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  • Public defence: 2018-10-26 09:00 Berzeliussalen, Linköping
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Dendritic cells are key players during HIV pathogenesis, and shape both the immediate immune response at the site of infection as well as directing the adaptive immune response against the virus. HIV has developed a plethora of immune evasion mechanisms that hijack dendritic cell functions, suppressing their ability to mount an accurate immune response and exploiting them for efficient viral transfer to target T cells.

    To achieve successful replication within dendritic cells without triggering danger signaling, HIV accomplishes a delicate balance where only a low level of transcription can be sustained without triggering antiviral responses that would harm the virus. Here, we describe how the presence of HSV2 coinfection, which is very common in geographic areas with a high HIV prevalence and almost triples the risk of HIV acquisition, alters dendritic cell state to support much higher levels of HIV infection. We found this effect to be mediated by the STING pathway, which is involved in the sensing of DNA in the cell cytosol. STING activation led to an upregulation of factors such as IRF3 and NFkB that can be used for HIV transcription and a degradation of factors that restrict HIV replication.

    In addition, we describe how HIV exploits the human complement system, a group of proteins that usually help the human body to identify dangerous pathogens while avoiding reaction towards self. HIV can coat itself, i.e. become opsonized, in complement fragments that are typically only present on the body’s own cells, allowing it to activate signaling pathways that are associated with tolerance. Dendritic cells that come into contact with complement opsonized HIV do not mount danger responses, despite the fact that HIV-derived single stranded RNA triggers the pathogen recognition receptor TLR8. The suppression of danger responses is mediated by activation of complement receptor 3, and leads to an increased infection of the dendritic cell and affects its interactions with other immune cells. There is a lack of recruitment of NK cells to the site of infection, and an inhibition of NK cell killing, which plays an important role in the destruction of HIV-infected cells in vivo. T cells primed by dendritic cells exposed to complement opsonized HIV have a lower ability to develop towards effector phenotype, and have an increased expression of the markers PD1, TIM3 and LAG3 which are associated with T cell dysfunction and exhaustion. In addition, T cells primed by these dendritic cells in the presence of NK cells upregulate markers CD38, CXCR3 and CCR4, which have been linked to an increased susceptibility to HIV infection.

    In summary, we add to the current knowledge on HIV immune evasion mechanisms that allow the virus to establish infection, as well as describing mechanisms that govern whether dendritic cells mount danger signaling and an immune response or not.  

    List of papers
    1. Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3
    Open this publication in new window or tab >>Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3
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    2014 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 9, p. 4590-4601Article in journal (Refereed) Published
    Abstract [en]

    Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-beta, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1 beta, IL-6, and TNF-alpha, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-kappa B pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.

    Place, publisher, year, edition, pages
    American Association of Immunologists, 2014
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-112625 (URN)10.4049/jimmunol.1401781 (DOI)000344079500033 ()25252956 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER for Vinnova; Linkoping University Hospital Research Fund Grant C-ALF; Swedish Society of Medicine; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Swedish Society for Medical Research

    Available from: 2014-12-08 Created: 2014-12-05 Last updated: 2018-09-28Bibliographically approved
    2. Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1
    Open this publication in new window or tab >>Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1
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    2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed) Published
    Abstract [en]

    Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFN gamma and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection.

    Place, publisher, year, edition, pages
    American Association of Immunologists, 2015
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-121313 (URN)10.4049/jimmunol.1500618 (DOI)000360013200039 ()26157174 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation [AI52731]; Swedish International Development Cooperation Agency/Swedish Agency for Research Cooperation with Developing Countries-Special Assistant; VINNMER for Vinnova; Linkoping University Hospital Research Fund; central regional agreement on medical training and clinical research (CALF) between Ostergotland County Council and Linkoping University; Swedish Society of Medicine; High Impact Research; University of Malaya [UM.C.625/1/HIR/139]

    Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2018-09-28
    3. Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells
    Open this publication in new window or tab >>Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells
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    2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 899Article in journal (Refereed) Published
    Abstract [en]

    Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with complement fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis.

    Place, publisher, year, edition, pages
    FRONTIERS MEDIA SA, 2018
    Keywords
    dendritic cells; natural killer cells; complement; HIV; cross talk; checkpoint inhibitors; CXCR3; CCR4
    National Category
    Immunology
    Identifiers
    urn:nbn:se:liu:diva-147922 (URN)10.3389/fimmu.2018.00899 (DOI)000431174300002 ()29760706 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; VINNMER for Vinnova; Linkoping University Hospital Research Fund; ALF Grants Region Ostergotland; FORSS; CERiA, University of Malaya [UM.C.625/1/HIR/139]

    Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2018-09-28
  • Public defence: 2018-10-26 09:00 ACAS A-huset, Linköping
    Yousefi Mojir, Kayvan
    Linköping University, Department of Management and Engineering, Information Systems. Linköping University, Faculty of Arts and Sciences.
    Information Systems Development for Emerging Public Sector Cross-sector Collaborations: The Case of Swedish Emergency Response2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Information systems (IS) seem prevalent in modern societies and have resulted in the rapid digitalisation of different societal sectors. One application domain of IS is emergency response, which is responsible for delivering essential services to save lives and minimise environmental damage in both small , frequent and large-scale emergencies. Specific IS applications are in turn used in emergency response to support such aspects as decision-making, communication, information sharing and the dispatching of resources. Public-sector cut-backs and a lack of professional resources have affected emergency response at the same time as natural disasters (e.g. forest fires, tsunamis, storms, terror attacks, and wars in the Middle East leading to mass migration) have intensified in recent decades. At the same time, frequent, small-scale accidents continue to occur on a regular basis, both in urban and sparsely populated areas. As a result, emergency response actors, first responders, are often placed under severe pressure. An emerging trend in response to these challenges, both in Sweden and internationally, is to create cross-sector forms of collaboration, by combining alternative resources from various sectors. Such collaborations are relatively new and involve heterogeneous stakeholders.

    Therefore, the thesis objective is to explore IS-related opportunities, challenges and needs aimed at supporting heterogeneous actors in emerging cross-sector collaborations in emergency response in order to enable and facilitate future related IS development. To achieve this, a user-centred approach was applied. A baseline study was performed followed by three case studies on ‘co-location of actors’, ‘co-operative use of resources’ and ‘semi-professionals as first responders’ by performing interviews, focus groups, participant observation, Future Workshops, an exercise and an after-action review. The thesis is based on case study research and qualitative research methods. Sociotechnical systems theory, the sociotechnical ensemble view, and network governance were used as the analytical framework. As part of achieving the thesis objectives, experiences from applying user participation in the context of cross-sector collaboration are also presented as part of the results. A context-specific framework developed to systematise and explore various important aspects of cross-sector collaboration in emergency response is also described.

    The results of this thesis indicate that the needs for IS in cross-sector collaborations vary from simple smartphone applications to manage alarms, positioning and the dispatching of new resources, to more sophisticated tools for sharing and viewing incident data. The results also indicate that these collaborations have the potential (e.g. resource redundancy, pooled competencies to increase total capacity) to improve Swedish emergency response if supported by adequate IS/IT support. The major challenges are organisational, economic and juridical and the most prominent are ambiguities in actors’ tasks and responsibilities, and how to prioritise between ordinary work and ‘new’ first-response tasks. They must be addressed to enable certain IS-functions, e.g. information sharing and positioning of resources The results also highlight several institutional factors (e.g. mutual interest between members, collective problem-solving, secrecy aspects) which are believed to play a key role in the success or failure of the collaborations and which must be adressed in the development of IS-support. The actors also have substantial basic needs for training (e.g. fire extinguishing, first aid) and emergency supplies (e.g. fire extinguishers, healthcare kits).

    Applying user participation also faced challenges, the major one being the development of a future cross-sector collaboration in a context that does not yet exist, and involving stakeholders from resource-strained organisations in doing so. The stakeholders, and sometimes also the primary end-users, are partly unknown and tasks are undefined. As a response to these challenges, a combination of activities based on multiple design groups, scenario-based Future Workshops, focus groups, the context-specific framework, a practical exercise and an after-action-review was provided. The framework, which was used to support data collection and user participation, includes 15 dimensions each intended to represent important aspects of cross-sector collaboration.

    The thesis major contributions are the identified opportunities, challenges and need as a ’sociotechnical ensemble’ and generated and from several studies, thus being comparable. The thesis more theoretical contributions is the combined application of the sociotechnical ensemble view and network governance where the studied collaboration forms are characterised as a hybrid form of networks and more traditional government mechanisms and where it is pointed out that network governance lacks explicit IS/IT aspects. In a wider perspective, the research fields of IS and political science may cross-fertilise each other when studying emerging cross-sector collaboration in the public sector. Identified user participation challenges relevant to the cross-sector collaboration context, suggestions on how they can be handled and the context-specific framework are contributions that can be used in practical user-centred IS development in similar contexts. 

    List of papers
    1. A Framework for “New Actors” in Emergency Response Systems
    Open this publication in new window or tab >>A Framework for “New Actors” in Emergency Response Systems
    2013 (English)In: ISCRAM2013. Conference Proceedings, Book of Papers, 10th International Conference on Information Systems for Crisis Response and Management / [ed] T. Comes, F. Fiedrich , S. Fortier, J. Geldermann and T. Müller, 2013, p. 741-746Conference paper, Published paper (Refereed)
    Abstract [en]

    Using actors from different societal sectors can improve the response operation quality in emergency management. The different roles, tasks and responsibilities these actors have in response operations and the legal frameworks they work within influence their needs for proper information system support. There is thus a substantial need to study and systemize the concept of “new actors” before providing them with technical solutions. In this study, a framework is constructed showing 14 dimensions of new actors that need to be considered when new actors are studied in more detail.

    Keywords
    Emergency response system, new actor, framework, first responder.
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-95995 (URN)9783923704804 (ISBN)
    Conference
    10th International Conference on Information Systems for Crisis Response and Management (ISCRAM 2013), 12-15 May 2013, Baden-Baden, Germany
    Available from: 2013-08-12 Created: 2013-08-12 Last updated: 2018-09-28Bibliographically approved
    2. Emerging communities of collaboration: co-location in emergency response systems in Sweden
    Open this publication in new window or tab >>Emerging communities of collaboration: co-location in emergency response systems in Sweden
    2014 (English)In: ISCRAM2014 Academic Papers 11th International Conference on Information Systems for Crisis Response and Management / [ed] S.R. Hiltz, M.S. Pfaff, L. Plotnick, and P.C. Shih, Information Systems for Crisis Response and Management , 2014, p. 546-555Conference paper, Published paper (Refereed)
    Abstract [en]

    Co-location as a form of network governance is a way of organizing response teams when responding to an emergency situation. At the ‘Safety house’ in the province of Jämtland in Sweden main emergency response actors and supporting actors work together in a shared physical place in order to facilitate the process of cooperation and joint decision making. In order to identify the strengths, weaknesses, obstacles, needs and information system role, we explored this case by looking at how the involved actors experience this new working context. We applied an analytical framework developed specifically for new forms of emergency response. It was found that co-location of actors increases the efficiency in using professional response resources and shortens the emergency response time. Information systems can have a significant role in improving the collaboration between actors at the ‘Safety house’. However secrecy issues, the problem of control and politics and the evaluation of the performance of actors are major challenges which face further development of the co-location concept.

    Place, publisher, year, edition, pages
    Information Systems for Crisis Response and Management, 2014
    Keywords
    Emergency, Crisis Management, Network governance
    National Category
    Other Engineering and Technologies not elsewhere specified
    Identifiers
    urn:nbn:se:liu:diva-109496 (URN)9780692211946 (ISBN)
    Conference
    11th International Conference on Information Systems for Crisis Response and Management (ISCRAM 2014), University Park, Pennsylvania, USA, 18 May 2014
    Available from: 2014-08-20 Created: 2014-08-20 Last updated: 2018-09-28Bibliographically approved
    3. Actor-centred emergency response systems: a framework for needs analysis and information systems development
    Open this publication in new window or tab >>Actor-centred emergency response systems: a framework for needs analysis and information systems development
    2016 (English)In: International Journal of Emergency Management, ISSN 1471-4825, E-ISSN 1741-5071, Vol. 12, no 4, p. 403-434Article in journal (Refereed) Published
    Abstract [en]

     A new trend in emergency response systems (ERS) is to create new forms of collaboration, for example, by involving new resources in response operations, in order to compensate for the limited number of professional resources. However, the fact that the new resources may come from different organisational contexts and social sectors creates new challenges which directly affect information systems development for these resources. This study presents a framework including 15 dimensions to analyse the new forms of collaboration. Socio-technical system theory and participatory design approaches are applied to make the framework applicable in the information systems field. The framework might also address general problems such as the lack of formalisation and difficulties in identifying relevant stakeholders in participatory design. A comparison with international research showed a potential to adapt the framework to ERSs in other countries or even to other parts of the public sector that are undergoing similar changes.

    Place, publisher, year, edition, pages
    InderScience Publishers, 2016
    Keywords
    ERSs; emergency response systems; new actors; new collaborations; cross-sector collaboration; information systems; socio-technical systems; STS; participatory design; needs analysis; emergency management
    National Category
    Information Systems
    Identifiers
    urn:nbn:se:liu:diva-132400 (URN)10.1504/IJEM.2016.10000709 (DOI)
    Available from: 2016-11-08 Created: 2016-11-08 Last updated: 2018-09-28
    4. User Participation in Information Systems Development for Emerging Public Sector Initiatives
    Open this publication in new window or tab >>User Participation in Information Systems Development for Emerging Public Sector Initiatives
    2018 (English)Conference paper, Oral presentation only (Refereed)
    Abstract [en]

    This study is a-posteriori analysis of information systems (IS) development in a cross-sector collaboration case to identify and address user participation challenges in emerging public sector initiatives. The major challenges in the studied case was to develop IS for future cross-sector collaboration in a setting that does not yet exist, i.e. where the tasks, stakeholders and end-users are undefined. To address identified challenges, we suggest a combination of activities based on multiple design groups, scenario-based Future Workshops, focus groups, context-specific frameworks, and practical exercises with after-action-review. We argue that while similar challenges have been discussed in relation to large-scale projects and, sometimes, cross-sector collaboration, IS development for emerging public sector initiatives pose specific issues that need to be addressed.

    Keywords
    User participation, future service design, cross-sector collaboration
    National Category
    Public Administration Studies Communication Studies
    Identifiers
    urn:nbn:se:liu:diva-150956 (URN)
    Conference
    27th International Conference on Information Systems Development (ISD2018), August 22-24, Lund, Sweden
    Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-09-28Bibliographically approved
    5. Semi-professionals: emergency response as an additional task in current occupations
    Open this publication in new window or tab >>Semi-professionals: emergency response as an additional task in current occupations
    2018 (English)In: International Journal of Emergency Services, ISSN 2047-0894, E-ISSN 2047-0908Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    Purpose The purpose of this paper is twofold: first, to identify occupational groups who can act as semi-professional first responders, in order to shorten the response times to frequent emergencies, and second, to identify related opportunities, challenges and needs of training, emergency supplies and information technology (IT) support. Design/methodology/approach A case study approach was taken, combining future workshops, focus groups and an exercise. Network governance was used as an analytical lens. Findings The identified potential groups are security guards, home care personnel, fire services day personnel and facility service personnel. The results show that semi-professionals have a large potential to complement professional resources by carrying out first response or supportive actions vital to the emergency, partly by using already existing cars and equipment. The identified needs include additional basic equipment such as fire extinguishers and first-aid kits, training in basic firefighting, first aid and risk assessment, as well as mobile phone application-based IT support to manage alarms. The major challenges are organisational, economic and juridical, including ambiguities in responsibilities and related insurances. The analysis recognises the new collaboration as a hybrid form of hierarchical government and network governance. Social implications The study suggests that using semi-professional resources can be one of many innovative solutions to recent public sector challenges that have put a huge strain on professional emergency response organisations. Originality/value The study provides a novel view of using semi-professional resources in emergency response, based on the joint perspectives of various occupational groups, and the fire services.

    Place, publisher, year, edition, pages
    Emerald Group Publishing Limited, 2018
    Keywords
    Network governance, Cross-sector collaboration with fire services, Semi-professionals
    National Category
    Communication Studies Public Administration Studies
    Identifiers
    urn:nbn:se:liu:diva-150834 (URN)10.1108/IJES-11-2017-0059 (DOI)
    Available from: 2018-09-03 Created: 2018-09-03 Last updated: 2018-09-28Bibliographically approved
  • Public defence: 2018-10-26 13:00 Berzeliussalen, Linköping
    Sigurdardottir, Gunnthorunn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Studies of the Systemic Inflammation in Psoriasis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Psoriasis is a common immune-mediated disease, where an increased prevalence of extra cutaneous diseases and mortality is observed. Common inflammatory mechanisms are implicated. The general aim of this thesis was to investigate markers of inflammation and cardiovascular disease in psoriasis, now considered a systemic disease, assumed to reflect the systemic inflammation.

    In Study I, Th1-, Th2- and Th17-associated chemokines were elevated in the blood of psoriasis patients in comparison to controls and, in Study II, six markers of cardiovascular risk were demonstrated to be systemically elevated. After adjustment for body mass index and waist: hip ratio in Study II, only one marker, the total plasminogen activator inhibitor-1, showed sustained elevated levels. The levels of the chemokines and the cardiovascular markers were unaffected after treatment with narrowband UVB therapy (NB-UVB), despite a significant improvement in skin lesions, indicating more local than systemic effects of NBUVB. This was further strengthened by the fact that the response to in-vitro stimulation in the peripheral blood mononuclear cells (PBMCs) of psoriasis patients before and after NB-UVB treatment was unaffected. In Study I, CCL20 was shown to correlate to the psoriasis area severity index (PASI), but this correlation was lost after phototherapy, suggesting sources of CCL20 other than the skin. Conversely, systemic treatment with TNF-α inhibition in Study II alleviated the elevated systemic levels of the cardiovascular risk markers. In Study III, the levels of 17 potential biomarkers, with the emphasis on endothelial and adipocyte dysfunction, soluble receptors and the innate mechanisms were studied. Endocan-1, CXCL16, and sVEGFR1, were found to be systemically decreased in psoriasis patients at baseline. Endocan-1 showed a negative correlation to the PASI. In contrast to the results in Studies I and II, NB-UVB therapy affected the systemic levels of investigated markers; Endocan-1 and CXCL16 were restored to normal levels, while sVEGF1, FABP3, FABP4 and sIL-1R1 showed a significant reduction following NB-UVB. In Study IV, the focus was on the contribution of innate immune mechanisms and the effects of the cytokines IL-17 and TNF-α on systemic inflammation. In keratinocytes, the gene and protein expression of inflammasome components was increased upon exposure to IL-17 and TNF-α. Systemically, the constitutive expression of the inflammasome components NLRP1, NLRP3 and AIM2 was detected in neutrophils, classical monocytes, CD4+ lymphocytes and B-cell subsets from psoriasis patients. Upon exposure to IL-17 and TNF-α, increased systemic caspase-1 levels were detected, confirming systemic inflammasome activity.

    In conclusion, these studies support the hypothesis that there is a systemic inflammation in psoriasis to which both innate and adaptive immune mechanisms contribute. The systemic inflammation may be explained, to some extent, but not completely, by body weight and fat distribution. The different effects of NB-UVB therapy on the systemic levels of the investigated markers may reflect their different roles in psoriasis, but the ameliorating effects of the TNF-α inhibitor on the elevated cardiovascular markers suggests that systemic treatment should be evaluated in psoriasis patients with signs of a systemic inflammatory burden.

    List of papers
    1. Systemically elevated Th1-, Th2- and Th17-associated chemokines in psoriasis vulgaris before and after ultraviolet B treatment
    Open this publication in new window or tab >>Systemically elevated Th1-, Th2- and Th17-associated chemokines in psoriasis vulgaris before and after ultraviolet B treatment
    Show others...
    2013 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 93, no 5, p. 527-531Article in journal (Refereed) Published
    Abstract [en]

    Chemokines may contribute to the systemic inflammation that is linked to the increased risk of co-morbidities in patients with psoriasis. The aim of this study was to investigate circulating chemokines in patients with psoriasis and their relationship to disease severity. Analysis of plasma levels of chemokines in patients with psoriasis before narrowband ultraviolet B (UVB) therapy revealed increased expression of Th1-associated CXCL9 and -10, Th2-associated CCL17 and CCL22, and Th17-associated CCL20. CCL20 correlated with disease severity. UVB therapy reduced skin symptoms, but did not affect the chemokine levels in plasma. Anti-CD3 and anti-CD28-mediated activation of peripheral blood mononuclear cells (PBMCs) caused a higher secretion of Th2 cytokine interleukin (IL)-13 by PBMCs from patients with psoriasis than from healthy controls. The sustained high expression of inflammatory chemokines is a potential link to systemic inflammation in psoriasis. UVB therapy may be a more effective treatment of local rather than systemic inflammation.

    Place, publisher, year, edition, pages
    Society for Publication of Acta Dermato-Venereologica, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102565 (URN)10.2340/00015555-1545 (DOI)000330327200006 ()23571825 (PubMedID)
    Available from: 2013-12-13 Created: 2013-12-13 Last updated: 2018-10-12Bibliographically approved
    2. Systemic treatment and narrowband ultraviolet B differentially affect cardiovascular risk markers in psoriasis.
    Open this publication in new window or tab >>Systemic treatment and narrowband ultraviolet B differentially affect cardiovascular risk markers in psoriasis.
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    2014 (English)In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 70, no 6, p. 1067-1075Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Psoriasis is associated with a systemic inflammation and an increased frequency of the metabolic syndrome, both of which are believed to link psoriasis to an increased risk of cardiovascular disease.

    OBJECTIVE: The study aimed to investigate the systemic expression of markers of cardiovascular risk and determine their response to ultraviolet B therapy and treatment with the tumor necrosis factor-alfa inhibitor, etanercept.

    METHODS: Six markers of cardiovascular risk were measured in 28 patients with psoriasis and 28 control subjects.

    RESULTS: Five of the 6 investigated markers were elevated in patients with psoriasis. Four of these correlated to the body mass index and waist-hip ratio, suggesting a link to the metabolic syndrome. Total plasminogen activator inhibitor-1 remained elevated independently of these factors. The levels of the investigated risk markers decreased considerably after tumor necrosis factor-alfa inhibitor treatment but remained unaffected by ultraviolet therapy.

    LIMITATIONS: A relatively limited study population and nonrandomization are limitations.

    CONCLUSION: These findings suggest that the choice of treatment in psoriasis may influence the cardiovascular risk in patients with psoriasis and the metabolic syndrome.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    National Category
    Dermatology and Venereal Diseases
    Identifiers
    urn:nbn:se:liu:diva-107732 (URN)10.1016/j.jaad.2013.12.044 (DOI)000336030400026 ()24656729 (PubMedID)
    Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2018-10-12
    3. Decreased Systemic Levels of Endocan-1 and CXCL16 in Psoriasis Are Restored following Narrowband UVB Treatment.
    Open this publication in new window or tab >>Decreased Systemic Levels of Endocan-1 and CXCL16 in Psoriasis Are Restored following Narrowband UVB Treatment.
    2018 (English)In: Dermatology, ISSN 1018-8665, E-ISSN 1421-9832Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    BACKGROUND: In psoriasis, a common immune-mediated disease affecting 2-3% of the population worldwide, there is an increased prevalence of extracutaneous diseases including obesity, the metabolic syndrome, and cardiovascular disease. This is believed to be linked to systemic inflammation. In previous studies, we have explored various markers in plasma and serum to characterize the ongoing systemic inflammation in psoriasis patients compared to controls. We have identified several markers that were altered in psoriasis patients, but which all were unresponsive to narrowband UVB (NB-UVB) treatment.

    OBJECTIVE: The objective of the study was to evaluate the effect of NB-UVB treatment on markers of cardiovascular risk and systemic inflammation in psoriasis.

    METHODS: The levels of 17 potential biomarkers with an association with cardiovascular risk were quantitated in plasma from 37 age- and gender-matched psoriasis patients and controls at baseline and in 21 psoriasis patients after 12 weeks of NB-UVB treatment to identify a systemic treatment response.

    RESULTS: We identified the mediators endocan-1, CXCL16, and sVEGFR1, which were systemically decreased in psoriasis at baseline, as well as FABP3, FABP4, and sIL-1R1, which showed normal baseline levels. After 10-12 weeks of NB-UVB treatment, endocan-1 and CXCL16 were restored to normal levels, while sVEGFR1, FABP3, FABP4, and sIL-1R1 showed a significant reduction.

    CONCLUSION: The current study expands the number of potential biomarkers in psoriasis by including a greater number and variety of mediators, approaching the systemic inflammation from additional vantage points, including soluble immune receptors and adipocyte contribution, to provide a more complete picture of the systemic inflammatory state in psoriasis.

    Place, publisher, year, edition, pages
    Basel: S. Karger, 2018
    Keywords
    Cardiovascular risk, Psoriasis, Skin, UVB
    National Category
    Dermatology and Venereal Diseases
    Identifiers
    urn:nbn:se:liu:diva-151989 (URN)10.1159/000491819 (DOI)30176661 (PubMedID)
    Funder
    Ingrid Asp Psoriasis Research Center
    Note

    This research was funded by the Ingrid Asp Foundation, the Welander Foundation, the Swedish Psoriasis Association, and the Medical Research Council.

    Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2018-10-12
  • Public defence: 2018-10-26 13:15 ACAS, A-huset, ingång 17, Linköping
    Öhrvall, Richard
    Linköping University, Department of Management and Engineering, Political Science. Linköping University, Faculty of Arts and Sciences. Institutet för Näringslivsforskning (IFN).
    Growing into Voting: Election Turnout among Young People and Habit Formation2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis contains an introduction and four essays that together address the issues of turnout and habitual voting. Although voting is less unequal than other forms of political participation, it is still biased in favour of more socially affluent citizens.  One way to achieve more equal participation is to increase the general turnout. This is the implication of the `law of dispersion', formulated by Tingsten in 1937, which states that as turnout increases, participatory equality also increases. In Essay I, co-written with Mikael Persson and Maria Solevid, we revisit Tingsten's law and find new empirical support for it.

    One possible path to improving general turnout is the formation of voting habits. It is argued by some scholars that voting is a habit formed early on in life, when young people encounter their first elections after coming of age. It is, however, still a matter of debate as to whether voting is an act of habit. Three of the four essays in this thesis tackle this question in various ways. In Essay II, I study voting among young people who encounter their first election in different social contexts depending on their age, and how these differing contexts affect their propensity to vote in their first and second election. In Essay III, I examine whether experiencing a European Parliament election with a low turnout as a first election affects the likelihood of casting a vote in a subsequent national parliamentary election. In Essay IV, co-written with Sven Oskarsson, we study student mock elections, which constitute the first, albeit hypothetical, election experience for many young people.

    The main result is that the first election a young person faces is not as important as has been claimed in previous research. Regardless of whether the initial experience takes place in a context that encourages turnout or the first election encountered is a low-stimulus election that fails to draw crowds to the polls, there is no substantial impact on turnout in subsequent elections. One implication of this finding is that lowering the voting age is not likely to increase voting rates, not even in the longer term.

    List of papers
    1. Voter Turnout and Political Equality: Testing the ‘Law of Dispersion’ in a Swedish Natural Experiment
    Open this publication in new window or tab >>Voter Turnout and Political Equality: Testing the ‘Law of Dispersion’ in a Swedish Natural Experiment
    2013 (English)In: Politics, ISSN 0263-3957, E-ISSN 1467-9256, Vol. 33, no 3, p. 172-184Article in journal (Refereed) Published
    Abstract [en]

    According to the ‘law of dispersion’, the level of inequality in political participation is higher when voter turnout is low. We empirically test this hypothesis by evaluating levels of voter turnout in the 2010 Swedish election to the Västra Götaland county council and in the 2011 re-election for the same county council. The re-election voter turnout was reduced by almost half, from 80.6 per cent to 44.1 per cent. Our results support the law of dispersion: the level of inequality in participation substantially increased between young and old, rich and poor, low and high educated and politically interested and uninterested.

    Keywords
    voter turnout, voter participation, political equality, law of dispersion, re-elections
    National Category
    Political Science (excluding Public Administration Studies and Globalisation Studies)
    Identifiers
    urn:nbn:se:liu:diva-124361 (URN)10.1111/1467-9256.12012 (DOI)
    Available from: 2016-01-27 Created: 2016-01-27 Last updated: 2018-08-14
  • Public defence: 2018-10-30 10:15 Planck, Fysikhuset, Linköping
    Halim, Joseph
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Synthesis and transport properties of 2D transition metal carbides (MXenes)2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Since the isolation and characterization of graphene, there has been a growing interest in 2D materials owing to their unique properties compared to their 3D counterparts. Recently, a family of 2D materials of early transition metal carbides and nitrides, labelled MXenes, has been discovered (Ti2CTz, Ti3C2Tz, Mo2TiC2Tz, Ti3CNTz, Ta4C3Tz, Ti4N3Tz among many others), where T stands for surface-terminating groups (O, OH, and F). MXenes are mostly produced by selectively etching A layers (where A stands for group A elements, mostly groups 13 and 14) from the MAX phases. The latter are a family of layered ternary carbides and/or nitrides and have a general formula of Mn+1AXn (n = 1-3), where M is a transition metal and X is carbon and/or nitrogen. The produced MXenes have a conductive carbide core and a non-conductive O-, OH- and/or F-terminated surface, which allows them to work as electrodes for energy storage applications, such as Li-ion batteries and supercapacitors.

    Prior to this work, MXenes were produced in the form of flakes of lateral dimension of about 1 to 2 microns; such dimensions and form are not suitable for electronic characterization and applications. I have synthesized various MXenes (Ti3C2Tz, Ti2CTz and Nb2CTz) as epitaxial thin films, a more suitable form for electronic and photonic applications. These films were produced by HF, NH4HF2 or LiF + HCl etching of magnetron sputtered epitaxial Ti3AlC2, Ti2AlC, and Nb2AlC thin films. For transport properties of the Ti-based MXenes, Ti2CTz and Ti3C2Tz, changing n from 1 to 2 resulted in an increase in conductivity but had no effect on the transport mechanism (i.e. both Ti3C2Tx and Ti2CTx were metallic). In order to examine whether the electronic properties of MXenes differ when going from a few layers to a single flake, similar to graphene, the electrical characterization of a single Ti3C2Tz flake with a lateral size of about 10 μm was performed. These measurements, the first for MXene, demonstrated its metallic nature, along with determining the nature of the charge carriers and their mobility. This indicates that Ti3C2Tz is inherently of 2D nature independent of the number of stacked layers, unlike graphene, where the electronic properties change based on the number of stacked layers.

    Changing the transition metal from Ti to Nb, viz. comparing Ti2CTz and Nb2CTz thin films, the electronic properties and electronic conduction mechanism differ. Ti2CTz showed metallic-like behavior (resistivity increases with increasing temperature) unlike Nb2CTz where the conduction occurs via variable range hopping mechanism (VRH) - where resistivity decreases with increasing temperature.

    Furthermore, these studies show the synthesis of pure Mo2CTz in the form of single flakes and freestanding films made by filtering Mo2CTz colloidal suspensions. Electronic characterization of free-standing films made from delaminated Mo2CTz flakes was investigated, showing that a VRH mechanism prevails at low temperatures (7 to ≈ 60 K). Upon vacuum annealing, the room temperature, RT, conductivity of Mo2CTx increased by two orders of magnitude. The conduction mechanism was concluded to be VRH most likely dominated by hopping within each flake.

    Other Mo-based MXenes, Mo2TiC2Tz and Mo2Ti2C3Tz, showed VRH mechanism at low temperature. However, at higher temperatures up to RT, the transport mechanism was not clearly understood. Therefore, a part of this thesis was dedicated to further investigating the transport properties of Mo-based MXenes. This includes Mo2CTz, out-of-plane ordered Mo2TiC2Tz and Mo2Ti2C3Tz, and vacancy ordered Mo1.33CTz. Magneto-transport of free-standing thin films of the Mo-based MXenes were studied, showing that all Mo-based MXenes have two transport regimes: a VRH mechanism at lower temperatures and a thermally activated process at higher temperatures. All Mo-based MXenes except Mo1.33CTz show that the electrical transport is dominated by inter-flake transfer. As for Mo1.33CTz, the primary electrical transport mechanism is more likely to be intra-flake.

    The synthesis of vacancy ordered MXenes (Mo1.33CTz and W1.33CTz) raised the question of possible introduction of vacancies in all MXenes. Vacancy ordered MXenes are produced by selective etching of Al and (Sc or Y) atoms from the parent 3D MAX phases, such as (Mo2/3Sc1/3)2AlC, with in-plane chemical ordering of Mo and Sc. However, not all quaternary parent MAX phases form the in-plane chemical ordering of the two M metals; thus the synthesis of the vacancy-ordered MXenes is restricted to a very limited number of MAX phases. I present a new method to obtain MXene flakes with disordered vacancies that may be generalized to all quaternary MAX phases. As proof of concept, I chose Nb-C MXene, as this 2D material has shown promise in several applications, including energy storage, photothermal cell ablation and photocatalysts for hydrogen evolution. Starting from synthetizing (Nb2/3Sc1/3)2AlC quaternary solid solution and etching both the Sc and Al atoms resulted in Nb1.33C material with a large number of vacancies and vacancy clusters. This method may be applicable to other quaternary or higher MAX phases wherein one of the transition metals is more reactive than the other, and it could be of vital importance in applications such as catalysis and energy storage.  

    List of papers
    1. Transparent Conductive Two-Dimensional Titanium Carbide Epitaxial Thin Films
    Open this publication in new window or tab >>Transparent Conductive Two-Dimensional Titanium Carbide Epitaxial Thin Films
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    2014 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 26, no 7, p. 2374-2381Article in journal (Refereed) Published
    Abstract [en]

    Since the discovery of graphene, the quest for two-dimensional (2D) materials has intensified greatly. Recently, a new family of 2D transition metal carbides and carbonitrides (MXenes) was discovered that is both conducting and hydrophilic, an uncommon combination. To date MXenes have been produced as powders, flakes, and colloidal solutions. Herein, we report on the fabrication of similar to 1 x 1 cm(2) Ti3C2 films by selective etching of Al, from sputter-deposited epitaxial Ti3AlC2 films, in aqueous HF or NH4HF2. Films that were about 19 nm thick, etched with NH4HF2, transmit similar to 90% of the light in the visible-to-infrared range and exhibit metallic conductivity down to similar to 100 K. Below 100 K, the films resistivity increases with decreasing temperature and they exhibit negative magnetoresistance-both observations consistent with a weak localization phenomenon characteristic of many 2D defective solids. This advance opens the door for the use of MXenes in electronic, photonic, and sensing applications.

    Place, publisher, year, edition, pages
    American Chemical Society, 2014
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-106852 (URN)10.1021/cm500641a (DOI)000334572300023 ()
    Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2018-09-28Bibliographically approved
    2. Electronic properties of freestanding Ti3C2Tx MXene monolayers
    Open this publication in new window or tab >>Electronic properties of freestanding Ti3C2Tx MXene monolayers
    2016 (English)In: Applied Physics Letters, ISSN 0003-6951, E-ISSN 1077-3118, Vol. 108, no 3, p. 033102-1-033102-4, article id 033102Article in journal (Refereed) Published
    Abstract [en]

    We report on the electrical characterization of single MXene Ti(3)C(2)Tx flakes ( where T is a surface termination) and demonstrate the metallic nature of their conductivities. We also show that the carrier density can be modulated by an external gate voltage. The density of free carriers is estimated to be 8 +/- 3 X 10(21) cm(-3) while their mobility is estimated to be 0.7 +/- 0.2 cm(2)/Vs. Electrical measurements, in the presence of a magnetic field, show a small, but clearly discernable, quadratic increase in conductance at 2.5 K. (C) 2016 AIP Publishing LLC.

    Place, publisher, year, edition, pages
    American Institute of Physics (AIP), 2016
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-127457 (URN)10.1063/1.4939971 (DOI)000373055500039 ()
    Note

    Funding Agencies|Ceramics program of the Division of Materials Research of the National Science Foundation [DMR-1310245]

    Available from: 2016-04-30 Created: 2016-04-26 Last updated: 2018-09-28Bibliographically approved
    3. Synthesis and Characterization of 2D Molybdenum Carbide (MXene)
    Open this publication in new window or tab >>Synthesis and Characterization of 2D Molybdenum Carbide (MXene)
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    2016 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 26, no 18, p. 3118-3127Article in journal (Refereed) Published
    Abstract [en]

    Large scale synthesis and delamination of 2D Mo2CTx (where T is a surface termination group) has been achieved by selectively etching gallium from the recently discovered nanolaminated, ternary transition metal carbide Mo2Ga2C. Different synthesis and delamination routes result in different flake morphologies. The resistivity of free-standing Mo2CTx films increases by an order of magnitude as the temperature is reduced from 300 to 10 K, suggesting semiconductor-like behavior of this MXene, in contrast to Ti3C2Tx which exhibits metallic behavior. At 10 K, the magnetoresistance is positive. Additionally, changes in electronic transport are observed upon annealing of the films. When 2 mu m thick films are tested as electrodes in supercapacitors, capacitances as high as 700 F cm(-3) in a 1 M sulfuric acid electrolyte and high capacity retention for at least 10,000 cycles at 10 A g(-1) are obtained. Free-standing Mo2CTx films, with approximate to 8 wt% carbon nanotubes, perform well when tested as an electrode material for Li-ions, especially at high rates. At 20 and 131 C cycling rates, stable reversible capacities of 250 and 76 mAh g(-1), respectively, are achieved for over 1000 cycles.

    Place, publisher, year, edition, pages
    WILEY-V C H VERLAG GMBH, 2016
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:liu:diva-130074 (URN)10.1002/adfm.201505328 (DOI)000377591500015 ()
    Note

    Funding Agencies|Swedish Research Council [621-2012-4430]; Swedish Foundation for Strategic Research through the Synergy Grant FUNCASE Functional Carbides for Advanced Surface Engineering; Laboratory Directed Research and Development Program of Oak Ridge National Laboratory; U.S. Army Research Office [W911NF-15-1-0133]

    Available from: 2016-07-06 Created: 2016-07-06 Last updated: 2018-09-28
    4. Variable range hopping and thermally activated transport in molybdenum-based MXenes
    Open this publication in new window or tab >>Variable range hopping and thermally activated transport in molybdenum-based MXenes
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    2018 (English)In: Physical Review B, ISSN 2469-9950, E-ISSN 2469-9969, Vol. 98, no 10, article id 104202Article in journal (Refereed) Published
    Abstract [en]

    The magnetotransport of freestanding, vacuum filtered, thin films of Mo2CTz, Mo1.33CTz, Mo2TiC2Tz, and Mo2Ti2C3Tz was measured in the 10-300-K temperature (T) range. Some of the films were annealed before measuring their transport properties. Analysis of the results suggest that-with the exception of the heavily defective Mo1.33CTz composition-in the 10- to 200-K temperature regime, variable range hopping between individual MXene sheets is the operative conduction mechanism. For Mo1.33CTz it is more likely that variable range hopping within individual flakes is rate limiting. At higher temperatures, a thermally activated process emerges in all cases. It follows that improved fabrication processes should lead to considerable improvements in the electrical transport of Mo-based MXenes.

    Place, publisher, year, edition, pages
    AMER PHYSICAL SOC, 2018
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:liu:diva-151642 (URN)10.1103/PhysRevB.98.104202 (DOI)000444204500005 ()
    Note

    Funding Agencies|Flag-ERA [JTC 2-17]; Knut and Alice Wallenberg (KAW) Foundation [2015.0043]; Stiftelsen fr Strategisk Forskning (SSF) Program [EM16-0004]; UGA Nanosciences Foundation, Grenoble, France

    Available from: 2018-09-27 Created: 2018-09-27 Last updated: 2018-10-19
    5. Synthesis of Two-Dimensional Nb1.33C (MXene) with Randomly Distributed Vacancies by Etching of the Quaternary Solid Solution (Nb2/3Sc1/3)2AlC MAX Phase
    Open this publication in new window or tab >>Synthesis of Two-Dimensional Nb1.33C (MXene) with Randomly Distributed Vacancies by Etching of the Quaternary Solid Solution (Nb2/3Sc1/3)2AlC MAX Phase
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    2018 (English)In: ACS Applied Nano Materials, ISSN 2574-0970, Vol. 1, no 6, p. 2455-2460Article in journal (Refereed) Published
    Abstract [en]

    Introducing point defects in two-dimensional (2D) materials can alter or enhance their properties. Here, we demonstrate how etching a laminated (Nb2/3Sc1/3)2AlC MAX phase (solid solution) of both the Sc and Al atoms results in a 2D Nb1.33C material (MXene) with a large number of vacancies and vacancy clusters. This method is applicable to any quaternary, or higher, MAX phase, wherein one of the transition metals is more reactive than the other and could be of vital importance in applications such as catalysis and energy storage. We also report, for the first time, on the existence of solid solution (Nb2/3Sc1/3)3AlC2 and (Nb2/3Sc1/3)4AlC3 phases.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2018
    Keywords
    2D material; electronic properties; MXene; synthesis; transition-metal carbide
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:liu:diva-151667 (URN)10.1021/acsanm.8b00332 (DOI)
    Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2018-10-19Bibliographically approved
  • Public defence: 2018-11-05 13:00 Belladonna, Hus 511, Ingång 76, Våning 9, Linköping
    Casas Garcia, Belén
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Towards Personalized Models of the Cardiovascular System Using 4D Flow MRI2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Current diagnostic tools for assessing cardiovascular disease mostly focus on measuring a given biomarker at a specific spatial location where an abnormality is suspected. However, as a result of the dynamic and complex nature of the cardiovascular system, the analysis of isolated biomarkers is generally not sufficient to characterize the pathological mechanisms behind a disease. Model-based approaches that integrate the mechanisms through which different components interact, and present possibilities for system-level analyses, give us a better picture of a patient’s overall health status.

    One of the main goals of cardiovascular modelling is the development of personalized models based on clinical measurements. Recent years have seen remarkable advances in medical imaging and the use of personalized models is slowly becoming a reality. Modern imaging techniques can provide an unprecedented amount of anatomical and functional information about the heart and vessels. In this context, three-dimensional, three-directional, cine phase-contrast (PC) magnetic resonance imaging (MRI), commonly referred to as 4D Flow MRI, arises as a powerful tool for creating personalized models. 4D Flow MRI enables the measurement of time-resolved velocity information with volumetric coverage. Besides providing a rich dataset within a single acquisition, the technique permits retrospective analysis of the data at any location within the acquired volume.

    This thesis focuses on improving subject-specific assessment of cardiovascular function through model-based analysis of 4D Flow MRI data. By using computational models, we aimed to provide mechanistic explanations of the underlying physiological processes, derive novel or improved hemodynamic markers, and estimate quantities that typically require invasive measurements. Paper I presents an evaluation of current markers of stenosis severity using advanced models to simulate flow through a stenosis. Paper II presents a framework to personalize a reduced-order, mechanistic model of the cardiovascular system using exclusively non-invasive measurements, including 4D Flow MRI data. The modelling approach can unravel a number of clinically relevant parameters from the input data, including those representing the contraction and relaxation patterns of the left ventricle, and provide estimations of the pressure-volume loop. In Paper III, this framework is applied to study cardiovascular function at rest and during stress conditions, and the capability of the model to infer load-independent measures of heart function based on the imaging data is demonstrated. Paper IV focuses on evaluating the reliability of the model parameters as a step towards translation of the model to the clinic.

    List of papers
    1. 4D Flow MRI-Based Pressure Loss Estimation in Stenotic Flows: Evaluation Using Numerical Simulations
    Open this publication in new window or tab >>4D Flow MRI-Based Pressure Loss Estimation in Stenotic Flows: Evaluation Using Numerical Simulations
    2016 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 75, no 4, p. 1808-1821Article in journal (Refereed) Published
    Abstract [en]

    Purpose: To assess how 4D flow MRI-based pressure and energy loss estimates correspond to net transstenotic pressure gradients (TPG(net)) and their dependence on spatial resolution. Methods: Numerical velocity data of stenotic flow were obtained from computational fluid dynamics (CFD) simulations in geometries with varying stenosis degrees, poststenotic diameters and flow rates. MRI measurements were simulated at different spatial resolutions. The simplified and extended Bernoulli equations, Pressure-Poisson equation (PPE), and integration of turbulent kinetic energy (TKE) and viscous dissipation were compared against the true TPG(net). Results: The simplified Bernoulli equation overestimated the true TPG(net) (8.74 +/- 0.67 versus 6.76 +/- 0.54 mmHg). The extended Bernoulli equation performed better (6.57 +/- 0.53 mmHg), although errors remained at low TPG(net). TPG(net) estimations using the PPE were always close to zero. Total TKE and viscous dissipation correlated strongly with TPG(net) for each geometry (r(2) > 0.93) and moderately considering all geometries (r(2) = 0.756 and r(2) = 0.776, respectively). TKE estimates were accurate and minorly impacted by resolution. Viscous dissipation was overall underestimated and resolution dependent. Conclusion: Several parameters overestimate or are not linearly related to TPG(net) and/or depend on spatial resolution. Considering idealized axisymmetric geometries and in absence of noise, TPG(net) was best estimated using the extended Bernoulli equation. (C) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 2016
    Keywords
    pressure loss; phase contrast magnetic resonance imaging; aortic valve disease; aortic coarctation
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-127426 (URN)10.1002/mrm.25772 (DOI)000372910900043 ()26016805 (PubMedID)
    Note

    Funding Agencies|European Research Council [310612]; Swedish Research Council

    Available from: 2016-05-01 Created: 2016-04-26 Last updated: 2018-10-10
    2. Bridging the gap between measurements and modelling: a cardiovascular functional avatar
    Open this publication in new window or tab >>Bridging the gap between measurements and modelling: a cardiovascular functional avatar
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    2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6214Article in journal (Refereed) Published
    Abstract [en]

    Lumped parameter models of the cardiovascular system have the potential to assist researchers and clinicians to better understand cardiovascular function. The value of such models increases when they are subject specific. However, most approaches to personalize lumped parameter models have thus far required invasive measurements or fall short of being subject specific due to a lack of the necessary clinical data. Here, we propose an approach to personalize parameters in a model of the heart and the systemic circulation using exclusively non-invasive measurements. The personalized model is created using flow data from four-dimensional magnetic resonance imaging and cuff pressure measurements in the brachial artery. We term this personalized model the cardiovascular avatar. In our proof-of-concept study, we evaluated the capability of the avatar to reproduce pressures and flows in a group of eight healthy subjects. Both quantitatively and qualitatively, the model-based results agreed well with the pressure and flow measurements obtained in vivo for each subject. This non-invasive and personalized approach can synthesize medical data into clinically relevant indicators of cardiovascular function, and estimate hemodynamic variables that cannot be assessed directly from clinical measurements.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2017
    National Category
    Biomedical Laboratory Science/Technology
    Identifiers
    urn:nbn:se:liu:diva-140069 (URN)10.1038/s41598-017-06339-0 (DOI)000406260100018 ()28740184 (PubMedID)2-s2.0-85025821468 (Scopus ID)
    Note

    Funding Agencies|European Research Council [310612]; Swedish Research Council [2014-6191]

    Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-10-10Bibliographically approved
  • Public defence: 2018-11-09 09:15 Planck, Fysikhuset, Linköping
    Arja, Katriann
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Organic compounds that interact both with certain biological targets and display specific photophysical properties can be utilized as molecular tools to visualize and possibly effect disease related processes taking place in living organisms. In this regard, porphyrins are a class of naturally occurring molecules that possess intriguingly interesting photophysical properties where they can act as luminescent probes by emitting detectable light, as well as photosensitizers in the light mediated therapy called photodynamic therapy. In this thesis, the porphyrin structure has been synthetically combined with other molecule classes to achieve compounds with desirable multimodal characteristics.

    Firstly, luminescent conjugated oligothiophenes (LCOs) that have extensively, and with great success, been utilized as fluorescent ligands for amyloid formations, have been conjugated to porphyrins to render oligothiophene porphyrin hybrids (OTPHs) comprising two optically active modalities. When applied as fluorescent amyloidophilic dyes for visualization of amyloid-β (Aβ), one of the pathological hallmarks in Alzheimer’s disease, an enhanced optical assignment of distinct aggregated forms of Aβ was afforded.  Thus, properly functionalized OTPHs could give us more information about pathological processes underlying devastating disorders, such as Alzheimer’s disease. In addition, the OTPHs can be associated with synthetic peptides inducing peptide folding into certain three-dimensional helical structures giving rise to novel optically active materials.

    Secondly, this thesis also embraces porphyrins’ potential as photosensitizers in photodynamic therapy to kill cancer cells. Grounded on the prerequisites for an optimal photosensitizer, we designed porphyrin-based conjugates equipped with common carbohydrates for improved cancer cell selectivity and with a fluorinated glucose derivative, 2-fluoro 2-deoxy glucose, for advantageous metabolism in cancer cells. Furthermore, incorporation of a radioisotopic fluorine-18 atom into the glycoporphyrins could give the means for diagnostic use of the conjugates in positron emission tomography (PET).

    In order to tether together the above-mentioned molecular moieties in a controlled fashion, we developed a robust synthetic strategy for asymmetrical functionalization of porphyrin core. The method involves chlorosulfonation of this otherwise inert tetrapyrrolic structure, followed by alkynylation. Parallelly to amide coupling reactions, copper(I)-catalyzed alkyne azide cycloaddition is used for fast and high-yielding late-stage conjugations. Overall, this thesis demonstrates how combining different molecular moieties in synthetic organic chemistry yields novel molecules with combined and improved multimodal properties for biological and medicinal applications, guided by the design-by-function methodology.      

    List of papers
    1. Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
    Open this publication in new window or tab >>Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
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    2013 (English)In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 34, no 9, p. 723-730Article in journal (Refereed) Published
    Abstract [en]

    Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant A 1-42 amyloid fibrils and A deposits in brain tissue sections from a transgenic mouse model with Alzheimers disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiopheneporphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.

    Place, publisher, year, edition, pages
    Wiley-VCH Verlag, 2013
    Keywords
    oligothiophene, porphyrin, protein deposits, imaging, fluorescence
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-93385 (URN)10.1002/marc.201200817 (DOI)000318354500004 ()
    Note

    Funding Agencies|Swedish Research Council||Knut and Alice Wallenberg Foundation||Swedish Foundation for Strategic Research||European Union FP7 HEALTH (Project LUPAS)||LiU Neuroscience Center||ERC Starting Independent Researcher grant (Project: MUMID)||

    Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2018-08-24
    2. Synthesis and Characterization of Oligothiophene-Porphyrin-Based Molecules That Can Be Utilized for Optical Assignment of Aggregated Amyloid-beta Morphotypes
    Open this publication in new window or tab >>Synthesis and Characterization of Oligothiophene-Porphyrin-Based Molecules That Can Be Utilized for Optical Assignment of Aggregated Amyloid-beta Morphotypes
    2018 (English)In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 6, article id 391Article in journal (Refereed) Published
    Abstract [en]

    Molecular tools for fluorescent imaging of protein aggregates are essential for understanding the significance of these pathological hallmarks in proteopathic neurodegenerative diseases, such as Alzheimers disease. Here, we report the synthesis of a series of oligothiophene porphyrin hybrids, OTPHs, and the evaluation of these dyes for fluorescent imaging of beta-amyloid aggregates in tissue sections from a transgenic mouse model with Alzheimers disease pathology. The OTPHs proved to be successful for spectral and lifetime imaging assessment of protein deposits and our findings confirm that the enhanced spectral range and distinct lifetime diversity of these novel tools allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye. In addition, the chemical identity of the porphyrin moiety, as well as the spacing between the two optical active moieties, influenced the OTPHs performance for fluorescent assignment of the protein deposits. We foresee that our findings will aid in the chemical design of dyes that can be utilized as optical tools for studying the polymorphic nature of protein aggregates associated with proteopathic neurodegenerative diseases.

    Place, publisher, year, edition, pages
    FRONTIERS MEDIA SA, 2018
    Keywords
    oligothiophene; porphyrin; protein deposits; imaging; fluorescence
    National Category
    Biophysics
    Identifiers
    urn:nbn:se:liu:diva-151479 (URN)10.3389/fchem.2018.00391 (DOI)000443424100001 ()30234103 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [621-2013-4754, 2016-00748]

    Available from: 2018-09-24 Created: 2018-09-24 Last updated: 2018-10-19
    3. Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents
    Open this publication in new window or tab >>Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents
    Show others...
    2018 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 7, no 7, p. 495-503Article in journal (Refereed) Published
    Abstract [en]

    Small molecules with modalities for a variety of imaging techniques as well as therapeutic activity are essential, as such molecules render opportunities to simultaneously conduct diagnosis and targeted therapy, so called theranostics. In this regard, glycoporphyrins have proven useful as theranostic agents towards cancer, as well as noncancerous conditions. Herein, the synthesis and characterization of heterobifunctional glycoconjugated porphyrins with two different sugar moieties, a common monosaccharide at three sites, and a 2-fluoro-2-deoxy glucose (FDG) moiety at the fourth site are presented. The fluoro-glycoconjugated porphyrins exhibit properties for multimodal imaging and photodynamic therapy, as well as specificity towards cancer cells. We foresee that our findings might aid in the chemical design of heterobifunctional glycoconjugated porphyrins that could be utilized as theranostic agents.

    Place, publisher, year, edition, pages
    Wiley-VCH Verlagsgesellschaft, 2018
    Keywords
    cancer; glycoporphyrins; imaging; photodynamic therapy; photosensitizers
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:liu:diva-150279 (URN)10.1002/open.201800020 (DOI)000440286200002 ()30003003 (PubMedID)2-s2.0-85051290816 (Scopus ID)
    Note

    Funding Agencies|Swedish Foundation for Strategic Research; Swedish Research Council

    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-09-07Bibliographically approved
  • Public defence: 2018-11-16 13:00 Hasselquistsalen, Hus 511, Linköping
    Sundberg, Sofie
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Neuromodulation, Short-Term and Long-Term Plasticity in Corticothalamic and Hippocampal Neuronal Networks2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Research in neuroscience relies to a large extent on the use of genetically modified animals. Extensive validation of new and existing models is a requirement for the acquisition of trustworthy data and to enable generalization to human physiology and disease. This thesis includes, as one part (project I and II), validation of a transgenic mouse model with the expression of the enzyme Cre-recombinase restricted to neurons in a band in the deepest layer of the cerebral cortex. Secondly, in project III we use this mouse model to study the process of short-term plasticity in neuronal cultures. Lastly, we investigate synaptic plasticity by studying the effect that the developmental signaling factor Hedgehog (Hh) has on mature hippocampal cultures (project IV). 

    In project I and II, we identified the transgenic mouse Neurotensin receptor 1-Cre GN220 (Ntsr1-Cre) to have Cre expression targeted to the corticothalamic (CT) pyramidal neuron population in neocortical layer 6. Further, we identified a small group of Ntsr1-Cre positive neurons present in the white matter that is distinct from the CT population. We also identified that the transcription factor Forkhead box protein 2 (FoxP2) was specifically expressed by CT neurons in neocortex. In project I, we further explored the sensitivity of CT neurons to cholinergic modulation and found that they are sensitive to even low concentrations of acetylcholine. Both nicotinic and muscarinic acetylcholine receptors depolarize the neurons. Presenting CT neurons as a potential target for cholinergic modulation in wakefulness and arousal. 

    In project III we studied Ntsr1-Cre neurons in cortical cultures and found that cultured neurons have similar properties to CT neurons in the intact nervous system. Ntsr1-Cre neurons in culture often formed synapses with itself, i. e. autapses, with short-term synaptic plasticity that was different to ordinary synapses. By expressing the light-controlled ion channel channelrhodopsin-2 (ChR2) in Ntsr1-Cre neurons we could compare paired pulse ratios with either electrical or light stimulation. Electrical stimulation typically produced paired-pulse facilitation while light stimulation produced paired pulse depression, presumably due to unphysiological Ca2+ influx in presynaptic terminals. Thus, cultured Ntsr1- Cre neurons can be used to study facilitation, and ChR2 could be used as a practical tool to further study the dependence of Ca2+ for short-term plasticity. 

    In project IV we investigated the role of Hedgehog (Hh) for hippocampal neuron plasticity. Non-canonical Hh-signaling negatively regulated NMDA- receptor function through an unknown mechanism resulting in changes in NMDA-receptor mediated currents and subsequent changes in AMPA- receptors in an LTP/LTD manner in mature neurons. Proposing Hh as a slow-acting factor with ability to scale down excitation for instances of excessive activity, e.g. during an epileptic seizure, as a mechanism to make the activity in the neuronal networks stable. 

     

    List of papers
    1. Cre-expressing neurons in visual cortex of Ntsr1-Cre GN220 mice are corticothalamic and are depolarized by acetylcholine
    Open this publication in new window or tab >>Cre-expressing neurons in visual cortex of Ntsr1-Cre GN220 mice are corticothalamic and are depolarized by acetylcholine
    2018 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 526, no 1, p. 120-132Article in journal (Refereed) Published
    Abstract [en]

    The Ntsr1-Cre GN220 mouse expresses Cre-recombinase in corticothalamic (CT) neurons in neocortical layer 6. It is not known if the other major types of pyramidal neurons in this layer also express this enzyme. By electrophysiological recordings in slices and histological analysis of the uptake of retrogradely transported beads we show that Cre-positive neurons are CT and not corticocortical or corticoclaustral types. Furthermore, we show that Ntsr1-Cre-positive cells are immuno-positive for the nuclear transcription factor Forkhead box protein P2 (FoxP2). We conclude that Cre-expression is limited to a specific type of pyramidal neuron: CT. However, it appears as not all CT neurons are Cre-expressing; there are indications that the penetrance of the gene is about 90%. We demonstrate the utility of assigning a specific identity to individual neurons by determining that the CT neurons are potently modulated by acetylcholine acting on both nicotinic and muscarinic acetylcholine receptors. These results corroborate the suggested function of these neurons in regulating the gain of thalamocortical transfer of sensory information depending on attentional demand and state of arousal.

    Place, publisher, year, edition, pages
    WILEY, 2018
    Keywords
    acetylcholine; corticothalamic; claustrum; FoxP2; Ntsr1; visual cortex; RRID: MMRRC_030648-UCD; RRID: AB_10000240; RRID: AB_2313516; RRID: AB_2107107; RRID: SCR_002074
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-144137 (URN)10.1002/cne.24323 (DOI)000418575500008 ()28884467 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [3050, 2862]; Linkoping University

    Available from: 2018-01-10 Created: 2018-01-10 Last updated: 2018-10-12
    2. Cre-expressing neurons in the cortical white matter of Ntsr1-Cre GN220 mice
    Open this publication in new window or tab >>Cre-expressing neurons in the cortical white matter of Ntsr1-Cre GN220 mice
    2018 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 675, p. 36-40Article in journal (Refereed) Published
    Abstract [en]

    Genetically modified mouse strains that express Cre-recombinase in specific neuronal sub-populations have become widely used tools for investigating neuronal function. The Ntsr1-Cre GN220 mouse expresses this enzyme in corticothalamic neurons in layer 6 of cerebral cortex. We observed that about 7% of Cre-expressing cells in the primary visual cortex are found within the white matter bordering layer 6. By using the immunohistochemical marker for layer 6 neurons, Forkhead box protein 2 (FoxP2), and fluorescently conjugated latex beads injected into the dorsal lateral geniculate nucleus, we show that about half of these cells are similar to and could belong to the layer 6 corticothalamic neuron population. The other half seems to be a distinct white matter (WM) neuron sub-population that we estimate to constitute 2-4% of the total cortical Cre expressing population. Staining for the neuronal marker Neuronal nuclei (NeuN) revealed that about 15-40% of WM neurons are Cre-expressing. Thus, the potential contribution from WM neurons needs to be considered when interpreting the results from experiments using the Ntsr1-Cre GN220 mouse for investigating corticothalamic neuronal function.

    Place, publisher, year, edition, pages
    ELSEVIER IRELAND LTD, 2018
    Keywords
    Corticothalamic; White matter; Neurotensin receptor 1; Layer 6; Visual cortex; Forkhead box protein 2
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-148387 (URN)10.1016/j.neulet.2018.03.053 (DOI)000432759500007 ()29580883 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [3050, 2862]; Linkoping University

    Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-10-12