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  • 1.
    Banch Clausen, Frederik
    et al.
    Copenhagen Univ Hosp, Denmark; Natl Univ Singapore, Singapore.
    Barrett, Angela Natalie
    Copenhagen Univ Hosp, Denmark; Natl Univ Singapore, Singapore.
    Akkok, Cigdem Akalin
    Oslo Univ Hosp, Norway.
    Armstrong-Fisher, Sylvia
    Scottish Natl Blood Transfus Serv, Scotland.
    Danielsson Bergstrom, Karolina
    Orebro Univ Hosp, Sweden.
    Trucco Boggione, Carolina
    Univ Nacl Rosario, Argentina.
    Sillhagen Baevre, Mette
    Oslo Univ Hosp, Norway.
    Choolani, Mahesh
    Natl Univ Singapore City, Singapore.
    Christiansen, Mette
    Aarhus Univ, Denmark.
    Cotorruelo, Carlos
    Univ Nacl Rosario, Argentina.
    Drnovsek, Tadeja Dovc
    Blood Transfus Ctr Slovenia, Slovenia.
    Finning, Kirstin
    NHS Blood and Transplant, England.
    Guz, Katarzyna
    Inst Hematol and Transfus Med, Poland.
    de Haas, Masja
    Sanquin Blood Supply Fdn, Netherlands.
    Haimila, Katri
    Finnish Red Cross Blood Serv, Finland.
    Halldorsdottir, Anna Margret
    Landspitali Univ Hosp, Iceland.
    Hellberg, Asa
    Lund Univ, Sweden.
    Henny, Christine
    Interreg Blood Transfus SRC, Switzerland.
    Holmertz, Camilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Al Houghton, Jayne
    Royal Devon and Exeter NHS Fdn Trust, England.
    Hyland, Catherine
    Australian Red Cross Blood Serv, Australia.
    Jakobsen, Marianne Antonius
    Odense Univ Hosp, Denmark.
    Kvitland, Mona Andersen
    St Olavs Hosp, Norway.
    Lambert, Mark
    Natl Blood Ctr, Ireland.
    Legler, Tobias J.
    Georg August Univ, Germany.
    Liew, Yew-Wah
    Australian Red Cross Blood Serv, Australia.
    Muniz-Diaz, Eduardo
    Banc Sang and Teixits, Spain.
    Mortberg, Anette
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Niederhauser, Christoph
    Interreg Blood Transfus SRC, Switzerland.
    Nogues, Nuria
    Banc Sang and Teixits, Spain.
    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.
    Olsson, Martin L.
    Lund Univ, Sweden; Lund Univ, Sweden.
    Orzinska, Agnieszka
    Inst Hematol and Transfus Med, Poland.
    Parks, Michael
    Nonacus Ltd, England.
    Rietkotter, Eva
    LADR GmbH MVZ Dr Kramer and Kollegen, Germany.
    Ryan, Helen
    Natl Blood Ctr, Ireland.
    Sachs, Ulrich J.
    Justus Liebig Univ, Germany.
    van der Schoot, Ellen
    Sanquin Res CLB, Netherlands.
    Silcock, Lee
    Nonacus Ltd, England.
    Steffensen, Rudi
    Aalborg Univ Hosp, Denmark.
    Sulin, Kati
    Finnish Red Cross Blood Serv, Finland.
    Sorensen, Anne Solling
    Naestved Hosp, Denmark.
    Tarrant, Sarah
    NHS Blood and Transplant, England.
    Thorlacius, Steinunn
    Landspitali Univ Hosp, Iceland.
    Wienzek-Lischka, Sandra
    Justus Liebig Univ, Germany.
    Wikman, Agneta
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Wulf-Johansson, Helle
    Naestved Hosp, Denmark.
    Zupan, Mojca
    Blood Transfus Ctr Slovenia, Slovenia.
    Dziegiel, Morten Hanefeld
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    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.

  • 2.
    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.
    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.

  • 3.
    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, 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.

  • 4.
    Berlin, Gösta
    et al.
    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.
    Hammar, Mats
    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.
    Tapper, Linus
    Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Tynngård, Nahreen
    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.
    Effects of age, gender and menstrual cycle on platelet function assessed by impedance aggregometry2019In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 30, no 4, p. 473-479Article in journal (Refereed)
    Abstract [en]

    Platelets are needed to prevent or arrest bleeding and aggregate at the site of injury upon vascular damage. Platelets express receptors for estrogens which might affect the function of the platelets and their hemostatic ability. The aim was to identify possible differences in platelet function related to age, gender, and phases of the menstrual cycle by use of impedance aggregometry with Multiplate. In the first part of the study, platelet function was assessed in 60 healthy individuals (30 men and 30 women) in each of three age groups (20-25, 40-45, and 60-65 years). In the second part of the study, the platelet function was analyzed on four occasions during the menstrual cycle in women without oral contraceptives (OCs) (n = 17) and compared to 19 women on OCs and 18 men of similar age (20-40 years). For the women on OCs, aggregation was analyzed once during the tablet-free week and once late during the period with OCs. The men were sampled once. Women of younger age (amp;lt;45 years) had significantly higher agonist-induced aggregation response than both men and post-menopausal women (60-65 years). The agonist-induced aggregation response did not differ between phases of the menstrual cycle or OC use. The results suggest that estradiol and/or progesterone affect spontaneous aggregation since it was found to be lowest in the mid-luteal phase. Spontaneous aggregation was significantly lower in women on OCs than in both men and women without OCs. Our findings indicate that fertile age is associated with higher aggregation response capacity of the platelets, possibly to prevent excessive bleeding during menstruation, but this response capacity is not altered during the menstrual cycle or by use of OCs.

  • 5.
    Bivik Stadler, Caroline
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Arefin, Md Badrul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Queensland, Australia.
    PIP degron-stabilized Dacapo/p21(Cip)(1) and mutations in ago act in an anti- versus pro-proliferative manner, yet both trigger an increase in Cyclin E levels2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 13, article id UNSP dev175927Article in journal (Refereed)
    Abstract [en]

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

  • 6.
    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.

  • 7.
    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 Surgery, Orthopedics and Oncology. 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.

  • 8.
    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

  • 9.
    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.

  • 10.
    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.

  • 11.
    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.

  • 12.
    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, 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.

    The full text will be freely available from 2020-07-15 00:01
  • 13.
    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.

  • 14.
    Rodriguez Curt, Jesús
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. 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.

  • 15.
    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.

  • 16.
    Stratmann, Johannes
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. 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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