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  • 251.
    Fard, Shahrzad Shirazi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Jarrin, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Boije, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Fillon, Valerie
    All-Eriksson, Charlotta
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Heterogenic Final Cell Cycle by Chicken Retinal Lim1 Horizontal Progenitor Cells Leads to Heteroploid Cells with a Remaining Replicated Genome2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e59133-Article in journal (Refereed)
    Abstract [en]

    Retinal progenitor cells undergo apical mitoses during the process of interkinetic nuclear migration and newly generated post-mitotic neurons migrate to their prospective retinal layer. Whereas this is valid for most types of retinal neurons, chicken horizontal cells are generated by delayed non-apical mitoses from dedicated progenitors. The regulation of such final cell cycle is not well understood and we have studied how Lim1 expressing horizontal progenitor cells (HPCs) exit the cell cycle. We have used markers for S-and G2/M-phase in combination with markers for cell cycle regulators Rb1, cyclin B1, cdc25C and p27Kip1 to characterise the final cell cycle of HPCs. The results show that Lim1+ HPCs are heterogenic with regards to when and during what phase they leave the final cell cycle. Not all horizontal cells were generated by a non-apical (basal) mitosis; instead, the HPCs exhibited three different behaviours during the final cell cycle. Thirty-five percent of the Lim1+ horizontal cells was estimated to be generated by non-apical mitoses. The other horizontal cells were either generated by an interkinetic nuclear migration with an apical mitosis or by a cell cycle with an S-phase that was not followed by any mitosis. Such cells remain with replicated DNA and may be regarded as somatic heteroploids. The observed heterogeneity of the final cell cycle was also seen in the expression of Rb1, cyclin B1, cdc25C and p27Kip1. Phosphorylated Rb1-Ser608 was restricted to the Lim1+ cells that entered S-phase while cyclin B1 and cdc25C were exclusively expressed in HPCs having a basal mitosis. Only HPCs that leave the cell cycle after an apical mitosis expressed p27Kip1. We speculate that the cell cycle heterogeneity with formation of heteroploid cells may present a cellular context that contributes to the suggested propensity of these cells to generate cancer when the retinoblastoma gene is mutated.

  • 252.
    Farooqi, A.
    et al.
    Umea Univ, Inst Clin Sci, Pediat, Umea, Sweden..
    Adamsson, M.
    Umea Univ, Inst Clin Sci, Pediat, Umea, Sweden..
    Serenius, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hägglöf, B.
    Umea Univ, Inst Clin Sci Child & Adolescent Psychiat, Umea, Sweden..
    Executive Functioning and Learning Skills of Adolescent Children Born at Fewer than 26 Weeks of Gestation2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0151819Article in journal (Refereed)
    Abstract [en]

    Aims To assess the cognitive and behavioral aspects of executive functioning (EF) and learning skills in extremely preterm (EPT) children compared with term control children aged 10 to 15 years. Methods A total of 132 of 134 (98% of all eligible survivors) EPT children born at the 2 Swedish regional tertiary care centers from 1992 to 1998 (mean age = 12 years, mean birth weight = 718 g, and mean gestational age = 24.4 weeks) and 103 matched term controls were assessed. General intelligence was assessed using the Wechsler Intelligence Scale for Children (WISC-III-R), and cognitive aspects of EF were analyzed using EF-sensitive sub-scales of the WISC-III-R and Tower test of the Delis-Kaplan Executive Function Scale (D-KEFS). Behaviors related to EF and learning skills were assessed using the Five to Fifteen questionnaire, which is a validated parent and teacher instrument. Academic performance in school was assessed by teachers' responses on Achenbach's Teachers Report Form. Analyses performed included multivariate analyses of covariance (ANCOVA and MANCOVA) and logistic regression analyses. Results The EPT children displayed significant deficits in cognitive aspects of EF compared with the controls, exhibiting decreases on the order of 0.9 SD to 1.2 SD for tasks of verbal conceptual reasoning, verbal and non-verbal working memory, processing speed and planning ability (P < 0.001 for all). After excluding the children with major neurosensory impairment (NSI) or a Full Scale intelligence quotient (FSIQ) of < 70, significant differences were observed on all tests. Compared with controls, parents and teachers of EPT children reported significantly more EF-related behavioral problems. MANCOVA of teacher-reported learning skills in children with FSIQ > 70 and without major NSI revealed no interactions, but significant main effects were observed for the behavioral composite executive function score, group status (EPT vs control) and FSIQ, for which all effect sizes were medium to large. The corresponding findings of MANCOVA of the parent-reported learning skills were very similar. According to the teachers' ratings, the EPT children were less well adjusted to the school environment. Conclusion EPT children born in the 1990s who received active perinatal care are at an increased risk of executive dysfunction, even after excluding children with significant neurodevelopmental disabilities. Even mild to moderate executive dysfunctions has a significant impact on learning skills. These findings suggest the need for timely interventions that address specific cognitive vulnerabilities and executive dysfunctions.

  • 253. Farshbaf, Mozhgan
    et al.
    Lindberg, Mikael J
    Truong, Anh
    Bevens, Zachery
    Chambers, Elaina
    Pournara, Angeliki
    Wallberg, Annika E
    White, J Brandon
    Mastermind-Like 1 Is Ubiquitinated: Functional Consequences for Notch Signaling.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7Article in journal (Refereed)
    Abstract [en]

    Early studies demonstrated the involvement of ubiquitination of the Notch intracellular domain for rapid turnover of the transcriptional complex at Notch target genes. It was shown that this ubiquitination was promoted by the co-activator Mastermind like 1 (MAML1). MAML1 also contains numerous lysine residues that may also be ubiquitinated and necessary for protein regulation. In this study, we show that over-expressed MAML1 is ubiquitinated and identify eight conserved lysine residues which are required for ubiquitination. We also show that p300 stimulates ubiquitination and that Notch inhibits ubiquitination. Furthermore, we show that a mutant MAML1 that has decreased ubiquitination shows increased output from a HES1 reporter gene assay. Therefore, we speculate that ubiquitination of MAML1 might be a mechanism to maintain low levels of the protein until needed for transcriptional activation. In summary, this study identifies that MAML1 is ubiquitinated in the absence of Notch signaling to maintain low levels of MAML1 in the cell. Our data supports the notion that a precise and tight regulation of the Notch pathway is required for this signaling pathway.

  • 254.
    Faulks, Leanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Univ Tsukuba, Sugadaira Montane Res Ctr, Sugadaira Kogen 1278-294, Ueda, Nagano 3862204, Japan..
    Östman, Örjan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Inst Coastal Res, Dept Aquat Resources, Skolvagen 6, S-74242 Oregrund, Sweden..
    Genetic Diversity and Hybridisation between Native and Introduced Salmonidae Fishes in a Swedish Alpine Lake2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0152732Article in journal (Refereed)
    Abstract [en]

    Understanding the processes underlying diversification can aid in formulating appropriate conservation management plans that help maintain the evolutionary potential of taxa, particularly under human-induced activities and climate change. Here we assessed the microsatellite genetic diversity and structure of three salmonid species, two native (Arctic charr, Salvelinus alpinus and brown trout, Salmo trutta) and one introduced (brook charr, Salvelinus fontinalis), from an alpine lake in sub-arctic Sweden, Lake Ann. The genetic diversity of the three species was similar and sufficiently high from a conservation genetics perspective: corrected total heterozygosity, H'(T) = 0.54, 0.66, 0.60 and allelic richness, A(R) = 4.93, 5.53 and 5.26 for Arctic charr, brown trout and brook charr, respectively. There were indications of elevated inbreeding coefficients in brown trout (G(IS) = 0.144) and brook charr (G(IS) = 0.129) although sibling relationships were likely a confounding factor, as a high proportion of siblings were observed in all species within and among sampling locations. Overall genetic structure differed between species, Fst = 0.01, 0.02 and 0.04 in Arctic charr, brown trout and brook charr respectively, and there was differentiation at only a few specific locations. There was clear evidence of hybridisation between the native Arctic charr and the introduced brook charr, with 6% of individuals being hybrids, all of which were sampled in tributary streams. The ecological and evolutionary consequences of the observed hybridisation are priorities for further research and the conservation of the evolutionary potential of native salmonid species.

  • 255. Fayad, Walid
    et al.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Brnjic, Slavica
    Olofsson, Maria Hägg
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Linder, Stig
    Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 10, p. e7238-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology.

    METHOD AND FINDINGS:

    A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo.

    CONCLUSIONS:

    The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

  • 256.
    Fegraeus, Kim Jäderkvist
    et al.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Lawrence, Chameli
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Petäjistö, Katrine
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Johansson, Maria K.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Wiklund, Maja
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Olsson, Christina
    Swedish Trotting Assoc, Bromma, Sweden..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA..
    Andersson, Lisa S.
    Capilet Genet AB, Vasteras, Sweden..
    Roed, Knut H.
    Norwegian Univ Life Sci, Dept Basic Sci & Aquat Med, Fac Vet Med, Oslo, Norway..
    Ihler, Carl-Fredrik
    Norwegian Univ Life Sci, Dept Compan Anim Clin Sci, Fac Vet Med, Oslo, Norway..
    Strand, Eric
    Norwegian Univ Life Sci, Dept Compan Anim Clin Sci, Fac Vet Med, Oslo, Norway..
    Lindgren, Gabriella
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Velie, Brandon D.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Lack of significant associations with early career performance suggest no link between the DMRT3 "Gait Keeper" mutation and precocity in Coldblooded trotters2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177351Article in journal (Refereed)
    Abstract [en]

    The Swedish-Norwegian Coldblooded trotter (CBT) is a local breed in Sweden and Norway mainly used for harness racing. Previous studies have shown that a mutation from cytosine (C) to adenine (A) in the doublesex and mab-3 related transcription factor 3 (DMRT3) gene has a major impact on harness racing performance of different breeds. An association of the DMRT3 mutation with early career performance has also been suggested. The aim of the current study was to investigate this proposed association in a randomly selected group of CBTs. 769 CBTs (485 raced, 284 unraced) were genotyped for the DMRT3 mutation. The association with racing performance was investigated for 13 performance traits and three different age intervals: 3 years, 3 to 6 years, and 7 to 10 years of age, using the statistical software R. Each performance trait was analyzed for association with DMRT3 using linear models. The results suggest no association of the DMRT3 mutation with precocity (i.e. performance at 3 years of age). Only two traits (race time and number of disqualifications) were significantly different between the genotypes, with AA horses having the fastest times and CC horses having the highest number of disqualifications at 3 years of age. The frequency of the AA genotype was significantly lower in the raced CBT sample compared with the unraced sample and less than 50% of the AA horses participated in a race. For the age intervals 3 to 6 and 7 to 10 years the AA horses also failed to demonstrate significantly better performance than the other genotypes. Although suggested as the most favorable genotype for racing performance in Standardbreds and Finnhorses across all ages, the AA genotype does not appear to be associated with superior performance, early or late, in the racing career of CBTs.

  • 257.
    Fehling, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Davidson, Keith
    Bolch, Christopher J. S.
    Brand, Tim D.
    Narayanaswamy, Bhavani E.
    The Relationship between Phytoplankton Distribution and Water Column Characteristics in North West European Shelf Sea Waters2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34098-Article in journal (Refereed)
    Abstract [en]

    Phytoplankton underpin the marine food web in shelf seas, with some species having properties that are harmful to human health and coastal aquaculture. Pressures such as climate change and anthropogenic nutrient input are hypothesized to influence phytoplankton community composition and distribution. Yet the primary environmental drivers in shelf seas are poorly understood. To begin to address this in North Western European waters, the phytoplankton community composition was assessed in light of measured physical and chemical drivers during the "Ellett Line" cruise of autumn 2001 across the Scottish Continental shelf and into adjacent open Atlantic waters. Spatial variability existed in both phytoplankton and environmental conditions, with clear differences not only between on and off shelf stations but also between different on shelf locations. Temperature/salinity plots demonstrated different water masses existed in the region. In turn, principal component analysis (PCA), of the measured environmental conditions (temperature, salinity, water density and inorganic nutrient concentrations) clearly discriminated between shelf and oceanic stations on the basis of DIN:DSi ratio that was correlated with both salinity and temperature. Discrimination between shelf stations was also related to this ratio, but also the concentration of DIN and DSi. The phytoplankton community was diatom dominated, with multidimensional scaling (MDS) demonstrating spatial variability in its composition. Redundancy analysis (RDA) was used to investigate the link between environment and the phytoplankton community. This demonstrated a significant relationship between community composition and water mass as indexed by salinity (whole community), and both salinity and DIN: DSi (diatoms alone). Diatoms of the Pseudo-nitzschia seriata group occurred at densities potentially harmful to shellfish aquaculture, with the potential for toxicity being elevated by the likelihood of DSi limitation of growth at most stations and depths.

  • 258. Feitosa, Eloi
    et al.
    Adati, Renata D.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Thermal and Structural Behavior of Dioctadecyldimethylammonium Bromide Dispersions Studied by Differential Scanning Calorimetry and X-Ray Scattering2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e44702-Article in journal (Refereed)
    Abstract [en]

    Dioctadecyldimethylammonium bromide (DODAB) is a double chain cationic lipid, which assembles as bilayer structures in aqueous solution. The precise structures formed depend on, e.g., lipid concentration and temperature. We here combine differential scanning calorimetry (DSC) and X-ray scattering (SAXS and WAXS) to investigate the thermal and structural behavior of up to 120 mM DODAB in water within the temperature range 1-70 degrees C. Below 1 mM, this system is dominated by unilamellar vesicles (ULVs). Between 1 and 65 mM, ULVs and multilamellar structures (MLSs) co-exist, while above 65 mM, the MLSs are the preferred structure. Depending on temperature, DSC and X-ray data show that the vesicles can be either in the subgel (SG), gel, or liquid crystalline (LC) state, while the MLSs (with lattice distance d = 36.7 angstrom) consist of interdigitated lamellae in the SG state, and ULVs in the LC state (no Bragg peak). Critical temperatures related to the thermal transitions of these bilayer structures obtained in the heating and cooling modes are reported, together with the corresponding transition enthalpies.

  • 259. Fernandez, Vincent
    et al.
    Buffetaut, Eric
    Suteethorn, Varavudh
    Rage, Jean-Claude
    Tafforeau, Paul
    Kundrat, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Evidence of Egg Diversity in Squamate Evolution from Cretaceous Anguimorph Embryos2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0128610Article in journal (Refereed)
    Abstract [en]

    Lizards are remarkable amongst amniotes, for they display a unique mosaic of reproduction modes ranging from egg-laying to live-bearing. Within this patchwork, geckoes are believed to represent the only group to ever have produced fully calcified rigid-shelled eggs, contrasting with the ubiquitous parchment shelled-eggs observed in other lineages. However, this hypothesis relies only on observations of modern taxa and fossilised gecko-like eggshells which have never been found in association with any embryonic or parental remains. We report here the first attested fossil eggs of lizards from the Early Cretaceous of Thailand, combining hard eggshells with exquisitely preserved embryos of anguimoph (e.g. Komodo dragons, mosasaurs). These fossils shed light on an apparently rare reproduction strategy of squamates, demonstrate that the evolution of rigid-shelled eggs are not an exclusive specialization of geckoes, and suggest a high plasticity in the reproductive organs mineralizing eggshells.

  • 260.
    Ferrando, Carlos
    et al.
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Inst Salud Carlos III, GIBER Enfermedades Resp, Madrid, Spain.
    Tusman, Gerardo
    Hosp Privado Comunidad Mar Del Plata, Dept Anesthesiol, Mar Del Plata, Buenos Aires, Argentina..
    Leon, Irene
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Romero, Esther
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Gracia, Estefania
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Mugarra, Ana
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Arocas, Blanca
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Pozo, Natividad
    Hosp Clin Univ, INCLIVA Clin Res Inst, Valencia, Spain..
    Soro, Marina
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Belda, Francisco J.
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Open lung approach versus standard protective strategies: Effects on driving pressure and ventilatory efficiency during anesthesia - A pilot, randomized controlled trial2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177399Article in journal (Refereed)
    Abstract [en]

    Background: Low tidal volume (VT) during anesthesia minimizes lung injury but may be associated to a decrease in functional lung volume impairing lung mechanics and efficiency. Lung recruitment (RM) can restore lung volume but this may critically depend on the post-RM selected PEEP. This study was a randomized, two parallel arm, open study whose primary outcome was to compare the effects on driving pressure of adding a RM to low-VT ventilation, with or without an individualized post-RM PEEP in patients without known previous lung disease during anesthesia.

    Methods: Consecutive patients scheduled for major abdominal surgery were submitted to low-VT ventilation (6 ml.kg(-1)) and standard PEEP of 5 cmH(2)O (pre-RM, n = 36). After 30 min estabilization all patients received a RM and were randomly allocated to either continue with the same PEEP (RM-5 group, n = 18) or to an individualized open-lung PEEP (OL-PEEP) (Open Lung Approach, OLA group, n = 18) defined as the level resulting in maximal Cdyn during a decremental PEEP trial. We compared the effects on driving pressure and lung efficiency measured by volumetric capnography.

    Results: OL-PEEP was found at 8 +/- 2 cmH(2)O. 36 patients were included in the final analysis. When compared with pre-RM, OLA resulted in a 22% increase in compliance and a 28% decrease in driving pressure when compared to pre-RM. These parameters did not improve in the RM-5. The trend of the DP was significantly different between the OLA and RM-5 groups (p = 0.002). VDalv/VTalv was significantly lower in the OLA group after the RM (p = 0.035).

    Conclusions: Lung recruitment applied during low-VT ventilation improves driving pressure and lung efficiency only when applied as an open-lung strategy with an individualized PEEP in patients without lung diseases undergoing major abdominal surgery.

  • 261. Fick, Jerker
    et al.
    Lindberg, Richard H.
    Tysklind, Mats
    Haemig, Paul D.
    Waldenström, Jonas
    Wallensten, Anders
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Antiviral Oseltamivir is not removed or degraded in normal sewage water treatment: Implications for development of resistance by influenza A virus2007In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 2, no 10, p. e986-Article in journal (Refereed)
    Abstract [en]

    Oseltamivir is the main antiviral for treatment and prevention of pandemic influenza. The increase in oseltamivir resistance reported recently has therefore sparked a debate on how to use oseltamivir in non pandemic influenza and the risks associated with wide spread use during a pandemic. Several questions have been asked about the fate of oseltamivir in the sewage treatment plants and in the environment. We have assessed the fate of oseltamivir and discuss the implications of environmental residues of oseltamivir regarding the occurrence of resistance. A series of batch experiments that simulated normal sewage treatment with oseltamivir present was conducted and the UV-spectra of oseltamivir were recorded. Findings: Our experiments show that the active moiety of oseltamivir is not removed in normal sewage water treatments and is not degraded substantially by UV light radiation, and that the active substance is released in waste water leaving the plant. Our conclusion is that a ubiquitous use of oseltamivir may result in selection pressures in the environment that favor development of drug-resistance.

  • 262. Figueiredo, Joana
    et al.
    Simoes-Correia, Joana
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Suriano, Gianpaolo
    Seruca, Raquel
    ADP-Ribosylation Factor 6 Mediates E-Cadherin Recovery by Chemical Chaperones2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23188-Article in journal (Refereed)
    Abstract [en]

    E-cadherin plays a powerful tumor suppressor role. Germline E-cadherin mutations justify 30% of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations are found in 30% of these families. We found possible to restore in vitro mutant E-cadherin associated to HDGC syndrome by using Chemical Chaperones (CCs). Herein, our aim was to disclose the molecular mechanisms underlying the CCs effects in E-cadherin regulation. Using cells stably expressing WT E-cadherin or two HDGC-associated missense mutations, we show that upon DMSO treatment, not only mutant E-cadherin is restored and stabilized at the plasma membrane (PM), but also Arf6 and PIPKI gamma expressions are altered. We show that modulation of Arf6 expression partially mimics the effect of CCs, suggesting that the cellular effects observed upon CCs treatment are mediated by Arf6. Further, we show that E-cadherin expression recovery is specifically linked to Arf6 due to its role on endocytosis and recycling pathways. Finally, we demonstrated that, as DMSO, several others CCs are able to modulate the trafficking machinery through an Arf6 dependent mechanism. Interestingly, the more effective compounds in E-cadherin recovery to PM are those that simultaneously inhibit Arf6 and stimulate PIPKI gamma expression and binding to E-cadherin. Here, we present the first evidence of a direct influence of CCs in cellular trafficking machinery and we show that this effect is of crucial importance in the context of juxtamembrane E-cadherin missense mutations associated to HDGC. We propose that this influence should be taken into account when exploring the therapeutic potential of this type of chemicals in genetic diseases associated to protein-misfolding.

  • 263.
    Filipek-Gorniok, Beata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlsson, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haitina, Tatjana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Habicher, Judith
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ledin, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Ndst Gene Family in Zebrafish: Role of Ndst1b in Pharyngeal Arch Formation2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) proteoglycans are ubiquitous components of the extracellular matrix and plasma membrane of metazoans. The sulfation pattern of the HS glycosaminoglycan chain is characteristic for each tissue and changes during development. The glucosaminyl N-deacetylase/N-sulfotransferase (NDST) enzymes catalyze N-deacetylation and N-sulfation during HS biosynthesis and have a key role in designing the sulfation pattern. We here report on the presence of five NDST genes in zebrafish. Zebrafish ndst1a, ndst1b, ndst2a and ndst2b represent duplicated mammalian orthologues of NDST1 and NDST2 that arose through teleost specific genome duplication. Interestingly, the single zebrafish orthologue ndst3, is equally similar to tetrapod Ndst3 and Ndst4. It is likely that a local duplication in the common ancestor of lobe-finned fish and tetrapods gave rise to these two genes. All zebrafish Ndst genes showed distinct but partially overlapping expression patterns during embryonic development. Morpholino knockdown of ndst1b resulted in delayed development, craniofacial cartilage abnormalities, shortened body and pectoral fin length, resembling some of the features of the Ndst1 mouse knockout.

  • 264.
    Finné, Martin
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Archaeology and Ancient History, Classical archaeology and ancient history. Stockholm Univ, Dept Phys Geog, Stockholm, Sweden.;Navarino Environm Observ, Costa Navarino, Messinia, Greece..
    Holmgren, Karin
    Stockholm Univ, Dept Phys Geog, Stockholm, Sweden.;Navarino Environm Observ, Costa Navarino, Messinia, Greece.;Swedish Univ Agr Sci, Uppsala, Sweden..
    Shen, Chuan-Chou
    Natl Taiwan Univ, High Precis Mass Spectrometry & Environm Change L, Dept Geosci, Taipei, Taiwan..
    Hu, Hsun-Ming
    Natl Taiwan Univ, High Precis Mass Spectrometry & Environm Change L, Dept Geosci, Taipei, Taiwan..
    Boyd, Meighan
    Stockholm Univ, Dept Phys Geog, Stockholm, Sweden.;Navarino Environm Observ, Costa Navarino, Messinia, Greece.;Royal Holloway Univ London, Dept Earth Sci, Egham, Surrey, England..
    Stocker, Sharon
    Univ Cincinnati, Dept Class, 410 Blegen Lib, Cincinnati, OH USA..
    Late Bronze Age climate change and the destruction of the Mycenaean Palace of Nestor at Pylos2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0189447Article in journal (Refereed)
    Abstract [en]

    This paper offers new high-resolution oxygen and carbon isotope data from Stalagmite S1 from Mavri Trypa Cave, SW Peloponnese. Our data provide the climate background to the destruction of the nearby Mycenaean Palace of Nestor at Pylos at the transition from Late Helladic (LH) IIIB to LH IIIC, similar to 3150-3130 years before present (before AD 1950, hereafter yrs BP) and the subsequent period. S1 is dated by 24 U-Th dates with an averaged precision of +/- 26 yrs (2s), providing one of the most robust paleoclimate records from the eastern Mediterranean for the end of the Late Bronze Age (LBA). The delta O-18 record shows generally wetter conditions at the time when the Palace of Nestor at Pylos was destroyed, but a brief period of drier conditions around 3200 yrs BP may have disrupted the Mycenaean agricultural system that at the time was likely operating close to its limit. Gradually developing aridity after 3150 yrs BP, i.e. subsequent to the destruction, probably reduced crop yields and helped to erode the basis for the reinstitution of a central authority and the Palace itself.

  • 265.
    Fiz-Palacios, Omar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Leander, Brian S.
    Heger, Thierry J.
    Old Lineages in a New Ecosystem: Diversification of Arcellinid Amoebae (Amoebozoa) and Peatland Mosses2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e95238-Article in journal (Refereed)
    Abstract [en]

    Arcellinid testate amoebae (Amoebozoa) form a group of free-living microbial eukaryotes with one of the oldest fossil records known, yet several aspects of their evolutionary history remain poorly understood. Arcellinids occur in a range of terrestrial, freshwater and even brackish habitats; however, many arcellinid morphospecies such as Hyalosphenia papilio are particularly abundant in Sphagnum-dominated peatlands, a relatively new ecosystem that appeared during the diversification of Sphagnum species in the Miocene (5-20 Myr ago). Here, we reconstruct divergence times in arcellinid testate amoebae after selecting several fossils for clock calibrations and then infer whether or not arcellinids followed a pattern of diversification that parallels the pattern described for Sphagnum. We found that the diversification of core arcellinids occurred during the Phanerozoic, which is congruent with most arcellinid fossils but not with the oldest known amoebozoan fossil (i.e. at ca. 662 or ca. 750 Myr). Overall, Sphagnum and the Hyalospheniidae exhibit different patterns of diversification. However, an extensive molecular phylogenetic analysis of distinct clades within H. papilio species complex demonstrated a correlation between the recent diversification of H. papilio, the recent diversification of Sphagnum mosses, and the establishment of peatlands.

  • 266.
    Fiz-Palacios, Omar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Romeralo, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Ahmadzadeh, Afsaneh
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Weststrand, Stina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Ahlberg, Per Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Baldauf, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Did terrestrial diversification of amoebas (Amoebozoa) occur in synchrony with land plants?2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74374-Article in journal (Refereed)
    Abstract [en]

    Evolution of lineage diversification through time is an active area of research where much progress has been made in the last decade. Contrary to the situation in animals and plants little is known about how diversification rates have evolved in most major groups of protist. This is mainly due to uncertainty about phylogenetic relationships, scarcity of the protist fossil record and the unknown diversity within these lineages. We have analyzed the evolutionary history of the supergroup Amoebozoa over the last 1000 million years using molecular dating and species number estimates. After an origin in the marine environment we have dated the colonization of terrestrial habitats by three distinct lineages of Amoebozoa: Dictyostelia, Myxogastria and Arcellinida. The common ancestor of the two sister taxa, Dictyostelia and Myxogastria, appears to have existed before the colonization of land by plants. In contrast Arcellinida seems to have diversify in synchrony with land plant radiation, and more specifically with that of mosses. Detection of acceleration of diversification rates in Myxogastria and Arcellinida points to a co-evolution within the terrestrial habitats, where land plants and the amoebozoans may have interacted during the evolution of these new ecosystems.

  • 267.
    Fletcher, Kevin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Xiong, Ye
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Fletcher, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gustafsson, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Glucocorticoid response to both predictable and unpredictable challenges detected as corticosterone metabolites in collared flycatcher droppings2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209289Article in journal (Refereed)
    Abstract [en]

    In most vertebrate animals, glucocorticoid hormones are the chief mediators of homeostasis in response to ecological conditions and as they progress through their lifecycle. In addition, glucocorticoids are a major part of the stress response and stress induced elevations of the hormone can make it difficult to assess glucocorticoid secretion in response to changes in life-stage and current environmental conditions in wild animals. Particularly when quantifying circulating levels of glucocorticoids in the blood which fluctuate rapidly in response to stress. An alternative method of quantifying glucocorticoids is as hormone metabolites in faeces or urine giving a historical sample related to the gut passage time and urinary tract that is less sensitive to stressful events which cause spikes in the circulating hormone level. Although the concentration of glucocorticoid metabolites are influenced by faecal mass thereby potentially affecting any differences in hormone metabolites detected amongst samples. In the present study, we aimed to detect changes in levels of corticosterone, the primary bird glucocorticoid, in relation to the phase of reproduction, in a breeding population of collared flycatchers by sampling corticosterone metabolites in droppings. We also tested how corticosterone metabolite concentrations were affected by ambient temperature and related to body condition in adult birds. Our results indicate that the upregulation of corticosterone between incubation and nestling feeding in female birds is crucial for successful reproduction in this species. Also, females appear to downregulate corticosterone during incubation in response to lower ambient temperature and poorer body condition. Our results did not indicate a relationship between dropping mass and corticosterone metabolite concentrations, which suggests that our findings were linked to the regulation of corticosterone in response to predictable and unpredictable challenges.

  • 268. Forinder, Ulla
    et al.
    Claesson, Lovisa
    Szybek, Katharina
    Norberg, Annika Lindahl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Exploring the Content of Post-Traumatic Stress Symptoms among Parents after Paediatric Stem Cell Transplant2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0126905Article in journal (Refereed)
    Abstract [en]

    In the present study the aim was to explore the content in a trauma reported in a self-report questionnaire by parents of children with a life threatening illness. Semi-structured interviews were performed, with the aim to explore the specific cognitive and behavioral content of the trauma related symptoms reported by the individual informant. The transcripts of the interviews were analyzed with content analysis using a direct approach with a-priori categories according to the B and C categories of the DSM-IV diagnostic criteria for PTSD. The results give us the picture of a complex situation, where the self-report instrument PCL captured a spectrum of qualitatively different cognitions. The parents described traumatic thoughts and images relating not only to experiences in the past (i.e., truly post-traumatic), but also to current stressors and expected future events.

  • 269. Forsberg, Simon K. G.
    et al.
    Kierczak, Marcin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ljungvall, Ingrid
    Merveille, Anne-Christine
    Gouni, Vassiliki
    Wiberg, Maria
    Willesen, Jakob Lundgren
    Hanas, Sofia
    Lequarre, Anne-Sophie
    Sorensen, Louise Mejer
    Tiret, Laurent
    McEntee, Kathleen
    Seppala, Eija
    Koch, Jorgen
    Battaille, Geraldine
    Lohi, Hannes
    Fredholm, Merete
    Chetboul, Valerie
    Haggstrom, Jens
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hoglund, Katja
    The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0123173Article in journal (Refereed)
    Abstract [en]

    Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (rho(corrected) approximate to 1:68 x 10(-6)) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (rho = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

  • 270.
    Forsgren, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Frykstrand, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Grandfield, Kathryn
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    A Template-Free, Ultra-Adsorbing, High Surface Area Carbonate Nanostructure2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68486-Article in journal (Refereed)
    Abstract [en]

    We report the template-free, low-temperature synthesis of a stable, amorphous, and anhydrous magnesium carbonate nanostructure with pore sizes below 6 nm and a specific surface area of ~ 800 m2 g−1, substantially surpassing the surface area of all previously described alkali earth metal carbonates. The moisture sorption of the novel nanostructure is featured by a unique set of properties including an adsorption capacity ~50% larger than that of the hygroscopic zeolite-Y at low relative humidities and with the ability to retain more than 75% of the adsorbed water when the humidity is decreased from 95% to 5% at room temperature. These properties can be regenerated by heat treatment at temperatures below 100°C.The structure is foreseen to become useful in applications such as humidity control, as industrial adsorbents and filters, in drug delivery and catalysis.

  • 271.
    Forsman, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Physics Didactics.
    Mann, Richard P.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Linder, Cedric
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Physics Didactics.
    Van den Bogaard, Maartje
    Delft University.
    Sandbox University: Estimating Influence of Institutional Action2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103261-Article in journal (Refereed)
    Abstract [en]

    The approach presented in this article represents a generalizable and adaptable methodology for identifying complexinteractions in educational systems and for investigating how manipulation of these systems may affect educationaloutcomes of interest. Multilayer Minimum Spanning Tree and Monte-Carlo methods are used. A virtual Sandbox Universityis created in order to facilitate effective identification of successful and stable initiatives within higher education, which canaffect students’ credits and student retention – something that has been lacking up until now. The results highlight theimportance of teacher feedback and teacher-student rapport, which is congruent with current educational findings,illustrating the methodology’s potential to provide a new basis for further empirical studies of issues in higher educationfrom a complex systems perspective.

  • 272.
    Fred, Rikard G
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bang-Berthelsen, Claus H
    Mandrup-Poulsen, Thomas
    Grunnet, Lars G
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    High glucose suppresses human islet insulin biosynthesis by inducing miR-133a leading to decreased polypyrimidine tract binding protein-expression2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 5, p. e10843-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prolonged periods of high glucose exposure results in human islet dysfunction in vitro. The underlying mechanisms behind this effect of high glucose are, however, unknown. The polypyrimidine tract binding protein (PTB) is required for stabilization of insulin mRNA and the PTB mRNA 3'-UTR contains binding sites for the microRNA molecules miR-133a, miR-124a and miR-146. The aim of this study was therefore to investigate whether high glucose increased the levels of these three miRNAs in association with lower PTB levels and lower insulin biosynthesis rates.

    METHODOLOGY/PRINCIPAL FINDINGS:

    Human islets were cultured for 24 hours in the presence of low (5.6 mM) or high glucose (20 mM). Islets were also exposed to sodium palmitate or the proinflammatory cytokines IL-1beta and IFN-gamma, since saturated free fatty acids and cytokines also cause islet dysfunction. RNA was then isolated for real-time RT-PCR analysis of miR-133a, miR-124a, miR-146, insulin mRNA and PTB mRNA contents. Insulin biosynthesis rates were determined by radioactive labeling and immunoprecipitation. Synthetic miR-133a precursor and inhibitor were delivered to dispersed islet cells by lipofection, and PTB was analyzed by immunoblotting following culture at low or high glucose. Culture in high glucose resulted in increased islet contents of miR-133a and reduced contents of miR-146. Cytokines increased the contents of miR-146. The insulin and PTB mRNA contents were unaffected by high glucose. However, both PTB protein levels and insulin biosynthesis rates were decreased in response to high glucose. The miR-133a inhibitor prevented the high glucose-induced decrease in PTB and insulin biosynthesis, and the miR-133a precursor decreased PTB levels and insulin biosynthesis similarly to high glucose.

    CONCLUSION:

    Prolonged high-glucose exposure down-regulates PTB levels and insulin biosynthesis rates in human islets by increasing miR-133a levels. We propose that this mechanism contributes to hyperglycemia-induced beta-cell dysfunction.

  • 273.
    Friberg, Urban
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Miller, Paige M.
    Stewart, Andrew D.
    Rice, William R.
    Mechanisms Promoting the Long-Term Persistence of a Wolbachia Infection in a Laboratory-Adapted Population of Drosophila melanogaster2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e16448-Article in journal (Refereed)
    Abstract [en]

    Intracellular bacteria of the genus Wolbachia are widespread endosymbionts across diverse insect taxa. Despite this prevalence, our understanding of how Wolbachia persists within populations is not well understood. Cytoplasmic incompatibility (CI) appears to be an important phenotype maintaining Wolbachia in many insects, but it is believed to be too weak to maintain Wolbachia in Drosophila melanogaster, suggesting that Wolbachia must also have other effects on this species. Here we estimate the net selective effect of Wolbachia on its host in a laboratory-adapted population of D. melanogaster, to determine the mechanisms leading to its persistence in the laboratory environment. We found i) no significant effects of Wolbachia infection on female egg-to-adult survival or adult fitness, ii) no reduced juvenile survival in males, iii) substantial levels of CI, and iv) a vertical transmission rate of Wolbachia higher than 99%. The fitness of cured females was, however, severely reduced (a decline of 37%) due to CI in offspring. Taken together these findings indicate that Wolbachia is maintained in our laboratory environment due to a combination of a nearly perfect transmission rate and substantial CI. Our results show that there would be strong selection against females losing their infection and producing progeny free from Wolbachia.

  • 274.
    Friberg, Urban
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Stewart, Andrew D.
    Rice, William R.
    Empirical Evidence for Son-Killing X Chromosomes and the Operation of SA-Zygotic Drive2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23508-Article in journal (Refereed)
    Abstract [en]

    Background: Diploid organisms have two copies of all genes, but only one is carried by each haploid gamete and diploid offspring. This causes a fundamental genetic conflict over transmission rate between alternative alleles. Single genes, or gene clusters, only rarely code for the complex phenotypes needed to give them a transmission advantage (drive phenotype). However, all genes on a male's X and Y chromosomes co-segregate, allowing different sex-linked genes to code for different parts of the drive phenotype. Correspondingly, the well-characterized phenomenon of male gametic drive, occurring during haploid gametogenesis, is especially common on sex chromosomes. The new theory of sexually antagonistic zygotic drive of the sex chromosomes (SA-zygotic drive) extends the logic of gametic drive into the diploid phase of the lifecycle, whenever there is competition among siblings or harmful sib-sib mating. The X and Y are predicted to gain a transmission advantage by harming offspring of the sex that does not carry them. Results: Here we analyzed a mutant X-chromosome in Drosophila simulans that produced an excess of daughters when transmitted from males. We developed a series of tests to differentiate between gametic and SA-zygotic drive, and provide multiple lines of evidence that SA-zygotic drive is responsible for the sex ratio bias. Driving sires produce about 50% more surviving daughters than sons. Conclusion: Sex-ratio distortion due to genetic conflict has evolved via gametic drive and maternally transmitted endosymbionts. Our data indicate that sex chromosomes can also drive by harming the non-carrier sex of offspring.

  • 275.
    Friederich Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Aslam, Shakil
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Welch, William J.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Wilcox, Christopher S.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e39635-Article in journal (Refereed)
    Abstract [en]

    Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (−30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.

  • 276.
    Friman, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafsson, Renata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stuhr, Linda B.
    Chidiac, Jean
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Reed, Rolf K.
    Oldberg, Åke
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Increased Fibrosis and Interstitial Fluid Pressure in Two Different Types of Syngeneic Murine Carcinoma Grown in Integrin β3-Subunit Deficient Mice2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34082-Article in journal (Refereed)
    Abstract [en]

    Stroma properties affect carcinoma physiology and direct malignant cell development. Here we present data showing that alpha(V)beta(3) expressed by stromal cells is involved in the control of interstitial fluid pressure (IFP), extracellular volume (ECV) and collagen scaffold architecture in experimental murine carcinoma. IFP was elevated and ECV lowered in syngeneic CT26 colon and LM3 mammary carcinomas grown in integrin beta(3)-deficient compared to wild-type BALB/ c mice. Integrin beta(3)-deficiency had no effect on carcinoma growth rate or on vascular morphology and function. Analyses by electron microscopy of carcinomas from integrin beta(3)-deficient mice revealed a coarser and denser collagen network compared to carcinomas in wild-type littermates. Collagen fibers were built from heterogeneous and thicker collagen fibrils in carcinomas from integrin beta(3)-deficient mice. The fibrotic extracellular matrix (ECM) did not correlate with increased macrophage infiltration in integrin beta(3)-deficient mice bearing CT26 tumors, indicating that the fibrotic phenotype was not mediated by increased inflammation. In conclusion, we report that integrin beta(3)-deficiency in tumor stroma led to an elevated IFP and lowered ECV that correlated with a more fibrotic ECM, underlining the role of the collagen network for carcinoma physiology.

  • 277. Frykman, Susanne
    et al.
    Hur, Ji-Yeun
    Frånberg, Jenny
    Aoki, Mikio
    Winblad, Bengt
    Nahalkova, Jarmila
    Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet Dainippon Sumitomo Pharma Alzheimer Center (KASPAC), Novum, Huddinge, Sweden.
    Behbahani, Homira
    Tjernberg, Lars O.
    Synaptic and Endosomal Localization of Active gamma-Secretase in Rat Brain2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, p. e8948-Article in journal (Refereed)
    Abstract [en]

    Background

    A key player in the development of Alzheimer's disease (AD) is the gamma-secretase complex consisting of at least four components: presenilin, nicastrin, Aph-1 and Pen-2. gamma-Secretase is crucial for the generation of the neurotoxic amyloid beta-peptide (A beta) but also takes part in the processing of many other substrates. In cell lines, active gamma-secretase has been found to localize primarily to the Golgi apparatus, endosomes and plasma membranes. However, no thorough studies have been performed to show the subcellular localization of the active gamma-secretase in the affected organ of AD, namely the brain.

    Principal Findings

    We show by subcellular fractionation of rat brain that high gamma-secretase activity, as assessed by production of A beta 40, is present in an endosome-and plasma membrane-enriched fraction of an iodixanol gradient. We also prepared crude synaptic vesicles as well as synaptic membranes and both fractions showed high A beta 40 production and contained high amounts of the gamma-secretase components. Further purification of the synaptic vesicles verified the presence of the gamma-secretase components in these compartments. The localization of an active gamma-secretase in synapses and endosomes was confirmed in rat brain sections and neuronal cultures by using a biotinylated gamma-secretase inhibitor together with confocal microscopy.

    Significance

    The information about the subcellular localization of gamma-secretase in brain is important for the understanding of the molecular mechanisms of AD. Furthermore, the identified fractions can be used as sources for highly active gamma-secretase.

  • 278. Fröbert, Ole
    et al.
    Sarno, Giovanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Saleh, Nawsad
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Effect of stent inflation pressure and post-dilatation on the outcome of coronary artery intervention: A report of more than 90 000 stent implantations2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, p. e56348-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Percutaneous coronary intervention (PCI) stent inflation pressure correlates to angiographic lumen improvement and stent expansion but the relation to outcome is not clarified. Using comprehensive registry data our aim was to evaluate how stent inflation pressure influences restenosis, stent thrombosis and death following PCI.

    METHODS:

    We evaluated all consecutive coronary stent implantations in Sweden during 46 months from 2008 using data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). We used logistic regression and Cox proportional hazard modeling to estimate risk of outcomes with different balloon pressures.

    RESULTS:

    In total, 93 697 stents were eligible for analysis and divided into five different pressure interval groups: ≤15 atm, 16-17 atm, 18-19 atm, 20-21 atm and ≥22 atm. The risks of stent thrombosis and restenosis were significantly higher in the ≤15 atm, 18-19 atm and ≥22 atm groups (but not in the 16-17 atm group) compared to the 20-21 atm group. There were no differences in mortality. Post-dilatation was associated with a higher restenosis risk ratio (RR) of 1.22 (95% confidence interval (CI) 1.14-1.32, P<0.001) but stent thrombosis did not differ statistically between procedures with or without post-dilatation. The risk of death was lower following post-dilatation (RR 0.81 (CI 0.71-0.93) P = 0.003) and the difference compared to no post-dilatation was seen immediately after PCI.

    CONCLUSION:

    Our retrospective study of stent inflation pressure identified a possible biological pattern--the risks of stent thrombosis and of restenosis appeared to be higher with low and very high pressures. Post-dilatation might increase restenosis risk.

  • 279.
    Fu, Xi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lindgren, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Wieslander, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Norbäck, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Respiratory Illness and Allergy Related to Work and Home Environment among Commercial Pilots2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164954Article in journal (Refereed)
    Abstract [en]

    The aim was to study associations between work and home environment and prevalence and incidence of respiratory health and a history of atopy in a 3-y cohort of commercial pilots. A questionnaire was mailed in 1997 to all pilots in a Scandinavian airline company (N = 622); 577 (93%) participated. The same questionnaire was sent to the participants 3 years later, 436 participated (76%). There were questions on asthma, respiratory symptoms and infections, allergies, the cabin environment, psychosocial environment and the home environment. Associations were analyzed by multiple logistic regression, calculating odds ratios (OR) with 95% confidence intervals (95% CI). The incidence of doctors' diagnosed asthma and atopy were 2.4 and 16.6 per 1000 person years, respectively. Pilots changing type of flight during follow-up got more airway infections (OR = 11.27; 95% CI 2.39-53.14). Those reporting decreased work control (OR = 1.85; 95% CI 1.03-3.31 for 1 unit change) and those with environmental tobacco smoke (ETS) at home (OR = 3.73; 95% CI 1.09-12.83) had a higher incidence of atopy during follow up. Dampness or mould at home was associated with a higher prevalence of asthma symptoms (OR = 3.55; 95% CI 1.43-8.82) and airway infections (OR = 3.12 95% CI 1.27-7.68). Window pane condensation in winter at home, reported at baseline, was associated with increased incidence of asthma symptoms (OR = 4.14; 95% CI 1.32-12.97) and pilots living in newer buildings at baseline had a higher incidence of airway infections (OR = 5.23; 95% CI 1.43-19.10). In conclusion, lack of work control and ETS at home can be a risk factors for development of allergic symptoms in pilots. Window pane condensation at home can be a risk factor for incidence of asthma symptoms. Dampness and mould at home can be a risk factor for prevalence of asthma symptoms and airway infections and living in newer buildings can be a risk factor for incidence of airway infections.

  • 280.
    Fu, Zhirong
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Thorpe, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Akula, Srinivas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Asp-ase Activity of the Opossum Granzyme B Supports the Role of Granzyme B as Part of Anti-Viral Immunity Already during Early Mammalian Evolution2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0154886Article in journal (Refereed)
    Abstract [en]

    Granzyme B is one of the key effector molecules in our defense against viruses and intracellular bacteria. This serine protease together with the pore forming protein perforin, induces caspase or Bid-dependent apoptosis in target cells. Here we present the first characterization of a granzyme B homolog, the grathepsodenase, in a non-placental mammal, the American opossum (Monodelphis domestica). The recombinant enzyme was produced in a human cell line and used to study its primary and extended cleavage specificity using a panel of chromogenic substrates and recombinant protein substrates. The opossum granzyme B was found to have a specificity similar to human granzyme B, although slightly less restrictive in its extended specificity. The identification of a granzyme B homolog with asp-ase (cleaving after aspartic acid) specificity in a non-placental mammal provides strong indications that caspase or Bid-dependent apoptosis by a serine protease with a conserved primary specificity has been part of anti-viral immunity since early mammalian evolution. This finding also indicates that an asp-ase together with a chymase were the first two serine protease genes to appear in the mammalian chymase locus.

  • 281.
    Fu, Zhirong
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Thorpe, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    rMCP-2, the Major Rat Mucosal Mast Cell Protease, an Analysis of Its Extended Cleavage Specificity and Its Potential Role in Regulating Intestinal Permeability by the Cleavage of Cell Adhesion and Junction Proteins2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0131720Article in journal (Refereed)
    Abstract [en]

    Mast cells of the rat intestinal mucosa express three chymotryptic enzymes named rMCP-2, -3 and 4. rMCP-2, the most abundant of these enzymes, has been shown to increase the permeability of the intestinal epithelium, most likely by cleavage of cell adhesion and junction proteins and thereby play a role in intestinal parasite clearance. However, no target for this effect has yet been identified. To address this question we here present its extended cleavage specificity. Phage display analysis showed that it is a chymase with a specificity similar to the corresponding enzyme in mice, mMCP-1, with a preference for Phe or Tyr in the P1 position, and a general preference for aliphatic amino acids both upstream and downstream of the cleavage site. The consensus sequence obtained from the phage display analysis was used to screen the rat proteome for potential targets. A few of the most interesting candidate substrates were cell adhesion and cell junction molecules. To see if these proteins were also susceptible to cleavage in their native conformation we cleaved 5 different recombinant cell adhesion and cell junction proteins. Three potential targets were identified: the loop 1 of occludin, protocadherin alpha 4 and cadherin 17, which indicated that these proteins were at least partly responsible for the previously observed prominent role of rMCP-2 in mucosal permeability and in parasite clearance.

  • 282.
    Fält, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sarkadi, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Fabian, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Exploring Nurses', Preschool Teachers' and Parents' Perspectives on Information Sharing Using SDQ in a Swedish Setting - A Qualitative Study Using Grounded Theory2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0168388Article in journal (Refereed)
    Abstract [en]

    Evidence-based methods to identify behavioural problems among children are not regularly used within the Swedish Child healthcare. A new procedure was therefore introduced to assess children through parent- and preschool teacher reports using the Strengths and Difficulties Questionnaire (SDQ). This study aims to explore nurses', preschool teachers' and parents' perspectives of this new information sharing model. Using the grounded theory methodology, semi-structured interviews with nurses (n = 10) at child health clinics, preschool teachers (n = 13) and parents (n = 11) of 3-, 4- and 5-year-old children were collected and analysed between March 2014 and June 2014. The analysis was conducted using constant comparative method. The participants were sampled purposively within a larger trial in Sweden. Results indicate that all stakeholders shared a desire to have a complete picture of the child's health. The perceptions that explain why the stakeholders were in favour of the new procedure-the 'causal conditions' in a grounded theory model included: (1) Nurses thought that visits after 18-months were unsatisfactory, (2) Preschool teachers wanted to identify children with difficulties and (3) Parents viewed preschool teachers as being qualified to assess children. However, all stakeholders had doubts as to whether there was a reliable way to assess children's behaviour. Although nurses found the SDQ to be useful for their clinical evaluation, they noticed that not all parents chose to participate. Both teachers and parents acknowledged benefits of information sharing. However, the former had concerns about parental reactions to their assessments and the latter about how personal information was handled. The theoretical model developed describes that the causal conditions and current context of child healthcare in many respects endorse the introduction of information sharing. However, successful implementation requires considerable work to address barriers: the tension between normative thinking versus helping children with developmental problems for preschool teachers and dealing with privacy issues and inequity in participation for parents.

  • 283.
    Fält, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Wallby, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Sarkadi, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Salari, Raziye
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Fabian, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Agreement between mothers', fathers', and teachers' ratings of behavioural and emotional problems in 3-5-year-old children2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 11, article id e0206752Article in journal (Refereed)
    Abstract [en]

    Background: The Strengths and Difficulties Questionnaire (SDQ), a valid and reliable instrument for measuring children's mental health, is available in parent- and teacher versions, making it an ideal tool for assessing behavioural and emotional problems in young children. However, few studies have evaluated inter-parent agreement on the SDQ, and in most studies on SDQ agreement, parent scores are either provided by only one parent or have been combined into one parent score. Furthermore, studies on SDQ inter-rater agreement usually only reflect degree of correlation, leaving the agreement between measurements unknown. The aim of the present study was therefore to examine both degree of correlation and agreement between parent and teacher SDQ reports, in a community sample of preschool-aged children in Sweden.

    Methods: Data were obtained from the Children and Parents in Focus trial. The sample comprised 4,46 children 3-5-years-old. Mothers, fathers and preschool teachers completed the SDQ as part of the routine health check-ups at Child Health Centres. Inter-rater agreement was measured using Pearson correlation coefficient and intraclass correlation (ICC).

    Results: Results revealed poor/fair agreement between parent and teacher ratings (ICC 0.25-0.54) and good/excellent agreement between mother and father ratings (ICC 0.66-0.76). The highest level of agreement between parents and teachers was found for the hyperactivity and peer problem subscales, whereas the strongest agreement between parents was found for the hyperactivity and conduct subscales.

    Conclusions: Low inter-rater agreement between parent and teacher ratings suggests that information from both teachers and parents is important when using the SDQ as a method to identify mental health problems in preschool children. Although mothers and fathers each provide unique information about their child's behaviour, good inter-parent agreement indicates that a single parent informant may be sufficient and simplify data collection.

  • 284.
    Fängström, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Salari, Raziye
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Eriksson, Maria
    Ersta Sköndal Bräcke University College.
    Sarkadi, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    The computer-assisted interview In My Shoes can benefit shy preschool children's communication2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0182978Article in journal (Refereed)
    Abstract [en]

    Interviewing children is a cognitively, socially, and emotionally challenging situation, especially for young and shy children. Thus, finding methods that aid rapport and increase these children's communication is important. The present study investigated whether children's verbal and non-verbal communicative behavior developed differently during the rapport phase, depending on whether children were situationally shy or not, and whether the interview was conducted using the computer-assisted interview In My Shoes (IMS) or a Standard verbal interview. The sample consisted of 60 children aged 4 to 5-years-old. The results showed that for the shy children in the IMS group their talkativeness increased and their answer latency decreased including the amount of encouragement the child needed to talk, while no changes were observed for the shy children in the Standard verbal interview group. There were no significant differences in the non-verbal behavior for the shy children regardless of the interview method used. For the non-shy children, overall, the interview method did not affect either the verbal or the non-verbal outcomes. Our findings indicate that IMS can be a useful tool during the rapport-building phase with shy children as it helps these children to improve their verbal communication.

  • 285.
    Galazka, Martyna A
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Roché, Laëtitia
    Nyström, Pär
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Falck-Ytter, Terje
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Human Infants Detect Other People's Interactions Based on Complex Patterns of Kinematic Information.2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112432-Article in journal (Refereed)
    Abstract [en]

    Do infants perceive other people's interactions by means of a mechanism that integrates biological motion information across the observed individuals? In support of this view, the present study demonstrates that infants (N = 28, Age  = 14 months) discriminate between point light displays representing disrupted and non-disrupted interactions between people, even though the two interaction types are identical at the level of individual point light agents. Moreover, a second experiment (sample 2: N = 28, Age  = 14 months) indicated that visual preference in this context is influenced by an audiovisual integration processes that takes into account the presence of an interaction between people. All these results were found exclusively for upright displays - when stimuli were shown upside-down (disrupting biological motion processing), performance was random. Collectively, these findings point to an important role for biological motion in social perception in human infants.

  • 286.
    Galindo-Romero, Caridad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Murcia, Inst Murciano Invest Biosanitaria, Hosp Virgen de la Arrixaca IMIB Virgen de la Arri, Murcia, Spain;Univ Murcia, Fac Med, Dept Oftalmol, Murcia, Spain.
    Harun-Or-Rashid, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Jiménez-López, Manuel
    Univ Murcia, Inst Murciano Invest Biosanitaria, Hosp Virgen de la Arrixaca IMIB Virgen de la Arri, Murcia, Spain;Univ Murcia, Fac Med, Dept Oftalmol, Murcia, Spain.
    Agudo-Barriuso, Manuel
    Univ Murcia, Inst Murciano Invest Biosanitaria, Hosp Virgen de la Arrixaca IMIB Virgen de la Arri, Murcia, Spain;Univ Murcia, Fac Med, Dept Oftalmol, Murcia, Spain.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neuroprotection by α2-Adrenergic Receptor Stimulation after Excitotoxic Retinal Injury: A Study of the Total Population of Retinal Ganglion Cells and Their Distribution in the Chicken Retina2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0161862Article in journal (Refereed)
    Abstract [en]

    We have studied the effect of α2-adrenergic receptor stimulation on the total excitotoxically injured chicken retinal ganglion cell population. N-methyl-D-aspartate (NMDA) was intraocularly injected at embryonic day 18 and Brn3a positive retinal ganglion cells (Brn3a+ RGCs) were counted in flat-mounted retinas using automated routines. The number and distribution of the Brn3a+ RGCs were analyzed in series of normal retinas from embryonic day 8 to post-hatch day 11 retinas and in retinas 7 or 14 days post NMDA lesion. The total number of Brn3a+ RGCs in the post-hatch retina was approximately 1.9x106 with a density of approximately 9.2x103 cells/mm2. The isodensity maps of normal retina showed that the density decreased with age as the retinal size increased. In contrast to previous studies, we did not find any specific region with increased RGC density, rather the Brn3a+ RGCs were homogeneously distributed over the central retina with decreasing density in the periphery and in the region of the pecten oculli. Injection of 5–10 μg NMDA caused 30–50% loss of Brn3a+ cells and the loss was more severe in the dorsal than in the ventral retina. Pretreatment with brimonidine reduced the loss of Brn3a+ cells both 7 and 14 days post lesion and the protective effect was higher in the dorsal than in the ventral retina. We conclude that α2-adrenergic receptor stimulation reduced the impact of the excitotoxic injury in chicken similarly to what has been shown in mammals. Furthermore, the data show that the RGCs are evenly distributed over in the retina, which challenges previous results that indicate the presence of specific high RGC-density regions of the chicken retina.

  • 287.
    Gallini, Radiosa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Huusko, Jenni
    Univ Kuopio, Dept Biotechnol & Mol Med, Al Virtanen Inst Mol Sci, Kuopio, Finland..
    Yla-Herttuala, Seppo
    Univ Kuopio, Dept Biotechnol & Mol Med, Al Virtanen Inst Mol Sci, Kuopio, Finland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160930Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFR alpha and PDGFR beta) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRa agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFR alpha-positive fibroblasts, PDGFR beta agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirusinduced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.

  • 288. Galloway, Aaron W. E.
    et al.
    Brett, Michael T.
    Holtgrieve, Gordon W.
    Ward, Eric J.
    Ballantyne, Ashley P.
    Burns, Carolyn W.
    Kainz, Martin J.
    Mueller-Navarra, Doerthe C.
    Persson, Jonas
    Ravet, Joseph L.
    Strandberg, Ursula
    Taipale, Sami J.
    Alhgren, Gunnel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    A Fatty Acid Based Bayesian Approach for Inferring Diet in Aquatic Consumers2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0129723Article in journal (Refereed)
    Abstract [en]

    We modified the stable isotope mixing model MixSIR to infer primary producer contributions to consumer diets based on their fatty acid composition. To parameterize the algorithm, we generated a 'consumer-resource library' of FA signatures of Daphnia fed different algal diets, using 34 feeding trials representing diverse phytoplankton lineages. This library corresponds to the resource or producer file in classic Bayesian mixing models such as MixSIR or SIAR. Because this library is based on the FA profiles of zooplankton consuming known diets, and not the FA profiles of algae directly, trophic modification of consumer lipids is directly accounted for. To test the model, we simulated hypothetical Daphnia comprised of 80% diatoms, 10% green algae, and 10% cryptophytes and compared the FA signatures of these known pseudo-mixtures to outputs generated by the mixing model. The algorithm inferred these simulated consumers were comprised of 82% (63-92%) [median (2.5th to 97.5th percentile credible interval)] diatoms, 11% (4-22%) green algae, and 6% (0-25%) cryptophytes. We used the same model with published phytoplankton stable isotope (SI) data for delta C-13 and delta N-15 to examine how a SI based approach resolved a similar scenario. With SI, the algorithm inferred that the simulated consumer assimilated 52% (4-91%) diatoms, 23% (1-78%) green algae, and 18% (1-73%) cyanobacteria. The accuracy and precision of SI based estimates was extremely sensitive to both resource and consumer uncertainty, as well as the trophic fractionation assumption. These results indicate that when using only two tracers with substantial uncertainty for the putative resources, as is often the case in this class of analyses, the underdetermined constraint in consumer-resource SI analyses may be intractable. The FA based approach alleviated the underdetermined constraint because many more FA biomarkers were utilized (n < 20), different primary producers (e.g., diatoms, green algae, and cryptophytes) have very characteristic FA compositions, and the FA profiles of many aquatic primary consumers are strongly influenced by their diets.

  • 289.
    Gallwitz, Maike
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Enoksson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Thorpe, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    The Extended Cleavage Specificity of Human Thrombin2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, p. e31756-Article in journal (Refereed)
    Abstract [en]

    Thrombin is one of the most extensively studied of all proteases. Its central role in the coagulation cascade as well as several other areas has been thoroughly documented. Despite this, its consensus cleavage site has never been determined in detail. Here we have determined its extended substrate recognition profile using phage-display technology. The consensus recognition sequence was identified as, P2-Pro, P1-Arg, P1'-Ser/Ala/Gly/Thr, P2'-not acidic and P3'-Arg. Our analysis also identifies an important role for a P3'-arginine in thrombin substrates lacking a P2-proline. In order to study kinetics of this cooperative or additive effect we developed a system for insertion of various pre-selected cleavable sequences in a linker region between two thioredoxin molecules. Using this system we show that mutations of P2-Pro and P3'-Arg lead to an approximate 20-fold and 14-fold reduction, respectively in the rate of cleavage. Mutating both Pro and Arg results in a drop in cleavage of 200-400 times, which highlights the importance of these two positions for maximal substrate cleavage. Interestingly, no natural substrates display the obtained consensus sequence but represent sequences that show only 1-30% of the optimal cleavage rate for thrombin. This clearly indicates that maximal cleavage, excluding the help of exosite interactions, is not always desired, which may instead cause problems with dysregulated coagulation. It is likely exosite cooperativity has a central role in determining the specificity and rate of cleavage of many of these in vivo substrates. Major effects on cleavage efficiency were also observed for residues as far away as 4 amino acids from the cleavage site. Insertion of an aspartic acid in position P4 resulted in a drop in cleavage by a factor of almost 20 times.

  • 290. Gambadauro, Pietro
    et al.
    Carli, V
    Hadlaczky, G
    Sarchiapone, M
    Apter, A
    Balazs, J
    Banzer, R
    Bobes, J
    Brunner, R
    Cosman, D
    Farkas, L
    Haring, C
    Hoven, C W
    Kaess, M
    Kahn, J P
    McMahon, E
    Postuvan, V
    Sisask, M
    Värnik, A
    ZadravecSedivy, N
    Wasserman, D
    Correlates of sexual initiation among European adolescents2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2Article in journal (Refereed)
  • 291.
    Gandasi, Nikhil R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vesto, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Helou, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yin, Peng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Saras, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Survey of Red Fluorescence Proteins as Markers for Secretory Granule Exocytosis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0127801Article in journal (Refereed)
    Abstract [en]

    Fluorescent proteins (FPs) have proven to be valuable tools for high-resolution imaging studies of vesicle transport processes, including exo- and endocytosis. Since the pH of the vesicle lumen changes between acidic and neutral during these events, pH-sensitive FPs with near neutral pKa, such as pHluorin, are particularly useful. FPs with pKa>6 are readily available in the green spectrum, while red-emitting pH-sensitive FPs are rare and often not well characterized as reporters of exo- or endocytosis. Here we tested a panel of ten orange/red and two green FPs in fusions with neuropeptide Y (NPY) for use as secreted vesicle marker and reporter of dense core granule exocytosis and release. We report relative brightness, bleaching rate, targeting accuracy, sensitivity to vesicle pH, and their performance in detecting exocytosis in live cells. Tandem dimer (td)-mOrange2 was identified as well-targeted, bright, slowly bleaching and pH-sensitive FP that performed similar to EGFP. Single exocytosis events were readily observed, which allowed measurements of fusion pore lifetime and the dynamics of the exocytosis protein syntaxin at the release site during membrane fusion and cargo release.

  • 292. Ganna, Andrea
    et al.
    Ortega-Alonso, Alfredo
    Havulinna, Aki
    Salomaa, Veikko
    Kaprio, Jaakko
    Pedersen, Nancy L.
    Sullivan, Patrick F.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Hultman, Christina M.
    Magnusson, Patrik K. E.
    Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e83101-Article in journal (Refereed)
    Abstract [en]

    Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10-5 were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10-8) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning.

  • 293.
    Garcia-Faroldi, Gianni
    et al.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BMC, Uppsala, Sweden..
    Melo, Fabio R.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BMC, Uppsala, Sweden..
    Bruemmer, Dennis
    Univ Kentucky, Coll Med, Saha Cardiovasc Res Ctr, Wethington, KY USA..
    Conneely, Orla M.
    Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA..
    Pejler, Gunnar
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BMC, Uppsala, Sweden..
    Lundequist, Anders
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BMC, Uppsala, Sweden..
    Nuclear Receptor 4a3 (Nr4a3) Regulates Murine Mast Cell Responses and Granule Content2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, article id e89311Article in journal (Refereed)
    Abstract [en]

    Nuclear receptor 4a3 (Nr4a3) is a transcription factor implicated in various settings such as vascular biology and inflammation. We have recently shown that mast cells dramatically upregulate Nuclear receptor 4a3 upon activation, and here we investigated the functional impact of Nuclear receptor 4a3 on mast cell responses. We show that Nuclear receptor 4a3 is involved in the regulation of cytokine/chemokine secretion in mast cells following activation via the high affinity IgE receptor. Moreover, Nuclear receptor 4a3 negatively affects the transcript and protein levels of mast cell tryptase as well as the mast cell's responsiveness allergen. Together, these findings identify Nuclear receptor 4a3 as a novel regulator of mast cell function.

  • 294. Gardberg, Maria
    et al.
    Kaipio, Katja
    Lehtinen, Laura
    Mikkonen, Piia
    Heuser, Vanina D.
    Talvinen, Kati
    Iljin, Kristiina
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Uhlen, Mathias
    Grenman, Reidar
    Koivisto, Mari
    Carpen, Olli
    FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74923-Article in journal (Refereed)
    Abstract [en]

    Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.

  • 295. Garg, Gaurav
    et al.
    Kumar, Jitender
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    McGuigan, Fiona E.
    Ridderstrale, Martin
    Gerdhem, Paul
    Luthman, Holger
    Akesson, Kristina
    Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e88565-Article in journal (Refereed)
    Abstract [en]

    Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2) = 0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs. CC: BUA: 100 vs. 103 vs. 103; p = 0.002); (SOS: 1521 vs. 1526 vs. 1524; p = 0.008); (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03) and vitamin D (93 vs. 91 vs. 90; p = 0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067). Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p <= 0.001). Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.

  • 296.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha Jane
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Riva, Giuseppe
    Nonvisual Multisensory Impairment of Body Perception in Anorexia Nervosa: A Systematic Review of Neuropsychological Studies2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e110087-Article in journal (Refereed)
    Abstract [en]

    Background: Body image distortion is a central symptom of Anorexia Nervosa (AN). Even if corporeal awareness is multisensory majority of AN studies mainly investigated visual misperception. We systematically reviewed AN studies that have investigated different nonvisual sensory inputs using an integrative multisensory approach to body perception. We also discussed the findings in the light of AN neuroimaging evidence. Methods: Pub Med and PsycINFO were searched until March, 2014. To be included in the review, studies were mainly required to: investigate a sample of patients with current or past AN and a control group and use tasks that directly elicited one or more nonvisual sensory domains. Results:Thirteen studies were included. They studied a total of 223 people with current or past AN and 273 control subjects. Overall, results show impairment in tactile and proprioceptive domains of body perception in AN patients. lnteroception and multisensory integration have been poorly explored directly in AN patients. A limitation of this review is the relatively small amount of literature available. Conclusions: Our results showed that AN patients had a multisensory impairment of body perception that goes beyond visual misperception and involves tactile and proprioceptive sensory components. Furthermore, impairment of tactile and proprioceptive components may be associated with parietal cortex alterations in AN patients. Interoception and multisensory integration have been weakly explored directly. Further research, using multisensory approaches as well as neuroimaging techniques, is needed to better define the complexity of body image distortion in AN. Key Findings: The review suggests an altered capacity of AN patients in processing and integration of bodily signals: body parts are experienced as dissociated from their holistic and perceptive dimensions. Specifically, it is likely that not only perception but memory, and in particular sensorimotor/proprioceptive memory, probably shapes bodily experience in patients with AN.

  • 297. Gerber, Sophie
    et al.
    Chadoeuf, Joel
    Gugerli, Felix
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Buiteveld, Joukje
    Cottrell, Joan
    Dounavi, Aikaterini
    Fineschi, Silvia
    Forrest, Laura L.
    Fogelqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Goicoechea, Pablo G.
    Jensen, Jan Svejgaard
    Salvini, Daniela
    Vendramin, Giovanni G.
    Kremer, Antoine
    High Rates of Gene Flow by Pollen and Seed in Oak Populations across Europe2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. e85130-Article in journal (Refereed)
    Abstract [en]

    Gene flow is a key factor in the evolution of species, influencing effective population size, hybridisation and local adaptation. We analysed local gene flow in eight stands of white oak (mostly Quercus petraea and Q. robur, but also Q. pubescens and Q. faginea) distributed across Europe. Adult trees within a given area in each stand were exhaustively sampled (range [239, 754], mean 423), mapped, and acorns were collected ([17,147], 51) from several mother trees ([3,47], 23). Seedlings ([65,387], 178) were harvested and geo-referenced in six of the eight stands. Genetic information was obtained from screening distinct molecular markers spread across the genome, genotyping each tree, acorn or seedling. All samples were thus genotyped at 5-8 nuclear microsatellite loci. Fathers/parents were assigned to acorns and seedlings using likelihood methods. Mating success of male and female parents, pollen and seed dispersal curves, and also hybridisation rates were estimated in each stand and compared on a continental scale. On average, the percentage of the wind-borne pollen from outside the stand was 60%, with large variation among stands (21-88%). Mean seed immigration into the stand was 40%, a high value for oaks that are generally considered to have limited seed dispersal. However, this estimate varied greatly among stands (20-66%). Gene flow was mostly intraspecific, with large variation, as some trees and stands showed particularly high rates of hybridisation. Our results show that mating success was unevenly distributed among trees. The high levels of gene flow suggest that geographically remote oak stands are unlikely to be genetically isolated, questioning the static definition of gene reserves and seed stands.

  • 298. Gerlee, Philip
    et al.
    Schmidt, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Monsefi, Naser
    Kling, Teresia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jornsten, Rebecka
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Searching for Synergies: Matrix Algebraic Approaches for Efficient Pair Screening2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68598-Article in journal (Refereed)
    Abstract [en]

    Functionally interacting perturbations, such as synergistic drugs pairs or synthetic lethal gene pairs, are of key interest in both pharmacology and functional genomics. However, to find such pairs by traditional screening methods is both time consuming and costly. We present a novel computational-experimental framework for efficient identification of synergistic target pairs, applicable for screening of systems with sizes on the order of current drug, small RNA or SGA (Synthetic Genetic Array) libraries (>1000 targets). This framework exploits the fact that the response of a drug pair in a given system, or a pair of genes' propensity to interact functionally, can be partly predicted by computational means from (i) a small set of experimentally determined target pairs, and (ii) pre-existing data (e.g. gene ontology, PPI) on the similarities between targets. Predictions are obtained by a novel matrix algebraic technique, based on cyclical projections onto convex sets. We demonstrate the efficiency of the proposed method using drug-drug interaction data from seven cancer cell lines and gene-gene interaction data from yeast SGA screens. Our protocol increases the rate of synergism discovery significantly over traditional screening, by up to 7-fold. Our method is easy to implement and could be applied to accelerate pair screening for both animal and microbial systems.

  • 299. Gertow, Karin
    et al.
    Cedervall, Jessica
    Jamil, Seema
    Ali, Rouknuddin
    Imreh, Marta P.
    Gulyas, Miklos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Sandstedt, Bengt
    Hrlund-Richter, Lars A.
    Early Events in Xenograft Development from the Human Embryonic Stem Cell Line HS181-Resemblance with an Initial Multiple Epiblast Formation2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e27741-Article in journal (Refereed)
    Abstract [en]

    Xenografting is widely used for assessing in vivo pluripotency of human stem cell populations. Here, we report on early to late events in the development of mature experimental teratoma from a well-characterized human embryonic stem cell (HESC) line, HS181. The results show an embryonic process, increasingly chaotic. Active proliferation of the stem cell derived cellular progeny was detected already at day 5, and characterized by the appearance of multiple sites of engraftment, with structures of single or pseudostratified columnar epithelium surrounding small cavities. The striking histological resemblance to developing embryonic ectoderm, and the formation of epiblast-like structures was supported by the expression of the markers OCT4, NANOG, SSEA-4 and KLF4, but a lack of REX1. The early neural marker NESTIN was uniformly expressed, while markers linked to gastrulation, such as BMP-4, NODAL or BRACHYURY were not detected. Thus, observations on day 5 indicated differentiation comparable to the most early transient cell populations in human post implantation development. Confirming and expanding on previous findings from HS181 xenografts, these early events were followed by an increasingly chaotic development, incorporated in the formation of a benign teratoma with complex embryonic components. In the mature HS181 teratomas not all types of organs/tissues were detected, indicating a restricted differentiation, and a lack of adequate spatial developmental cues during the further teratoma formation. Uniquely, a kinetic alignment of rare complex structures was made to human embryos at diagnosed gestation stages, showing minor kinetic deviations between HS181 teratoma and the human counterpart.

  • 300.
    Ghilotti, Francesca
    et al.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;Univ Milano Bicocca, Dept Stat & Quantitat Methods, Milan, Italy..
    Pesonen, Ann-Sofie
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Raposo, Sara E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA..
    Winell, Henric
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Nyren, Olof
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lagerros, Ylva Trolle
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Med, Clin Endocrinol Metab & Diabet, Stockholm, Sweden..
    Plymoth, Amelie
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Physical activity, sleep and risk of respiratory infections: A Swedish cohort study2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0190270Article in journal (Refereed)
    Abstract [en]

    Objectives

    Previous studies found higher levels of physical activity to be protective against infections and that short and long sleep negatively affects the immune response. However, these relationships remain debatable. We aimed to investigate if physical activity and sleep habits affect incidence of upper respiratory tract infections (URTI) in a prospective cohort study.

    Methods

    A total of 2,038 adults aged 25-64 years served as a random sample of the gainfully employed population of an industrial town in Sweden. Physical activity and sleep habits were estimated through self-reported questionnaires. Physical activity was expressed as metabolic energy turnover hours per day. Sleep was assessed as number of hours slept per night and its perceived quality. URTI outcome was prospectively self-reported during a 9-month follow-up period. Associations of physical activity and sleep with URTI were estimated using hurdle regression models adjusted for potential confounders.

    Results

    During 1,583 person-years 1,597 URTI occurred, resulting in an incidence of 1.01 infections/person-year (95% CI 0.96-1.06). The fitted regression models did not provide support for an association with physical activity or sleep habits. Factors positively associated with experiencing URTI were having children <= 6 years, female gender, higher education and treatment for allergy, asthma or lung cancer. Having children <= 6 years and female gender were related to a higher number of URTI among those experiencing URTI.

    Conclusions

    We did not find any association between physical activity, sleep duration or sleep quality and the occurrence of upper respiratory tract infections in adult Swedish population.

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