitution of a rotator methyl group with a methoxy group. Specifically, using density functional theory methods that reproduce the rate-limiting 35 kJ mol−1 thermal free-energy barriers shown by the methyl-bearing motor with errors of 5 kJ mol−1 only, it is predicted that this substitution reduces these barriers by a significant 15–20 kJ mol−1. This prediction is preceded by a series of benchmark calculations for assessing how well density functional theory methods account for available experimental data (crystallographic, UV-vis absorption, thermodynamic) on the rotary cycles of overcrowded alkenes, and a detailed examination of the thermal and photochemical reaction mechanisms of the original motor of this type.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2014
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-104688 (URN)10.1039/C3RA46880A (DOI)000332061300048 ()2-s2.0-84894247198 (ScopusID)
    Available from: 2014-02-22 Created: 2014-02-22 Last updated: 2016-11-16Bibliographically approved
    2. Computational design of faster rotating second-generation light-driven molecular motors by control of steric effects
    Open this publication in new window or tab >>Computational design of faster rotating second-generation light-driven molecular motors by control of steric effects
    2015 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 33, 21740-21751 p.Article in journal (Refereed) Published
    Abstract [en]

    We report a systematic computational investigation of the possibility to accelerate the rate-limiting thermal isomerizations of the rotary cycles of synthetic light-driven overcrowded alkene-based molecular motors through modulation of steric interactions. Choosing as a reference system a second-generation motor known to accomplish rotary motion in the MHz regime and using density functional theory methods, we propose a three-step mechanism for the thermal isomerizations of this motor and show that variation of the steric bulkiness of the substituent at the stereocenter can reduce the (already small) free-energy barrier of the rate-determining step by a further 15-17 kJ mol(-1). This finding holds promise for future motors of this kind to reach beyond the MHz regime. Furthermore, we demonstrate and explain why one particular step is kinetically favored by decreasing and another step is kinetically favored by increasing the steric bulkiness of this substituent, and identify a possible back reaction capable of impeding the rotary rate.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2015
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:liu:diva-121153 (URN)10.1039/c5cp02303c (DOI)000359596600080 ()26234787 (PubMedID)
    Note

    Funding Agencies|Linkoping University; Swedish Research Council; Olle Engkvist Foundation; Wenner-Gren Foundations; NSFC [11404141]; National Supercomputer Centre (NSC) in Linkoping

    Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2016-11-16
    3. On the possibility to accelerate the thermal isomerizations of overcrowded alkene-based rotary molecular motors with electron-donating or electron-withdrawing substituents
    Open this publication in new window or tab >>On the possibility to accelerate the thermal isomerizations of overcrowded alkene-based rotary molecular motors with electron-donating or electron-withdrawing substituents
    2016 (English)In: Journal of Molecular Modeling, ISSN 1610-2940, E-ISSN 0948-5023, Vol. 22, no 9, 219- p.Article in journal (Refereed) Published
    Abstract [en]

    We employ computational methods to investigate the possibility of using electron-donating or electron-withdrawing substituents to reduce the free-energy barriers of the thermal isomerizations that limit the rotational frequencies achievable by synthetic overcrowded alkene-based molecular motors. Choosing as reference systems one of the fastest motors known to date and two variants thereof, we consider six new motors obtained by introducing electron-donating methoxy and dimethylamino or electron-withdrawing nitro and cyano substituents in conjugation with the central olefinic bond connecting the two (stator and rotator) motor halves. Performing density functional theory calculations, we then show that electron-donating (but not electron-withdrawing) groups at the stator are able to reduce the already small barriers of the reference motors by up to 18 kJ mol(-1). This result outlines a possible strategy for improving the rotational frequencies of motors of this kind. Furthermore, exploring the origin of the catalytic effect, it is found that electron-donating groups exert a favorable steric influence on the thermal isomerizations, which is not manifested by electron-withdrawing groups. This finding suggests a new mechanism for controlling the critical steric interactions of these motors.

    Place, publisher, year, edition, pages
    SPRINGER, 2016
    Keyword
    Electronic effects; Molecular motors; Quantum chemistry; Rotary rates; Steric effects
    National Category
    Theoretical Chemistry
    Identifiers
    urn:nbn:se:liu:diva-131672 (URN)10.1007/s00894-016-3085-y (DOI)000382748100024 ()27553304 (PubMedID)
    Note

    Funding Agencies|Linkoping University; Swedish Research Council [621-2011-4353]; Olle Engkvist Foundation; Carl Trygger Foundation

    Available from: 2016-10-03 Created: 2016-09-30 Last updated: 2016-11-16
    4. Computational Insight to Improve the Thermal Isomerisation Performance of Overcrowded Alkene-Based Molecular Motors through Structural Redesign
    Open this publication in new window or tab >>Computational Insight to Improve the Thermal Isomerisation Performance of Overcrowded Alkene-Based Molecular Motors through Structural Redesign
    2016 (English)In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 17, no 21, 3399-3408 p.Article in journal (Refereed) Published
    Abstract [en]

    Synthetic overcrowded alkene-based molecular motors achieve 360° unidirectional rotary motion of one motor half (rotator) relative to the other (stator) through sequential photochemical and thermal isomerisation steps. In order to facilitate and expand the use of these motors for various applications, it is important to investigate ways to increase the rates and efficiencies of the reactions governing the rotary motion. Here, we use computational methods to explore whether the thermal isomerisation performance of some of the fastest available motors of this type can be further improved by reducing the sizes of the motor halves. Presenting three new redesigned motors that combine an indanylidene rotator with a cyclohexadiene, pyran or thiopyran stator, we first use multiconfigurational quantum chemical methods to verify that the photoisomerisations of these motors sustain unidirectional rotary motion. Then, by performing density functional calculations, we identify both stepwise and concerted mechanisms for the thermal isomerisations of the motors and show that the rate-determining free-energy barriers of these processes are up to 25 kJ mol−1 smaller than those of the original motors. Furthermore, the thermal isomerisations of the redesigned motors proceed in fewer steps. Altogether, the results suggest that the redesigned motors are useful templates for improving the thermal isomerisation performance of existing overcrowded alkene-based motors.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2016
    Keyword
    Density functional calculations, isomerisation, molecular motors, rotary rates, stepwise versus concerted mechanisms
    National Category
    Theoretical Chemistry Materials Chemistry Chemical Engineering
    Identifiers
    urn:nbn:se:liu:diva-132609 (URN)10.1002/cphc.201600766 (DOI)27550708 (PubMedID)
    Available from: 2016-11-16 Created: 2016-11-16 Last updated: 2016-11-22Bibliographically approved
    5. How method-dependent are calculated differences between vertical, adiabatic, and 0-0 excitation energies?
    Open this publication in new window or tab >>How method-dependent are calculated differences between vertical, adiabatic, and 0-0 excitation energies?
    2014 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 118, no 23, 4157-4171 p.Article in journal (Refereed) Published
    Abstract [en]

    Through a large number of benchmark studies, the performance of different quantum chemical methods in calculating vertical excitation energies is today quite well established. Furthermore, these efforts have in recent years been complemented by a few benchmarks focusing instead on adiabatic excitation energies. However, it is much less well established how calculated differences between vertical, adiabatic and 0-0 excitation energies vary between methods, which may be due to the cost of evaluating zero-point vibrational energy corrections for excited states. To fill this gap, we have calculated vertical, adiabatic, and 0-0 excitation energies for a benchmark set of molecules covering both organic and inorganic systems. Considering in total 96 excited states and using both TD-DFT with a variety of exchange-correlation functionals and the ab initio CIS and CC2 methods, it is found that while the vertical excitation energies obtained with the various methods show an average (over the 96 states) standard deviation of 0.39 eV, the corresponding standard deviations for the differences between vertical, adiabatic, and 0-0 excitation energies are much smaller: 0.10 (difference between adiabatic and vertical) and 0.02 eV (difference between 0-0 and adiabatic). These results provide a quantitative measure showing that the calculation of such quantities in photochemical modeling is well amenable to low-level methods. In addition, we also report on how these energy differences vary between chemical systems and assess the performance of TD-DFT, CIS, and CC2 in reproducing experimental 0-0 excitation energies.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2014
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-109132 (URN)10.1021/jp501974p (DOI)000337497300017 ()24848558 (PubMedID)
    Available from: 2014-08-13 Created: 2014-08-11 Last updated: 2016-11-16Bibliographically approved
    6. Assessment of a composite CC2/DFT procedure for calculating 0-€“0 excitation energies of organic molecules
    Open this publication in new window or tab >>Assessment of a composite CC2/DFT procedure for calculating 0-€“0 excitation energies of organic molecules
    2016 (English)In: Molecular Physics, ISSN 0026-8976, E-ISSN 1362-3028, 1-16 p.Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    The task to assess the performance of quantum chemical methods in describing electronically excited states has in recent years started to shift from calculation of vertical (ΔEve) to calculation of 0-€“0 excitation energies (ΔE00). Here, based on a set of 66 excited states of organic molecules for which high-resolution experimental ΔE00 energies are available and for which the approximate coupled-cluster singles and doubles (CC2) method performs particularly well, we explore the possibility to simplify the calculation of CC2-quality ΔE00 energies using composite procedures that partly replace CC2 with more economical methods. Specifically, we consider procedures that employ CC2 only for the ΔEve part and density functional theory methods for the cumbersome excited-state geometry optimisations and frequency calculations required to obtain ΔE00 energies from ΔEve ones. The results demonstrate that it is indeed possible to both closely (to within 0.06-€“0.08 eV) and consistently approximate ‘true’ CC2 ΔE00 energies in this way, especially when CC2 is combined with hybrid density functionals. Overall, the study highlights the unexploited potential of composite procedures, which hitherto have found widespread use mostly in ground-state chemistry, to also play an important role in facilitating accurate studies of excited states.

    Place, publisher, year, edition, pages
    Taylor & Francis, 2016
    National Category
    Theoretical Chemistry Atom and Molecular Physics and Optics Chemical Sciences
    Identifiers
    urn:nbn:se:liu:diva-132610 (URN)10.1080/00268976.2016.1235736 (DOI)
    Available from: 2016-11-16 Created: 2016-11-16 Last updated: 2016-11-17Bibliographically approved
  • Public defence: 2016-12-16 09:00 Berzeliussalen, Linköping
    Vikström Eckevall, Josefin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Vikström Eckevall, Josefin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    The influence of infertility and in vitro fertilization treatment on postpartum and long-term mental health in women2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Introduction: It is estimated that about 10-15% of couples suffer from infertility, i.e. the inability to achieve a clinical pregnancy after at least one year of regular, unprotected intercourse and that between 2-5% of births are a result of in vitro fertilization (IVF) treatment. Infertility and its treatment can have adverse effects on psychological well-being. While previous studies on postpartum depression (PPD) in IVF women suffer some methodological issues, there are no published studies on the risk of postpartum psychosis (PPP) after IVF pregnancies. Long-term, most women adjust well emotionally after IVF treatment but some, especially the childless, still suffer negative consequences. Meanwhile, few studies have extended beyond the first decade after treatment. Some studies have found that the childless elderly have social networks of less support potential but most show that psychological well-being is not affected by parental status. None of the studies have focused on the oldest old (≥85 years) and many have excluded those who live in institutional care, thus the frailest.

    Objective: The overall aim of this thesis was to study postpartum mental health in women who have undergone IVF treatment, using psychiatric diagnoses as outcomes, while controlling for major PPD and PPP risk factors as well as to determine the influences of childlessness, infertility and IVF treatment on long-term mental health in women. Materials and methods: Studies I-II are register-based, case control studies of 3532 (I) and 10,412 (II) primiparous women included in the Swedish IVF register. A control group of 8,553 (I) and 18,624 (II) primiparous women with spontaneous conceptions was selected from the Medical Birth Register. The main outcomes were PPD and PPP diagnoses the 1st year postpartum collected from the National Patient Register. Studies III-IV are cross-sectional. Study III included 470 women who had undergone IVF treatment 20-23 years previously. The Symptom Checklist-90 was used to investigate self-reported mental health. The results were compared with those from a population-based study and by parental status group. Study IV included 496 85-year olds. Psychological well-being, living situation, demographics and social network was investigated through a questionnaire and an interview.

    Results: Study I-II: There were no differences between the IVF and control group in the risk of receiving a PPD or PPP diagnosis. Having previously been diagnosed with any psychiatric, an affective or personality disorder increased  the risk of PPD while any previous psychiatric, psychotic, bipolar, depressive, anxiety or personality disorder diagnosis increased the risk of PPP. None of the women had committed suicide. Study III: The IVF women reported symptoms of higher intensity and were at increased risk of symptoms of depression, obsessive-compulsion and somatisation compared with the reference group. Childless women, compared with parents, reported a higher level of mental health problems as well as symptoms of depression and phobic anxiety. Study IV: No differences in psychological wellbeing, living situation or having friends close by were found across parental status groups. The childless 85-year olds were less likely to have relatives close by and to receive help.

    Discussion: This thesis indicates that the risk of receiving a PPD or PPP diagnosis from in- or outpatient psychiatric care or of committing suicide during the first year postpartum is not increased in women who have undergone IVF treatment. Any negative effects of infertility and its treatment might have been mitigated by the “healthy patient effect”; those who choose to enter treatment are generally psychologically robust. A history of mental illness is a major risk factor for PPD and PPP. The risk of some adverse symptoms of mental illness might be increased in women who have undergone IVF treatment twenty years previously, especially in those who have remained childless. The childless elderly appear to have social networks of less support potential but are not more likely to live in institutional care and do not experience more adverse effects on psychological well-being than the elderly who are parents.

    List of papers
    1. Risk of postnatal depression or suicide after in vitro fertilisation treatment: a nationwide case–control study
    Open this publication in new window or tab >>Risk of postnatal depression or suicide after in vitro fertilisation treatment: a nationwide case–control study
    Show others...
    2016 (English)In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    Objective

    To examine whether women who undergo in vitro fertilisation (IVF) treatment are at greater risk of postnatal suicide or postnatal depression (PND) requiring psychiatric care, compared with women who conceive spontaneously.

    Design

    Case–control study using data from national registers.

    Setting

    Sweden during the period 2003–2009.

    Population

    Cases were 3532 primiparous women who had given birth following IVF treatment. An aged-matched control group of 8553 mothers was randomly selected from the medical birth register.

    Methods

    Logistic regression analyses were performed with PND as the outcome, and with known risk factors of PND as well as IVF/spontaneous birth as covariates.

    Main outcome measures

    Postnatal depression (PND), defined as diagnoses F32–F39 of the tenth edition of the International Classification of Diseases (ICD–10), within 12 months of childbirth.

    Results

    Initial analyses showed that PND was more common in the control group than in the IVF group (0.8 versus 0.4%; P = 0.04); however, these differences disappeared when confounding factors were controlled for. A history of any psychiatric illness (P = 0.000; odds ratio, OR = 25.5; 95% confidence interval, 95% CI = 11.7–55.5), any previous affective disorder (P = 0.000; OR = 26.0; 95% CI = 10.5–64.0), or specifically a personality disorder (P = 0.028; OR = 3.8; 95% CI = 1.2–12.7) increased the risk of PND. No woman in either group committed suicide during the first year after childbirth.

    Conclusions

    Whereas mothers who receive IVF treatment are not at increased risk of PND, the risk is increased among mothers with a history of mental illness. Tweetable abstract A Swedish study on 3532 women showed that IVF treatment does not increase the risk of postnatal depression.

    Place, publisher, year, edition, pages
    Chichester: Wiley-Blackwell Publishing Inc., 2016
    Keyword
    In vitro fertilisation, infertility treatment, postnatal depression, postnatal mental illness
    National Category
    Obstetrics, Gynecology and Reproductive Medicine Public Health, Global Health, Social Medicine and Epidemiology Geriatrics Family Medicine
    Identifiers
    urn:nbn:se:liu:diva-132763 (URN)10.1111/1471-0528.13788 (DOI)26663705 (PubMedID)
    Available from: 2016-11-23 Created: 2016-11-23 Last updated: 2016-12-01Bibliographically approved
    2. Mental health in women 20-23 years after IVF treatment: a Swedish cross-sectional study
    Open this publication in new window or tab >>Mental health in women 20-23 years after IVF treatment: a Swedish cross-sectional study
    2015 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 10, e009426- p.Article in journal (Refereed) Published
    Abstract [en]

    Objective To assess self-perceived mental health in women treated with in vitro fertilisation (IVF) 20-23years previously, while comparing them to a reference group, and to determine any differences in mental health between those who had given birth, those who had adopted a child, those who had given birth and adopted a child and those who remained childless. Design A cross-sectional study. Setting A Center of Reproductive Medicine (RMC) at a Swedish University hospital. Participants 520 women who had undergone at least one IVF cycle at the University Hospital in Linkoping between 1986 and 1989. 504 of 520 women (97%) were eligible for follow-up. While 34 women declined, 93 per cent (n=470) of the women agreed to participate. The reference group consisted of 150 women of the Swedish population included in a study that was used to validate the Symptom CheckList (SCL)-90. Interventions Follow-up was conducted in 2008-2009. The SCL-90 was used to measure the womens self-perceived mental health and a questionnaire specific for this study was used to retain demographic information. Outcome measures The SCL-90 assesses 9 primary dimensions; somatisation, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation and psychoticism. There is also a global index of distress. Results Women who had previously undergone IVF treatment were at increased risk of symptoms of depression (p=0.017), obsessive-compulsion (p=0.02) and somatisation (p0.001) when compared to a reference group. In addition, the women who have remained childless are at increased risk of symptoms of depression (p=0.009) and phobic anxiety (p=0.017). Conclusions The majority of the women who have been treated with IVF 20-23years previously appear to be in good mental health. However, women who remain childless and/or without partner after unsuccessful infertility treatment constitute a vulnerable group even later on in life.

    Place, publisher, year, edition, pages
    BMJ PUBLISHING GROUP, 2015
    Keyword
    Infertility; childlessness; MENTAL HEALTH; IVF; depression
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-123849 (URN)10.1136/bmjopen-2015-009426 (DOI)000365467600111 ()26510732 (PubMedID)
    Note

    Funding Agencies|Health Research Council in the south east of Sweden

    Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2016-11-23
    3. The influences of childlessness on the psychological well-being and social network of the oldest old
    Open this publication in new window or tab >>The influences of childlessness on the psychological well-being and social network of the oldest old
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    2011 (English)In: BMC Geriatrics, ISSN 1471-2318, Vol. 11, no 78Article in journal (Refereed) Published
    Abstract [en]

    Background: The ELSA 85 project is a population-based study with the purpose to learn more about the “elderly elderly”. The aim of this part of the ELSA 85 study is to explore the effects of childlessness on the psychological wellbeing, living situation and social support of 85-year old individuals.

    Methods: A postal questionnaire was sent to all (650) 85-year old men and women living in Linköping Municipality in 2007. Psychological well-being and social network was measured using a number of questions.

    Results: 496 individuals participated in the study. No differences in psychological wellbeing were found between the 85-year olds who were childless and those who were parents. The childless 85-year olds were less likely to have relatives close by and to receive help than those who were parents. Individuals of both groups were equally likely to end up in institutional care, to have friends close by and to be in contact with neighbours.

    Conclusions: Even though elderly childless individuals have social networks of less support potential than those who are parents there are no differences in certain psychological wellbeing indicators between the two groups. Apparently, childless elderly individuals find ways to cope with whatever negative effects of childlessness they may have experienced.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-73616 (URN)10.1186/1471-2318-11-78 (DOI)000208731700078 ()
    Available from: 2012-01-10 Created: 2012-01-10 Last updated: 2016-11-23Bibliographically approved
  • Public defence: 2016-12-16 10:15 Transformen, B-huset, Linköping
    Unnikrishnan, Vishnu
    Linköping University, Department of Electrical Engineering, Integrated Circuits and Systems. Linköping University, Faculty of Science & Engineering.
    Unnikrishnan, Vishnu
    Linköping University, Department of Electrical Engineering, Integrated Circuits and Systems. Linköping University, Faculty of Science & Engineering.
    Design of VCO-based ADCs2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today's complex electronic systems with billions of transistors on a single die are enabled by the aggressive scaling down of the device feature size at an exponential rate as predicted by the Moore's law. Digital circuits benefit from technology scaling to become faster, more energy efficient as well as more area efficient as the feature size is scaled down. Moreover, digital design also benefits from mature CAD tools that simplify the design and cross-technology porting of complex systems, leveraging on a cell-based design methodology. On the other hand, the design of analog circuits is getting increasingly difficult as the feature size scales down into the deep nanometer regime due to a variety of reasons like shrinking voltage headroom, reducing intrinsic gain of the devices, increasing noise coupling between circuit nodes due to shorter distances etc. Furthermore, analog circuits are still largely designed with a full custom design ow that makes their design and porting tedious, slow, and expensive. In this context, it is attractive to consider realizing analog/mixed-signal circuits using standard digital components. This leads to scaling-friendly mixed-signal blocks that can be designed and ported using the existing CAD framework available for digital design. The concept is already being applied to mixed-signal components like frequency synthesizers where all-digital architectures are synthesized using standard cells as basic components. This can be extended to other mixed-signal blocks like digital-to-analog and analog to- digital converters as well, where the latter is of particular interest in this thesis.

    A voltage-controlled oscillator (VCO)-based analog-to-digital converter (ADC) is an attractive architecture to achieve all-digital analog-to digital conversion due to favorable properties like shaping of the quantization error, inherent anti-alias filtering etc. Here a VCO operates as a signal integrator as well as a quantizer. A converter employing a ring oscillator as the VCO lends itself to an all-digital implementation.

    In this dissertation, we explore the design of VCO-based ADCs synthesized using digital standard cells with the long-term goal of achieving high performance data converters built from low accuracy switch components. In a first step, an ADC is designed using vendor supplied standard cells and fabricated in a 65 nm CMOS process. The converter delivers an 8-bit ENOB over a 25 MHz bandwidth while consuming 3.3 mW of power resulting in an energy efficiency of 235 fJ/step (Walden FoM). Then we utilize standard digital CAD tools to synthesize converter designs that are fully described using a hardware description language. A polynomial-based digital post-processing scheme is proposed to correct for the VCO nonlinearity. In addition, pulse modulation schemes like delta modulation and asynchronous sigma-delta modulation are used as a signal pre-coding scheme, in an attempt to reduce the impact of VCO nonlinearity on converter performance. In order to investigate the scaling benefits of all-digital data conversion, a VCO-based converter is designed in a 28 nm CMOS process. The design delivers a 13.4-bit ENOB over a 5 MHz bandwidth achieving an energy efficiency of 4.3 fJ/step according to post-synthesis schematic simulation, indicating that such converters have the potential of achieving good performance in deeply scaled processes by exploiting scaling benefits. Furthermore, large conversion errors caused by non-ideal sampling of the oscillator phase are studied. An encoding scheme employing ones counters is proposed to code the sampled ring oscillator output into a number, which is resilient to a class of sampling induced errors modeled by temporal reordering of the transitions in the ring. The proposed encoding reduces the largest error caused by random reordering of up to six subsequent bits in the sampled signal from 31 to 2 LSBs. Finally, the impact of process, voltage, and temperature (PVT) variations on the performance while operating the converter from a subthreshold supply is investigated. PVT-adaptive solutions are suggested as a means to achieve energy-efficient operation over a wide range of PVT conditions.

    List of papers
    1. Time-Mode Analog-to-Digital Conversion Using Standard Cells
    Open this publication in new window or tab >>Time-Mode Analog-to-Digital Conversion Using Standard Cells
    2014 (English)In: IEEE Transactions on Circuits and Systems Part 1: Regular Papers, ISSN 1549-8328, E-ISSN 1558-0806, Vol. 61, no 12, 3348-3357 p.Article in journal (Refereed) Published
    Abstract [en]

    Synthesizable all-digital ADCs that can be designed, verified and taped out using a digital design flow are of interest due to a consequent reduction in design cost and an improved technology portability. As a step towards high performance synthesizable ADCs built using generic and low accuracy components, an ADC designed exclusively with standard digital cell library components is presented. The proposed design is a time-mode circuit employing a VCO based multi-bit quantizer. The ADC has first order noise-shaping due to inherent error feedback of the oscillator and sinc anti-aliasing filtering due to continuous-time sampling. The proposed architecture employs a Gray-counter based quantizer design, which mitigates the problem of partial sampling of digital data in multi-bit VCO-based quantizers. Furthermore, digital correction employing polynomial-fit estimation is proposed to correct for VCO non-linearity. The design occupies 0.026 mm when fabricated in a 65 nm CMOS process and delivers an ENOB of 8.1 bits over a signal bandwidth of 25.6 MHz, while sampling at 205 MHz. The performance is comparable to that of recently reported custom designed single-ended open-loop VCO-based ADCs, while being designed exclusively with standard cells, and consuming relatively low average power of 3.3 mW achieving an FoM of 235 fJ/step.

    Place, publisher, year, edition, pages
    Institute of Electrical and Electronics Engineers (IEEE), 2014
    Keyword
    ADC; all-digital; analog-to-digital; Gray-counter; linearization; polynomial-fit; standard cell; synthesizable; time-domain; time-mode; VCO-based ADC
    National Category
    Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:liu:diva-113048 (URN)10.1109/TCSI.2014.2340551 (DOI)000345581200004 ()
    Available from: 2015-01-09 Created: 2015-01-08 Last updated: 2016-11-25
    2. A Fully Synthesized All-Digital VCO-Based Analog-to-Digital Converter
    Open this publication in new window or tab >>A Fully Synthesized All-Digital VCO-Based Analog-to-Digital Converter
    2015 (English)In: 2015 NORDIC CIRCUITS AND SYSTEMS CONFERENCE (NORCAS) - NORCHIP and INTERNATIONAL SYMPOSIUM ON SYSTEM-ON-CHIP (SOC), Institute of Electrical and Electronics Engineers (IEEE), 2015Conference paper (Refereed)
    Abstract [en]

    Synthesis of all-digital ADCs leads to significant reduction in design cost and design time, besides improving cross-technology portability. In this work, an ADC which is fully described in digital HDL is synthesized, placed and routed using standard digital design tools. A VCO-based architecture is chosen for its synthesizability. The design flow employed is discussed. The circuit is synthesized using the standard cell library in a 65 nm CMOS process, delivering a resolution of 9 ENOB over 10 MHz bandwidth according to post layout parasitic extracted simulations using the Spectre simulator. Post synthesis and post place-and-route performances are provided.

    Place, publisher, year, edition, pages
    Institute of Electrical and Electronics Engineers (IEEE), 2015
    National Category
    Aerospace Engineering
    Identifiers
    urn:nbn:se:liu:diva-131246 (URN)10.1109/NORCHIP.2015.7364386 (DOI)000380441400033 ()9781467365765 (online) (ISBN)9781467365758 (USB) (ISBN)9781467365772 (PoD) (ISBN)
    Conference
    Nordic Circuits Systems Conference (NORCAS): NORCHIP & International Symposium on System Chip (SoC) 2015, 26-28 October, Oslo, Norway
    Available from: 2016-09-16 Created: 2016-09-12 Last updated: 2016-11-25
    3. A NAND Gate Based Standard Cell VCO for Use in Synthesizable ADCs
    Open this publication in new window or tab >>A NAND Gate Based Standard Cell VCO for Use in Synthesizable ADCs
    2015 (English)In: 2015 NORDIC CIRCUITS AND SYSTEMS CONFERENCE (NORCAS) - NORCHIP and INTERNATIONAL SYMPOSIUM ON SYSTEM-ON-CHIP (SOC), IEEE , 2015Conference paper (Refereed)
    Abstract [en]

    Synthesizable all-digital ADCs lead to reduced design cost and design time as well as to low cross-technology porting costs. VCO-based ADC is an attractive candidate for the synthesis of ADCs using standard cells. However, a VCO, which is controlled by an analog input signal, is difficult to implement using standard digital circuits. Supply controlled ring oscillators using static CMOS inverters are used in prior works. In this work, an alternative VCO built using NAND gates is proposed for use in synthesizable converters. The circuit is demonstrated by employing it in an ADC synthesized from an HDL description. Transistor level simulation of the resulting netlist using the Spectre simulator shows that a performance of 10 bit ENOB over a 10 MHz bandwidth can be achieved after digital correction, using the proposed VCO.

    Place, publisher, year, edition, pages
    IEEE, 2015
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:liu:diva-131245 (URN)10.1109/NORCHIP.2015.7364398 (DOI)000380441400045 ()9781467365765 (online) (ISBN)9781467365758 (USB) (ISBN)9781467365772 (PoD) (ISBN)
    Conference
    Nordic Circuits Systems Conference (NORCAS): NORCHIP & International Symposium on System Chip (SoC) 2015,26-28 October, Oslo, Norway
    Available from: 2016-09-16 Created: 2016-09-12 Last updated: 2016-11-25
    4. Linearization of Synthesizable VCO-Based ADCs Using Delta Modulation
    Open this publication in new window or tab >>Linearization of Synthesizable VCO-Based ADCs Using Delta Modulation
    2015 (English)In: 2015 European Conference on Circuit Theory and Design (ECCTD), Institute of Electrical and Electronics Engineers (IEEE), 2015, 280-283 p.Conference paper (Refereed)
    Abstract [en]

    VCO-based ADC is an attractive candidate for the synthesis of all-digital ADCs using standard cells. However, the non-linearity of a synthesizable VCO requires digital post-processing to obtain good performance. We propose another solution where the input analog signal is pre-coded into a delta-modulated pulse stream which is used to drive a VCO-based converter. This causes the oscillator to operate at two distinct frequencies thereby eliminating the VCO non-linearity from the converter transfer function. A circuit is proposed that consists of a synthesized digital block realizing all the active parts of the circuit and a passive RC net used as an integrator. Spectre simulation of the netlist synthesized using a 65 nm standard cell library shows a performance of 8.2 bit ENOB over a 3 MHz bandwidth without using any digital post-processing.

    Place, publisher, year, edition, pages
    Institute of Electrical and Electronics Engineers (IEEE), 2015
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering
    Identifiers
    urn:nbn:se:liu:diva-131533 (URN)10.1109/ECCTD.2015.7300003 (DOI)000380498200005 ()9781479998777 (online) (ISBN)9781479998760 (USB) (ISBN)9781479998784 (PoD) (ISBN)
    Conference
    European Conference on Circuit Theory and Design (ECCTD), 24-26 August, Trondheim, Norway
    Available from: 2016-09-25 Created: 2016-09-23 Last updated: 2016-11-25
    5. Mixed-Signal Design Using Digital CAD
    Open this publication in new window or tab >>Mixed-Signal Design Using Digital CAD
    2016 (English)In: Proceedings IEEE Computer Society Annual Symposium on VLSI ISVLSI 2016, 2016, 6-11 p.Conference paper (Refereed)
    Abstract [en]

    The paper investigates the use of the existing CAD framework for digital circuit synthesis to design and synthesize a select set of mixed-signal functions like analog-to-digital and digital-to-analog conversions. This approach leads to fast and low cost design of technology portable system-on-chip solutions with analog interfaces. Some circuit examples for implementation of data conversion using digital circuits are discussed, leveraging on time-domain signal processing. Some of the signal corruption mechanisms in time-domain signal processing systems are considered in order to suggest adaptations to the existing digital design flow for the synthesis of mixed-signal circuits. As an example to show that high performance data conversion circuits can be realized using low accuracy general purpose components, an ADC is designed and synthesized with the vendor supplied standard cell library in a 65 nm CMOS process. Spectre simulation results show the feasibility of employing a digital CAD framework to synthesize high performance mixed-signal circuits, by applying time-domain signal processing.

    Series
    , IEEE Computer Society Annual Symposium on VLSI, ISSN 2159-3477
    Keyword
    CAD;analogue-digital conversion;digital-analogue conversion;electronic engineering computing;integrated circuit design;mixed analogue-digital integrated circuits;signal processing;system-on-chip;time-domain analysis;ADC design;CAD framework;CMOS process;Spectre simulation;analog interfaces;analog-to-digital conversion;corruption mechanisms;data conversion;digital CAD framework;digital circuit synthesis;digital design flow;digital-to-analog conversion;high-performance data conversion circuits;mixed-signal circuit synthesis;mixed-signal design;mixed-signal functions;size 65 nm;system-on-chip design;time-domain signal processing;time-domain signal processing systems;vendor supplied standard cell library;Delays;Digital circuits;Inverters;Logic gates;Signal processing;Standards;Time-domain analysis;ADC;CAD;DAC;Mixed-signal;VHDL;Verilog;all-digital;analog;analog-to-digital;comparator;design flow;digital;digital-to-analog;opamp;place-and-route;signal processing;synthesis;synthesizable;time-domain;time-mode
    National Category
    Electrical Engineering, Electronic Engineering, Information Engineering Computer Engineering
    Identifiers
    urn:nbn:se:liu:diva-132788 (URN)10.1109/ISVLSI.2016.79 (DOI)9781467390392 (online (ISBN)9781467390408 (PoD) (ISBN)
    Conference
    IEEE Computer Society Annual Symposium on VLSI, 11-13 July 2016, Pittsburgh, Pennsylvania, USA
    Available from: 2016-11-25 Created: 2016-11-25 Last updated: 2016-11-25Bibliographically approved
  • Public defence: 2016-12-16 13:00 Berzeliussalen, Linköping
    Charitakis, Emmanouil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Charitakis, Emmanouil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Neurohormonal activation, Symptoms and health-related quality of life in patients with atrial fibrillation eligible for radiofrequency ablation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Atrial fibrillation (AF) is the most common cardiac arrhythmia. In order to improve the management of patients with AF, a better understanding of patients’ arrhythmia-related symptoms and health-related quality of life (HRQoL), as well as a finer grasp of the effect of AF initiation and the revolutionary treatment of radiofrequency ablation (RFA) on neurohormonal balance are of great importance.

    The aim of this dissertation was to study the effects of RFA and AF initiation on four different neurohormonal systems represented by two cardiac biomarkers: the N-terminal fragment of the proB-type natriuretic peptide (NT-proBNP), the mid-regional fragment of the N-terminal of pro-atrial natriuretic peptide (MR-proANP); and two extra-cardiac biomarkers: the C-terminal fragment of the prodromal molecule of arginine vasopressin (copeptin) and the mid-regional portion of pro-adrenomedullin (MR-proADM). Furthermore, we aimed to correlate objective indicators with the variety of arrhythmiarelated symptoms and HRQoL in patients with AF.

    We studied 192 consecutive AF patients, eligible for RFA, referred to the University Hospital, Linköping, Sweden between January 2012 and April 2014. Forty-five patients, out of the initially selected sample, were included in the interventional part of the study. Biomarkers were collected from the femoral vein (fv), the coronary sinus (CS) and the left atrium (LA), and from fv immediately and the day after RFA. With regard to the interventional part of the study, 36 patients were randomized to AF initiation and 19 to control group. Biomarkers were retrieved from fv, CS and LA prior to AF initiation (baseline) and 30 minutes later. The Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia (ASTA) symptom scale was used in order to assess patients’ arrhythmiarelated symptoms. The ASTA HRQoL scale and the generic short-form 36 (SF-36) physical and mental component summaries were used in order to express patients’ disease-specific and overall HRQoL respectively.

    While analysing the effect of RFA on biomarkers, it was noticed that the level of NTproBNP decreased the day after RFA in participants in AF, compared with the participants in sinus rhythm who showed a slight increase. Regardless of the actual rhythm, the level of MR-proANP showed an increase immediately after RFA was carried out, followed by a decrease the day after. The copeptin level showed a six-fold increase, compared with baseline, immediately after the RFA procedure, while the MR-proADM level increased the day after. The levels of copeptin and MR-proADM were similar in the CS compared to peripheral blood.

    When it came to the effects of AF initiation on biomarkers, compared with the control group, MR-proANP and NT-proBNP concentrations were increased. Copeptin levels in patients without ischemic heart disease were decreased after the initiation of AF.

    We also found that signs of anxiety, low-grade inflammation (defined by high-sensitive C-reactive protein levels>3mg/l) and LA dilatation significantly predicted arrhythmiarelated symptoms. Probable depression was the most important predictor of arrhythmiaspecific HRQoL, and obesity and signs of anxiety were the most important predictors of the physical and mental component summaries respectively.

    AF is a complex arrhythmia that affects the cardiac and extra-cardiac neurohormonal balance directly after its initiation. RFA causes a neurohormonal imbalance not only due to secondary myocardial injury, but also due to other factors such as patient’s actual rhythm, volume overload and procedural stress. Treatable factors such as anxiety, depression and obesity, which can affect HRQoL and symptoms in patients with AF, should be addressed, and possibly a more intensive life style factor modification can be of value.

    List of papers
    1. Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation (SMURF): a protocol for an observational study with a randomised interventional component
    Open this publication in new window or tab >>Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation (SMURF): a protocol for an observational study with a randomised interventional component
    Show others...
    2015 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 12, e008723Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia, with an estimated prevalence of 1.5-2%. It is an independent risk factor for ischaemic stroke and is estimated to cause about 20-25% of all stroke cases. AF has a great impact on health-related quality of life (HRQoL); however, one unresolved issue related to AF is the wide variation in its symptoms.

    METHODS AND ANALYSIS: The symptom burden, metabolic profile, ultrasound findings, rhythm, neurohormonal activation, haemodynamics and HRQoL in patients with AF (Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation, SMURF) study is a prospective observational, cohort study, with a randomised interventional part. The aim of the study is to investigate, in patients with AF, the relationship between symptom burden and metabolic aspects, atrial function and different neurohormones, and the effect of radiofrequency ablation (RFA). The interventional part of the study will give an insight into the neurohormonal and intracardiac pressure changes directly after initiation of AF. Consecutive patients with symptomatic AF accepted for treatment with RFA for the first time at Linköping University Hospital are eligible for participation. The enrolment started in January 2012, and a total of 200 patients are to be included into the study, with 45 of them being enrolled into the interventional study with initiation of AF. The sample size of the interventional study is based on a small pilot study with 5 patients induced to AF while 2 served as controls. The results indicated that, in order to find a statistically significant difference, there was a need to include 28 patients; for safety reasons, 45 patients will be included.

    ETHICS AND DISSEMINATION: The SMURF study is approved by the Regional Ethical Review Board at the Faculty of Health Sciences, Linköping, Sweden. The results will be presented through peer-review journals and conference presentation.

    TRIAL REGISTRATION NUMBER: NCT01553045; Pre-results.

    Place, publisher, year, edition, pages
    BMJ Publishing Group, 2015
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:liu:diva-124290 (URN)10.1136/bmjopen-2015-008723 (DOI)000368839100047 ()26692555 (PubMedID)
    Note

    Funding agencies: ALF grants (County Council of Ostergotland); Carldavid Jonsson Research Foundation; Heart Foundation; Linkoping University; Biosense Webster; Johnson and Johnson

    Available from: 2016-01-25 Created: 2016-01-25 Last updated: 2016-11-21
    2. Short‐Term Influence of Radiofrequency Ablation on NT‐proBNP, MR‐proANP, Copeptin, and MR‐proADM in Patients With Atrial Fibrillation: Data From the Observational SMURF Study
    Open this publication in new window or tab >>Short‐Term Influence of Radiofrequency Ablation on NT‐proBNP, MR‐proANP, Copeptin, and MR‐proADM in Patients With Atrial Fibrillation: Data From the Observational SMURF Study
    2016 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 9Article in journal (Refereed) Published
    Abstract [en]

    Background There is limited knowledge on the short‐term influence of radiofrequency ablation (RFA) of atrial fibrillation (AF) on 2 cardiac biomarkers; the N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and the midregional fragment of the N‐terminal of pro‐ANP (MR‐proANP) and 2 extracardiac biomarkers; the c‐terminal provasopressin (copeptin) and the midregional portion of proadrenomedullin (MR‐proADM). There are also limited data concerning cardiac production of the latter two.

    Methods and Results We studied 192 consecutive patients eligible for RFA of AF referred to the University Hospital, Linköping, Sweden. NT‐proBNP, MR‐proANP, copeptin, and MR‐proADM levels were measured in peripheral blood, the coronary sinus (CS), and the left atrium before ablation, and in peripheral blood immediately and the day after RFA. The level of NT‐proBNP decreased the day after RFA in participants in AF at the time of RFA, compared to the participants in sinus rhythm who showed a slight increase (P<0.001). Furthermore, regardless of the actual rhythm, the level of MR‐proANP showed an increase immediately after RFA (P<0.001), followed by a decrease the day after ablation (P<0.001). Copeptin level showed a 6‐fold increase immediately after RFA compared to baseline (P<0.001), whereas MR‐proADM level increased the day after RFA (P<0.001). Levels of copeptin and MR‐proADM were not higher in the CS compared to peripheral blood.

    Conclusions RFA of AF is a strong stimulus with a significant and direct impact on different neurohormonal systems. We found no sign of a cardiac release of MR‐proADM or copeptin.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2016
    Keyword
    Atrial fibrillation, biomarkers, catheter ablation
    National Category
    Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:liu:diva-132725 (URN)10.1161/JAHA.116.003557 (DOI)27633393 (PubMedID)
    Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2016-11-28Bibliographically approved
    The full text will be freely available from 2017-04-21 08:00
  • Public defence: 2016-12-19 13:00 Berzeliussalen, Linköping
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies: Implications for pathogenesis, classification and diagnosis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of diseases with severe consequences for the life of affected patients. Dermatomyositis, polymyositis and inclusion body myositis (IBM) are the classical representatives of this group. The treatments given today often have limited effects, and are taken at the cost of side effects. Major obstacles in the search for more effective treatments are; (1) an incomplete understanding of the disease mechanisms, (2) difficulties to delineate homogeneous disease groups for clinical studies and (3) the sometimes challenging task to diagnose these diseases.

    Aims: We addressed a number of “loose ends” in the areas of pathogenesis, classification and diagnosis; mechanisms of muscle fiber degeneration in IIM, with a focus of programmed cell death (apoptosis) and invasion of muscle  fibers by inflammatory cells (partial invasion); protecting and mediating factors present in muscle; the association of other diseases with IIM, in particular celiac disease ; the evaluation of two classification systems and laboratory methods for increased diagnostic performance.

    The studies: We included 106 patients, diagnosed at the Neuromuscular unit in Linköping, Sweden, with pathological muscle findings consistent with IIM. The incidence in the county of Östergötland (during 5 years) was 7.3 per million/year (3 patients each year). Of 88 patients with confirmed IIM 4 (4.5 %) had celiac disease, 33 (38%) had an associated systemic inflammatory disease and 5 (5.7 %) had a malignancy. Ninety-nine patients were included for a comparison of two classification systems using criteria of the European Neuromuscle Centre (Amato/ENMC), and the widely used Bohan and Peter classification, both with the addition of IBM according to Griggs et al. Using the Amato/ENMC criteria the most prevalent diagnostic group after IBM (30%) was nonspecific myositis (23%), followed by polymyositis (20%) and dermatomyositis 17%). A substantial number of patients meeting Bohan and Peter (or Griggs) criteria were excluded by Amato/ENMC criteria, most (21/23) due to lack of detectable muscle weakness. Extended muscle sectioning increased the sensitivity of a muscle biopsy by 15 % and the specificity by 22%, and showed an overlap between disease groups. Muscle biopsies from patients with IIM and controls were used to investigate pathological findings considered specific for disease groups, and for the presence of programmed cell death (apoptosis) and disease protecting and mediating factors in muscle. The presence of apoptotic muscle fiber nuclei was detected in muscle with partial invasion (however not in the invaded fibers) in the presence of granzyme B and CD8+ cytotoxic T cells. The major apoptosis inhibiting protein Bcl-2 was shown to be constitutionally expressed in healthy muscle but weakened in IIM.

    Conclusion: We present apoptosis as a possible disease mechanism in parallel with partial invasion of fibers. Furthermore, partial invasion may not be a suitable distinguishing feature in the pathogenesis, or for classification and diagnosis of IIM. We also introduce the anti-apoptotic Bcl-2 as a possible relevant muscle fiber protecting factor. A more extensive pathological work-up improves classification and diagnosis of IIM. The proposed Amato/ENMC creates a substantial portion of patients with non-specific or unclassified myositis. Associated diseases are common in IIM, and also include celiac disease.

    List of papers
    1. Classification and Diagnostic Investigation in Inflammatory Myopathies: A Study of 99 Patients
    Open this publication in new window or tab >>Classification and Diagnostic Investigation in Inflammatory Myopathies: A Study of 99 Patients
    2013 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 40, no 7, 1173-1182 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective. Insights into the pathogenesis of inflammatory myopathies have led to new diagnostic methods. The aims of our study were (1) to evaluate the consequences of using the classification of Amato/European Neuromuscular Centre Workshop (ENMC), compared to that of Bohan and Peter; and (2) to evaluate any diagnostic benefit in using an extended pathological investigation. less thanbrgreater than less thanbrgreater thanMethods. From a consecutive retrospective database, we evaluated 99 patients for classification. Patients with inclusion body myositis (IBM) were classified according to Griggs, et al. In addition to routine stainings and immunohistochemistry, a multilevel serial sectioning procedure was performed on paraffin-embedded material, to identify scarce pathological findings. less thanbrgreater than less thanbrgreater thanResults. Classification according to Bohan and Peter could be performed for 83 of the 99 patients, whereas only 60 patients met the Amato/ENMC criteria, the latter resulting in the following diagnostic groups: IBM (n = 18), nonspecific myositis (n = 14), polymyositis (n = 12), dermatomyositis (n = 10), dermatomyositis sine dermatitis (n = 5), and immune-mediated necrotizing myopathy (n = 1). Most of the Amato/ENMC diagnostic groups harbored patients from several of the Bohan and Peter groups, which included a substantial group lacking proximal muscle weakness. The serial sectioning procedure was essential for classification of 9 patients (15%), and led to a more specific diagnosis for 13 patients (22%) according to Amato/ENMC. less thanbrgreater than less thanbrgreater thanConclusion. The classification of Amato/ENMC was more restrictive, forming groups based on clinical criteria and specified myopathological findings, which clearly differed from the groups of the Bohan and Peter classification. An extended pathological investigation increased the diagnostic yield of a muscle biopsy and highlights the quantity and specificity of certain pathological findings.

    Place, publisher, year, edition, pages
    Journal of Rheumatology, 2013
    Keyword
    INFLAMMATORY MYOPATHIES, IDIOPATHIC INFLAMMATORY MYOPATHIES, POLYMYOSITIS, DERMATOMYOSITIS, INCLUSION BODY MYOSITIS
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-96992 (URN)10.3899/jrheum.120804 (DOI)000321993800023 ()
    Note

    Funding Agencies|University Hospital Linkoping||County Council of Ostergotland||

    Available from: 2013-09-02 Created: 2013-09-02 Last updated: 2016-11-23
    2. Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle
    Open this publication in new window or tab >>Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle
    2009 (English)In: NEUROMUSCULAR DISORDERS, ISSN 0960-8966, Vol. 19, no 6, 412-417 p.Article in journal (Refereed) Published
    Abstract [en]

    The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle. we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.

    Keyword
    Inflammatory myopathy, Apoptosis, Bcl-2, TRAIL, Fas and Fas-L
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19795 (URN)10.1016/j.nmd.2009.03.008 (DOI)
    Available from: 2009-08-10 Created: 2009-08-10 Last updated: 2016-11-23
  • Public defence: 2016-12-19 13:15 ACAS, A-huset, Linköping
    Söderström, Fredrik
    Linköping University, Department of Management and Engineering, Information Systems. Linköping University, Faculty of Arts and Sciences.
    Söderström, Fredrik
    Linköping University, Department of Management and Engineering, Information Systems. Linköping University, Faculty of Arts and Sciences.
    Introducing public sector eIDs: The power of actors’ translations and institutional barriers2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The electronic identification (eID) is a digital representation of our analogue identity used for authentication in order to gain access to personalized restricted online content. Despite its limited and clearly defined scope, the eID has a unique role to play in information society as an enabler of public digital services for citizens as well as businesses and a prerequisite for the development of electronic government (eGovernment). This study shows a tendency of treating public sector eIDs like Information and Communications Technology (ICT) artefacts in general. Hence, a narrow focus on technology is often applied thus placing non-technical aspects in the background. Consequently, social and organizational implications are often unproblematized which in turn becomes problematic in the case of the public sector eID.

    This study puts forth a need for a broader focus in this area and contributes by focusing on the challenges related to the resistance to introductions of eIDs among affected actors in the public sector. This study assumes that affected actors’ perceptions (translations) of the eID have a potential impact on its introduction on organizational as well as operational level. Research questions focus on the influence of resistance on the introduction and the relationship between resistance and actors’ translations of the eID. The aim is to further develop existing concepts and bring new insights to research as well as practice. The analytical perspectives of sociology and institutionalism aim at developing a tentative analytical framework for investigations of this relationship. Introductions, therefore, become institutional pressures facing resistance as related to affected actors’ translations. The empirical basis consists of two interpretive case studies of eID introductions –a national eID to cover the entire public sector and a professional eID in health care.

    The result shows that resistance in the form of institutional barriers develops from actors’ negative translations of the eID and main coordinating actors’ tend to fail in their attempts to negotiate these barriers. This confirms a closer relationship between institutional pressures and barriers and a view of pressures, barriers and eIDs as translated institutions transferred across organizational settings is put forth. To facilitate future research and practice related to public sector eID introductions, three propositions are put forth. (1) The importance of acknowledging pressures to introduce eIDs as closely related to barriers. (2) The institutions involved in this process as all translated by the government, coordinating actors as well as affected actors. (3) The importance of a developed understanding of these institutions, translations and relationships in order to facilitate cooperative efforts shaping future public sector eIDs.

  • Public defence: 2016-12-20 10:15 ACAS, building A, Linköping
    Paramonova, Svetlana
    Linköping University, Department of Management and Engineering, Energy Systems. Linköping University, Faculty of Science & Engineering.
    Paramonova, Svetlana
    Linköping University, Department of Management and Engineering, Energy Systems. Linköping University, Faculty of Science & Engineering.
    Re-viewing industrial energy-efficiency improvement using a widened system boundary2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Improved energy efficiency in industry is important for reaching the targets within the EU strategy for increased sustainability. However, energy efficiency is not always prioritised within companies, and the improvement potential remains large. This paradox called an energyefficiency gap is explained by energy-efficiency barriers. The low interest in energy efficiency is also explained by the fact that it is not within companies’ core competences and not perceived as strategic. The public policies aiming at closing the gap have thus far been concentrated on the faster diffusion of energy-efficient technologies. This is not sufficient, and the gap can be extended by including energy management practices. To bridge the extended gap, there is a need to introduce an extended system perspective. The aim of this thesis is to  investigate the industrial energy-efficiency potential and possibilities for reaching this potential using an extended system boundary.

    In this thesis, the extended gap was quantified by means of classification of the energy data covering the most electricity-intensive Swedish industrial companies. The results show that technology-related measures represent 61% of energy savings, whereas management-related measures account for 38%. Energy efficiency due to management-related measures can be improved with lower costs. The energy-efficiency potentials for different levels of industrial motor systems were quantified, showing that the highest potential is found in the measures that include personal involvement and the optimisation of routines. This proves that the general approaches based on technological diffusion seem to not be sufficient to solve the energy paradox.

    The evaluation of the Swedish energy audit programme for small and medium-sized enterprises (SMEs) proved that there is a lack of energy-related knowledge among SMEs. The implementation rate of measures proposed in the audits is only 54%, while there is also a need to reach the SMEs not covered by the programme. The international study of energy-efficiency potentials did not indicate energy management to be considered by SMEs at all.

    To bridge the extended gap, the external experts’ knowledge on how to work with energy efficiency has to stay within companies. For this, there is a need for methods based on longterm orientation as well as a systematic view of complicated processes. The methods should be universal and applied in a particular context. An example of such a method for large industries is presented in this thesis, whereas applying it to SMEs is problematic due to limited resources. Participating in networks for energy efficiency can be a way to initiate energy-efficiency work within SMEs on a continuous basis. Moreover, this thesis shows that there is a need for the development of a common taxonomy for energy data as well as the development of a central portal where energy data can be reported and stored. This would simplify the monitoring of energy end-use, the control of measures implementation and the comparison between processes, companies and sectors.

    List of papers
    1. Outsourcing Industrial Energy Management: Industrial Energy Efficiency Networks Provided As an Energy Service
    Open this publication in new window or tab >>Outsourcing Industrial Energy Management: Industrial Energy Efficiency Networks Provided As an Energy Service
    2014 (English)In: Outsourcing: strategies, challenges and effects on organizations / [ed] Andre Deering, New York: Nova Science Publishers, Inc., 2014, 71-98 p.Chapter in book (Other academic)
    Abstract [en]

    Improving industrial energy efficiency (IEE) is of the outmost importance for both individual industrial companies, and governments. Improved IEE leads to reduced energy costs for companies, and improved sustainability through reduced CO2 emissions. Despite a large untapped potential for improved IEE, many energy efficiency measures (EEM) remain unexploited due to the existence of various barriers to IEE. One of the reasons for the large untapped IEE potential is the apparent low level of energy management practices in industry. A promising approach to stress improved IEE, and improved energy management practices, are industrial energy efficiency networks (IEEN), which in essence is a type of energy service where energy management is partly outsourced to a third party. There is a need to study how IEENs could and should be structured. Successful networks have been under operation in many different areas and disciplines. A large part of the organizational issues of previous research on networks, could thus be transformed to IEENs, e.g. in terms of transition theory, transformation etc. The aim of this book chapter is to present a general model for the management of IEEN.

    Place, publisher, year, edition, pages
    New York: Nova Science Publishers, Inc., 2014
    Keyword
    Energy efficiency networks, energy management practices, double-loop learning
    National Category
    Social Sciences Interdisciplinary
    Identifiers
    urn:nbn:se:liu:diva-112281 (URN)978-1-63463-288-1 (ISBN)