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  • 1.
    Arefin, Md Badrul
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Parvin, Farjana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bahrampour, Shahrzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Hosp Sick Children, Canada; Karolinska Inst, Sweden.
    Bivik Stadler, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Queensland, Australia; Univ Queensland, Australia.
    Drosophila Neuroblast Selection Is Gated by Notch, Snail, SoxB, and EMT Gene Interplay2019In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 29, no 11, p. 3636-3651.e3Article in journal (Refereed)
    Abstract [en]

    In the developing Drosophila central nervous system (CNS), neural progenitor (neuroblast [NB]) selection is gated by lateral inhibition, controlled by Notch signaling and proneural genes. However, proneural mutants still generate many NBs, indicating the existence of additional proneural genes. Moreover, recent studies reveal involvement of key epithelial-mesenchymal transition (EMT) genes in NB selection, but the regulatory interplay between Notch signaling and the EMT machinery is unclear. We find that SoxNeuro (SoxB family) and worniu (Snail family) are integrated with the Notch pathway, and constitute the missing proneural genes. Notch signaling, the proneural, SoxNeuro, and worniu genes regulate key EMT genes to orchestrate the NB selection process. Hence, we uncover an expanded lateral inhibition network for NB selection and demonstrate its link to key players in the EMT machinery. The evolutionary conservation of the genes involved suggests that the Notch-SoxB-Snail-EMT network may control neural progenitor selection in many other systems.

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  • 2.
    Azharuddin, Mohammad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology.
    Dhara, Ashis Kumar
    Natl Inst Technol Durgapur, India.
    Jain, Mayur Vilas
    Lund Univ, Sweden.
    D´arcy, Padraig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Slater, Nigel K. H.
    Univ Cambridge, England.
    Patra, Hirak Kumar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Cambridge, England.
    Dissecting multi drug resistance in head and neck cancer cells using multicellular tumor spheroids2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 20066Article in journal (Refereed)
    Abstract [en]

    One of the hallmarks of cancers is their ability to develop resistance against therapeutic agents. Therefore, developing effective in vitro strategies to identify drug resistance remains of paramount importance for successful treatment. One of the ways cancer cells achieve drug resistance is through the expression of efflux pumps that actively pump drugs out of the cells. To date, several studies have investigated the potential of using 3-dimensional (3D) multicellular tumor spheroids (MCSs) to assess drug resistance; however, a unified system that uses MCSs to differentiate between multi drug resistance (MDR) and non-MDR cells does not yet exist. In the present report we describe MCSs obtained from post-diagnosed, pre-treated patient-derived (PTPD) cell lines from head and neck squamous cancer cells (HNSCC) that often develop resistance to therapy. We employed an integrated approach combining response to clinical drugs and screening cytotoxicity, monitoring real-time drug uptake, and assessing transporter activity using flow cytometry in the presence and absence of their respective specific inhibitors. The report shows a comparative response to MDR, drug efflux capability and reactive oxygen species (ROS) activity to assess the resistance profile of PTPD MCSs and two-imensional (2D) monolayer cultures of the same set of cell lines. We show that MCSs provide a robust and reliable in vitro model to evaluate clinical relevance. Our proposed strategy can also be clinically applicable for profiling drug resistance in cancers with unknown resistance profiles, which consequently can indicate benefit from downstream therapy.

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  • 3.
    Bahrampour, Shahrzad
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Inst Rech Clin Montreal, Canada; Karolinska Inst, Sweden.
    Jönsson, Carolin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Queensland, Australia.
    Brain expansion promoted by polycomb-mediated anterior enhancement of a neural stem cell proliferation program2019In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 17, no 2, article id e3000163Article in journal (Refereed)
    Abstract [en]

    During central nervous system (CNS) development, genetic programs establish neural stem cells and drive both stem and daughter cell proliferation. However, the prominent anterior expansion of the CNS implies anterior-posterior (A-P) modulation of these programs. In Drosophila, a set of neural stem cell factors acts along the entire A-P axis to establish neural stem cells. Brain expansion results from enhanced stem and daughter cell proliferation, promoted by a Polycomb Group (PcG)-amp;gt;Homeobox (Hox) homeotic network. But how does PcG-amp;gt;Hox modulate neural-stem-cell-factor activity along the A-P axis? We find that the PcG-amp;gt;Hox network creates an A-P expression gradient of neural stem cell factors, thereby driving a gradient of proliferation. PcG mutants can be rescued by misexpression of the neural stem cell factors or by mutation of one single Hox gene. Hence, brain expansion results from anterior enhancement of core neural-stem-cell-factor expression, mediated by PcG repression of brain Hox expression.

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  • 4.
    Banch Clausen, Frederik
    et al.
    Copenhagen Univ Hosp, Denmark; Natl Univ Singapore, Singapore.
    Barrett, Angela Natalie
    Copenhagen Univ Hosp, Denmark; Natl Univ Singapore, Singapore.
    Nyström, Sofia N. (Contributor)
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Noninvasive fetal RHD genotyping to guide targeted anti-D prophylaxis-an external quality assessment workshop2019In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 114, no 4, p. 386-393Article in journal (Refereed)
    Abstract [en]

    Background and Objectives Fetal RHD genotyping of cell-free fetal DNA from RhD-negative pregnant women can be used to guide targeted antenatal and postnatal anti-D prophylaxis for the prevention of RhD immunization. To assure the quality of clinical testing, we conducted an external quality assessment workshop with the participation of 28 laboratories. Materials and Methods Aliquots of pooled maternal plasma were sent to each laboratory. One sample was positive, and the second sample was negative for fetal RHD, verified by pre-workshop testing using quantitative real-time PCR (qPCR) analysis of RHD exons 4, 5, 7 and 10. Plasma samples were shipped at room temperature. A reporting scheme was supplied for data collection, including questions regarding the methodological setup, results and clinical recommendations. Different methodological approaches were used, all employing qPCR with a total of eight different combinations of RHD exon targets. The samples were tested blindly. Results Fetal RHD genotyping was performed with no false-negative and no false-positive results. One inconclusive result was reported for the RHD-positive sample, and four inconclusive results were reported for the RHD-negative sample. All clinical conclusions were satisfactory. Conclusion This external quality assessment workshop demonstrates that despite the different approaches taken to perform the clinical assays, fetal RHD genotyping is a reliable laboratory assay to guide targeted use of Rh prophylaxis in a clinical setting.

  • 5.
    Barcenilla, Hugo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Mass Cytometry Identifies Distinct Subsets of Regulatory T Cells and Natural Killer Cells Associated With High Risk for Type 1 Diabetes2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 982Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin producing beta-cells. The time from onset of islet autoimmunity to manifest clinical disease can vary widely in length, and it is fairly uncharacterized both clinically and immunologically. In the current study, peripheral blood mononuclear cells from autoantibody-positive children with high risk for T1D, and from age-matched healthy individuals, were analyzed by mass cytometry using a panel of 32 antibodies. Surface markers were chosen to identify multiple cell types including T, B, NK, monocytes, and DC, and antibodies specific for identification of differentiation, activation and functional markers were also included in the panel. By applying dimensional reduction and computational unsupervised clustering approaches, we delineated in an unbiased fashion 132 phenotypically distinct subsets within the major immune cell populations. We were able to identify an effector memory Treg subset expressing HLA-DR, CCR4, CCR6, CXCR3, and GATA3 that was increased in the high-risk group. In addition, two subsets of NK cells defined by CD16(+) CD8(+) CXCR3(+) and CD16(+) CD8(+) CXCR3(+) CD11c(+) were also higher in the same subjects. High-risk individuals did not show impaired glucose tolerance at the time of sampling, suggesting that the changes observed were not the result of metabolic imbalance, and might be potential biomarkers predictive of T1D.

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  • 6.
    Baroni de Moraes, Marcia Terezinha
    et al.
    Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Olivares Olivares, Alberto Ignacio
    Univ Fed Roraima, Brazil; Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Fialho, Alexandre Madi
    Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Malta, Fabio Correia
    Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    da Silva e Mouta Junior, Sergio
    Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Bispo, Romanul de Souza
    Univ Fed Roraima, Brazil.
    Velloso, Alvaro Jorge
    Oswaldo Cruz Fdn FIOCRUZ, Brazil; Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Alves Leitao, Gabriel Azevedo
    Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Cantelli, Carina Pacheco
    Oswaldo Cruz Fdn FIOCRUZ, Brazil; Oswaldo Cruz Fdn FIOCRUZ, Brazil; Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Nordgren, Johan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Svensson, Lennart
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Miagostovich, Marize Pereira
    Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Gagliardi Leite, Jose Paulo
    Oswaldo Cruz Fdn FIOCRUZ, Brazil.
    Phenotyping of Lewis and secretor HBGA from saliva and detection of new FUT2 gene SNPs from young children from the Amazon presenting acute gastroenteritis and respiratory infection2019In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 70, p. 61-66Article in journal (Refereed)
    Abstract [en]

    The Histo-blood group antigens (HBGA) are host genetic factors associated with susceptibility to rotavirus (RV) and human norovirus (HuNoV), the major etiological agents of viral acute gastroenteritis (AGE) worldwide. The FUT2 gene expressing the alpha-1, 2-L- fucosyltransferase enzyme is important for gut HBGA expression, and also provides a composition of the phenotypic profile achieved through mutations occurring in populations with different evolutionary histories; as such, it can be considered a genetic population marker. In this study, Lewis and secretor HBGA phenotyping was performed using 352 saliva samples collected from children between three months and five years old born in the Amazon (Brazil, Venezuela and English Guyana) presenting AGE or acute respiratory infection (ARI), the latter considered as control samples. The total of children phenotyped as secretors was 323, corresponding to 91.80%. From these, 207 (58.80%) had a Le (a + b +) profile. The HBGA profiles were equally found in children with AGE as well as with ARI. The rs1047781 of the FUT2 gene was not detected in DNA from saliva cells with a Le (a + b +) profile. However, mutations not yet described in the FUT2 gene were observed: missense 325A amp;gt; T, 501C amp;gt; T, 585C amp;gt; T, 855A amp;gt; T and missense substitutions 327C amp;gt; T [S (Ser) amp;gt; C (Cys)], 446 T amp;gt; C [L(Leu) amp;gt; P(Pro)], 723C amp;gt; A [N(Asn) amp;gt; K(Lys)], 724A amp;gt; T [I(Ile) amp;gt; F(Phe)], 736C amp;gt; A [H(His) amp;gt; N(Asn)]. The SNP distribution in the FUT2 gene of the analyzed samples was very similar to that described in Asian populations, including indigenous tribes.

  • 7.
    Baumgartner, Johanna
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Jönsson, Jan-Ingvar
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Jager, Edwin W. H.
    Linköping University, Department of Physics, Chemistry and Biology, Sensor and Actuator Systems. Linköping University, Faculty of Science & Engineering.
    Switchable presentation of cytokines on electroactive polypyrrole surfaces for hematopoietic stem and progenitor cells2018In: Journal of Materials Chemistry B, ISSN 2050-750X, Vol. 6, no 28, p. 4665-4675Article in journal (Refereed)
    Abstract [en]

    Hematopoietic stem cells are used in transplantations for patients with hematologic malignancies. Scarce sources require efficient strategies of expansion, including polymeric biomaterials mimicking architectures of bone marrow tissue. Tissue microenvironment and mode of cytokine presentation strongly influence cell fate. Although several cytokines with different functions as soluble or membrane-bound mediators have already been identified, their precise roles have not yet been clarified. A need exists for in vitro systems that mimic the in vivo situation to enable such studies. One way is to establish surfaces mimicking physiological presentation using protein-immobilization onto polymer films. However these films merely provide a static presentation of the immobilized proteins. It would be advantageous to also dynamically change protein presentation and functionality to better reflect the in vivo conditions. The electroactive polymer polypyrrole shows excellent biocompatibility and electrochemically alters its surface properties, becoming an interesting choice for such setups. Here, we present an in vitro system for switchable presentation of membrane-bound cytokines. We use interleukin IL-3, known to affect hematopoiesis, and show that when immobilized on polypyrrole films, IL-3 is bioavailable for the bone marrow-derived FDC-P1 progenitor cell line. Moreover, IL-3 presentation can be successfully altered by changing the redox state of the film, in turn influencing FDC-P1 cell viability. This novel in vitro system provides a valuable tool for stimuli-responsive switchable protein presentation allowing the dissection of relevant mediators in stem and progenitor cell behavior.

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    Switchable presentation of cytokines on electroactive polypyrrole surfaces for hematopoietic stem and progenitor cells
  • 8.
    Bivik Stadler, Caroline
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Arefin, Md Badrul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Queensland, Australia.
    PIP degron-stabilized Dacapo/p21(Cip)(1) and mutations in ago act in an anti- versus pro-proliferative manner, yet both trigger an increase in Cyclin E levels2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 13, article id UNSP dev175927Article in journal (Refereed)
    Abstract [en]

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

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  • 9.
    Bucardo, Filemon
    et al.
    Natl Autonomous Univ Nicaragua, Nicaragua.
    Reyes, Yaoska
    Natl Autonomous Univ Nicaragua, Nicaragua.
    Rönnelid, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Gonzalez, Fredman
    Natl Autonomous Univ Nicaragua, Nicaragua.
    Sharma, Sumit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Histo-blood group antigens and rotavirus vaccine shedding in Nicaraguan infants2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 10764Article in journal (Refereed)
    Abstract [en]

    ABO, Lewis and secretor histo-blood group antigens (HBGA) are susceptibility factors for rotavirus in a P-genotype dependent manner and can influence IgA seroconversion rates following rotavirus vaccination. To investigate the association between HBGA phenotypes and rotavirus vaccine shedding fecal samples (n = 304) from a total of 141 infants vaccinated with Rotarix (n = 71) and RotaTeq (n = 70) were prospectively sampled in three time frames (= 3, 4-7 and = 8 days) after first vaccination dose. Rotavirus was detected with qPCR and genotypes determined by G/P multiplex PCR and/or sequencing. HBGAs were determined by hemagglutination and saliva based ELISA. Low shedding rates were observed, with slightly more children vaccinated with RotaTeq (19%) than Rotarix (11%) shedding rotavirus at = 4 days post vaccination (DPV). At = 4 DPV no infant of Lewis A (n = 6) or nonsecretor (n = 9) phenotype in the Rotarix cohort shed rotavirus; the same observation was made for Lewis A infants (n = 7) in the RotaTeq cohort. Putative in-vivo gene reassortment among RotaTeq strains occurred, yielding mainly G1P[8] strains. The bovine derived P[5] genotype included in RotaTeq was able to replicate and be shed at long time frames (amp;gt;13 DPV). The results of this study are consistent with that HBGA phenotype influences vaccine strain shedding as similarly observed for natural infections. Due to the low overall shedding rates observed, additional studies are however warranted.

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  • 10.
    Crisci, Elisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. North Carolina State Univ, NC USA.
    Svanberg, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Khalid, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. King Khalid Univ, Saudi Arabia.
    Hellblom, Julia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Okuyama, Kazuki
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Bhattacharya, Pradyot
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Shankar, Esaki M.
    Cent Univ Tamil Nadu, India.
    Eriksson, Kristina
    Univ Gothenburg, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    HSV-2 Cellular Programming Enables Productive HIV Infection in Dendritic Cells2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2889Article in journal (Refereed)
    Abstract [en]

    Genital herpes is a common sexually transmitted infection caused by herpes simplex virus type 2 (HSV-2). Genital herpes significantly enhances the acquisition and transmission of HIV-1 by creating a microenvironment that supports HIV infection in the host. Dendritic cells (DCs) represent one of the first innate cell types that encounter HIV-1 and HSV-2 in the genital mucosa. HSV-2 infection has been shown to modulate DCs, rendering them more receptive to HIV infection. Here, we investigated the potential mechanisms underlying HSV-2-mediated augmentation of HIV-1 infection. We demonstrated that the presence of HSV-2 enhanced productive HIV-1 infection of DCs and boosted inflammatory and antiviral responses. The HSV-2 augmented HIV-1 infection required intact HSV-2 DNA, but not active HSV-2 DNA replication. Furthermore, the augmented HIV infection of DCs involved the cGAS-STING pathway. Interestingly, we could not see any involvement of TLR2 or TLR3 nor suppression of infection by IFN-beta production. The conditioning by HSV-2 in dual exposed DCs decreased protein expression of IFI16, cGAS, STING, and TBK1, which is associated with signaling through the STING pathway. Dual exposure to HSV-2 and HIV-1 gave decreased levels of several HIV-1 restriction factors, especially SAMHD1, TREX1, and APOBEC3G. Activation of the STING pathway in DCs by exposure to both HSV-2 and HIV-1 most likely led to the proteolytic degradation of the HIV-1 restriction factors SAMHD1, TREX1, and APOBEC3G, which should release their normal restriction of HIV infection in DCs. This released their normal restriction of HIV infection in DCs. We showed that HSV-2 reprogramming of cellular signaling pathways and protein expression levels in the DCs provided a setting where HIV-1 can establish a higher productive infection in the DCs. In conclusion, HSV-2 reprogramming opens up DCs for HIV-1 infection and creates a microenvironment favoring HIV-1 transmission.

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  • 11.
    Fernlund, Eva
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala. Lund Univ, Sweden.
    Andersson, Oskar
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Klang Årstrand, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood2019In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 43, article id UNSP 102111Article in journal (Refereed)
    Abstract [en]

    Introduction: Sudden cardiac death (SCD) in the young is rare and should always lead to suspicion of a genetic cardiac disorder. We describe a family, in which the proband was a girl deceased by sudden cardiac death in the playground at thirteen years of age. The index-patient had short stature, cleft palate but no previous cardiac symptoms. We found an uncommon cause of cardiomyopathy, due to a congenital disorder of glycosylation (CDG), previously described to cause a variable range of usually mild symptoms, and not previously found to cause SCD as the first symptom of the condition. Methods: The index patient underwent postmortem genetic testing/molecular autopsy for genes known to cause SCD, without a detection of causative agent, why two siblings of similar phenotype as the deceased sister underwent clinical-exome genetic sequencing (next generation sequencing). All first-degree relatives underwent clinical examination including cardiac ultrasound, Holzer-ECG, exercise stress test and biochemistry panel. Results: A genetic variant in the gene for phosphoglucomutase 1 (PGM1) was identified in the index patient and her two brothers, all were found to be homozygous for the genetic variant (G230E) NM_002633.2:c.689 G amp;gt; A in PGM1. This variant has been linked to a congenital disorder of glycosylation (PGM1-CDG), explaining the clinical picture of short stature, cleft palate, liver engagement and cardiomyopathy. During follow-up one of the brothers died unexpectedly after physical exertion during daily life at the age of twelve years. The other brother fainted during similar circumstances at the age of thirteen years. Both parents and three other siblings were found to be heterozygous gene carriers without risk for the disease. Conclusion: Our findings suggest that there is a need of multidisciplinary discussion and genetic testing after unexpected cardiac death in the young. We have to be more flexible in our evaluation of diseases and to consider even uncommon diseases including rare recessive inherited disorders. Our findings also suggest that the autosomal recessive PGM1-CDG might be highly associated with life-threatening cardiomyopathy with arrhythmia or sudden cardiac death as the first symptom presenting from childhood and adolescence.

  • 12.
    Green, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Tillmar, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Pettersson, Gisela
    Natl Board Forens Med, Sweden.
    Montelius, Kerstin
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    The use of FTA cards to acquire DNA profiles from postmortem cases2019In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 133, no 6, p. 1651-1657Article in journal (Refereed)
    Abstract [en]

    Filter papers have been used for many years in different applications of molecular biology and have been proven to be a stable way to store DNA waiting to be analyzed. Sampling of DNA on FTA (Flinders Technology Associates) cards is convenient and cost effective compared to alternative approaches involving DNA extractions and storage of DNA extracts. FTA cards are analyzed at many forensic laboratories, and the way to perform direct genetic profiling on buccal swab cards has developed into an almost industrial process. The possibility to include postmortem (PM) samples into an FTA-based workflow would facilitate and speed up the genetic identification process compared to conventional methods, both on a regular basis and in a mass casualty event. In this study, we investigated if FTA cards may be used to carry tissue DNA from deceased and present a high-quality DNA profile from the individual in order to be useful for the identification process. The study also aimed to investigate if a specific body tissue would be preferable, and if decomposed tissue is suitable at all to put on an FTA card in order to obtain a DNA profile. We have compared the quality of the DNA profiles acquired from postmortem tissue on FTA cards, with the results acquired with conventional methods from reference bone/muscle samples from the same individual. Several types of tissues have been tested from different identification cases and scenarios. We concluded that tissue cells from inner organs are suitable to put on FTA cards, and that the obtained DNA profiles have the potential to serve as PM data for identification purposes. In cases including compromised samples, however, it is recommended to keep the tissue sample as a backup if further DNA has to be extracted.

  • 13.
    Halvarsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rörby, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lang, Stefan
    Lund Stem Cell Center, Lund University, Lund, Sweden.
    Soneji, Shamit
    Lund Stem Cell Center, Lund University, Lund, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Putative Role of Nuclear Factor-Kappa B But Not Hypoxia-Inducible Factor-1α in Hypoxia-Dependent Regulation of Oxidative Stress in Hematopoietic Stem and Progenitor Cells2019In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 31, no 3, p. 211-226Article in journal (Refereed)
    Abstract [en]

    Aims: Adaptation to low oxygen of hematopoietic stem cells (HSCs) in the bone marrow has been demonstrated to depend on the activation of hypoxia-inducible factor (HIF)-1α as well as the limited production of reactive oxygen species (ROS). In this study, we aimed at determining whether HIF-1α is involved in protecting HSCs from ROS.

    Results: Oxidative stress was induced by DL-buthionine-(S,R)-sulfoximine (BSO)-treatment, which increases the mitochondrial ROS level. Hypoxia rescued Lineage-Sca-1+c-kit+ (LSK) cells from BSO-induced apoptosis, whereas cells succumbed to apoptosis in normoxia. Apoptosis in normoxia was inhibited with the antioxidant N-acetyl-L-cysteine or by overexpression of anti-apoptotic BCL-2. Moreover, stabilized expression of oxygen-insensitive HIFs could not protect LSK cells from oxidative stress-induced apoptosis at normoxia, neither could short hairpin RNA to Hif-1α inhibit the protective effects by hypoxia in LSK cells. Likewise, BSO treatment of LSK cells from Hif-1α knockout mice did not suppress the effects seen in hypoxia. Microarray analysis identified the nuclear factor-kappa B (NF-κB) pathway as a pathway induced by hypoxia. By using NF-κB lentiviral construct and DNA-binding assay, we found increased NF-κB activity in cells cultured in hypoxia compared with normoxia. Using an inhibitor against NF-κB activation, we could confirm the involvement of NF-κB signaling as BSO-mediated cell death was significantly increased in hypoxia after adding the inhibitor.

    Innovation: HIF-1α is not involved in protecting HSCs and progenitors to elevated levels of ROS on glutathione depletion during hypoxic conditions.

    Conclusion: The study proposes a putative role of NF-κB signaling as a hypoxia-induced regulator in early hematopoietic cells.

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    Putative Role of Nuclear Factor-Kappa B But Not Hypoxia-Inducible Factor-1a in Hypoxia-Dependent Regulation of Oxidative Stress in Hematopoietic Stem and Progenitor Cells
  • 14.
    Hinkula, Jorma
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sanna
    Karolinska Inst, Sweden.
    Devito, Claudia
    HD Immun, Sweden.
    Bråve, Andreas
    Publ Hlth Agcy Sweden, Sweden.
    Applequist, Steven E.
    Karolinska Inst, Sweden.
    Long-Lasting Mucosal and Systemic Immunity against Influenza A Virus Is Significantly Prolonged and Protective by Nasal Whole Influenza Immunization with Mucosal Adjuvant N3 and DNA-Plasmid Expressing Flagellin in Aging In- and Outbred Mice2019In: VACCINES, ISSN 2076-393X, Vol. 7, no 3, article id 64Article in journal (Refereed)
    Abstract [en]

    Background: Vaccination is commonly used to prevent and control influenza infection in humans. However, improvements in the ease of delivery and strength of immunogenicity could markedly improve herd immunity. The aim of this pre-clinical study is to test the potential improvements to existing intranasal delivery of formalin-inactivated whole Influenza A vaccines (WIV) by formulation with a cationic lipid-based adjuvant (N3). Additionally, we combined WIV and N3 with a DNA-encoded TLR5 agonist secreted flagellin (pFliC(-gly)) as an adjuvant, as this adjuvant has previously been shown to improve the effectiveness of plasmid-encoded DNA antigens. 

    Methods: Outbred and inbred mouse strains were intranasally immunized with unadjuvanted WIV A/H1N1/SI 2006 or WIV that was formulated with N3 alone. Additional groups were immunized with WIV and N3 adjuvant combined with pFliC(-gly). Homo and heterotypic humoral anti-WIV immune responses were assayed from serum and lung by ELISA and hemagglutination inhibition assay. Homo and heterotypic cellular immune responses to WIV and Influenza A NP were also determined. 

    Results: WIV combined with N3 lipid adjuvant the pFliC(-gly) significantly increased homotypic influenza specific serum antibody responses (>200-fold), increased the IgG2 responses, indicating a mixed Th1/Th2-type immunity, and increased the HAI-titer (>100-fold). Enhanced cell-mediated IFNγ secreting influenza directed CD4+ and CD8+ T cell responses (>40-fold) to homotypic and heterosubtypic influenza A virus and peptides. Long-term and protective immunity was obtained. 

    Conclusions: These results indicate that inactivated influenza virus that was formulated with N3 cationic adjuvant significantly enhanced broad systemic and mucosal influenza specific immune responses. These responses were broadened and further increased by incorporating DNA plasmids encoding FliC from S. typhimurum as an adjuvant providing long lasting protection against heterologous Influenza A/H1N1/CA09pdm virus challenge. View Full-Text

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  • 15.
    Jonson, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Carlback, Marcus
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Michno, Wojciech
    Univ Gothenburg, Sweden.
    Hanrieder, Jorg
    Univ Gothenburg, Sweden; UCL, England.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Peter, K.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Amyloid fibril polymorphism and cell-specific toxicity in vivo2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, no sup1, p. 136-137Article in journal (Refereed)
    Abstract [en]

    n/a

  • 16.
    Junker, Klara
    et al.
    National Forensic Centre, Sweden.
    Staadig, Adam
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. National Board of Forensic Medicine, Sweden.
    Sidstedt, Maja
    National Forensic Centre, Sweden; Lund Univ, Sweden.
    Tillmar, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. National Board of Forensic Medicine, Sweden.
    Hedman, Johannes
    National Forensic Centre, Sweden; Lund Univ, Sweden.
    Phenotype prediction accuracy: A Swedish perspective2019In: Forensic Science International: Genetics Supplement Series, ISSN 1875-1768, E-ISSN 1875-175X, Vol. 7, no 1, p. 384-386Article in journal (Refereed)
    Abstract [en]

    Methods for SNP-based phenotype prediction have recently been developed, but prediction accuracy data for several populations and regions are missing. We analysed the accuracy of hair and eye colour predictions for 111 individuals residing in Sweden, using the ForenSeq system and the MiSeq FGx instrument (Verogen). Observed colours were compared to predicted colours, using the colour with the highest probability value for each prediction. Overall, 80% of eye colour predictions were correct, but the system failed to predict intermediate/green eye colour in our cohort. For hair colour, 58% of predictions were correct, and the majority of incorrect predictions were related to brown hair. To assess if prediction accuracy could be improved by the exclusion of predictions with low probabilities, we applied a threshold of amp;gt;= 0.7. The threshold improved eye colour prediction, from 80% to 85% correct predictions, whereas hair colour prediction accuracy was virtually unaffected (58% versus 57% correct predictions). In summary, the phenotype prediction accuracy was acceptable in our cohort and the use of a threshold was only useful for eye colour predictions.

  • 17.
    Kling, Daniel
    et al.
    Oslo Univ Hosp, Norway.
    Tillmar, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Forensic genealogy-A comparison of methods to infer distant relationships based on dense SNP data2019In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 42, p. 113-124Article in journal (Refereed)
    Abstract [en]

    The concept forensic genealogy was discussed already in 2005 but has recently emerged in relation to the use of public genealogy databases to find relatives of the donor of a crime stain. In this study we explored the results and evaluation of searches conducted in such databases. In particular, we focused on the statistical classification that entails from the search and study the variation observed for different relationship classes. The forensic guidelines advocate the use of the likelihood ratio (LR) as a mean to measure the weight of evidence, which requires exact formulation of competing hypotheses. We contrast the LR approach with alternative approaches relying on identical by state (IBS) measures to estimate the total length of shared genomic segments as well as identical by descent (IBD) coefficients for a pair of individuals. We used freely accessible data from the 1000 Genome project to perform extensive simulations, generating data for a number of distinct relationships. Specifically we studied some overarching relationship classes and the performance of the above-mentioned evaluative approaches to classify a known pair of relatives into each class. The results indicate that the traditional LR approach as a single source of classification is as good as, and in some cases even better than, the alternative approaches. In particular the true classification rate is higher for some distant relationship. However, the LR approach is both computer-intensive and sensitive to population frequencies as well as genetic maps (positions of the markers). We further showed that when combining different classification approaches, a lower false classification rate was achieved while still maintaining a high true classification rate.

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  • 18.
    Kuruvilla, Jacob
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Bayat, Narges
    Stockholm Univ, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country, Spain.
    Proteomic Analysis of Endothelial Cells Exposed to Ultrasmall Nanoparticles Reveals Disruption in Paracellular and Transcellular Transport2019In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 19, no 5, article id 1800228Article in journal (Refereed)
    Abstract [en]

    The large interactive surfaces of nanoparticles (NPs) increase the opportunities to develop NPs for vascular targeting. Proteomic analysis of endothelial cells exposed to NPs reveals the cellular response and turns the focus into the impairment of the endothelial permeability. Here, quantitative proteomics and transcriptome sequencing are combined to evaluate the effects of exposure to sub-lethal concentrations of TiO2-USNPs and TiO2-NPs on human dermal microvascular endothelial cells. Endothelial cells react to preserve the semi-permeable properties that are essential for vascular tissue fluid homeostasis, vascular development, and angiogenesis. The main impact of the exposure was alteration of functional complexes involved in cell adhesion, vesicular transport, and cytoskeletal structure. Those are the core cellular structures that are linked to the permeability and the integrity of the endothelial tissue. Moreover, the extracellular proteins uptake along wih the NPs into the endothelial cells escape the lysosomal degradation pathway. These findings improve the understanding of the interaction of NPs with endothelial cell. The effects of the studied NPs modulating cell-cell adhesion and vesicular transport can help to evaluate the distribution of NPs via intravenous administration.

  • 19.
    Liu, Na
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Xi An Jiao Tong Univ, Peoples R China.
    Cui, Weiyingqi
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Jiang, Xia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Hebei Med Univ, Peoples R China.
    Zhang, Zhiyong
    Fourth Mil Med Univ, Peoples R China.
    Gnosa, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ali, Zaheer
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Blockhuys, Stephanie
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lam, Eric W-F
    Imperial Coll London, England.
    Zhao, Zengren
    Hebei Med Univ, Peoples R China.
    Ping, Jie
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Xie, Ning
    Xi An Jiao Tong Univ, Peoples R China.
    Kopsida, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Wang, Xin
    Fourth Mil Med Univ, Peoples R China.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    The Critical Role of Dysregulated RhoB Signaling Pathway in Radioresistance of Colorectal Cancer2019In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 104, no 5, p. 1153-1164Article in journal (Refereed)
    Abstract [en]

    Purpose

    To explore whether the Rho protein is involved in the radioresistance of colorectal cancer and investigate the underlying mechanisms.

    Methods and Materials

    Rho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established using the CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was used to detect RhoB downstream signaling factors. RhoB and Forkhead box M1 (FOXM1) expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiation therapy trial.

    Results

    RhoB expression was related to radiation resistance. Complete depletion of the RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish models. Probing signaling using mass cytometry–based single-cell analysis showed that the Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells, and the inhibition of FOXM1 led to lower survival rates and attenuated migration and invasion abilities of the cells after radiation. In the patients who underwent radiation therapy, RhoB overexpression was related to high FOXM1, late Tumor, Node, Metastasis stage, high distant recurrence, and poor survival independent of other clinical factors.

    Conclusions

    RhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathways.

  • 20.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Genetic Susceptibility to Human Norovirus Infection: An Update2019In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 11, no 3, article id 226Article, review/survey (Refereed)
    Abstract [en]

    Noroviruses are the most common etiological agent of acute gastroenteritis worldwide. Despite their high infectivity, a subpopulation of individuals is resistant to infection and disease. This susceptibility is norovirus genotype-dependent and is largely mediated by the presence or absence of human histo-blood group antigens (HBGAs) on gut epithelial surfaces. The synthesis of these HBGAs is mediated by fucosyl- and glycosyltransferases under the genetic control of the FUT2 (secretor), FUT3 (Lewis) and ABO(H) genes. The so-called non-secretors, having an inactivated FUT2 enzyme, do not express blood group antigens and are resistant to several norovirus genotypes, including the predominant GII.4. Significant genotypic and phenotypic diversity of HBGA expression exists between different human populations. Here, we review previous in vivo studies on genetic susceptibility to norovirus infection. These are discussed in relation to population susceptibility, vaccines, norovirus epidemiology and the impact on public health.

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  • 21.
    Okuyama, Kazuki
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    Kuruvilla, Jacob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    Somasundaram, Rajesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Smith, Emma
    Lund Univ, Sweden.
    Prasad, Mahadesh
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Fioretos, Thoas
    Lund Univ, Sweden.
    Lilljebjorn, Henrik
    Lund Univ, Sweden.
    Soneji, Shamit
    Lund Univ, Sweden.
    Lang, Stefan
    Lund Univ, Sweden.
    Ungerback, Jonas
    Lund Univ, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    PAX5 is part of a functional transcription factor network targeted in lymphoid leukemia2019In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 8, article id e1008280Article in journal (Refereed)
    Abstract [en]

    One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5. These mutations often result in partial rather than complete loss of function of the transcription factor. While the functional dose of PAX5 has a clear connection to human malignancy, there is limited evidence for that heterozygote loss of PAX5 have a dramatic effect on the development and function of B-cell progenitors. One possible explanation comes from the finding that PAX5 mutated B-ALL often display complex karyotypes and additional mutations. Thus, PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we used BioID technology to isolate proteins associated with this transcription factor in the living cell. This identified 239 proteins out of which several could be found mutated in human B-ALL. Most prominently we identified the commonly mutated IKZF1 and RUNX1, involved in the formation of ETV6-AML1 fusion protein, among the interaction partners. ChIP- as well as PLAC-seq analysis supported the idea that these factors share a multitude of target genes in human B-ALL cells. Gene expression analysis of mouse models and primary human leukemia suggested that reduced function of PAX5 increased the ability of an oncogenic form of IKZF1 or ETV6-AML to modulate gene expression. Our data reveals that PAX5 belong to a regulatory network frequently targeted by multiple mutations in B-ALL shedding light on the molecular interplay in leukemia cells. Author summary The use of modern high throughput DNA-sequencing has dramatically increased our ability to identify genetic alterations associated with cancer. However, while the mutations per se are rather easily identified, our understanding of how these mutations impact cellular functions and drive malignant transformation is more limited. We have explored the function of the transcription factor PAX5, commonly mutated in human B-lymphocyte leukemia, to identify a regulatory network of transcription factors often targeted in human disease. Hence, we propose that malignant conversion of B-lymphocyte progenitors involves multiple targeting of a central transcription factor network aggravating the impact of the individual mutations. These data increase our understanding for how individual mutations collaborate to drive the formation of B-lineage leukemia.

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  • 22.
    Patra, Hirak Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Department of Chemical Engineering and Biotechnology, Cambridge University, Cambridge, UK; Wolfson College, University of Cambridge, Cambridge, UK.
    Azharuddin, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, USA.
    Papapavlou, Georgia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Deb, Suryyani
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Biochemistry, University of Calcutta, Calcutta, India; Department of Biotechnology, Maulana Abul Kalam Azad University of Technology (MAKAUT), West Bengal, India.
    Osterrieth, Johannes
    Department of Chemical Engineering and Biotechnology, Cambridge University, Philippa Fawcett Drive, Cambridge, UK.
    Zhu, Geyunjian Harry
    Department of Chemical Engineering and Biotechnology, Cambridge University, Philippa Fawcett Drive, Cambridge, UK.
    Romu, Thobias
    Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dhara, Ashis K.
    Centre for Image Analysis, Uppsala University, Uppsala, Sweden; Department of Electrical Engineering, National Institute of Technology Durgapur, West Bengal, India.
    Jafari, Mohammad Javad
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Gadheri, Amineh
    Department of Oncology‐Pathology, Karolinska Institute, Stockholm, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rajan, Madhavan S.
    Department of Ophthalmology, Cambridge University Hospitals NHS Trust and Vision and Eye Research Institute (VERI), Anglia Ruskin University, Cambridge, UK.
    Slater, Nigel K. H.
    Department of Chemical Engineering and Biotechnology, Cambridge University, Philippa Fawcett Drive, Cambridge, UK.
    Rational Nanotoolbox with Theranostic Potential for Medicated Pro-Regenerative Corneal Implants2019In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 29, no 38, article id 1903760Article in journal (Refereed)
    Abstract [en]

    Cornea diseases are a leading cause of blindness and the disease burden is exacerbated by the increasing shortage around the world for cadaveric donor corneas. Despite the advances in the field of regenerative medicine, successful transplantation of laboratory‐made artificial corneas is not fully realized in clinical practice. The causes of failure of such artificial corneal implants are multifactorial and include latent infections from viruses and other microbes, enzyme overexpression, implant degradation, extrusion or delayed epithelial regeneration. Therefore, there is an urgent unmet need for developing customized corneal implants to suit the host environment and counter the effects of inflammation or infection, which are able to track early signs of implant failure in situ. This work reports a nanotoolbox comprising tools for protection from infection, promotion of regeneration, and noninvasive monitoring of the in situ corneal environment. These nanosystems can be incorporated within pro‐regenerative biosynthetic implants, transforming them into theranostic devices, which are able to respond to biological changes following implantation.

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  • 23.
    Piedade, Joao
    et al.
    Univ Nova Lisboa, Portugal.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Esteves, Filipa
    Univ Nova Lisboa, Portugal.
    Esteves, Aida
    Univ Nova Lisboa, Portugal.
    Teodosio, Rosa
    Univ Nova, Portugal.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Istrate, Claudia
    Univ Nova Lisboa, Portugal.
    Molecular epidemiology and host genetics of norovirus and rotavirus infections in Portuguese elderly living in aged care homes2019In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 91, no 6, p. 1014-1021Article in journal (Refereed)
    Abstract [en]

    Norovirus (NoV) and rotavirus group A (RVA) are major agents of acute gastroenteritis worldwide. This study aimed to investigate their epidemiological profile in Portuguese elderly living in long-term care facilities and to assess the host genetic factors mediating infection susceptibility. From November 2013 to June 2015, 636 faecal specimens from 169 elderly, mainly asymptomatic, living in nursing homes in Greater Lisbon and Faro district, Portugal, were collected. NoV and RVA were detected by real-time polymerase chain reaction and NoV genotyped by phylogenetic analysis. NoV detection rate was 7.1% (12 of 169). Three GI.3 and one GII.6 strains were genotyped. RVA detection rate was 3.6% (6 of 169), exclusively in asymptomatic individuals. Host genetic factors associated with infection susceptibility were described on 250 samples by saliva-based enzyme-linked immunosorbent assays. The Lewis-negative phenotype was 8.8% (22 of 250) and the rate of nonsecretors was 16.8% (42 of 250). Association to NoV and RVA infection was performed in the subgroup of individuals (n = 147) who delivered both faecal and saliva samples. The majority of NoV- and RVA-positive individuals (90.9% and 83.3%, respectively) were secretor-positive, with Lewis B phenotype. In a subset of individuals, FUT2 and FUT3 genes were genotyped to assess mutations and validate the secretor and Lewis phenotypes. All sequenced nonsecretors were homozygous for FUT2 nonsense mutation G428A. In this study, low detection rates of NoV and RVA infections were found during two winter seasons. However, even in the absence of any outbreak, the importance of finding these infections in a nonepidemic situation in long-term care facilities may have important implications for infection control.

  • 24.
    Rodriguez Curt, Jesús
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Univ Cambridge, England.
    Yaghmaeian Salmani, Behzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Queensland, Australia.
    Anterior CNS expansion driven by brain transcription factors2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e45274Article in journal (Refereed)
    Abstract [en]

    During CNS development, there is prominent expansion of the anterior region, the brain. In Drosophila, anterior CNS expansion emerges from three rostral features: (1) increased progenitor cell generation, (2) extended progenitor cell proliferation, (3) more proliferative daughters. We find that tailless (mouse Nr2E1/Tlx), otp/Rx/hbn (Otp/Arx/Rax) and Doc1/2/3 (Tbx2/3/6) are important for brain progenitor generation. These genes, and earmuff (FezF1/2), are also important for subsequent progenitor and/or daughter cell proliferation in the brain. Brain TF comisexpression can drive brain-profile proliferation in the nerve cord, and can reprogram developing wing discs into brain neural progenitors. Brain TF expression is promoted by the PRC2 complex, acting to keep the brain free of anti-proliferative and repressive action of Hox homeotic genes. Hence, anterior expansion of the Drosophila CNS is mediated by brain TF driven super-generation of progenitors, as well as hyper-proliferation of progenitor and daughter cells, promoted by PRC2-mediated repression of Hox activity.

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  • 25.
    Roepke, E. Rasmark
    et al.
    Malmo and Lund Univ, Sweden.
    Bruno, Valentina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Tor Vergata Univ Hosp, Italy; Tor Vergata Univ Hosp, Italy.
    Nedstrand, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Boij, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, C. Petersson
    Kalmar Hosp, Sweden.
    Piccione, E.
    Tor Vergata Univ Hosp, Italy.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Svensson Arvelund, Judit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Low-molecular-weight-heparin increases Th1-and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 12314Article in journal (Refereed)
    Abstract [en]

    Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects. Although in vitro studies have suggested additional immunological effects, these are debated. We therefore investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomised controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analysed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. Mixed linear models test on LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p amp;lt; 0.001) and the Th17-associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Subsequent Students t-test showed significantly higher plasma levels of CXCL10 and CXCL11 in treated than untreated women at gw 28 and 34. The consistent increase in the two Th1-associated chemokines suggests a potential proinflammatory and unfavourable effect of LMWH treatment during later stages of pregnancy, when Th1 immunity is known to disrupt immunological tolerance.

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  • 26.
    Sharma, Sumit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Hagbom, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Carlsson, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nederby Ohd, Johanna
    Stockholm Cty Council, Sweden; Karolinska Inst, Sweden.
    Insulander, Mona
    Stockholm Cty Council, Sweden.
    Eriksson, Ronnie
    Natl Food Agcy, Sweden.
    Simonsson, Magnus
    Natl Food Agcy, Sweden.
    Widerstrom, Micael
    Stockholm Cty Council, Sweden; Umea Univ, Sweden.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Secretor Status is Associated with Susceptibility to Disease in a Large GII.6 Norovirus Foodborne Outbreak2020In: Food and Environmnetal Virology, ISSN 1867-0334, E-ISSN 1867-0342, Vol. 12, p. 28-34Article in journal (Refereed)
    Abstract [en]

    Norovirus is commonly associated with food and waterborne outbreaks. Genetic susceptibility to norovirus is largely dependent on presence of histo-blood group antigens (HBGA), specifically ABO, secretor, and Lewis phenotypes. The aim of the study was to determine the association between HBGAs to norovirus susceptibility during a large norovirus foodborne outbreak linked to genotype GII.6 in an office-based company in Stockholm, Sweden, 2015. A two-episode outbreak with symptoms of diarrhea and vomiting occurred in 2015. An online questionnaire was sent to all 1109 employees that had worked during the first outbreak episode. Food and water samples were collected from in-house restaurant and tested for bacterial and viral pathogens. In addition, fecal samples were collected from 8 employees that had diarrhea. To investigate genetic susceptibility during the outbreak, 98 saliva samples were analyzed for ABO, secretor, and Lewis phenotypes using ELISA. A total of 542 of 1109 (49%) employees reported gastrointestinal symptoms. All 8 fecal samples tested positive for GII norovirus, which was also detected in coleslaw collected from the in-house restaurant. Eating at the in-house restaurant was significantly associated with risk of symptom development. Nucleotide sequencing was successful for 5/8 fecal samples and all belonged to the GII.6 genotype. HBGA characterization showed a strong secretor association to norovirus-related symptoms (P = 0.014). No association between norovirus disease and ABO phenotypes was observed. The result of this study shows that non-secretors were significantly less likely to report symptoms in a large foodborne outbreak linked to the emerging GII.6 norovirus strain.

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  • 27.
    Sharma, Sumit
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Hagbom, Marie
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Nordgren, Johan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Frodlund, Jonas
    Vastervik Hosp, Sweden.
    Hinkula, Jorma
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Ledin, Torbjörn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Speech language pathology, Audiology and Otorhinolaryngology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology.
    Svensson, Lennart
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Karolinska Inst, Sweden.
    Detection of rotavirus- and norovirus-specific IgG memory B cells in tonsils2019In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 91, no 2, p. 326-329Article in journal (Refereed)
    Abstract [en]

    Because rotavirus (RV) and norovirus (NoV) are transmitted through the fecal-oral route, tonsils due to their location within the oropharynx may sample or become infected with these viruses. We investigated if RV and NoV RNA/antigen, or virus-specific memory/plasma B cells can be detected in the tonsils. While neither RV/NoV antigen, nor genomic RNA was detected, 90% (27/30) of tonsils tested had RV- and NoV-specific IgG memory B cells. However, the mechanism explaining how these cells get there (whether because of local induction or homing after induction at other sites) and the role these cells might play during active infection is not yet clear.

  • 28.
    Singh, Susmita K.
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation.
    Larsson, Marie
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Schön, Thomas
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Kalmar Cty Hosp, Sweden.
    Stendahl, Olle
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation.
    Blomgran, Robert
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation.
    HIV Interferes with the Dendritic Cell-T Cell Axis of Macrophage Activation by Shifting Mycobacterium tuberculosis-Specific CD4 T Cells into a Dysfunctional Phenotype2019In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 202, no 3, p. 816-826Article in journal (Refereed)
    Abstract [en]

    HIV coinfection is the greatest risk factor for transition of latent Mycobacterium tuberculosis infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of M. tuberculosis-specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. M. tuberculosis-specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)-T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV-M. tuberculosis-infected (coinfected) human DCs can dysregulate the M. tuberculosis-specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control M. tuberculosis infection in macrophages. After coculture with coinfected DCs, M. tuberculosis Ag-specific CD4 T cells lost their ability to enhance control of M. tuberculosis infection in infected macrophages. Coinfection of DCs reduced proliferation of M. tuberculosis Ag-specific CD4 T cells without affecting their viability, led to increased expression of coinhibitory factors CTLA-4, PD-1, and Blimp-1, and decreased expression of costimulatory molecules CD40L, CD28, and ICOS on the T cells. Expression of the regulatory T cell markers FOXP3 and CD25, together with the immunosuppressive cytokines TGF-beta and IL-10, was also significantly increased by coinfection compared with M. tuberculosis single infection. Our data suggest a pattern in which HIV, through its effect on DCs, impairs the ability of M. tuberculosis-specific CD4 T cells to maintain a latent TB within human macrophages, which could play an early role in the subsequent development of TB.

  • 29.
    Staadig, A.
    et al.
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Artillerigatan 12, SE-58758 Linkoping, Sweden.
    Tillmar, Andreas
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Artillerigatan 12, SE-58758 Linkoping, Sweden.
    An overall limited effect on the weight-of-evidence when taking STR DNA sequence polymorphism into account in kinship analysis2019In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 39, p. 44-49Article in journal (Refereed)
    Abstract [en]

    The recent years development of massively parallel sequencing (MPS) instruments and assays have now made it a compatible complement to the established capillary electrophoresis (CE) analysis for different forensic genetic applications. It is well known that short tandem repeat (STR) alleles of the same fragment size could have different DNA sequences. Thus, there will be an expected increase in the population genetic diversity for the present set of forensic STRs when performing the analysis with MPS technologies and taking the internal DNA sequence into account. In order to study the additional value of this increase of information for kinship analysis casework, we set up an allele frequency database for the Swedish population for the autosomal markers included in the ForenSeq (TM) DNA Signature Prep Kit (Illumina). A total of 298 individuals with Swedish origin were analyzed and allele frequency distributions based on DNA sequence polymorphisms for 27 autosomal STRs were established. As expected, the results showed an addition in number of observed alleles with 55% in total compared with fragment length based allele definitions, however, a majority only appeared in a few number of observations. In addition, simulations were performed in order to study the impact of the increase in number of observed alleles for the expected likelihood ratios (LRs) for different kinship case scenarios. Only a minor increase of the LRs were, however, observed when taking allele sequence variations in addition with fragment length variations into account compared to only considering fragment length variations. Further studies are required to see if it is cost effective to implement this technique that, according to this study, only has a limited overall additive effect for kinship testing. Although, in specific cases MPS methods will increase the discrimination power due to that, even if in a low frequency, a high genetic diversity exist and the differentiation could be more significant. The establishment of the allele frequency database will enable biostatistical calculations to be performed in casework.

  • 30.
    Stratmann, Johannes
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
    Ekman, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. School of Biomedical Sciences, University of Queensland, Australia.
    A branching gene regulatory network dictating different aspects of a neuronal cell identity2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 6, article id UNSP 174300Article in journal (Refereed)
    Abstract [en]

    The nervous system displays a daunting cellular diversity. Neuronal subtypes differ from each other in several aspects, including their neurotransmitter expression and axon projection. These aspects can converge, but can also diverge, such that neurons expressing the same neurotransmitter may project axons to different targets. It is not well understood how regulatory programs converge/ diverge to associate/dissociate different cell fate features. Studies of the Drosophila Tv1 neurons have identified a regulatory cascade, ladybird early -amp;gt; collier -amp;gt; apterous/eyes absent -amp;gt; dimmed, that specifies Tv1 neurotransmitter expression. Here, we conduct genetic and transcriptome analysis to address how other aspects of Tv1 cell fate are governed. We find that an initiator terminal selector gene triggers a feedforward loop that branches into different subroutines, each of which establishes different features of this one unique neuronal cell fate.

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  • 31.
    Vanhee, Stijn
    et al.
    Lund Univ, Sweden.
    Akerstrand, Hugo
    Lund Univ, Sweden.
    Kristiansen, Trine Ahn
    Lund Univ, Sweden.
    Datta, Sebak
    Lund Univ, Sweden.
    Montano, Giorgia
    Lund Univ, Sweden.
    Vergani, Stefano
    Lund Univ, Sweden.
    Lang, Stefan
    Lund Univ, Sweden.
    Ungerback, Jonas
    Lund Univ, Sweden.
    Doyle, Alexander
    Lund Univ, Sweden.
    Olsson, Karin
    Lund Univ, Sweden.
    Beneventi, Giulia
    Lund Univ, Sweden.
    Jensen, Christina T.
    Lund Univ, Sweden.
    Bellodi, Cristian
    Lund Univ, Sweden.
    Soneji, Shamit
    Lund Univ, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Gyllenback, Elin Jaensson
    Lund Univ, Sweden; Lund Univ, Sweden.
    Yuan, Joan
    Lund Univ, Sweden.
    Lin28b controls a neonatal to adult switch in B cell positive selection2019In: SCIENCE IMMUNOLOGY, ISSN 2470-9468, Vol. 4, no 39, article id eaax4453Article in journal (Refereed)
    Abstract [en]

    The ability of B-1 cells to become positively selected into the mature B cell pool, despite being weakly self-reactive, has puzzled the field since its initial discovery. Here, we explore changes in B cell positive selection as a function of developmental time by exploiting a link between CD5 surface levels and the natural occurrence of self-reactive B cell receptors (BCRs) in BCR wild-type mice. We show that the heterochronic RNA binding protein Lin28b potentiates a neonatal mode of B cell selection characterized by enhanced overall positive selection in general and the developmental progression of CD5(+) immature B cells in particular. Lin28b achieves this by amplifying the CD19/PI3K/c-Myc positive feedback loop, and ectopic Lin28b expression restores both positive selection and mature B cell numbers in CD19(-/-) adult mice. Thus, the temporally restricted expression of Lin28b relaxes the rules for B cell selection during ontogeny by modulating tonic signaling. We propose that this neonatal mode of B cell selection represents a cell-intrinsic cue to accelerate the de novo establishment of the adaptive immune system and incorporate a layer of natural antibody-mediated immunity throughout life.

  • 32.
    Yong, Yean K.
    et al.
    Xiamen Univ Malaysia, Malaysia.
    Tan, Hong Y.
    Xiamen Univ Malaysia, Malaysia; Xiamen Univ Malaysia, Malaysia.
    Saeidi, Alireza
    Emory Vaccine Ctr, GA USA.
    Wong, Won F.
    Univ Malaya, Malaysia.
    Vignesh, Ramachandran
    Xiamen Univ Malaysia, Malaysia.
    Velu, Vijayakumar
    Emory Vaccine Ctr, GA USA.
    Eri, Rajaraman
    Univ Tasmania, Australia.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    CUTN, India.
    Immune Biomarkers for Diagnosis and Treatment Monitoring of Tuberculosis: Current Developments and Future Prospects2019In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 2789Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis (TB) treatment monitoring is paramount to clinical decision-making and the host biomarkers appears to play a significant role. The currently available diagnostic technology for TB detection is inadequate. Although GeneXpert detects total DNA present in the sample regardless live or dead bacilli present in clinical samples, all the commercial tests available thus far have low sensitivity. Humoral responses against Mycobacterium tuberculosis (Mtb) antigens are generally low, which precludes the use of serological tests for TB diagnosis, prognosis, and treatment monitoring. Mtb-specific CD4(+) T cells correlate with Mtb antigen/bacilli burden and hence might serve as good biomarkers for monitoring treatment progress. Omics-based techniques are capable of providing a more holistic picture for disease mechanisms and are more accurate in predicting TB disease outcomes. The current review aims to discuss some of the recent advances on TB biomarkers, particularly host biomarkers that have the potential to diagnose and differentiate active TB and LTBI as well as their use in disease prognosis and treatment monitoring.

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