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  • 501.
    Sandholm, Kerstin
    et al.
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Henningsson, Anna J.
    Ryhov Cty Hosp, Dept Clin Microbiol, Jonkoping, Sweden.
    Save, Susanne
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Forsberg, Pia
    Linkoping Univ, Dept Infect Med, Linkoping, Sweden.
    Jonsson, Nina
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Ernerudh, Jan
    Linkoping Univ, Dept Clin Immunol & Transfus Med, Linkoping, Sweden.
    Ekdahl, Kristina N.
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Early cytokine release in response to live Borrelia burgdorferi sensu lato spirochetes is largely complement independent2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108013-Article in journal (Refereed)
    Abstract [en]

    Aim: Here we investigated the role of complement activation in phagocytosis and the release of cytokines and chemokines in response to two clinical isolates: Borrelia afzelii K78, which is resistant to complement-mediated lysis, and Borrelia garinii LU59, which is complement-sensitive.

    Methods: Borrelia spirochetes were incubated in hirudin plasma, or hirudin-anticoagulated whole blood. Complement activation was measured as the generation of C3a and sC5b-9. Binding of the complement components C3, factor H, C4, and C4BP to the bacterial surfaces was analyzed. The importance of complement activation on phagocytosis, and on the release of cytokines and chemokines, was investigated using inhibitors acting at different levels of the complement cascade.

    Results: 1) Borrelia garinii LU59 induced significantly higher complement activation than did Borrelia afzelii K78. 2) Borrelia afzelii K78 recruited higher amounts of factor H resulting in significantly lower C3 binding. 3) Both Borrelia strains were efficiently phagocytized by granulocytes and monocytes, with substantial inhibition by complement blockade at the levels of C3 and C5. 4) The release of the pro-inflammatory cytokines and chemokines IL-1 beta, IL-6, TNF, CCL20, and CXCL8, together with the anti-inflammatory IL-10, were increased the most (by>10-fold after exposure to Borrelia). 5) Both strains induced a similar release of cytokines and chemokines, which in contrast to the phagocytosis, was almost totally unaffected by complement blockade.

    Conclusions: Our results show that complement activation plays an important role in the process of phagocytosis but not in the subsequent cytokine release in response to live Borrelia spirochetes.

  • 502. Santoro, Ana Lúcia
    et al.
    Bastviken, David
    Gudasz, Cristian
    Department of Ecology and Evolution - Limnology, Uppsala University, Uppsala, Sweden.
    Tranvik, Lars
    Enrich-Prast, Alex
    Dark Carbon Fixation: An Important Process in Lake Sediments2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, article id e65813Article in journal (Refereed)
    Abstract [en]

    Close to redox boundaries, dark carbon fixation by chemoautotrophic bacteria may be a large contributor to overall carbon fixation. Still, little is known about the relative importance of this process in lake systems, in spite the potentially high chemoautotrophic potential of lake sediments. We compared rates of dark carbon fixation, bacterial production and oxygen consumption in sediments from four Swedish boreal and seven tropical Brazilian lakes. Rates were highly variable and dark carbon fixation amounted up to 80% of the total heterotrophic bacterial production. The results indicate that non-photosynthetic carbon fixation can represent a substantial contribution to bacterial biomass production, especially in sediments with low organic matter content.

  • 503.
    Santosa, Ailiana
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Diverse empirical evidence on epidemiological transition in low- and middle-income countries: population-based findings from INDEPTH Network data2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0155753Article in journal (Refereed)
    Abstract [en]

    Background Low-and middle-income countries are often described as being at intermediate stages of epidemiological transition, but there is little population-based data with reliable cause of death assignment to examine the situation in more detail. Non-communicable diseases are widely seen as a coming threat to population health, alongside receding burdens of infection. The INDEPTH Network has collected empirical population data in a number of health and demographic surveillance sites in low-and middle-income countries which permit more detailed examination of mortality trends over time.

    Objective To examine cause-specific mortality trends across all ages at INDEPTH Network sites in Africa and Asia during the period 1992-2012. Emphasis is given to the 15-64 year age group, which is the main focus of concern around the impact of the HIV pandemic and emerging non-communicable disease threats.

    Methods INDEPTH Network public domain data from 12 sites that each reported at least five years of cause-specific mortality data were used. Causes of death were attributed using standardised WHO verbal autopsy methods, and mortality rates were standardised for comparison using the INDEPTH standard population. Annual changes in mortality rates were calculated for each site.

    Results A total of 96,255 deaths were observed during 9,487,418 person years at the 12 sites. Verbal autopsies were completed for 86,039 deaths (89.4%). There were substantial variations in mortality rates between sites and over time. HIV-related mortality played a major part at sites in eastern and southern Africa. Deaths in the age group 15-64 years accounted for 43% of overall mortality. Trends in mortality were generally downwards, in some cases quite rapidly so. The Bangladeshi sites reflected populations at later stages of transition than in Africa, and were largely free of the effects of HIV/AIDS.

    Conclusions To some extent the patterns of epidemiological transition observed followed theoretical expectations, despite the impact of the HIV pandemic having a major effect in some locations. Trends towards lower overall mortality, driven by decreasing infections, were the general pattern. Low-and middle-income country populations appear to be in an era of rapid transition.

  • 504. Saville, Naomi M.
    et al.
    Shrestha, Bhim P.
    Style, Sarah
    Harris-Fry, Helen
    Beard, B. James
    Sen, Aman
    Jha, Sonali
    Rai, Anjana
    Paudel, Vikas
    Sah, Raghbendra
    Paudel, Puskar
    Copas, Andrew
    Bhandari, Bishnu
    Neupane, Rishi
    Morrison, Joanna
    Gram, Lu
    Pulkki-Brännström, Anni-Maria
    UCL Institute for Global Health, University College London, London, United Kingdom.
    Skordis-Worrall, Jolene
    Basnet, Machhindra
    de Pee, Saskia
    Hall, Andrew
    Harthan, Jayne
    Thondoo, Meelan
    Klingberg, Sonja
    Messick, Janice
    Manandhar, Dharma S.
    Osrin, David
    Costello, Anthony
    Impact on birth weight and child growth of Participatory Learning and Action women’s groups with and without transfers of food or cash during pregnancy: Findings of the low birth weight South Asia cluster-randomised controlled trial (LBWSAT) in Nepal2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0194064Article in journal (Refereed)
    Abstract [en]

    Background Undernutrition during pregnancy leads to low birthweight, poor growth and inter-generational undernutrition. We did a non-blinded cluster-randomised controlled trial in the plains districts of Dhanusha and Mahottari, Nepal to assess the impact on birthweight and weight-for-age z-scores among children aged 0–16 months of community-based participatory learning and action (PLA) women’s groups, with and without food or cash transfers to pregnant women. Methods We randomly allocated 20 clusters per arm to four arms (average population/cluster = 6150). All consenting married women aged 10–49 years, who had not had tubal ligation and whose husbands had not had vasectomy, were monitored for missed menses. Between 29 Dec 2013 and 28 Feb 2015 we recruited 25,092 pregnant women to surveillance and interventions: PLA alone (n = 5626); PLA plus food (10 kg/month of fortified wheat-soya ‘Super Cereal’, n = 6884); PLA plus cash (NPR750≈US$7.5/month, n = 7272); control (existing government programmes, n = 5310). 539 PLA groups discussed and implemented strategies to improve low birthweight, nutrition in pregnancy and hand washing. Primary outcomes were birthweight within 72 hours of delivery and weight-for-age z-scores at endline (age 0–16 months). Only children born to permanent residents between 4 June 2014 and 20 June 2015 were eligible for intention to treat analyses (n = 10936), while in-migrating women and children born before interventions had been running for 16 weeks were excluded. Trial status: completed. Results In PLA plus food/cash arms, 94–97% of pregnant women attended groups and received a mean of four transfers over their pregnancies. In the PLA only arm, 49% of pregnant women attended groups. Due to unrest, the response rate for birthweight was low at 22% (n = 2087), but response rate for endline nutritional and dietary measures exceeded 83% (n = 9242). Compared to the control arm (n = 464), mean birthweight was significantly higher in the PLA plus food arm by 78·0 g (95% CI 13·9, 142·0; n = 626) and not significantly higher in PLA only and PLA plus cash arms by 28·9 g (95% CI -37·7, 95·4; n = 488) and 50·5 g (95% CI -15·0, 116·1; n = 509) respectively. Mean weight-for-age z-scores of children aged 0–16 months (average age 9 months) sampled cross-sectionally at endpoint, were not significantly different from those in the control arm (n = 2091). Differences in weight for-age z-score were as follows: PLA only -0·026 (95% CI -0·117, 0·065; n = 2095); PLA plus cash -0·045 (95% CI -0·133, 0·044; n = 2545); PLA plus food -0·033 (95% CI -0·121, 0·056; n = 2507). Amongst many secondary outcomes tested, compared with control, more institutional deliveries (OR: 1.46 95% CI 1.03, 2.06; n = 2651) and less colostrum discarding (OR:0.71 95% CI 0.54, 0.93; n = 2548) were found in the PLA plus food arm but not in PLA alone or in PLA plus cash arms. Interpretation Food supplements in pregnancy with PLA women’s groups increased birthweight more than PLA plus cash or PLA alone but differences were not sustained. Nutrition interventions throughout the thousand-day period are recommended. Trial registration ISRCTN75964374.

  • 505. Sayinzoga, Felix
    et al.
    Tetui, Moses
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Department of Health Policy, Planning and Management, Makerere University School of Public Health, Kampala, Uganda.
    van der Velden, Koos
    van Dillen, Jeroen
    Bijlmakers, Leon
    Understanding variation in health service coverage and maternal health outcomes among districts in Rwanda - A qualitative study of local health workers' perceptions2019In: PLoS ONE, E-ISSN 1932-6203, Vol. 14, no 10, article id e0223357Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To obtain the perspectives of health professionals and community health workers on factors that determine health service coverage and maternal health outcomes so as to understand variations between districts.

    METHODS: 16 Focus group discussions involving four different groups of participants were conducted in May 2015 in four purposively selected districts, complemented by three key informant interviews in one of the districts.

    RESULTS: The solidarity support for poor people and the interconnectedness between local leaders and heads of health facilities were identified as enablers of health service utilization. Geographical factors, in particular location close to borders with mobile populations and migrants, and large populations with sparsely distributed health infrastructure, exacerbated by hilly topography and muddy roads were identified as barriers. Shortages of skilled health providers at the level of district hospitals were cited as contributing to poor maternal health outcomes.

    CONCLUSION: There is a need to take into account disparities between districts when allocating staff and financial resources in order to achieve universal coverage for high-quality maternal health services and better outcomes. Local innovations such as the use of SMS and WhatsApp text messages by health workers and financial protection schemes for poor patients improve solidarity and are worth to be scaled up.

  • 506.
    Schantz, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Research Unit for Movement, Health and Environment, The Åstrand Laboratory, The Swedish School of Sport and Health Sciences, GIH, Stockholm, Sweden.
    Wahlgren, Lina
    Research Unit for Movement, Health and Environment, The Åstrand Laboratory, The Swedish School of Sport and Health Sciences, GIH, Stockholm, Sweden..
    Salier Eriksson, Jane
    Research Unit for Movement, Health and Environment, The Åstrand Laboratory, The Swedish School of Sport and Health Sciences, GIH, Stockholm, Sweden..
    Nilsson Sommar, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Rosdahl, Hans
    Research Unit for Movement, Health and Environment, The Åstrand Laboratory, The Swedish School of Sport and Health Sciences, GIH, Stockholm, Sweden..
    Estimating duration-distance relations in cycle commuting in the general population2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 11, article id e0207573Article in journal (Refereed)
    Abstract [en]

    It is important to estimate the duration-distance relation in cycle commuting in the general population since this enables analyses of the potential for various public health outcomes. Therefore, the aim is to estimate this relation in the Swedish adult population of 2015. For that purpose, the first step was to establishit for adult male and female cycle commuters in Greater Stockholm, Sweden. Whether or not the slopes of these relations needed to be altered in order to make them representative of the general population was evaluated by comparing the levels of maximal oxygen uptake in samples of commuter cyclists and the population. The measure used was the maximal oxygen uptake divided by both the body weight and a cycle weight of 18.5 kg. The body weights in the population samples were adjusted to mirror relevant levels in 2015. Age adjustments for the duration-distance relations were calculated on the basis of the maximal oxygen uptake in the population samples aged 20-65 years. The duration-distance relations of the cycle commuters were downscaled by about 24-28% to mirror levels in the general population. The empirical formula for the distance (D, km) was based on duration (T, minutes) · speed (km/min) · a correction factor from cycle commuter to the general population · age adjustment (A, years). For the males in the general population the formula was: D = T · 20.76 km/h · 0.719 · (1.676-0.0147 · A). For females, the formula was: D = T · 16.14 km/h · 0.763 · (1.604-0.0129 · A). These formulas, combined with distributions of route distances between home and work in the population, enable realistic evaluations of the potential for different public health outcomes through cycle commuting.

  • 507. Scheffer, Marten
    et al.
    Vergnon, Remi
    van Nes, Egbert H.
    Cuppen, Jan G. M.
    Peeters, Edwin T. H. M.
    Leijs, Remko
    Nilsson, Anders N.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    The Evolution of Functionally Redundant Species; Evidence from Beetles2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, article id e0137974Article in journal (Refereed)
    Abstract [en]

    While species fulfill many different roles in ecosystems, it has been suggested that numerous species might actually share the same function in a near neutral way. So-far, however, it is unclear whether such functional redundancy really exists. We scrutinize this question using extensive data on the world's 4168 species of diving beetles. We show that across the globe these animals have evolved towards a small number of regularly-spaced body sizes, and that locally co-existing species are either very similar in size or differ by at least 35%. Surprisingly, intermediate size differences (10-20%) are rare. As body-size strongly reflects functional aspects such as the food that these generalist predators can eat, these beetles thus form relatively distinct groups of functional look-a-likes. The striking global regularity of these patterns support the idea that a self-organizing process drives such species-rich groups to self-organize evolutionary into clusters where functional redundancy ensures resilience through an insurance effect.

  • 508.
    Schelin, Lina
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Tengman, Eva
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Häger, Charlotte
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    A statistically compiled test battery for feasible evaluation of knee function after rupture of the Anterior Cruciate Ligament - derived from long-term follow-up data.2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176247Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Clinical test batteries for evaluation of knee function after injury to the Anterior Cruciate Ligament (ACL) should be valid and feasible, while reliably capturing the outcome of rehabilitation. There is currently a lack of consensus as to which of the many available assessment tools for knee function that should be included. The present aim was to use a statistical approach to investigate the contribution of frequently used tests to avoid redundancy, and filter them down to a proposed comprehensive and yet feasible test battery for long-term evaluation after ACL injury.

    METHODS: In total 48 outcome variables related to knee function, all potentially relevant for a long-term follow-up, were included from a cross-sectional study where 70 ACL-injured (17-28 years post injury) individuals were compared to 33 controls. Cluster analysis and logistic regression were used to group variables and identify an optimal test battery, from which a summarized estimator of knee function representing various functional aspects was derived.

    RESULTS: As expected, several variables were strongly correlated, and the variables also fell into logical clusters with higher within-correlation (max ρ = 0.61) than between clusters (max ρ = 0.19). An extracted test battery with just four variables assessing one-leg balance, isokinetic knee extension strength and hop performance (one-leg hop, side hop) were mathematically combined to an estimator of knee function, which acceptably classified ACL-injured individuals and controls. This estimator, derived from objective measures, correlated significantly with self-reported function, e.g. Lysholm score (ρ = 0.66; p<0.001).

    CONCLUSIONS: The proposed test battery, based on a solid statistical approach, includes assessments which are all clinically feasible, while also covering complementary aspects of knee function. Similar test batteries could be determined for earlier phases of ACL rehabilitation or to enable longitudinal monitoring. Such developments, established on a well-grounded consensus of measurements, would facilitate comparisons of studies and enable evidence-based rehabilitation.

  • 509.
    Schiffthaler, Bastian
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Bernhardsson, Carolina
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Ingvarsson, Par K.
    Street, Nathaniel R.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    BatchMap: A parallel implementation of the OneMap R package for fast computation of F-1 linkage maps in outcrossing species2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0189256Article in journal (Refereed)
    Abstract [en]

    With the rapid advancement of high throughput sequencing, large numbers of genetic markers can be readily and cheaply acquired, but most current software packages for genetic map construction cannot handle such dense input. Modern computer architectures and server farms represent untapped resources that can be used to enable higher marker densities to be processed in tractable time. Here we present a pipeline using a modified version of OneMap that parallelizes over bottleneck functions and achieves substantial speedups for producing a high density linkage map (N = 20,000). Using simulated data we show that the outcome is as accurate as the traditional pipeline. We further demonstrate that there is a direct relationship between the number of markers used and the level of deviation between true and estimated order, which in turn impacts the final size of a genetic map.

  • 510. Schikora, Adam
    et al.
    Carreri, Alessandro
    Charpentier, Emmanuelle
    Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, Vienna, Austria.
    Hirt, Heribert
    The dark side of the salad: Salmonella typhimurium overcomes the innate immune response of Arabidopsis thaliana and shows an endopathogenic lifestyle2008In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, no 5, p. e2279-Article in journal (Refereed)
    Abstract [en]

    Salmonella enterica serovar typhimurium contaminated vegetables and fruits are considerable sources of human infections. Bacteria present in raw plant-derived nutrients cause salmonellosis, the world wide most spread food poisoning. This facultative endopathogen enters and replicates in host cells and actively suppresses host immune responses. Although Salmonella survives on plants, the underlying bacterial infection mechanisms are only poorly understood. In this report we investigated the possibility to use Arabidopsis thaliana as a genetically tractable host system to study Salmonella-plant interactions. Using green fluorescent protein (GFP) marked bacteria, we show here that Salmonella can infect various Arabidopsis tissues and proliferate in intracellular cellular compartments. Salmonella infection of Arabidopsis cells can occur via intact shoot or root tissues resulting in wilting, chlorosis and eventually death of the infected organs. Arabidopsis reacts to Salmonella by inducing the activation of mitogen-activated protein kinase (MAPK) cascades and enhanced expression of pathogenesis related (PR) genes. The induction of defense responses fails in plants that are compromised in ethylene or jasmonic acid signaling or in the MKK3-MPK6 MAPK pathway. These findings demonstrate that Arabidopsis represents a true host system for Salmonella, offering unique possibilities to study the interaction of this human pathogen with plants at the molecular level for developing novel drug targets and addressing current safety issues in human nutrition.

  • 511.
    Schmid, Martin R.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Anderl, Ines
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). BioMediTech, University of Tampere, Tampere, Finland.
    Vo, Hoa T. M.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Valanne, Susanna
    Yang, Hairu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kronhamn, Jesper
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ramet, Mika
    Rusten, Tor Erik
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). BioMediTech, University of Tampere, Tampere, Finland.
    Genetic Screen in Drosophila Larvae Links ird1 Function to Toll Signaling in the Fat Body and Hemocyte Motility2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159473Article in journal (Refereed)
    Abstract [en]

    To understand how Toll signaling controls the activation of a cellular immune response in Drosophila blood cells (hemocytes), we carried out a genetic modifier screen, looking for deletions that suppress or enhance the mobilization of sessile hemocytes by the gain-of-function mutation Toll(10b) (Tl-10b). Here we describe the results from chromosome arm 3R, where five regions strongly suppressed this phenotype. We identified the specific genes immune response deficient 1 (ird1), headcase (hdc) and possibly Rab23 as suppressors, and we studied the role of ird1 in more detail. An ird1 null mutant and a mutant that truncates the N-terminal kinase domain of the encoded Ird1 protein affected the Tl-10b phenotype, unlike mutations that affect the C-terminal part of the protein. The ird1 null mutant suppressed mobilization of sessile hemocytes, but enhanced other Tl-10b hemocyte phenotypes, like the formation of melanotic nodules and the increased number of circulating hemocytes. ird1 mutants also had blood cell phenotypes on their own. They lacked crystal cells and showed aberrant formation of lamellocytes. ird1 mutant plasmatocytes had a reduced ability to spread on an artificial substrate by forming protrusions, which may explain why they did not go into circulation in response to Toll signaling. The effect of the ird1 mutation depended mainly on ird1 expression in hemocytes, but ird1-dependent effects in other tissues may contribute. Specifically, the Toll receptor was translocated from the cell membrane to intracellular vesicles in the fat body of the ird1 mutant, and Toll signaling was activated in that tissue, partially explaining the Tl-10b-like phenotype. As ird1 is otherwise known to control vesicular transport, we conclude that the vesicular transport system may be of particular importance during an immune response.

  • 512.
    Schmid, Martin Rudolf
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Anderl, Ines
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical Technology (BioMediTech), University of Tampere, Tampere, Finland.
    Vesala, L
    Vanha-aho, L-M
    Deng, Xiao-Juan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). College of Animal Science, South China Agricultural University, Guangzhou, China.
    Rämet, M
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical Technology (BioMediTech), University of Tampere, Tampere, Finland.
    Control of Drosophila blood cell activation via toll signaling in the fat body2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, article id e102568Article in journal (Refereed)
    Abstract [en]

    The Toll signaling pathway, first discovered in Drosophila, has a well-established role in immune responses in insects as well as in mammals. In Drosophila, the Toll-dependent induction of antimicrobial peptide production has been intensely studied as a model for innate immune responses in general. Besides this humoral immune response, Toll signaling is also known to activate blood cells in a reaction that is similar to the cellular immune response to parasite infections, but the mechanisms of this response are poorly understood. Here we have studied this response in detail, and found that Toll signaling in several different tissues can activate a cellular immune defense, and that this response does not require Toll signaling in the blood cells themselves. Like in the humoral immune response, we show that Toll signaling in the fat body (analogous to the liver in vertebrates) is of major importance in the Toll-dependent activation of blood cells. However, this Toll-dependent mechanism of blood cell activation contributes very little to the immune response against the parasitoid wasp, Leptopilina boulardi, probably because the wasp is able to suppress Toll induction. Other redundant pathways may be more important in the defense against this pathogen.

  • 513.
    Schröders, Julia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wall, Stig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hakimi, Mohammad
    Dewi, Fatwa Sari Tetra
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Nichter, Mark
    Nilsson, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Kusnanto, Hari
    Rahajeng, Ekowati
    Ng, Nawi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    How is Indonesia coping with its epidemic of chronic noncommunicable diseases?: A systematic review with meta-analysis2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179186Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic noncommunicable diseases (NCDs) have emerged as a huge global health problem in low- and middle-income countries. The magnitude of the rise of NCDs is particularly visible in Southeast Asia where limited resources have been used to address this rising epidemic, as in the case of Indonesia. Robust evidence to measure growing NCD-related burdens at national and local levels and to aid national discussion on social determinants of health and intra-country inequalities is needed. The aim of this review is (i) to illustrate the burden of risk factors, morbidity, disability, and mortality related to NCDs; (ii) to identify existing policy and community interventions, including disease prevention and management strategies; and (iii) to investigate how and why an inequitable distribution of this burden can be explained in terms of the social determinants of health.

    METHODS: Our review followed the PRISMA guidelines for identifying, screening, and checking the eligibility and quality of relevant literature. We systematically searched electronic databases and gray literature for English- and Indonesian-language studies published between Jan 1, 2000 and October 1, 2015. We synthesized included studies in the form of a narrative synthesis and where possible meta-analyzed their data.

    RESULTS: On the basis of deductive qualitative content analysis, 130 included citations were grouped into seven topic areas: risk factors; morbidity; disability; mortality; disease management; interventions and prevention; and social determinants of health. A quantitative synthesis meta-analyzed a subset of studies related to the risk factors smoking, obesity, and hypertension.

    CONCLUSIONS: Our findings echo the urgent need to expand routine risk factor surveillance and outcome monitoring and to integrate these into one national health information system. There is a stringent necessity to reorient and enhance health system responses to offer effective, realistic, and affordable ways to prevent and control NCDs through cost-effective interventions and a more structured approach to the delivery of high-quality primary care and equitable prevention and treatment strategies. Research on social determinants of health and policy-relevant research need to be expanded and strengthened to the extent that a reduction of the total NCD burden and inequalities therein should be treated as related and mutually reinforcing priorities.

  • 514.
    Schröders, Julia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wall, Stig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Kusnanto, Hari
    Ng, Nawi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Millennium Development Goal Four and Child Health Inequities in Indonesia: A Systematic Review of the Literature2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0123629Article, review/survey (Refereed)
    Abstract [en]

    Introduction Millennium Development Goal (MDG) 4 calls for reducing mortality of children under-five years by two-thirds by 2015. Indonesia is on track to officially meet the MDG 4 targets by 2015 but progress has been far from universal. It has been argued that national level statistics, on which MDG 4 relies, obscure persistent health inequities within the country. Particularly inequities in child health are a major global public health challenge both for achieving MDG 4 in 2015 and beyond. This review aims to map out the situation of MDG 4 with respect to disadvantaged populations in Indonesia applying the Social Determinants of Health (SDH) framework. The specific objectives are to answer: Who are the disadvantaged populations? Where do they live? And why and how is the inequitable distribution of health explained in terms of the SDH framework?

    Methods and Findings We retrieved studies through a systematic review of peer-reviewed and gray literature published in 1995-2014. The PRISMA-Equity 2012 statement was adapted to guide the methods of this review. The dependent variables were MDG 4-related indicators; the independent variable "disadvantaged populations" was defined by different categories of social differentiation using PROGRESS. Included texts were analyzed following the guidelines for deductive content analysis operationalized on the basis of the SDH framework. We identified 83 studies establishing evidence on more than 40 different determinants hindering an equitable distribution of child health in Indonesia. The most prominent determinants arise from the shortcomings within the rural health care system, the repercussions of food poverty coupled with low health literacy among parents, the impact of low household decision-making power of mothers, and the consequences of high persistent use of traditional birth attendants among ethnic minorities.

    Conclusion This review calls for enhanced understanding of the determinants and pathways that create, detain, and overcome inequities in child health in resource constraint settings like Indonesia and the promotion of actionable health policy recommendations and tailored investments.

  • 515. Schueler, Wolfgang
    et al.
    Bunikis, Ignas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Weber-Lehman, Jacqueline
    Comstedt, Paer
    Kutschan-Bunikis, Sabrina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Stanek, Gerold
    Huber, Jutta
    Meinke, Andreas
    Bergstrom, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundberg, Urban
    Complete Genome Sequence of Borrelia afzelii K78 and Comparative Genome Analysis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3Article in journal (Refereed)
    Abstract [en]

    The main Borrelia species causing Lyme borreliosis in Europe and Asia are Borrelia afzelii, B. garinii, B. burgdorferi and B. bavariensis. This is in contrast to the United States, where infections are exclusively caused by B. burgdorferi. Until to date the genome sequences of four B. afzelii strains, of which only two include the numerous plasmids, are available. In order to further assess the genetic diversity of B. afzelii, the most common species in Europe, responsible for the large variety of clinical manifestations of Lyme borreliosis, we have determined the full genome sequence of the B. afzelii strain K78, a clinical isolate from Austria. The K78 genome contains a linear chromosome (905,949 bp) and 13 plasmids (8 linear and 5 circular) together presenting 1,309 open reading frames of which 496 are located on plasmids. With the exception of lp28-8, all linear replicons in their full length including their telomeres have been sequenced. The comparison with the genomes of the four other B. afzelii strains, ACA-1, PKo, HLJ01 and Tom3107, as well as the one of B. burgdorferi strain B31, confirmed a high degree of conservation within the linear chromosome of B. afzelii, whereas plasmid encoded genes showed a much larger diversity. Since some plasmids present in B. burgdorferi are missing in the B. afzelii genomes, the corresponding virulence factors of B. burgdorferi are found in B. afzelii on other unrelated plasmids. In addition, we have identified a species specific region in the circular plasmid, cp26, which could be used for species determination. Different non-coding RNAs have been located on the B. afzelii K78 genome, which have not previously been annotated in any of the published Borrelia genomes.

  • 516.
    Schumann, Barbara
    et al.
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Häggström Lundevaller, Erling
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Lena, Karlsson
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Social Sciences, Department of Sociology.
    Weather extremes and perinatal mortality - Seasonal and ethnic differences in northern Sweden, 1800-18952019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 10, article id e0223538Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Many studies have shown the impact of heat and cold on total and age-specific mortality, but knowledge gaps remain regarding weather vulnerability of very young infants. This study assessed the association of temperature extremes with perinatal mortality (stillbirths and deaths in the first week of life), among two ethnic groups in pre-industrial northern Sweden.

    METHODS: We used population data of indigenous Sami and non-Sami in selected parishes of northern Sweden, 1800-1895, and monthly temperature data. Multiple logistic regression models were conducted to estimate the association of cold (<10th percentile of temperature) and warmth (>90th percentile) in the month of birth with perinatal mortality, adjusted for cold and warmth in the month prior birth and period, stratified by season and ethnicity.

    RESULTS: Perinatal mortality was slightly higher in Sami than in non-Sami (46 vs. 42 / 1000 live and stillbirths), but showed large variations across the region and over time. Both groups saw the highest perinatal mortality in autumn. For Sami, winter was a high-risk time as well, while for non-Sami, seasonality was less distinct. We found an association between exposure to cold and perinatal mortality among winter-born Sami [Odds ratio (OR) 1.91, 95% confidence interval (CI) 1.26-2.92, compared to moderate temperature], while there was little effect of cold or warmth during other seasons. Non-Sami, meanwhile, were affected in summer by warmth (OR 0.20, CI 0.05-0.81), and in autumn by cold (OR 0.39, CI 0.19-0.82).

    CONCLUSIONS: In this pre-industrial, subarctic setting, the indigenous Sami's perinatal mortality was influenced by extreme cold in winter, while non-Sami seemed to benefit from high temperature in summer and low temperature in autumn. Climate vulnerability of these two ethnic groups sharing the same environment was shaped by their specific lifestyles and living conditions.

  • 517.
    Semasaka Sengoma, Jean Paul
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. University of Rwanda College of Medicine and Health Sciences School of Public Health, Kigali, Rwanda.
    Krantz, Gunilla
    University of Gothenburg.
    Nzayirambaho, Manasse
    University of Rwanda.
    Munyanshongore, Cyprien
    University of Rwanda.
    Edvardsson, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Judith Lumley Centre, La Trobe University, Melbourne, Australia.
    Mogren, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Judith Lumley Centre, La Trobe University, Melbourne, Australia.
    “Not taken seriously”: A qualitative interview study of postpartum Rwandan women who have experienced pregnancy-related complications2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0212001Article in journal (Refereed)
    Abstract [en]

    Background: There is limited knowledge on the women’s experiences of pregnancy-related complications in Rwanda. This study aimed to investigate women’s experiences and perceptions of specific complications during pregnancy and delivery and the consequences of these complications on postpartum health and family situation.

    Methods: Data were collected through individual in-depth interviews (N = 15). Participants who experienced complications such as postpartum haemorrhage, caesarean section due to prolonged labour/dystocia, pre-eclampsia, or fistula and who were 13–24 months postpartum were invited to participate in the study in July 2015. Interviews were held in Kinyarwanda, digitally recorded, transcribed verbatim, translated into English, and analysed using qualitative content analysis.

    Results: Most participants reported that they were previously unaware of the complications they had developed, and they claimed that at discharge they should have been better informed about the potential consequences of these complications. Most participants blamed the health care system as the cause of their problems due to the provision of inadequate care. Participants elaborated different strategies for coping with persistent health problems. Pregnancy-related complications negatively affected participants’ economic situation due to increased health care expenses and lowered income because of impaired working capacity, and participants expressed fear of encountering the same pregnancy-related health problems during future pregnancies.

    Conclusions: The findings of this study demonstrate how participants felt that inadequate health care provision during pregnancy, delivery, and the postpartum period was the source of their problems. Participants reported different coping strategies to improve their respective life situation despite persistent health problems. Women’s individual postpartum experiences need to be considered and actions taken at the policy level and also by the local community, in terms of the quality of antenatal and postpartum care services, and in sensitizing the local community about the existence of these complications and preparing the community to support the affected women.

  • 518.
    Sewe, Maquins Odhiambo
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. KEMRI Centre for Global Health Research, Kisumu, Kenya.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Remotely Sensed Environmental Conditions and Malaria Mortality in Three Malaria Endemic Regions in Western Kenya2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0154204Article in journal (Refereed)
    Abstract [en]

    Background

    Malaria is an important cause of morbidity and mortality in malaria endemic countries. The malaria mosquito vectors depend on environmental conditions, such as temperature and rainfall, for reproduction and survival. To investigate the potential for weather driven early warning systems to prevent disease occurrence, the disease relationship to weather conditions need to be carefully investigated. Where meteorological observations are scarce, satellite derived products provide new opportunities to study the disease patterns depending on remotely sensed variables. In this study, we explored the lagged association of Normalized Difference Vegetation Index (NVDI), day Land Surface Temperature (LST) and precipitation on malaria mortality in three areas in Western Kenya.

    Methodology and Findings

    The lagged effect of each environmental variable on weekly malaria mortality was modeled using a Distributed Lag Non Linear Modeling approach. For each variable we constructed a natural spline basis with 3 degrees of freedom for both the lag dimension and the variable. Lag periods up to 12 weeks were considered. The effect of day LST varied between the areas with longer lags. In all the three areas, malaria mortality was associated with precipitation. The risk increased with increasing weekly total precipitation above 20 mm and peaking at 80 mm. The NDVI threshold for increased mortality risk was between 0.3 and 0.4 at shorter lags.

    Conclusion

    This study identified lag patterns and association of remote- sensing environmental factors and malaria mortality in three malaria endemic regions in Western Kenya. Our results show that rainfall has the most consistent predictive pattern to malaria transmission in the endemic study area. Results highlight a potential for development of locally based early warning forecasts that could potentially reduce the disease burden by enabling timely control actions.

  • 519.
    Shen, Yue
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Guo, Yongzhi
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Du, Chun
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wilczynska, Malgorzata
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hellström, Sten
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51303-Article in journal (Refereed)
    Abstract [en]

    Mice deficient in plasminogen, the precursor of plasmin, show completely arrested healing of tympanic membrane (TM) perforations, indicating that plasmin plays an essential role in TM healing. The activation of plasminogen to plasmin is performed by two plasminogen activators (PAs), urokinase-type PA (uPA) and tissue-type PA (tPA). To elucidate the functional roles of PAs in the healing of TM perforations, we investigated the phenotypes of single gene-deficient mice lacking uPA (uPA(-/-)) or tPA (tPA(-/-)) after TM perforation. Delayed healing of TM perforations was observed in uPA(-/-) mice but not tPA(-/-) mice. The migration of keratinocytes was clearly delayed and seemed to be misoriented in uPA(-/-) mice. Furthermore, fibrin deposition and the inflammatory response were persistent in these mice. Our findings demonstrate that uPA plays a role in the healing of TM perforations. The observed phenotypes in uPA(-/-) mice are most likely due to the reduced generation of plasmin.

  • 520.
    Sheng, Ming
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hosseinzadeh, Ava
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Muralidharan, Somsundar Veppil
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gaur, Rahul
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Selstam, Eva
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Tuck, Simon
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Aberrant Fat Metabolism in Caenorhabditis elegans Mutants with Defects in the Defecation Motor Program2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0124515Article in journal (Refereed)
    Abstract [en]

    The molecular mechanisms by which dietary fatty acids are absorbed by the intestine, and the way in which the process is regulated are poorly understood. In a genetic screen for mutations affecting fat accumulation in the intestine of Caenorhabditis elegans, nematode worms, we have isolated mutations in the aex-5 gene, which encodes a Kex2/subtilisinfamily, Ca2+-sensitive proprotein convertase known to be required for maturation of certain neuropeptides, and for a discrete step in an ultradian rhythmic phenomenon called the defecation motor program. We demonstrate that aex-5 mutants have markedly lower steadystate levels of fat in the intestine, and that this defect is associated with a significant reduction in the rate at which labeled fatty acid derivatives are taken up from the intestinal lumen. Other mutations affecting the defecation motor program also affect steady-state levels of triglycerides, suggesting that the program is required per se for the proper accumulation of neutral lipids. Our results suggest that an important function of the defecation motor program in C. elegans is to promote the uptake of an important class of dietary nutrients. They also imply that modulation of the program might be one way in which worms adjust nutrient uptake in response to altered metabolic status.

  • 521.
    Shirinian, Margret
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Popovic, Milica
    Grabbe, Caroline
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Varshney, Gaurav
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hugosson, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bos, Hans
    Rehmann, Holger
    Palmer, Ruth H
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The Rap1 guanine nucleotide exchange factor C3G is required for preservation of larval muscle integrity in Drosophila melanogaster2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 3, article id e9403Article in journal (Refereed)
    Abstract [en]

    C3G is a guanine nucleotide exchange factor (GEF) and modulator of small G-protein activity, which primarily acts on members of the Rap GTPase subfamily. Via promotion of the active GTP bound conformation of target GTPases, C3G has been implicated in the regulation of multiple cellular and developmental events including proliferation, differentiation and apoptosis. The Drosophila C3G orthologue exhibits a domain organization similar to that of vertebrate C3G. Through deletion of the C3G locus, we have observed that loss of C3G causes semi-lethality, and that escaping adult flies are characterized by a reduction in lifespan and general fitness. In situ hybridization reveals C3G expression in the developing embryonic somatic and visceral muscles, and indeed analysis of C3G mutants suggests essential functions of C3G for normal body wall muscle development during larval stages. C3G mutants display abnormal muscle morphology and attachment, as well as failure to properly localize betaPS integrins to muscle attachment sites. Moreover, we show that C3G stimulates guanine nucleotide exchange on Drosophila Rap GTPases in vitro. Taken together, we conclude that Drosophila C3G is a Rap1-specific GEF with important functions in maintaining muscle integrity during larval stages.

  • 522. Shrestha, Niraj
    et al.
    Boucher, Justin
    Bahnan, Wael
    Clark, Emily S.
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Fields, Kenneth A.
    Khan, Wasif N.
    Schesser, Kurt
    The Host-Encoded Heme Regulated Inhibitor (HRI) Facilitates Virulence-Associated Activities of Bacterial Pathogens2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68754-Article in journal (Refereed)
    Abstract [en]

    Here we show that cells lacking the heme-regulated inhibitor (HRI) are highly resistant to infection by bacterial pathogens. By examining the infection process in wild-type and HRI null cells, we found that HRI is required for pathogens to execute their virulence-associated cellular activities. Specifically, unlike wild-type cells, HRI null cells infected with the gram-negative bacterial pathogen Yersinia are essentially impervious to the cytoskeleton-damaging effects of the Yop virulence factors. This effect is due to reduced functioning of the Yersinia type 3 secretion (T3S) system which injects virulence factors directly into the host cell cytosol. Reduced T3S activity is also observed in HRI null cells infected with the bacterial pathogen Chlamydia which results in a dramatic reduction in its intracellular proliferation. We go on to show that a HRI-mediated process plays a central role in the cellular infection cycle of the Gram-positive pathogen Listeria. For this pathogen, HRI is required for the post-invasion trafficking of the bacterium to the infected host cytosol. Thus by depriving Listeria of its intracellular niche, there is a highly reduced proliferation of Listeria in HRI null cells. We provide evidence that these infection-associated functions of HRI (an eIF2 alpha kinase) are independent of its activity as a regulator of protein synthesis. This is the first report of a host factor whose absence interferes with the function of T3S secretion and cytosolic access by pathogens and makes HRI an excellent target for inhibitors due to its broad virulence-associated activities.

  • 523.
    Silver, Jim
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Transduction and oncolytic profile of a potent replication-competent adenovirus 11p vector (RCAd11pGFP) in colon carcinoma cells2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e17532-Article in journal (Refereed)
    Abstract [en]

    Replication-competent adenovirus type 5 (Ad5) vectors promise to be more efficient gene delivery vehicles than their replication-deficient counterparts, and chimeric Ad5 vectors that are capable of targeting CD46 are more effective than Ad5 vectors with native fibers. Although several strategies have been used to improve gene transduction and oncolysis, either by modifying their tropism or enhancing their replication capacity, some tumor cells are still relatively refractory to infection by chimeric Ad5. The oncolytic effects of the vectors are apparent in certain tumors but not in others. Here, we report the biological and oncolytic profiles of a replication-competent adenovirus 11p vector (RCAd11pGFP) in colon carcinoma cells. CD46 was abundantly expressed in all cells studied; however, the transduction efficiency of RCAd11pGFP varied. RCAd11pGFP efficiently transduced HT-29, HCT-8, and LS174T cells, but it transduced T84 cells, derived from a colon cancer metastasis in the lung, less efficiently. Interestingly, RCAd11p replicated more rapidly in the T84 cells than in HCT-8 and LS174T cells and as rapidly as in HT-29 cells. Cell toxicity and proliferation assays indicated that RCAd11pGFP had the highest cell-killing activities in HT29 and T84 cells, the latter of which also expressed the highest levels of glycoproteins of the carcinoma embryonic antigen (CEA) family. In vivo experiments showed significant growth inhibition of T84 and HT-29 tumors in xenograft mice treated with either RCAd11pGFP or Ad11pwt compared to untreated controls. Thus, RCAd11pGFP has a potent cytotoxic effect on colon carcinoma cells.

  • 524. Sinclair, Rachael
    et al.
    Millar, Lynne
    Allender, Steven
    Snowdon, Wendy
    Waqa, Gade
    Jacka, Felice
    Moodie, Marj
    Petersen, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Swinburn, Boyd
    The Cross-Sectional Association between Diet Quality and Depressive Symptomology amongst Fijian Adolescents2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0161709Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the relationship between diet quality and depressive symptomology amongst a community-based sample of Fijian adolescents.

    METHODS: Participants included 7,237 adolescents (52.6% girls; mean age 15.6 years) at baseline (2005) and 2,948 (56% girls; mean age 17.4 years) at follow-up (2007/2008), from the Pacific Obesity Prevention in Communities Project. Intervention schools (n = 7) were selected from Nasinu, near Suva on the main Fijian island Viti Levu, and comparison schools (n = 11) were chosen from towns on the opposite, west side of the island. A dietary questionnaire was used to measure diet quality. Factor analysis clustered dietary variables into two unique and independent factors, referred to as healthy diet quality and unhealthy diet quality. Depressive symptomology was assessed via the emotional subscale of the Paediatric Quality of Life Inventory. Both measures were self-reported and self-administered. Multiple linear regression was used to test cross-sectional associations (at baseline and follow-up) between diet quality and depressive symptomology. Variables controlled for included gender, age, ethnicity, study condition, BMI-z scores, and physical activity.

    FINDINGS: Strong, positive dose-response associations between healthy diet and high emotional scores (lower depressive symptomology) were found in cross-sectional analyses at baseline and follow-up, among boys and girls. No association was found between emotional health and unhealthy diet.

    CONCLUSIONS: This study suggests that cross-sectional relationships exist between a high quality diet during adolescence and less depressive symptoms, however more evidence is required to determine if these two variables are linked causally. Trial population health strategies that use dietary interventions as a mechanism for mental health promotion provide an opportunity to further test these associations. If this is indeed a true relationship, these forms of interventions have the potential to be inexpensive and have substantial reach, especially in Low and Middle Income Countries.

    TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12608000345381.

  • 525. Singer, Andrew C.
    et al.
    Järhult, Josef D.
    Grabic, Roman
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Khan, Ghazanfar A.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fedorova, Ganna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fick, Jerker
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindberg, Richard H.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bowes, Michael J.
    Olsen, Björn
    Söderström, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Compliance to Oseltamivir among two populations in Oxfordshire, United Kingdom affected by influenza A(H1N1)pdm09, November 2009: a waste water epidemiology study2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, article id e60221Article in journal (Refereed)
    Abstract [en]

    Antiviral provision remains the focus of many pandemic preparedness plans, however, there is considerable uncertainty regarding antiviral compliance rates. Here we employ a waste water epidemiology approach to estimate oseltamivir (Tamiflu®) compliance. Oseltamivir carboxylate (oseltamivir's active metabolite) was recovered from two waste water treatment plant (WWTP) catchments within the United Kingdom at the peak of the autumnal wave of the 2009 Influenza A (H1N1)pdm09 pandemic. Predictions of oseltamivir consumption from detected levels were compared with two sources of national government statistics to derive compliance rates. Scenario and sensitivity analysis indicated between 3-4 and 120-154 people were using oseltamivir during the study period in the two WWTP catchments and a compliance rate between 45-60%. With approximately half the collected antivirals going unused, there is a clear need to alter public health messages to improve compliance. We argue that a near real-time understanding of drug compliance at the scale of the waste water treatment plant (hundreds to millions of people) can potentially help public health messages become more timely, targeted, and demographically sensitive, while potentially leading to less mis- and un-used antiviral, less wastage and ultimately a more robust and efficacious pandemic preparedness plan.

  • 526. Singer, Andrew C
    et al.
    Järhult, Josef D
    Grabic, Roman
    Umeå University, Faculty of Science and Technology, Department of Chemistry. University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Vodnany, Czech Republic.
    Khan, Ghazanfar A
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindberg, Richard H
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fedorova, Ganna
    Umeå University, Faculty of Science and Technology, Department of Chemistry. University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Vodnany, Czech Republic.
    Fick, Jerker
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bowes, Michael J
    Olsen, Björn
    Söderström, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108621-Article in journal (Refereed)
    Abstract [en]

    The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin), three decongestants (naphazoline, oxymetazoline, xylometazoline) and the antiviral drug oseltamivir's active metabolite, oseltamivir carboxylate (OC), were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010) and the inter-pandemic periods (May 2011). A large and small wastewater treatment plant (WWTP) were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP's influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively). Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max = 6,870 and 2,930 ng/L, respectively). Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L) and effluent (696 and 307 ng/L), respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009's weekly river samples (max = 193 ng/L), but only in 5% and 0% of the late-and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17-74 ng/L, with clarithromycin (max = 292 ng/L) and erythromycin (max = 448 ng/L) yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater epidemiology approach owing to its nature as a prodrug, recalcitrance and temporally-and spatially-resolved prescription statistics.

  • 527.
    Sircova, Anna
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology. Independent researcher, Copenhagen, Denmark.
    Karimi, Fariba
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Osin, Evgeny N.
    Lee, Sungmin
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Holme, Petter
    Umeå University, Faculty of Science and Technology, Department of Physics. Department of Energy Science, Sungkyunkwan University, Suwon, Korea.
    Strömbom, Daniel
    Simulating irrational human behavior to prevent resource depletion2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0117612Article in journal (Refereed)
    Abstract [en]

    In a situation with a limited common resource, cooperation between individuals sharing the resource is essential. However, people often act upon self-interest in irrational ways that threaten the long-term survival of the whole group. A lack of sustainable or environmentally responsible behavior is often observed. In this study, we examine how the maximization of benefits principle works in a wider social interactive context of personality preferences in order to gain a more realistic insight into the evolution of cooperation. We used time perspective (TP), a concept reflecting individual differences in orientation towards past, present, or future, and relevant for making sustainable choices. We developed a personality-driven agent-based model that explores the role of personality in the outcomes of social dilemmas and includes multiple facets of diversity: (1) The agents have different behavior strategies: individual differences derived by applying cluster analysis to survey data from 22 countries (N = 10,940) and resulting in 7 cross-cultural profiles of TP; (2) The non-uniform distribution of the types of agents across countries; (3) The diverse interactions between the agents; and (4) diverse responses to those interactions in a well-mixed population. As one of the results, we introduced an index of overall cooperation for each of the 22 countries, which was validated against cultural, economic, and sustainability indicators (HDI, dimensions of national culture, and Environment Performance Index). It was associated with higher human development, higher individualism, lower power distance, and better environmental performance. The findings illustrate how individual differences in TP can be simulated to predict the ways people in different countries solve the personal vs. common gain dilemma in the global limited-resource situation. This interdisciplinary approach to social simulation can be adopted to explain the possible causes of global environmental issues and to predict their possible outcomes.

  • 528.
    Sjöberg, Veronika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hedberg, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Intestinal T-cell responses in celiac disease: impact of celiac disease associated bacteria2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53414-Article in journal (Refereed)
    Abstract [en]

    A hallmark of active celiac disease (CD), an inflammatory small-bowel enteropathy caused by permanent intolerance to gluten, is cytokine production by intestinal T lymphocytes. Prerequisites for contracting CD are that the individual carries the MHC class II alleles HLA-DQ2 and/or HLA-DQ8 and is exposed to gluten in the diet. Dysbiosis in the resident microbiota has been suggested to be another risk factor for CD. In fact, rod shaped bacteria adhering to the small intestinal mucosa were frequently seen in patients with CD during the "Swedish CD epidemic" and bacterial candidates could later be isolated from patients born during the epidemic suggesting long-lasting changes in the gut microbiota. Interleukin-17A (IL-17A) plays a role in both inflammation and anti-bacterial responses. In active CD IL-17A was produced by both CD8(+) T cells (Tc17) and CD4(+) T cells (Th17), with intraepithelial Tc17 cells being the dominant producers. Gluten peptides as well as CD associated bacteria induced IL-17A responses in ex vivo challenged biopsies from patients with inactive CD. The IL-17A response was suppressed in patients born during the epidemic when a mixture of CD associated bacteria was added to gluten, while the reverse was the case in patients born after the epidemic. Under these conditions Th17 cells were the dominant producers. Thus Tc17 and Th17 responses to gluten and bacteria seem to pave the way for the chronic disease with interferon-γ-production by intraepithelial Tc1 cells and lamina propria Th1 cells. The CD associated bacteria and the dysbiosis they might cause in the resident microbiota may be a risk factor for CD either by directly influencing the immune responses in the mucosa or by enhancing inflammatory responses to gluten.

  • 529.
    Sjödin, Andreas
    et al.
    Division of CBRN Security and Defence, FOI - Swedish Defence Research Agency, Umeå, Sweden.
    Svensson, Kerstin
    Division of CBRN Security and Defence, FOI - Swedish Defence Research Agency, Umeå, Sweden.
    Lindgren, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Forsman, Mats
    Division of CBRN Security and Defence, FOI - Swedish Defence Research Agency, Umeå, Sweden.
    Larsson, Pär
    Division of CBRN Security and Defence, FOI - Swedish Defence Research Agency, Umeå, Sweden.
    Whole-genome sequencing reveals distinct mutational patterns in closely related laboratory and naturally propagated Francisella tularensis strains2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 7, p. e11556-Article in journal (Refereed)
    Abstract [en]

    The F. tularensis type A strain FSC198 from Slovakia and a second strain FSC043, which has attenuated virulence, are both considered to be derivatives of the North American F. tularensis type A strain SCHU S4. These strains have been propagated under different conditions: the FSC198 has undergone natural propagation in the environment, while the strain FSC043 has been cultivated on artificial media in laboratories. Here, we have compared the genome sequences of FSC198, FSC043, and SCHU S4 to explore the possibility that the contrasting propagation conditions may have resulted in different mutational patterns. We found four insertion/deletion events (INDELs) in the strain FSC043, as compared to the SCHU S4, while no single nucleotide polymorphisms (SNPs) or variable number of tandem repeats (VNTRs) were identified. This result contrasts with previously reported findings for the strain FSC198, where eight SNPs and three VNTR differences, but no INDELs exist as compared to the SCHU S4 strain. The mutations detected in the laboratory and naturally propagated type A strains, respectively, demonstrate distinct patterns supporting that analysis of mutational spectra might be a useful tool to reveal differences in past growth conditions. Such information may be useful to identify leads in a microbial forensic investigation.

  • 530.
    Sjögren, Vilhelm
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Byström, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Renlund, Henrik
    Svensson, Peter J.
    Oldgren, Jonas
    Norrving, Bo
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Non-vitamin K oral anticoagulants are non-inferior for stroke prevention but cause fewer major bleedings than well-managed warfarin: a retrospective register study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, article id e0181000Article in journal (Refereed)
    Abstract [en]

    Background For patients with atrial fibrillation, non-vitamin K oral anticoagulants, or NOACs (dabigatran, rivaroxaban, edoxaban, and apixaban) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, and in risk of haemorrhage. In the pivotal NOAC studies, quality of warfarin treatment was poor with mean time in therapeutic range (TTR) 55-65%, compared with >= 70% in Swedish clinical practice. Methods We compared NOACs (as a group) to warfarin in non-valvular atrial fibrillation, studying all 12,694 patients starting NOAC treatment within the Swedish clinical register and dosing system Auricula, from July 1, 2011 to December 31, 2014, and matching them to 36,317 patients starting warfarin using propensity scoring. Endpoints were thromboembolic events and major bleedings that were fatal or required hospital care. Outcome data were collected from validated Swedish hospital administrative and clinical registers. Results Mean age was 72.2 vs 72.3 years, proportion of males 58.2% vs 57.0%, and mean follow-up time 299 vs 283 days for NOACs and warfarin. Distribution of NOACs was: dabigatran 40.3%, rivaroxaban 31.2%, and apixaban 28.5%. Mean TTR was 70%. There were no significant differences in rates of thromboembolic/thrombotic events or gastrointestinal bleeding. NOAC treated patients had lower rates of major bleeding overall, hazard ratio 0.78 (95% confidence interval 0.67-0.92), intracranial bleeding 0.59 (0.40-0.87), haemorrhagic stroke 0.49 (0.28-0.86), and other major bleeding 0.71 (0.57-0.89). Conclusion For patients with atrial fibrillation, NOACs are as effective for stroke prevention as well-managed warfarin but cause fewer major bleedings.

  • 531. Sjölund, Jonas
    et al.
    Boström, Anna-Karin
    Lindgren, David
    Manna, Sugata
    Moustakas, Aristidis
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Martin
    Fredlund, Erik
    Axelson, Håkan
    The notch and TGF-β signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23057-Article in journal (Refereed)
    Abstract [en]

    An extensive cross-talk between the Notch and TGF-β signaling cascades is present in CCRCC and the functional properties of these two pathways are associated with the aggressiveness of this disease.

  • 532. Sjöwall, Johanna
    et al.
    Fryland, Linda
    Nordberg, Marika
    Sjögren, Florence
    Garpmo, Ulf
    Jansson, Christian
    Carlsson, Sten-Anders
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ernerudh, Jan
    Nyman, Dag
    Forsberg, Pia
    Ekerfelt, Christina
    Decreased Th1-type inflammatory cytokine expression in the skin is associated with persisting symptoms after treatment of erythema migrans2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e18220-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e.g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome.

    METHODS: A prospective follow-up study of 109 patients with EM was conducted at the Åland Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-γ, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines.

    FINDINGS: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-γ in the EM biopsies (p=0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels.

    CONCLUSION: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.

  • 533. Skogberg, Gabriel
    et al.
    Gudmundsdottir, Judith
    van der Post, Sjoerd
    Sandström, Kerstin
    Bruhn, Sören
    Benson, Mikael
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Telemo, Esbjörn
    Ekwall, Olov
    Characterization of human thymic exosomes2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e67554-Article in journal (Refereed)
    Abstract [en]

    Exosomes are nanosized membrane-bound vesicles that are released by various cell types and are capable of carrying proteins, lipids and RNAs which can be delivered to recipient cells. Exosomes play a role in intercellular communication and have been described to mediate immunologic information. In this article we report the first isolation and characterization of exosomes from human thymic tissue. Using electron microscopy, particle size determination, density gradient measurement, flow cytometry, proteomic analysis and microRNA profiling we describe the morphology, size, density, protein composition and microRNA content of human thymic exosomes. The thymic exosomes share characteristics with previously described exosomes such as antigen presentation molecules, but they also exhibit thymus specific features regarding surface markers, protein content and microRNA profile. Interestingly, thymic exosomes carry proteins that have a tissue restricted expression in the periphery which may suggest a role in T cell selection and the induction of central tolerance. We speculate that thymic exosomes may provide the means for intercellular information exchange necessary for negative selection and regulatory T cell formation of the developing thymocytes within the human thymic medulla.

  • 534.
    Sloniecka, Marta
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Le Roux, Sandrine
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Boman, Peter
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Zhou, Qingjun
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Qingdao, China.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Expression Profiles of Neuropeptides, Neurotransmitters, and Their Receptors in Human Keratocytes In Vitro and In Situ2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0134157Article in journal (Refereed)
    Abstract [en]

    Keratocytes, the quiescent cells of the corneal stroma, play a crucial role in corneal wound healing. Neuropeptides and neurotransmitters are usually associated with neuronal signaling, but have recently been shown to be produced also by non-neuronal cells and to be involved in many cellular processes. The aim of this study was to assess the endogenous intracellular and secreted levels of the neuropeptides substance P (SP) and neurokinin A (NKA), and of the neurotransmitters acetylcholine (ACh), catecholamines (adrenaline, noradrenaline and dopamine), and glutamate, as well as the expression profiles of their receptors, in human primary keratocytes in vitro and in keratocytes of human corneal tissue sections in situ. Cultured keratocytes expressed genes encoding for SP and NKA, and for catecholamine and glutamate synthesizing enzymes, as well as genes for neuropeptide, adrenergic and ACh (muscarinic) receptors. Keratocytes in culture produced SP, NKA, catecholamines, ACh, and glutamate, and expressed neurokinin-1 and -2 receptors (NK-1R and NK-2R), dopamine receptor D-2, muscarinic ACh receptors, and NDMAR1 glutamate receptor. Human corneal sections expressed SP, NKA, NK-1R, NK-2R, receptor D2, choline acetyl transferase (ChAT), M-3, M4 and M-5 muscarinic ACh receptors, glutamate, and NMDAR1, but not catecholamine synthesizing enzyme or the alpha(1) and beta(2) adrenoreceptors, nor M1 receptor. In addition, expression profiles assumed significant differences between keratocytes from the peripheral cornea as compared to those from the central cornea, as well as differences between keratocytes cultured under various serum concentrations. In conclusion, human keratocytes express an array of neuropeptides and neurotransmitters. The cells furthermore express receptors for neuropeptides/neurotransmitters, which suggests that they are susceptible to stimulation by these substances in the cornea, whether of neuronal or non-neuronal origin. As it has been shown that neuropeptides/neurotransmitters are involved in cell proliferation, migration, and angiogenesis, it is possible that they play a role in corneal wound healing.

  • 535. Sluik, Diewertje
    et al.
    Boeing, Heiner
    Montonen, Jukka
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Sandbaek, Annelli
    Overvad, Kim
    Arriola, Larraitz
    Ardanaz, Eva
    Saieva, Calogero
    Grioni, Sara
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Spijkerman, Annemieke M. W.
    van der A, Daphne L.
    Beulens, Joline W. J.
    van Dieren, Susan
    Nilsson, Peter M.
    Groop, Leif C.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Bueno-de-Mesquita, Bas
    Noethlings, Ute
    HbA(1c) Measured in Stored Erythrocytes Is Positively Linearly Associated with Mortality in Individuals with Diabetes Mellitus2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e38877-Article in journal (Refereed)
    Abstract [en]

    Introduction: Observational studies have shown that glycated haemoglobin (HbA(1c)) is related to mortality, but the shape of the association is less clear. Furthermore, disease duration and medication may modify this association. This observational study explored the association between HbA(1c) measured in stored erythrocytes and mortality. Secondly, it was assessed whether disease duration and medication use influenced the estimates or were independently associated with mortality. Methods: Within the European Prospective Investigation into Cancer and Nutrition a cohort was analysed of 4,345 individuals with a confirmed diagnosis of diabetes at enrolment. HbA(1c) was measured in blood samples stored up to 19 years. Multivariable Cox proportional hazard regression models for all-cause mortality investigated HbA(1c) in quartiles as well as per 1% increment, diabetes medication in seven categories of insulin and oral hypoglycaemic agents, and disease duration in quartiles. Results: After a median follow-up of 9.3 years, 460 participants died. Higher HbA(1c) was associated with higher mortality: Hazard Ratio for 1%-increase was 1.11 (95% CI 1.06, 1.17). This association was linear (P-nonlinearity = 0.15) and persistent across categories of medication use, disease duration, and co-morbidities. Compared with metformin, other medication types were not associated with mortality. Longer disease duration was associated with mortality, but not after adjustment for HbA(1c) and medication. Conclusion: This prospective study showed that persons with lower HbA(1c) had better survival than those with higher HbA(1c). The association was linear and independent of disease duration, type of medication use, and presence of co-morbidities. Any improvement of HbA(1c) appears to be associated with reduced mortality risk.

  • 536. Sluik, Diewertje
    et al.
    Jankovic, Nicole
    O'Doherty, Mark G.
    Geelen, Anouk
    Schöttker, Ben
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Kiefte-de Jong, Jessica C.
    Ferrieres, Jean
    Bamia, Christina
    Fransen, Heidi P.
    Boer, Jolanda M. A.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Martinez, Begoña
    María Huerta, José
    Kromhout, Daan
    de Groot, Lisette C. P. G. M.
    Franco, Oscar H.
    Trichopoulou, Antonia
    Boffetta, Paolo
    Kee, Frank
    Feskens, Edith J. M.
    Alcoholic Beverage Preference and Dietary Habits in Elderly across Europe: Analyses within the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) Project2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0161603Article in journal (Refereed)
    Abstract [en]

    Introduction: The differential associations of beer, wine, and spirit consumption on cardiovascular risk found in observational studies may be confounded by diet. We described and compared dietary intake and diet quality according to alcoholic beverage preference in European elderly. Methods: From the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES), seven European cohorts were included, i.e. four sub-cohorts from EPIC-Elderly, the SENECA Study, the Zutphen Elderly Study, and the Rotterdam Study. Harmonized data of 29,423 elderly participants from 14 European countries were analyzed. Baseline data on consumption of beer, wine, and spirits, and dietary intake were collected with questionnaires. Diet quality was assessed using the Healthy Diet Indicator (HDI). Intakes and scores across categories of alcoholic beverage preference (beer, wine, spirit, no preference, non-consumers) were adjusted for age, sex, socio-economic status, self-reported prevalent diseases, and lifestyle factors. Cohort-specific mean intakes and scores were calculated as well as weighted means combining all cohorts. Results: In 5 of 7 cohorts, persons with a wine preference formed the largest group. After multivariate adjustment, persons with a wine preference tended to have a higher HDI score and intake of healthy foods in most cohorts, but differences were small. The weighted estimates of all cohorts combined revealed that non-consumers had the highest fruit and vegetable intake, followed by wine consumers. Non-consumers and persons with no specific preference had a higher HDI score, spirit consumers the lowest. However, overall diet quality as measured by HDI did not differ greatly across alcoholic beverage preference categories. Discussion: This study using harmonized data from ~30,000 elderly from 14 European countries showed that, after multivariate adjustment, dietary habits and diet quality did not differ greatly according to alcoholic beverage preference.

  • 537. Smits, Michiel
    et al.
    Mir, Shahryar E
    Nilsson, Jonas
    Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
    van der Stoop, Petra M
    Niers, Johanna M
    Marquez, Victor E
    Cloos, Jacqueline
    Breakefield, Xandra O
    Krichevsky, Anna M
    Noske, David P
    Tannous, Bakhos A
    Würdinger, Thomas
    Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH22011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e16282-Article in journal (Refereed)
    Abstract [en]

    Angiogenesis is a balanced process controlled by pro- and anti-angiogenic molecules of which the regulation is not fully understood. Besides classical gene regulation, miRNAs have emerged as post-transcriptional regulators of angiogenesis. Furthermore, epigenetic changes caused by histone-modifying enzymes were shown to modulate angiogenesis as well. However, a possible interplay between miRNAs and histone-modulating enzymes during angiogenesis has not been described. Here we show that VEGF-mediated down-regulation of miR-101 caused pro-angiogenic effects. We found that the pro-angiogenic effects are partly mediated through reduced repression by miR-101 of the histone-methyltransferase EZH2, a member of the Polycomb group family, thereby increasing methylation of histone H3 at lysine 27 and transcriptome alterations. In vitro, the sprouting and migratory properties of primary endothelial cell cultures were reduced by inhibiting EZH2 through up-regulation of miR-101, siRNA-mediated knockdown of EZH2, or treatment with 3-Deazaneplanocin-A (DZNep), a small molecule inhibitor of EZH2 methyltransferase activity. In addition, we found that systemic DZNep administration reduced the number of blood vessels in a subcutaneous glioblastoma mouse model, without showing adverse toxicities. Altogether, by identifying a pro-angiogenic VEGF/miR-101/EZH2 axis in endothelial cells we provide evidence for a functional link between growth factor-mediated signaling, post-transcriptional silencing, and histone-methylation in the angiogenesis process. Inhibition of EZH2 may prove therapeutic in diseases in which aberrant vascularization plays a role.

  • 538. Sniegula, Szymon
    et al.
    Nilsson-Örtman, Viktor
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Johansson, Frank
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Growth Pattern Responses to Photoperiod across Latitudes in a Northern Damselfly2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e46024-Article in journal (Refereed)
    Abstract [en]

    Background: Latitudinal clines in temperature and seasonality impose strong seasonal constraints on ectotherms. Studies of population differentiation in phenotypic plasticity of life history traits along latitudinal gradients are important for understanding how organisms have adapted to seasonal environments and predict how they respond to climate changes. Such studies have been scarce for species with a northern distribution. Methodology/Principle Finding: Larvae of the northern damselfly Coenagrion johanssoni originating from semivoltine central, partivoltine northern, and partivoltine northernmost Swedish populations were reared in the laboratory. To investigate whether larvae use photoperiodic cues to induce compensatory growth along this latitudinal gradient, larvae were reared under two different photoperiods corresponding to a northern and southern latitude. In addition, field adult size was assessed to test the strength of possible compensatory growth mechanisms under natural conditions and hatchling size was measured to test for maternal effects. We hypothesized that populations originating from lower latitudes would be more time constrained than high-latitude populations because they have a shorter life cycle. The results showed that low-latitude populations had higher growth rates in summer/fall. In general northern photoperiods induced higher growth rates, but this plastic response to photoperiod was strongest in the southernmost populations and negligible in the northernmost population. During spring, central populations grew faster under the southern rather than the northern photoperiod. On the other hand, northern and northernmost populations did not differ between each other and grew faster in the northern rather than in the southern photoperiod. Field sampled adults did not differ in size across the studied regions. Conclusion/Significance: We found a significant differentiation in growth rate across latitudes and latitudinal difference in growth rate response to photoperiod. Importantly, growth responses measured at a single larval developmental stage in one season may not always generalize to other developmental stages or seasons.

  • 539.
    Sondell, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Rosendahl, Erik
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nilsson Sommar, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Littbrand, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Lundin-Olsson, Lillemor
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Lindelöf, Nina
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Motivation to participate in high-intensity functional exercise compared with a social activity in older people with dementia in nursing homes2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 11, article id e0206899Article in journal (Refereed)
    Abstract [en]

    Background: Motivation to participate in exercise among people with dementia has not been well studied. The symptoms of dementia, including apathy, may lead to low motivation to participate in exercise. The aim of this study was to evaluate the motivation of older people with dementia to participate in a high-intensity exercise program compared with motivation of those participating in a social group activity.

    Methods: The Umeå Dementia and Exercise Study (UMDEX) was a cluster-randomized controlled intervention trial including 186 people (mean age; 85, 75% female) with dementia in nursing homes. Participants were randomized to participate in the High-Intensity Functional Exercise (HIFE) Program (n = 93) or a seated social group activity (n = 93). The activities were conducted in groups of 3–8 participants for 45 minutes, five times per two-week period, for 4 months (40 sessions in total). Participants’ motivation to go to and during activity sessions were assessed by the activity leaders and nursing homes staff using a five-point Likert scale. Data were analyzed using cumulative link mixed models.

    Results: Motivation was high or very high during 61.0% of attended sessions in the exercise group and 62.6% in the social activity group. No overall significant difference between groups was observed, but motivation increased over time in the exercise group and decreased in the social activity group (p < 0.05). Motivation during the sessions was significantly higher than motivation to go to the sessions, especially in the exercise group [OR 2.39 (95% CI 2.38–2.40) and 1.50 (95% CI 1.32–1.70), respectively].

    Conclusions: Among older people with dementia in nursing homes, motivation to participate in a high-intensity functional exercise program seems to be high, comparable to motivation to participate in a social activity, and increase over time. Since motivation during activity sessions was higher than motivation to go to sessions the promotion of strategies to encourage people with dementia to join exercise groups is of great importance.

  • 540.
    Song, Tianyan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sabharwal, Dharmesh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gurung, Jyoti Mohan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Cheng, Andrew T.
    Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, United States of America.
    Sjöström, Annika E.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Yildiz, Fitnat H.
    Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, United States of America.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Vibrio cholerae Utilizes Direct sRNA Regulation in Expression of a Biofilm Matrix Protein2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e101280Article in journal (Refereed)
    Abstract [en]

    Vibrio cholerae biofilms contain exopolysaccharide and three matrix proteins RbmA, RbmC and Bap1. While much is known about exopolysaccharide regulation, little is known about the mechanisms by which the matrix protein components of biofilms are regulated. VrrA is a conserved, 140-nt sRNA of V. cholerae, whose expression is controlled by sigma factor sigma(E). In this study, we demonstrate that VrrA negatively regulates rbmC translation by pairing to the 5' untranslated region of the rbmC transcript and that this regulation is not stringently dependent on the RNA chaperone protein Hfq. These results point to VrrA as a molecular link between the sigma(E)-regulon and biofilm formation in V. cholerae. In addition, VrrA represents the first example of direct regulation of sRNA on biofilm matrix component, by-passing global master regulators.

  • 541.
    Song, Yafeng
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Yu, Ji-Guo
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Unilateral muscle overuse causes bilateral changes in muscle fiber composition and vascular supply2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. e116455-Article in journal (Refereed)
    Abstract [en]

    Unilateral strength training can cause cross-transfer strength effects to the homologous contralateral muscles. However, the impact of the cross-over effects on the muscle tissue is unclear. To test the hypothesis that unilateral muscle overuse causes bilateral alterations in muscle fiber composition and vascular supply, we have used an experimental rabbit model with unilateral unloaded overstrain exercise via electrical muscle stimulation (E/EMS). The soleus (SOL) and gastrocnemius (GA) muscles of both exercised (E) and contralateral non-exercised (NE) legs (n = 24) were morphologically analyzed after 1w, 3w and 6w of EMS. Non-exercised rabbits served as controls (n = 6). After unilateral intervention the muscles of both E and NE legs showed myositis and structural and molecular tissue changes that to various degrees mirrored each other. The fiber area was bilaterally smaller than in controls after 3w of E/EMS in both SOL (E 4420 and NE 4333 µm2 vs. 5183 µm2, p<0.05) and GA (E 3572 and NE 2983 µm2 vs. 4697 µm2, p<0.02) muscles. After 6w of E/EMS, the percentage of slow MyHCI fibers was lower than in controls in the NE legs of SOL (88.1% vs. 98.1%, p<0.009), while the percentage of fast MyHCIIa fibers was higher in the NE legs of GA (25.7% vs. 15.8%, p = 0.02). The number of capillaries around fibers in the E and NE legs was lower (SOL 13% and 15%, respectively, GA 25% and 23%, respectively, p<0.05) than in controls. The overall alterations were more marked in the fast GA muscle than in the slow SOL muscle, which on the other hand showed more histopathological muscle changes. We conclude that unilateral repetitive unloaded overuse exercise via EMS causes myositis and muscle changes in fiber type proportions, fiber area and fiber capillarization not only in the exercised leg, but also in the homologous muscles in the non-exercised leg.

  • 542.
    Song, Yafeng
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Yu, Jiguo
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Effects on contralateral muscles after unilateral electrical muscle stimulation and exercise2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e52230-Article in journal (Refereed)
    Abstract [en]

    It is well established that unilateral exercise can produce contralateral effects. However, it is unclear whether unilateral exercise that leads to muscle injury and inflammation also affects the homologous contralateral muscles. To test the hypothesis that unilateral muscle injury causes contralateral muscle changes, an experimental rabbit model with unilateral muscle overuse caused by a combination of electrical muscle stimulation and exercise (EMS/E) was used. The soleus and gastrocnemius muscles of both exercised and non-exercised legs were analyzed with enzyme-and immunohistochemical methods after 1, 3 and 6 weeks of repeated EMS/E. After 1 w of unilateral EMS/E there were structural muscle changes such as increased variability in fiber size, fiber splitting, internal myonuclei, necrotic fibers, expression of developmental MyHCs, fibrosis and inflammation in the exercised soleus muscle. Only limited changes were found in the exercised gastrocnemius muscle and in both non-exercised contralateral muscles. After 3 w of EMS/E, muscle fiber changes, presence of developmental MyHCs, inflammation, fibrosis and affections of nerve axons and AChE production were observed bilaterally in both the soleus and gastrocnemius muscles. At 6 w of EMS/E, the severity of these changes significantly increased in the soleus muscles and infiltration of fat was observed bilaterally in both the soleus and the gastrocnemius muscles. The affections of the muscles were in all three experimental groups restricted to focal regions of the muscle samples. We conclude that repetitive unilateral muscle overuse caused by EMS/E overtime leads to both degenerative and regenerative tissue changes and myositis not only in the exercised muscles, but also in the homologous non-exercised muscles of the contralateral leg. Although the mechanism behind the contralateral changes is unclear, we suggest that the nervous system is involved in the cross-transfer effects.

  • 543.
    Spoerry, Christian
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hessle, Pontus
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lewis, Melanie J
    Paton, Lois
    Woof, Jenny M
    von Pawel-Rammingen, Ulrich
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Novel IgG-Degrading Enzymes of the IgdE Protease Family Link Substrate Specificity to Host Tropism of Streptococcus Species.2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10Article in journal (Refereed)
    Abstract [en]

    Recently we have discovered an IgG degrading enzyme of the endemic pig pathogen S. suis designated IgdE that is highly specific for porcine IgG. This protease is the founding member of a novel cysteine protease family assigned C113 in the MEROPS peptidase database. Bioinformatical analyses revealed putative members of the IgdE protease family in eight other Streptococcus species. The genes of the putative IgdE family proteases of S. agalactiae, S. porcinus, S. pseudoporcinus and S. equi subsp. zooepidemicus were cloned for production of recombinant protein into expression vectors. Recombinant proteins of all four IgdE family proteases were proteolytically active against IgG of the respective Streptococcus species hosts, but not against IgG from other tested species or other classes of immunoglobulins, thereby linking the substrate specificity to the known host tropism. The novel IgdE family proteases of S. agalactiae, S. pseudoporcinus and S. equi showed IgG subtype specificity, i.e. IgdE from S. agalactiae and S. pseudoporcinus cleaved human IgG1, while IgdE from S. equi was subtype specific for equine IgG7. Porcine IgG subtype specificities of the IgdE family proteases of S. porcinus and S. pseudoporcinus remain to be determined. Cleavage of porcine IgG by IgdE of S. pseudoporcinus is suggested to be an evolutionary remaining activity reflecting ancestry of the human pathogen to the porcine pathogen S. porcinus. The IgG subtype specificity of bacterial proteases indicates the special importance of these IgG subtypes in counteracting infection or colonization and opportunistic streptococci neutralize such antibodies through expression of IgdE family proteases as putative immune evasion factors. We suggest that IgdE family proteases might be valid vaccine targets against streptococci of both human and veterinary medical concerns and could also be of therapeutic as well as biotechnological use.

  • 544.
    Stewart Williams, Jennifer
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Univ Newcastle, Fac Hlth, Res Ctr Gender Hlth & Ageing, Newcastle, NSW 2300, Australia.
    Ng, Nawi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Peltzer, Karl
    Yawson, Alfred
    Biritwum, Richard
    Maximova, Tamara
    Wu, Fan
    Arokiasamy, Perianayagam
    Kowal, Paul
    Chatterji, Somnath
    Risk Factors and Disability Associated with Low Back Pain in Older Adults in Low- and Middle-Income Countries. Results from the WHO Study on Global AGEing and Adult Health (SAGE)2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, p. e0127880-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Back pain is a common disabling chronic condition that burdens individuals, families and societies. Epidemiological evidence, mainly from high-income countries, shows positive association between back pain prevalence and older age. There is an urgent need for accurate epidemiological data on back pain in adult populations in low- and middle-income countries (LMICs) where populations are ageing rapidly. The objectives of this study are to: measure the prevalence of back pain; identify risk factors and determinants associated with back pain, and describe association between back pain and disability in adults aged 50 years and older, in six LMICs from different regions of the world. The findings provide insights into country-level differences in self-reported back pain and disability in a group of socially, culturally, economically and geographically diverse LMICs.

    METHODS: Standardized national survey data collected from adults (50 years and older) participating in the World Health Organization (WHO) Study on global AGEing and adult health (SAGE) were analysed. The weighted sample (n = 30, 146) comprised respondents in China, Ghana, India, Mexico, South Africa and the Russian Federation. Multivariable regressions describe factors associated with back pain prevalence and intensity, and back pain as a determinant of disability.

    RESULTS: Prevalence was highest in the Russian Federation (56%) and lowest in China (22%). In the pooled multi-country analyses, female sex, lower education, lower wealth and multiple chronic morbidities were significant in association with past-month back pain (p<0.01). About 8% of respondents reported that they experienced intense back pain in the previous month.

    CONCLUSIONS: Evidence on back pain and its impact on disability is needed in developing countries so that governments can invest in cost-effective education and rehabilitation to reduce the growing social and economic burden imposed by this disabling condition.

  • 545.
    Stocks, Tanja
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ängquist, Lars
    Banasik, Karina
    Harder, Marie N
    Taylor, Moira A
    Hager, Jörg
    Arner, Peter
    Oppert, Jean-Michel
    Alfredo Martinez, J
    Polak, Jan
    Rousseau, Francis
    Langin, Dominique
    Rössner, Stephan
    Holst, Claus
    MacDonald, Ian A
    Kamatani, Yoichiro
    Pfeiffer, Andreas FH
    Kunesova, Marie
    Saris, Wim HM
    Hansen, Torben
    Pedersen, Oluf
    Astrup, Arne
    Sorensen, Thorkild IA
    TFAP2B influences the effect of dietary fat on weight loss under energy restriction2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8, p. e43212-Article in journal (Refereed)
    Abstract [en]

    Background: Numerous gene loci are related to single measures of body weight and shape. We investigated if 55 SNPs previously associated with BMI or waist measures, modify the effects of fat intake on weight loss and waist reduction under energy restriction.

    Methods and Findings: Randomized controlled trial of 771 obese adults. (Registration: ISRCTN25867281.) One SNP was selected for replication in another weight loss intervention study of 934 obese adults. The original trial was a 10-week 600 kcal/d energy-deficient diet with energy percentage from fat (fat%) in range of 20-25 or 40-45. The replication study used an 8-weeks diet of 880 kcal/d and 20 fat%; change in fat% intake was used for estimation of interaction effects. The main outcomes were intervention weight loss and waist reduction. In the trial, mean change in fat% intake was -12/+4 in the low/high-fat groups. In the replication study, it was -23/-12 among those reducing fat% more/less than the median. TFAP2B-rs987237 genotype AA was associated with 1.0 kg (95% CI, 0.4; 1.6) greater weight loss on the low-fat, and GG genotype with 2.6 kg (1.1; 4.1) greater weight loss on the high-fat (interaction p-value; p=0.00007). The replication study showed a similar (non-significant) interaction pattern. Waist reduction results generally were similar. Study-strengths include (i) the discovery study randomised trial design combined with the replication opportunity (ii) the strict dietary intake control in both studies (iii) the large sample sizes of both studies. Limitations are (i) the low minor allele frequency of the TFAP2B polymorphism, making it hard to investigate non-additive genetic effects (ii) the different interventions preventing identical replication-discovery study designs (iii) some missing data for non-completers and dietary intake. No adverse effects/outcomes or side-effects were observed.

    Conclusions: Under energy restriction, TFAP2B may modify the effect of dietary fat intake on weight loss and waist reduction.

  • 546. Stoltz, Malin
    et al.
    Sundström, Karin B.
    Hidmark, Åsa
    Tolf, Conny
    Vene, Sirkka
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lindberg, A. Michael
    Lundkvist, Åke
    Klingström, Jonas
    A model system for In vitro studies of bank vole borne viruses2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, p. e28992-Article in journal (Refereed)
    Abstract [en]

    The bank vole (Myodes glareolus) is a common small mammal in Europe and a natural host for several important emerging zoonotic viruses, e. g. Puumala hantavirus (PUUV) that causes hemorrhagic fever with renal syndrome (HFRS). Hantaviruses are known to interfere with several signaling pathways in infected human cells, and HFRS is considered an immunemediated disease. There is no in vitro-model available for infectious experiments in bank vole cells, nor tools for analyses of bank vole immune activation and responses. Consequently, it is not known if there are any differences in the regulation of virus induced responses in humans compared to natural hosts during infection. We here present an in vitro-model for studies of bank vole borne viruses and their interactions with natural host cell innate immune responses. Bank vole embryonic fibroblasts (VEFs) were isolated and shown to be susceptible for PUUV-infection, including a wild-type PUUV strain (only passaged in bank voles). The significance of VEFs as a model system for bank vole associated viruses was further established by infection studies showing that these cells are also susceptible to tick borne encephalitis, cowpox and Ljungan virus. The genes encoding bank vole IFN-beta and Mx2 were partially sequenced and protocols for semi-quantitative RT-PCR were developed. Interestingly, PUUV did not induce an increased IFN-beta or Mx2 mRNA expression. Corresponding infections with CPXV and LV induced IFN-beta but not Mx2, while TBEV induced both IFN-beta and Mx2. In conclusion, VEFs together with protocols developed for detection of bank vole innate immune activation provide valuable tools for future studies of how PUUV and other zoonotic viruses affect cells derived from bank voles compared to human cells. Notably, wild-type PUUV which has been difficult to cultivate in vitro readily infected VEFs, suggesting that embryonic fibroblasts from natural hosts might be valuable for isolation of wild-type hantaviruses.

  • 547.
    Storm, Patrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Tibiletti, Tania
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Hall, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Refolding and enzyme kinetic studies on the ferrochelatase of the cyanobacterium synechocystis sp. PCC 68032013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, article id e55569Article in journal (Refereed)
    Abstract [en]

    Heme is a cofactor for proteins participating in many important cellular processes, including respiration, oxygen metabolism and oxygen binding. The key enzyme in the heme biosynthesis pathway is ferrochelatase (protohaem ferrolyase, EC 4.99.1.1), which catalyzes the insertion of ferrous iron into protoporphyrin IX. In higher plants, the ferrochelatase enzyme is localized not only in mitochondria, but also in chloroplasts. The plastidic type II ferrochelatase contains a C-terminal chlorophyll a/b (CAB) motif, a conserved hydrophobic stretch homologous to the CAB domain of plant light harvesting proteins and light-harvesting like proteins. This type II ferrochelatase, found in all photosynthetic organisms, is presumed to have evolved from the cyanobacterial ferrochelatase. Here we describe a detailed enzymological study on recombinant, refolded and functionally active type II ferrochelatase (FeCh) from the cyanobacterium Synechocystis sp. PCC 6803. A protocol was developed for the functional refolding and purification of the recombinant enzyme from inclusion bodies, without truncation products or soluble aggregates. The refolded FeCh is active in its monomeric form, however, addition of an N-terminal His6-tag has significant effects on its enzyme kinetics. Strikingly, removal of the C-terminal CAB-domain led to a greatly increased turnover number, kcat, compared to the full length protein. While pigments isolated from photosynthetic membranes decrease the activity of FeCh, direct pigment binding to the CAB domain of FeCh was not evident.

  • 548.
    Stoverud, Karen-Helene
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Center for Biomedical Computing, Simula Research Laboratory and Department of Informatics, University of Oslo, Oslo, Norway.
    Langtangen, Hans Petter
    Ringstad, Geir Andre
    Eide, Per Kristian
    Mardal, Kent-Andre
    Computational Investigation of Cerebrospinal Fluid Dynamics in the Posterior Cranial Fossa and Cervical Subarachnoid Space in Patients with Chiari I Malformation2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0162938Article in journal (Refereed)
    Abstract [en]

    Purpose Previous computational fluid dynamics (CFD) studies have demonstrated that the Chiari malformation is associated with abnormal cerebrospinal fluid (CSF) flow in the cervical part of the subarachnoid space (SAS), but the flow in the SAS of the posterior cranial fossa has received little attention. This study extends previous modelling efforts by including the cerebellomedullary cistern, pontine cistern, and 4th ventricle in addition to the cervical subarachnoid space. Methods The study included one healthy control, Con1, and two patients with Chiari I malformation, P1 and P2. Meshes were constructed by segmenting images obtained from T2-weighted turbo spin-echo sequences. CFD simulations were performed with a previously verified and validated code. Patient-specific flow conditions in the aqueduct and the cervical SAS were used. Two patients with the Chiari malformation and one control were modelled. Results The results demonstrated increased maximal flow velocities in the Chiari patients, ranging from factor 5 in P1 to 14.8 in P2, when compared to Con1 at the level of Foramen Magnum (FM). Maximal velocities in the cervical SAS varied by a factor 2.3, while the maximal flow in the aqueduct varied by a factor 3.5. The pressure drop from the pontine cistern to the cervical SAS was similar in Con1 and P1, but a factor two higher in P2. The pressure drop between the aqueduct and the cervical SAS varied by a factor 9.4 where P1 was the one with the lowest pressure jump and P2 and Con1 differed only by a factor 1.6. Conclusion This pilot study demonstrates that including the posterior cranial fossa is feasible and suggests that previously found flow differences between Chiari I patients and healthy individuals in the cervical SAS may be present also in the SAS of the posterior cranial fossa.

  • 549.
    Strandberg, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hashemi, Armin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Optimization of PET reconstruction algorithm, SUV thresholding algorithm and PET acquisition time in clinical 11C-acetate PET/CT2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209169Article in journal (Refereed)
    Abstract [en]

    Introduction 11C-acetate (ACE)-PET/CT is used for staging of high-risk prostate cancer. PET data is reconstructed with iterative algorithms, such as VUEPointHD ViP (VPHD) and VUEPoint HD Sharp IR (SharpIR), the latter with additional resolution recovery. It is expected that the resolution recovery algorithm should render more accurate maximum and mean standardized uptake values (SUVmax and SUVmean) and functional tumor volumes (FTV) than the ordinary OSEM. Performing quantitative analysis, choice of volume-of-interest delineation algorithm (SUV threshold) may influence FTV. Optimizing PET acquisition time is justified if image quality and quantitation do not deteriorate. The aim of this study is to identify the optimal reconstruction algorithm, SUV threshold and acquisition time for ACE-PET/CT. Methods ACE-PET/CT data acquired with a General Electric Discovery 690 PET/CT from 16 consecutive high-risk prostate cancer patients was reconstructed with VPHD and SharpIR. Forty pelvic lymph nodes (LNs) and 14 prostate glands were delineated with 42% and estimated threshold. SUVmax, SUVmean, FTV and total lesion uptake were measured. Default acquisition time was four minutes per bed position. In a subset of lesions, acquisition times of one, two and four minutes were evaluated. Structural tumor volumes (STV) of the LNs were measured with CT for correlation with functional volumetric parameters. To validate SUV quantification under different conditions with SharpIR 42%, recovery coefficients (RCs) of SUVmean and FTV were calculated from a phantom with 18F-fluoro-deoxy-glucose (FDG)-filled volumes 0.1–9.2cm3 and signal-to-background (S/B) ratios 4.3–15.9. Results With SharpIR, SUVmax and SUVmean were higher and FTV lower compared with VPHD, regardless of threshold method, in both prostates and LNs. Total lesion uptake determined with both threshold methods was lower with SharpIR compared with VPHD with both threshold methods, except in subgroup analysis of prostate targets where estimated threshold returned higher values. Longer acquisition times returned higher FTV for both threshold methods, regardless of reconstruction algorithm. The FTV difference was most pronounced with one minute’s acquisition per bed position, which also produced visually the highest noise. SUV parameters were unaffected by varying acquisition times. FTV with SharpIR 42% showed the best correspondence with STV. SharpIR 42% gave higher RCs of SUVmean and FTV with increasing phantom size and S/B-ratio, as expected. Conclusions Delineation with SharpIR 42% seems to provide the most accurate combined information from SUVmax, SUVmean, FTV and total lesion uptake. Acquisition time may be shortened to two minutes per bed position with preserved image quality.

  • 550. Strohmaier, Susanne
    et al.
    Edlinger, Michael
    Manjer, Jonas
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bjorge, Tone
    Borena, Wegene
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Engeland, Anders
    Nagel, Gabriele
    Almquist, Martin
    Selmer, Randi
    Tretli, Steinar
    Concin, Hans
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ulmer, Hanno
    Total Serum Cholesterol and Cancer Incidence in the Metabolic Syndrome and Cancer Project (Me-Can)2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e54242-Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the association between total serum cholesterol (TSC) and cancer incidence in the Metabolic syndrome and Cancer project (Me-Can).

    Methods: Me-Can consists of seven cohorts from Norway, Austria, and Sweden including 289,273 male and 288,057 female participants prospectively followed up for cancer incidence (n = 38,978) with a mean follow-up of 11.7 years. Cox regression models with age as the underlying time metric were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for quintiles of cholesterol levels and per 1 mmol/l, adjusting for age at first measurement, body mass index (BMI), and smoking status. Estimates were corrected for regression dilution bias. Furthermore, we performed lag time analyses, excluding different times of follow-up, in order to check for reverse causation.

    Results: In men, compared with the 1st quintile, TSC concentrations in the 5th quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95% CI: 0.88, 1.00). Significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95% CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95% CI: 0.46, 0.95), and cancers of the lymph-/hematopoietic tissue (HR = 0.68, 95% CI: 0.54, 0.87). In women, hazard ratios for the 5th quintile were associated with decreasing risk of total cancer (HR = 0.86, 95% CI: 0.79, 0.93) and for cancers of the gallbladder (HR = 0.23, 95% CI: 0.08, 0.62), breast (HR = 0.70, 95% CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95% CI: 0.42, 0.88), and cancers of the lymph-/hematopoietic tissue (HR = 0.61, 95% CI: 0.44, 0.83).

    Conclusion: TSC was negatively associated with risk of cancer overall in females and risk of cancer at several sites in both males and females. In lag time analyses some associations persisted, suggesting that for these cancer sites reverse causation did not apply.

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