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  • 101. Chaturvedi, Sarika
    et al.
    Randive, Bharat
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Department of Public Health and Environment, R D Gardi Medical College, Ujjain, India.
    Diwan, Vishal
    De Costa, Ayesha
    Quality of Obstetric Referral Services in India's JSY Cash Transfer Programme for Institutional Births: A Study from Madhya Pradesh Province2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, article id e96773Article in journal (Refereed)
    Abstract [en]

    Background:

    India launched JSY cash transfer programme to increase access to emergency obstetric and neonatal care (EmONC) by incentivising in-facility births. This increased in-facility births from 30% in 2005 to 73% in 2012 however, decline in maternal mortality follows a secular trend. Dysfunctional referral services can contribute to poor programme impact on outcomes. We hence describe inter-facility referrals and study quality of referral services in JSY.

    Methods and Results:

    Women accessing intra natal care (n = 1182) at facilities (reporting >10 deliveries/month, n = 96) were interviewed in a 5 day cross sectional survey in 3 districts of Madhya Pradesh province. A nested matched case control study (n = 68 pairs) was performed to study association between maternal referral and adverse birth outcomes. There were 111 (9.4%) in referrals and 69 (5.8%) out referrals. Secondary level facilities sent most referrals and 40% were for conditions expected to be treated at this level. There were 36 adverse birth outcomes (intra partum and in-facility deaths). After matching for type of complication and place of delivery, conditional logistic regression model showed maternal referral at term delivery was associated with higher odds of adverse birth outcomes (OR-2.6, 95% CI: 1.0-6.6 p = 0.04). Maternal death record review (April 10-March 12) was conducted at the CEmOC facility in one district. Spatial analysis of transfer time from sending to the receiving CEmOC facility among in-facility maternal deaths was conducted in ArcGIS10 applying two hours (equated to 100 Km) as desired transfer time. There were 124 maternal deaths, 55 of which were among mothers referred in. Buffer analysis revealed 98% mothers were referred from <2 hours. Median time between arrival and death was 6.75 hours.

    Conclusions:

    High odds of adverse birth outcomes associated with maternal referral and high maternal deaths despite spatial access to referral care indicate poor quality of referral services.

  • 102.
    Chen, Changchun
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Huang, Bo
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Anderson, James T
    Byström, Anders S
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Unexpected accumulation of ncm5U and ncm5s2U in a trm9 mutant suggests an additional step in the synthesis of mcm5U and mcm5s2U.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, p. e20783-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transfer RNAs are synthesized as a primary transcript that is processed to produce a mature tRNA. As part of the maturation process, a subset of the nucleosides are modified. Modifications in the anticodon region often modulate the decoding ability of the tRNA. At position 34, the majority of yeast cytosolic tRNA species that have a uridine are modified to 5-carbamoylmethyluridine (ncm(5)U), 5-carbamoylmethyl-2'-O-methyluridine (ncm(5)Um), 5-methoxycarbonylmethyl-uridine (mcm(5)U) or 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U). The formation of mcm(5) and ncm(5) side chains involves a complex pathway, where the last step in formation of mcm(5) is a methyl esterification of cm(5) dependent on the Trm9 and Trm112 proteins.

    METHODOLOGY AND PRINCIPAL FINDINGS: Both Trm9 and Trm112 are required for the last step in formation of mcm(5) side chains at wobble uridines. By co-expressing a histidine-tagged Trm9p together with a native Trm112p in E. coli, these two proteins purified as a complex. The presence of Trm112p dramatically improves the methyltransferase activity of Trm9p in vitro. Single tRNA species that normally contain mcm(5)U or mcm(5)s(2)U nucleosides were isolated from trm9Δ or trm112Δ mutants and the presence of modified nucleosides was analyzed by HPLC. In both mutants, mcm(5)U and mcm(5)s(2)U nucleosides are absent in tRNAs and the major intermediates accumulating were ncm(5)U and ncm(5)s(2)U, not the expected cm(5)U and cm(5)s(2)U.

    CONCLUSIONS: Trm9p and Trm112p function together at the final step in formation of mcm(5)U in tRNA by using the intermediate cm(5)U as a substrate. In tRNA isolated from trm9Δ and trm112Δ strains, ncm(5)U and ncm(5)s(2)U nucleosides accumulate, questioning the order of nucleoside intermediate formation of the mcm(5) side chain. We propose two alternative explanations for this observation. One is that the intermediate cm(5)U is generated from ncm(5)U by a yet unknown mechanism and the other is that cm(5)U is formed before ncm(5)U and mcm(5)U.

  • 103. Chen, Chih-Mei
    et al.
    Thiering, Elisabeth
    Zock, Jan-Paul
    Villani, Simona
    Olivieri, Mario
    Modig, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Jarvis, Deborah
    Norbaeck, Dan
    Verlato, Giuseppe
    Heinrich, Joachim
    Is There a Threshold Concentration of Cat Allergen Exposure on Respiratory Symptoms in Adults?2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0127457Article in journal (Refereed)
    Abstract [en]

    Background and Objective Cat allergen concentrations higher than 8 mu g/g in settled house dust, have been suggested to provoke exacerbation of allergic respiratory symptoms. However, whether the 8 mu g/g of indoor cat allergen concentration is indeed the minimal exposure required for triggering the asthma related respiratory symptoms or the development of sensitization has not yet been confirmed. We studied the associations between domestic cat allergen concentrations and allergic symptoms in the European Community Respiratory Health Survey II, with the aim of confirming this suggested threshold. Methods Cat allergen concentrations were measured in the mattress dust of 3003 participants from 22 study centres. Levels of specific immunoglobulin E to cat allergens were measured in serum samples using an immunoassay. Information on allergic symptoms, medication use, home environment and smoking was obtained from a face-to-face interview. Results Domestic cat allergen concentrations were not associated with allergic/asthmatic symptoms in the entire study population, nor in the subset sensitized to cat allergen. We also found no association among individuals exposed to concentrations higher than 8 mu g/g. However, exposure to medium cat allergen concentrations (0.24-0.63 mu g/g) was positively associated with reported asthmatic respiratory symptoms in subjects who have experienced allergic symptoms when near animals. Conclusions The proposed 8 mu g/g threshold of cat allergen concentrations for the exacerbation of allergic/respiratory symptoms was not confirmed in a general European adult population. Potential biases attributable to avoidance behaviours and an imprecise exposure assessment cannot be excluded.

  • 104. Chen, Dongmei
    et al.
    Zhang, Xianxian
    Kang, Hongzhang
    Sun, Xiao
    Yin, Shan
    Du, Hongmei
    Yamanaka, Norikazu
    Gapare, Washington
    Wu, Harry X.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Commonwealth Sci & Ind Res Org Plant Ind, Canberra, ACT, Australia.
    Liu, Chunjiang
    Phylogeography of Quercus variabilis Based on Chloroplast DNA Sequence in East Asia: Multiple Glacial Refugia and Mainland-Migrated Island Populations2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47268-Article in journal (Refereed)
    Abstract [en]

    The biogeographical relationships between far-separated populations, in particular, those in the mainland and islands, remain unclear for widespread species in eastern Asia where the current distribution of plants was greatly influenced by the Quaternary climate. Deciduous Oriental oak (Quercus variabilis) is one of the most widely distributed species in eastern Asia. In this study, leaf material of 528 Q. variabilis trees from 50 populations across the whole distribution (Mainland China, Korea Peninsular as well as Japan, Zhoushan and Taiwan Islands) was collected, and three cpDNA intergenic spacer fragments were sequenced using universal primers. A total of 26 haplotypes were detected, and it showed a weak phylogeographical structure in eastern Asia populations at species level, however, in the central-eastern region of Mainland China, the populations had more haplotypes than those in other regions, with a significant phylogeographical structure (N-ST = 0.751 > G(ST) = 0.690, P < 0.05). Q. variabilis displayed high interpopulation and low intrapopulation genetic diversity across the distribution range. Both unimodal mismatch distribution and significant negative Fu's F-S indicated a demographic expansion of Q. variabilis populations in East Asia. A fossil calibrated phylogenetic tree showed a rapid speciation during Pleistocene, with a population augment occurred in Middle Pleistocene. Both diversity patterns and ecological niche modelling indicated there could be multiple glacial refugia and possible bottleneck or founder effects occurred in the southern Japan. We dated major spatial expansion of Q. variabilis population in eastern Asia to the last glacial cycle(s), a period with sea-level fluctuations and land bridges in East China Sea as possible dispersal corridors. This study showed that geographical heterogeneity combined with climate and sea-level changes have shaped the genetic structure of this wide-ranging tree species in East Asia.

  • 105. Chen, Xingchen
    et al.
    Riley, Blake T.
    de Veer, Simon J.
    Hoke, David E.
    Van Haeften, Jessica
    Leahy, Darren
    Swedberg, Joakim E.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hartfield, Perry J.
    Buckle, Ashley M.
    Harris, Jonathan M.
    Potent, multi-target serine protease inhibition achieved by a simplified beta-sheet motif2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 1, article id e0210842Article in journal (Refereed)
    Abstract [en]

    Engagement of an extended beta-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like beta-sheet to enzyme inhibition. Here we report the crystal structure of an simplified beta-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by beta-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design.

  • 106.
    Cherif, Mehdi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Granados, Monica
    Duffy, Sean
    Robert, Pauline
    Pequin, Berangere
    Mohit, Vani
    McKindsey, Christopher W.
    Archambault, Philippe
    Myrand, Bruno
    Lovejoy, Connie
    Tremblay, Rejean
    Plourde, Stephane
    Fussmann, Gregor F.
    Potential for Local Fertilization: A Benthocosm Test of Long-Term and Short-Term Effects of Mussel Excretion on the Plankton2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0156411Article in journal (Refereed)
    Abstract [en]

    Mussel aquaculture has expanded worldwide and it is important to assess its impact on the water column and the planktonic food web to determine the sustainability of farming practices. Mussel farming may affect the planktonic food web indirectly by excreting bioavailable nutrients in the water column (a short-term effect) or by increasing nutrient effluxes from bio-deposit-enriched sediments (a long-term effect). We tested both of these indirect effects in a lagoon by using plankton-enclosing benthocosms that were placed on the bottom of a shallow lagoon either inside of a mussel farm or at reference sites with no history of aquaculture. At each site, half of the benthocosms were enriched with seawater that had held mussels (excretion treatment), the other half received non-enriched seawater as a control treatment. We monitored nutrients ([PO43-] and [NH4+]), dissolved oxygen and plankton components (bacteria, the phytoplankton and the zooplankton) over 5 days. We found a significant relationship between long-term accumulation of mussel biodeposits in sediments, water-column nutrient concentrations and plankton growth. Effects of mussel excretion were not detected, too weak to be significant given the spatial and temporal variability observed in the lagoon. Effects of mussels on the water column are thus likely to be coupled to benthic processes in such semi-enclosed water bodies.

  • 107. Chikovore, Jeremiah
    et al.
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lindmark, Gunilla
    Ahlberg, Beth Maina
    "How Can I Gain Skills if I Don't Practice?'' The Dynamics of Prohibitive Silence against Pre-Marital Pregnancy and Sex in Zimbabwe2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53058-Article in journal (Refereed)
    Abstract [en]

    Young people face sexual and reproductive health (SRH) problems including Human immunodeficiency virus (HIV) and Acquired immunodeficiency syndrome (AIDS). It is critical to continue documenting their situation including the contexts they live in. As part of a larger study that explored perspectives of men to SRH and more specifically abortion and contraceptive use, 546 pupils (51% female; age range 9-25 years) from a rural area in Zimbabwe were invited to write anonymously questions about growing up or other questions they could not ask adults for fear or shame. The pupils were included following descriptions by adults of the violence that is unleashed on unmarried young people who engaged in sex, used contraceptives, or simply suggested doing so. The questions by the young people pointed to living in a context of prohibitive silence; their sexuality was silenced and denied. As a consequence they had poor knowledge and their fears and internal conflicts around sexuality and pregnancy were not addressed. Current action suggests concerted effort at the policy level to deal with young people's SRH in Zimbabwe. It nevertheless remains necessary, as a way to provide support to these efforts, to continue examining what lessons can be drawn from the past, and how the past continues to reflect in and shape present dynamics and relations. There is also need to look more critically at life skill education, which has previously been described as having failed to address adequately the practical needs of young people. Life skill education in Zimbabwe has rarely been systematically evaluated. A fuller understanding is also needed of the different factors co-existing in contemporary African societies and how they have been and continue to be constituted within history, and the implications to the promotion of adolescent SRH.

  • 108.
    Chorell, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, Emma
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Evans, Margery L.
    Jain, Neha
    Götheson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Åden, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chapman, Matthew R.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bacterial Chaperones CsgE and CsgC Differentially Modulate Human α-Synuclein Amyloid Formation via Transient Contacts2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, p. 1-11, article id e0140194Article in journal (Refereed)
    Abstract [en]

    Amyloid formation is historically associated with cytotoxicity, but many organisms produce functional amyloid fibers (e.g., curli) as a normal part of cell biology. Two E. coli genes in the curli operon encode the chaperone-like proteins CsgC and CsgE that both can reduce in vitro amyloid formation by CsgA. CsgC was also found to arrest amyloid formation of the human amyloidogenic protein α-synuclein, which is involved in Parkinson’s disease. Here, we report that the inhibitory effects of CsgC arise due to transient interactions that promote the formation of spherical α-synuclein oligomers. We find that CsgE also modulates α-synuclein amyloid formation through transient contacts but, in contrast to CsgC, CsgE accelerates α-synuclein amyloid formation. Our results demonstrate the significance of transient protein interactions in amyloid regulation and emphasize that the same protein may inhibit one type of amyloid while accelerating another.

  • 109.
    Christensen, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Svensson, Karin
    Thelin, Lisa
    Zhang, Wenjing
    Tintor, Nico
    Prins, Daniel
    Funke, Norma
    Michalak, Marek
    Schulze-Lefert, Paul
    Saijo, Yusuke
    Sommarin, Marianne
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Widell, Susanne
    Persson, Staffan
    Higher plant calreticulins have acquired specialized functions in arabidopsis2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 6, p. e11342-Article in journal (Refereed)
    Abstract [en]

    Background: Calreticulin (CRT) is a ubiquitous ER protein involved in multiple cellular processes in animals, such as protein folding and calcium homeostasis. Like in animals, plants have evolved divergent CRTs, but their physiological functions are less understood. Arabidopsis contains three CRT proteins, where the two CRTs AtCRT1a and CRT1b represent one subgroup, and AtCRT3 a divergent member. Methodology/Principal Findings: Through expression of single Arabidopsis family members in CRT-deficient mouse fibroblasts we show that both subgroups have retained basic CRT functions, including ER Ca2+-holding potential and putative chaperone capabilities. However, other more general cellular defects due to the absence of CRT in the fibroblasts, such as cell adhesion deficiencies, were not fully restored. Furthermore, in planta expression, protein localization and mutant analyses revealed that the three Arabidopsis CRTs have acquired specialized functions. The AtCRT1a and CRT1b family members appear to be components of a general ER chaperone network. In contrast, and as recently shown, AtCRT3 is associated with immune responses, and is essential for responsiveness to the bacterial Pathogen-Associated Molecular Pattern (PAMP) elf18, derived from elongation factor (EF)-Tu. Whereas constitutively expressed AtCRT1a fully complemented Atcrt1b mutants, AtCRT3 did not. Conclusions/Significance: We conclude that the physiological functions of the two CRT subgroups in Arabidopsis have diverged, resulting in a role for AtCRT3 in PAMP associated responses, and possibly more general chaperone functions for AtCRT1a and CRT1b.

  • 110.
    Cipriano, Mariateresa
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Association between cannabinoid CB1 receptor expression and Akt signalling in prostate cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e65798-Article in journal (Refereed)
    Abstract [en]

    Background: In prostate cancer, tumour expression of cannabinoid CB1 receptors is associated with a poor prognosis. One explanation for this association comes from experiments with transfected astrocytoma cells, where a high CB receptor expression recruits the Akt signalling survival pathway. In the present study, we have investigated the association between CB1 receptor expression and the Akt pathway in a well-characterised prostate cancer tissue microarray.

    Methodology/Principal Findings: Phosphorylated Akt immunoreactivity (pAkt-IR) scores were available in the database. CB1 receptor immunoreactivity (CB1IR) was rescored from previously published data using the same scale as pAkt-IR. There was a highly significant correlation between CB1IR and pAkt-IR. Further, cases with high expression levels of both biomarkers were much more likely to have a more severe form of the disease at diagnosis than those with low expression levels. The two biomarkers had additive effects, rather than an interaction, upon disease-specific survival.

    Conclusions/Significance: The present study provides data that is consistent with the hypothesis that at a high CB1 receptor expression, the Akt signalling pathway becomes operative.

  • 111. Clementi, Emily A.
    et al.
    Wilhelm, Kristina R.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Schleucher, Juergen
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hakansson, Anders P.
    A Complex of Equine Lysozyme and Oleic Acid with Bactericidal Activity against Streptococcus pneumoniae2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. Article Number: UNSP e80649-Article in journal (Refereed)
    Abstract [en]

    HAMLET and ELOA are complexes consisting of oleic acid and two homologous, yet functionally different, proteins with cytotoxic activities against mammalian cells, with HAMLET showing higher tumor cells specificity, possibly due to the difference in propensity for oleic acid binding, as HAMLET binds 5-8 oleic acid molecules per protein molecule and ELOA binds 11-48 oleic acids. HAMLET has been shown to possess bactericidal activity against a number of bacterial species, particularly those with a respiratory tropism, with Streptococcus pneumoniae displaying the greatest degree of sensitivity. We show here that ELOA also displays bactericidal activity against pneumococci, which at lower concentrations shows mechanistic similarities to HAMLET's bactericidal activity. ELOA binds to S. pneumoniae and causes perturbations of the plasma membrane, including depolarization and subsequent rupture, and activates an influx of calcium into the cells. Selective inhibition of calcium channels and sodium/calcium exchange activity significantly diminished ELOA's bactericidal activity, similar to what we have observed with HAMLET. Finally, ELOA-induced death was also accompanied by DNA fragmentation into high molecular weight fragments - an apoptosis-like morphological phenotype that is seen during HAMLET-induced death. Thus, in contrast to different mechanisms of eukaryote cell death induced by ELOA and HAMLET, these complexes are characterized by rather similar activities towards bacteria. Although the majority of these events could be mimicked using oleic acid alone, the concentrations of oleic acid required were significantly higher than those present in the ELOA complex, and for some assays, the results were not identical between oleic acid alone and the ELOA complex. This indicates that the lipid, as a common denominator in both complexes, is an important component for the complexes' bactericidal activities, while the proteins are required both to solubilize and/or present the lipid at the bacterial membrane and likely to confer other and separate functions during the bacterial death.

  • 112. Clendenen, Tess V.
    et al.
    Ge, Wenzhen
    Koenig, Karen L.
    Axelsson, Tomas
    Liu, Mengling
    Afanasyeva, Yelena
    Andersson, Anne
    Arslan, Alan A.
    Chen, Yu
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lenner, Per
    Kirchhoff, Tomas
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Shore, Roy E.
    Sund, Malin
    Zeleniuch-Jacquotte, Anne
    Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: a nested case-control study2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, article id e0140478Article in journal (Refereed)
    Abstract [en]

    Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH) D concentration in GWAS were also associated with plasma 25(OH) D in our study (p-trend < 0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH) D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.

  • 113. Clendenen, Tess
    et al.
    Zeleniuch-Jacquotte, Anne
    Wirgin, Isaac
    Koenig, Karen L
    Afanasyeva, Yelena
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Arslan, Alan A
    Axelsson, Tomas
    Försti, Asta
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, Kari
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roy, Nirmal
    Shore, Roy E
    Chen, Yu
    Genetic variants in hormone-related genes and risk of breast cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e69367-Article in journal (Refereed)
    Abstract [en]

    Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

  • 114. Cobb, Joanna E.
    et al.
    Plant, Darren
    Flynn, Edward
    Tadjeddine, Meriem
    Dieude, Philippe
    Cornelis, Francois
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Goulielmos, George
    Boumpas, Dimitrios T.
    Sidiropoulos, Prodromos
    Krintel, Sophine B.
    Ornbjerg, Lykke M.
    Hetland, Merete L.
    Klareskog, Lars
    Haeupl, Thomas
    Filer, Andrew
    Buckley, Christopher D.
    Raza, Karim
    Witte, Torsten
    Schmidt, Reinhold E.
    FitzGerald, Oliver
    Veale, Douglas
    Eyre, Stephen
    Worthington, Jane
    Identification of the Tyrosine-Protein Phosphatase Non-Receptor Type 2 as a Rheumatoid Arthritis Susceptibility Locus in Europeans2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e66456-Article in journal (Refereed)
    Abstract [en]

    Objectives: Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA.

    Methods: A cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data.

    Results: Significant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4x10(-9)).

    Conclusions: This study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase) with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene.

  • 115. Cohen, Cheryl
    et al.
    Moyes, Jocelyn
    Tempia, Stefano
    Groome, Michelle
    Walaza, Sibongile
    Pretorius, Marthi
    Dawood, Halima
    Chhagan, Meera
    Haffejee, Summaya
    Variava, Ebrahim
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    von Gottberg, Anne
    Wolter, Nicole
    Cohen, Adam L.
    Malope-Kgokong, Babatyi
    Venter, Marietjie
    Madhi, Shabir A.
    Mortality amongst Patients with Influenza-Associated Severe Acute Respiratory Illness, South Africa, 2009-20132015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0118884Article in journal (Refereed)
    Abstract [en]

    Introduction Data on the burden and risk groups for influenza-associated mortality from Africa are limited. We aimed to estimate the incidence and risk-factors for in-hospital influenza-associated severe acute respiratory illness (SARI) deaths.

    Methods Hospitalised patients with SARI were enrolled prospectively in four provinces of South Africa from 2009-2013. Using polymerase chain reaction, respiratory samples were tested for ten respiratory viruses and blood for pneumococcal DNA. The incidence of influenza-associated SARI deaths was estimated at one urban hospital with a defined catchment population.

    Results We enrolled 1376 patients with influenza-associated SARI and 3% (41 of 1358 with available outcome data) died. In patients with available HIV-status, the case-fatality proportion (CFP) was higher in HIV-infected (5%, 22/419) than HIV-uninfected individuals (2%, 13/620; p = 0.006). CFPs varied by age group, and generally increased with increasing age amongst individuals >5 years (p<0.001). On multivariable analysis, factors associated with death were age-group 45-64 years (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.01-16.3) and >= 65 years (OR 6.5, 95% CI 1.2-34.3) compared to 1-4 year age-group who had the lowest CFP, HIV-infection (OR 2.9, 95% CI 1.1-7.8), underlying medical conditions other than HIV (OR 2.9, 95% CI 1.2-7.3) and pneumococcal co-infection (OR 4.1, 95% CI 1.5-11.2). The estimated incidence of influenza-associated SARI deaths per 100,000 population was highest in children <1 year (20.1, 95% CI 12.1-31.3) and adults aged 45-64 years (10.4, 95% CI 8.4-12.9). Adjusting for age, the rate of death was 20-fold (95% CI 15.0-27.8) higher in HIV-infected individuals than HIV-uninfected individuals.

    Conclusion Influenza causes substantial mortality in urban South Africa, particularly in infants aged <1 year and HIV-infected individuals. More widespread access to antiretroviral treatment and influenza vaccination may reduce this burden.

  • 116. Cohen, Cheryl
    et al.
    Walaza, Sibongile
    Moyes, Jocelyn
    Groome, Michelle
    Tempia, Stefano
    Pretorius, Marthi
    Hellferscee, Orienka
    Dawood, Halima
    Haffejee, Summaya
    Variava, Ebrahim
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Tshangela, Akhona
    von Gottberg, Anne
    Wolter, Nicole
    Cohen, Adam L.
    Kgokong, Babatyi
    Venter, Marietjie
    Madhi, Shabir A.
    Epidemiology of Severe Acute Respiratory Illness (SARI) among Adults and Children Aged >= 5 Years in a High HIV-Prevalence Setting, 2009-20122015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 2, article id e0117716Article in journal (Refereed)
    Abstract [en]

    Objective There are few published studies describing severe acute respiratory illness ( SARI) epidemiology amongst older children and adults from high HIV-prevalence settings. We aimed to describe SARI epidemiology amongst individuals aged >= 5 years in South Africa. Methods We conducted prospective surveillance for individuals with SARI from 2009-2012. Using polymerase chain reaction, respiratory samples were tested for ten viruses, and blood for pneumococcal DNA. Cumulative annual SARI incidence was estimated at one site with population denominators. Findings We enrolled 7193 individuals, 9% (621/7067) tested positive for influenza and 9%(600/6519) for pneumococcus. HIV-prevalence was 74% (4663/6334). Among HIV-infected individuals with available data, 41% of 2629 were receiving antiretroviral therapy (ART). The annual SARI hospitalisation incidence ranged from 325-617/100,000 population. HIV-infected individuals experienced a 13-19 times greater SARI incidence than HIV-uninfected individuals (p<0.001). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals were more likely to be receiving tuberculosis treatment (odds ratio (OR): 1.7; 95% CI:1.1-2.7), have pneumococcal infection (OR 2.4; 95% CI: 1.7-3.3) be hospitalised for >7 days rather than <2 days (OR1.7; 95% CI: 1.2-2.2) and had a higher case-fatality ratio (8% vs 5%; OR1.7; 95% CI: 1.2-2.3), but were less likely to be infected with influenza (OR 0.6; 95% CI: 0.5-0.8). On multivariable analysis, independent risk indicators associated with death included HIV infection (OR 1.8; 95% CI: 1.3-2.4), increasing age-group, receiving mechanical ventilation (OR 6.5; 95% CI: 1.3-32.0) and supplemental-oxygen therapy (OR 2.6; 95% CI: 2.1-3.2). Conclusion The burden of hospitalized SARI amongst individuals aged >= 5 years is high in South Africa. HIV-infected individuals are the most important risk group for SARI hospitalization and mortality in this setting.

  • 117. Cortes-Bratti, Ximena
    et al.
    Bassères, Eugénie
    Herrera-Rodriguez, Fabiola
    Botero-Kleiven, Silvia
    Coppotelli, Giuseppe
    Andersen, Jens B
    Masucci, Maria G
    Holmgren, Arne
    Chaves-Olarte, Esteban
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Avila-Cariño, Javier
    Thioredoxin 80-activated-monocytes (TAMs) inhibit the replication of intracellular pathogens2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, article id e16960Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Thioredoxin 80 (Trx80) is an 80 amino acid natural cleavage product of Trx, produced primarily by monocytes. Trx80 induces differentiation of human monocytes into a novel cell type, named Trx80-activated-monocytes (TAMs).

    PRINCIPAL FINDINGS: In this investigation we present evidence for a role of TAMs in the control of intracellular bacterial infections. As model pathogens we have chosen Listeria monocytogenes and Brucella abortus which replicate in the cytosol and the endoplasmic reticulum respectively. Our data indicate that TAMs efficiently inhibit intracellular growth of both L. monocytogenes and B. abortus. Further analysis shows that Trx80 activation prevents the escape of GFP-tagged L. monocytogenes into the cytosol, and induces accumulation of the bacteria within the lysosomes. Inhibition of the lysosomal activity by chloroquine treatment resulted in higher replication of bacteria in TAMs compared to that observed in control cells 24 h post-infection, indicating that TAMs kill bacteria by preventing their escape from the endosomal compartments, which progress into a highly degradative phagolysosome.

    SIGNIFICANCE: Our results show that Trx80 potentiates the bactericidal activities of professional phagocytes, and contributes to the first line of defense against intracellular bacteria.

  • 118. Crona, Mikael
    et al.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Astorga-Wells, Juan
    Sjöberg, Britt-Marie
    Tholander, Fredrik
    Biochemical Characterization of the Split Class II Ribonucleotide Reductase from Pseudomonas aeruginosa2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0134293Article in journal (Refereed)
    Abstract [en]

    The opportunistic pathogen Pseudomonas aeruginosa can grow under both aerobic and anaerobic conditions. Its flexibility with respect to oxygen load is reflected by the fact that its genome encodes all three existing classes of ribonucleotides reductase (RNR): the oxygen-dependent class I RNR, the oxygen-indifferent class II RNR, and the oxygen-sensitive class III RNR. The P. aeruginosa class II RNR is expressed as two separate polypeptides (NrdJa and NrdJb), a unique example of a split RNR enzyme in a free-living organism. A split class II RNR is also found in a few closely related gamma-Proteobacteria. We have characterized the P. aeruginosa class II RNR and show that both subunits are required for formation of a biologically functional enzyme that can sustain vitamin B12-dependent growth. Binding of the B12 coenzyme as well as substrate and allosteric effectors resides in the NrdJa subunit, whereas the NrdJb subunit mediates efficient reductive dithiol exchange during catalysis. A combination of activity assays and activity-independent methods like surface plasmon resonance and gas phase electrophoretic macromolecule analysis suggests that the enzymatically active form of the enzyme is a (NrdJa-NrdJb) 2 homodimer of heterodimers, and a combination of hydrogen-deuterium exchange experiments and molecular modeling suggests a plausible region in NrdJa that interacts with NrdJb. Our detailed characterization of the split NrdJ from P. aeruginosa provides insight into the biochemical function of a unique enzyme known to have central roles in biofilm formation and anaerobic growth.

  • 119. Cuenca, Miguelangel
    et al.
    Pfister, Simona P.
    Buschor, Stefanie
    Bayramova, Firuza
    Hernandez, Sara B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kuru, Erkin
    Van Nieuwenhze, Michael S.
    Brun, Yves V.
    Coelho, Fernanda M.
    Hapfelmeier, Siegfried
    D-Alanine-Controlled Transient Intestinal Mono-Colonization with Non-Laboratory-Adapted Commensal E. coli Strain HS2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0151872Article in journal (Refereed)
    Abstract [en]

    Soon after birth the mammalian gut microbiota forms a permanent and collectively highly resilient consortium. There is currently no robust method for re-deriving an already microbially colonized individual again-germ-free. We previously developed the in vivo growth-incompetent E. coli K-12 strain HA107 that is auxotrophic for the peptidoglycan components D-alanine (D-Ala) and meso-diaminopimelic acid (Dap) and can be used to transiently associate germ-free animals with live bacteria, without permanent loss of germ-free status. Here we describe the translation of this experimental model from the laboratory-adapted E. coli K-12 prototype to the better gut-adapted commensal strain E. coli HS. In this genetic background it was necessary to complete the D-Ala auxotrophy phenotype by additional knockout of the hypothetical third alanine racemase metC. Cells of the resulting fully auxotrophic strain assembled a peptidoglycan cell wall of normal composition, as long as provided with D-Ala and Dap in the medium, but could not proliferate a single time after D-Ala/Dap removal. Yet, unsupplemented bacteria remained active and were able to complete their cell cycle with fully sustained motility until immediately before autolytic death. Also in vivo, the transiently colonizing bacteria retained their ability to stimulate a live-bacteria-specific intestinal Immunoglobulin (Ig) A response. Full D-Ala auxotrophy enabled rapid recovery to again-germ-free status. E. coli HS has emerged from human studies and genomic analyses as a paradigm of benign intestinal commensal E. coli strains. Its reversibly colonizing derivative may provide a versatile research tool for mucosal bacterial conditioning or compound delivery without permanent colonization.

  • 120.
    Córdoba-Doña, Juan Antonio
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Delegación Territorial de la Consejería de Salud de la Junta de Andalucía, Cádiz, Spain.
    Escolar-Pujolar, Antonio
    San Sebastián, Miguel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Gustafsson, Per E.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Withstanding austerity: equity in health services utilisation in the first stage of the economic recession in Southern Spain2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 3, article id e0195293Article in journal (Refereed)
    Abstract [en]

    Scant research is available on the impact of the current economic crisis and austerity policies on inequality in health services utilisation in Europe. This study aimed to describe the trends in horizontal inequity in the use of health services in Andalusia, Spain, during the early years of the Great Recession, and the contribution of demographic, economic and social factors. Consultation with a general practitioner (GP) and specialist, hospitalisation and emergency care were studied through the Andalusian Health Survey 2007 (pre-crisis) and 2011-2012 (crisis), using a composite income index as socioeconomic status (SES) indicator. Horizontal inequity indices (HII) were calculated to take differential healthcare needs into account, and a decomposition analysis of change in inequality between periods was performed. Results showed that before the crisis, the HII was positive (greater access for people with higher SES) for specialist visits but negative (greater access for people with lower SES) in the other three utilisation models. During the crisis no change was observed in inequalities in GP visits, but a pro-poor development was seen for the other types of utilisation, with hospital and emergency care showing significant inequality in favour of low income groups. Overall, the main contributors to pro-poor changes in utilisation were socioeconomic variables and poor mental health, due to changes in their elasticities. Our findings show that inequalities in healthcare utilisation largely remained in favour of the less well-off, despite the cuts in welfare benefits and health services provision during the early years of the recession in Andalusia. Further research is needed to monitor the potential impact of such measures in subsequent years.

  • 121.
    Dahlin, Anna M.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Relation between Established Glioma Risk Variants and DNA Methylation in the Tumor2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0163067Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies and candidate gene studies have identified several genetic variants that increase glioma risk. The majority of these variants are non-coding and the mechanisms behind the increased risk in carriers are not known. In this study, we hypothesize that some of the established glioma risk variants induce aberrant DNA methylation in the developing tumor, either locally (gene-specific) or globally (genome-wide). In a pilot data set including 77 glioma patients, we used Illumina beadchip technology to analyze genetic variants in blood and DNA methylation in matched tumor samples. To validate our findings, we used data from the Cancer Genome Atlas, including 401 glioblastoma patients. Consensus clustering identified the glioma CpG island methylator phenotype (gCIMP) and two additional subgroups with distinct patterns of global DNA methylation. In the pilot dataset, gCIMP was associated with two genetic variants in CDKN2B-AS1, rs1412829 and rs4977756 (9p21.3, p = 8.1 x 10(-7) and 4.8 x 10(-5), respectively). The association was in the same direction in the TCGA dataset, although statistically significant only when combining individuals with AG and GG genotypes. We also investigated the relation between glioma risk variants and DNA methylation in the promoter region of genes located within 30 kb of each variant. One association in the pilot dataset, between the TERT risk variant rs2736100 and lower methylation of cg23827991 (in TERT; p = 0.001), was confirmed in the TCGA dataset (p = 0.001). In conclusion, we found an association between rs1412829 and rs4977756 (9p21.3, CDKN2B-AS1) and global DNA methylation pattern in glioma, for which a trend was seen also in the TCGA glioblastoma dataset. We also found an association between rs2736100 (in TERT) and levels of methylation at cg23827991 (localized in the same gene, 3.3 kbp downstream of the risk variant), which was validated in the TCGA dataset. Except for this one association, we did not find strong evidence for gene-specific DNA methylation mediated by glioma risk variants.

  • 122. Dantoft, Thomas Meinertz
    et al.
    Skovbjerg, Sine
    Andersson, Linus
    Umeå University, Faculty of Social Sciences, Department of Psychology. Department of Occupational and Public Health Sciences, University of Gävle, Sweden.
    Claeson, Anna-Sara
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Lind, Nina
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Brix, Susanne
    Inflammatory Mediator Profiling of n-butanol Exposed Upper Airways in Individuals with Multiple Chemical Sensitivity2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143534Article in journal (Refereed)
    Abstract [en]

    Background Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by reports of recurrent symptoms in response to low level exposure to various chemical substances. Recent findings suggests that dysregulation of the immune system may play a role in MCS pathophysiology. Objectives The aim of this study was to examine baseline and low dose n-butanol-induced upper airway inflammatory response profiles in MCS subjects versus healthy controls. Method Eighteen participants with MCS and 18 age- and sex-matched healthy controls were enrolled in the study. Epithelial lining fluid was collected from the nasal cavity at three time points: baseline, within 15 minutes after being exposed to 3.7 ppm n-butanol in an exposure chamber and four hours after exposure termination. A total of 19 cytokines and chemokines were quantified. Furthermore, at baseline and during the exposure session, participants rated the perceived intensity, valence and levels of symptoms and autonomic recordings were obtained. Results The physiological and psychophysical measurements during the n-butanol exposure session verified a specific response in MCS individuals only. However, MCS subjects and healthy controls displayed similar upper airway inflammatory mediator profiles (P>0.05) at baseline. Likewise, direct comparison of mediator levels in the MCS group and controls after n-butanol exposure revealed no significant group differences. Conclusion We demonstrate no abnormal upper airway inflammatory mediator levels in MCS subjects before or after a symptom-eliciting exposure to low dose n-butanol, implying that upper airways of MCS subjects are functionally intact at the level of cytokine and chemokine production and secretory capacity. This suggests that previous findings of increased cytokine plasma levels in MCS are unlikely to be caused by systemic priming via excessive upper airway inflammatory processes.

  • 123.
    Davoine, Celine
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Abreu, Ilka N.
    Khajeh, Khalil
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kidd, Brendan N.
    Kazan, Kemal
    Schenk, Peer M.
    Gerber, Lorenz
    Nilsson, Ove
    Moritz, Thomas
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Functional metabolomics as a tool to analyze Mediator function and structure in plants2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179640Article in journal (Refereed)
    Abstract [en]

    Mediator is a multiprotein transcriptional co-regulator complex composed of four modules; Head, Middle, Tail, and Kinase. It conveys signals from promoter-bound transcriptional regulators to RNA polymerase II and thus plays an essential role in eukaryotic gene regulation. We describe subunit localization and activities of Mediator in Arabidopsis through metabolome and transcriptome analyses from a set of Mediator mutants. Functional metabolomic analysis based on the metabolite profiles of Mediator mutants using multivariate statistical analysis and heat-map visualization shows that different subunit mutants display distinct metabolite profiles, which cluster according to the reported localization of the corresponding subunits in yeast. Based on these results, we suggest localization of previously unassigned plant Mediator subunits to specific modules. We also describe novel roles for individual subunits in development, and demonstrate changes in gene expression patterns and specific metabolite levels in med18 and med25, which can explain their phenotypes. We find that med18 displays levels of phytoalexins normally found in wild type plants only after exposure to pathogens. Our results indicate that different Mediator subunits are involved in specific signaling pathways that control developmental processes and tolerance to pathogen infections.

  • 124.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Söderström, Lars
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, Martin
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Dept of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm.
    Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2, article id e0192516Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC).

    METHOD: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis.

    RESULTS: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab.

    CONCLUSION: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.

  • 125. De Pascalis, Roberto
    et al.
    Hahn, Andrew
    Brook, Helen M.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Donart, Nathaniel
    Mittereder, Lara
    Frey, Blake
    Wu, Terry H.
    Elkins, Karen L.
    A panel of correlates predicts vaccine-induced protection of rats against respiratory challenge with virulent Francisella tularensis2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0198140Article in journal (Refereed)
    Abstract [en]

    There are no defined correlates of protection for any intracellular pathogen, including the bacterium Francisella tularensis, which causes tularemia. Evaluating vaccine efficacy against sporadic diseases like tularemia using field trials is problematic, and therefore alternative strategies to test vaccine candidates like the Francisella Live Vaccine Strain (LVS), such as testing in animals and applying correlate measurements, are needed. Recently, we described a promising correlate strategy that predicted the degree of vaccine-induced protection in mice given parenteral challenges, primarily when using an attenuated Francisella strain. Here, we demonstrate that using peripheral blood lymphocytes (PBLs) in this approach predicts LVS-mediated protection against respiratory challenge of Fischer 344 rats with fully virulent F. tularensis, with exceptional sensitivity and specificity. Rats were vaccinated with a panel of LVS-derived vaccines and subsequently given lethal respiratory challenges with Type A F. tularensis. In parallel, PBLs from vaccinated rats were evaluated for their functional ability to control intramacrophage Francisella growth in in vitro co-culture assays. PBLs recovered from co-cultures were also evaluated for relative gene expression using a large panel of genes identified in murine studies. In vitro control of LVS intramacrophage replication reflected the hierarchy of protection. Further, despite variability between individuals, 22 genes were significantly more up-regulated in PBLs from rats vaccinated with LVS compared to those from rats vaccinated with the variant LVS-R or heat killed LVS, which were poorly protective. These genes included IFN-gamma, IL-21, NOS2, LTA, T-bet, IL-12rβ2, and CCL5. Most importantly, combining quantifications of intramacrophage growth control with 5-7 gene expression levels using multivariate analyses discriminated protected from non-protected individuals with greater than 95% sensitivity and specificity. The results therefore support translation of this approach to non-human primates and people to evaluate new vaccines against Francisella and other intracellular pathogens.

  • 126. De Samber, Bjorn
    et al.
    Niemiec, Maria J.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Microbial Immunology Research Group, Hans Knöll Institute / Leibniz-Institute for Natural Product Research and Infection Biology, Jena, Germany.
    Laforce, Brecht
    Garrevoet, Jan
    Vergucht, Eva
    De Rycke, Riet
    Cloetens, Peter
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vincze, Laszlo
    Probing Intracellular Element Concentration Changes during Neutrophil Extracellular Trap Formation Using Synchrotron Radiation Based X-Ray Fluorescence2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0165604Article in journal (Refereed)
    Abstract [en]

    High pressure frozen (HPF), cryo-substituted microtome sections of 2 mu m thickness containing human neutrophils (white blood cells) were analyzed using synchrotron radiation based X-ray fluorescence (SR nano-XRF) at a spatial resolution of 50 nm. Besides neutrophils from a control culture, we also analyzed neutrophils stimulated for 1-2 h with phorbol myristate acetate (PMA), a substance inducing the formation of so-called Neutrophil Extracellular Traps (or NETs), a defense system again pathogens possibly involving proteins with metal chelating properties. In order to gain insight in metal transport during this process, precise local evaluation of elemental content was performed reaching limits of detection (LODs) of 1 ppb. Mean weight fractions within entire neutrophils, their nuclei and cytoplasms were determined for the three main elements P, S and Cl, but also for the 12 following trace elements: K, Ca, Mn, Fe, Co, Ni, Cu, Zn, Se, Br, Sr and Pb. Statistical analysis, including linear regression provided objective analysis and a measure for concentration changes. The nearly linear Ca and Cl concentration changes in neutrophils could be explained by already known phenomena such as the induction of Ca channels and the uptake of Cl under activation of NET forming neutrophils. Linear concentration changes were also found for P, S, K, Mn, Fe, Co and Se. The observed linear concentration increase for Mn could be related to scavenging of this metal from the pathogen by means of the neutrophil protein calprotectin, whereas the concentration increase of Se may be related to its antioxidant function protecting neutrophils from the reactive oxygen species they produce against pathogens. We emphasize synchrotron radiation based nanoscopic X-ray fluorescence as an enabling analytical technique to study changing (trace) element concentrations throughout cellular processes, provided accurate sample preparation and data-analysis.

  • 127.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Domellöf, Magdalena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lundin, Mathias
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Long Leukocyte Telomere Length at Diagnosis Is a Risk Factor for Dementia Progression in Idiopathic Parkinsonism2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, article id e113387Article in journal (Refereed)
    Abstract [en]

    Telomere length (TL) is regarded as a marker of cellular aging due to the gradual shortening by each cell division, but is influenced by a number of factors including oxidative stress and inflammation. Parkinson's disease and atypical forms of parkinsonism occur mainly in the elderly, with oxidative stress and inflammation in afflicted cells. In this study the relationship between blood TL and prognosis of 168 patients with idiopathic parkinsonism (136 Parkinson's disease [PD], 17 Progressive Supranuclear Palsy [PSP], and 15 Multiple System Atrophy [MSA]) and 30 controls was investigated. TL and motor and cognitive performance were assessed at baseline (diagnosis) and repeatedly up to three to five years follow up. No difference in TL between controls and patients was shown at baseline, nor any significant difference in TL stability or attrition during follow up. Interestingly, a significant relationship between TL at diagnosis and cognitive phenotype at follow up in PD and PSP patients was found, with longer mean TL at diagnosis in patients that developed dementia within three years.

  • 128. Dehghan, Abbas
    et al.
    Bis, Joshua C.
    White, Charles C.
    Smith, Albert Vernon
    Morrison, Alanna C.
    Cupples, L. Adrienne
    Trompet, Stella
    Chasman, Daniel I.
    Lumley, Thomas
    Voelker, Uwe
    Buckley, Brendan M.
    Ding, Jingzhong
    Jensen, Majken K.
    Folsom, Aaron R.
    Kritchevsky, Stephen B.
    Girman, Cynthia J.
    Ford, Ian
    Doerr, Marcus
    Salomaa, Veikko
    Uitterlinden, Andre G.
    Eiriksdottir, Gudny
    Vasan, Ramachandran S.
    Franceschini, Nora
    Carty, Cara L.
    Virtamo, Jarmo
    Demissie, Serkalem
    Amouyel, Philippe
    Arveiler, Dominique
    Heckbert, Susan R.
    Ferrieres, Jean
    Ducimetiere, Pierre
    Smith, Nicholas L.
    Wang, Ying A.
    Siscovick, David S.
    Rice, Kenneth M.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Taylor, Kent D.
    Evans, Alun
    Kee, Frank
    Rotter, Jerome I.
    Karvanen, Juha
    Kuulasmaa, Kari
    Heiss, Gerardo
    Kraft, Peter
    Launer, Lenore J.
    Hofman, Albert
    Markus, Marcello R. P.
    Rose, Lynda M.
    Silander, Kaisa
    Wagner, Peter
    Benjamin, Emelia J.
    Lohman, Kurt
    Stott, David J.
    Rivadeneira, Fernando
    Harris, Tamara B.
    Levy, Daniel
    Liu, Yongmei
    Rimm, Eric B.
    Jukema, J. Wouter
    Voelzke, Henry
    Ridker, Paul M.
    Blankenberg, Stefan
    Franco, Oscar H.
    Gudnason, Vilmundur
    Psaty, Bruce M.
    Boerwinkle, Eric
    O'Donnell, Christopher J.
    Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0144997Article in journal (Refereed)
    Abstract [en]

    Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5x10(-6) in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5x10(-6); 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8x10(-3)) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2x10(-9)). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2x10(-3)). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

  • 129. Delahaye-Sourdeix, Manon
    et al.
    Oliver, Javier
    Timofeeva, Maria N
    Gaborieau, Valérie
    Johansson, Mattias
    Genetic Epidemiology group (GEP), International Agency for Research on Cancer (IARC), Lyon, France .
    Chabrier, Amélie
    Wozniak, Magdalena B
    Brenner, Darren R
    Vallée, Maxime P
    Anantharaman, Devasena
    Lagiou, Pagona
    Holcátová, Ivana
    Richiardi, Lorenzo
    Kjaerheim, Kristina
    Agudo, Antonio
    Castellsagué, Xavier
    Macfarlane, Tatiana V
    Barzan, Luigi
    Canova, Cristina
    Thakker, Nalin S
    Conway, David I
    Znaor, Ariana
    Healy, Claire M
    Ahrens, Wolfgang
    Zaridze, David
    Szeszenia-Dabrowska, Neonilia
    Lissowska, Jolanta
    Fabianova, Eleonora
    Mates, Ioan Nicolae
    Bencko, Vladimir
    Foretova, Lenka
    Janout, Vladimir
    Curado, Maria Paula
    Koifman, Sergio
    Menezes, Ana
    Wünsch-Filho, Victor
    Eluf-Neto, José
    Boffetta, Paolo
    Garrote, Leticia Fernández
    Serraino, Diego
    Lener, Marcin
    Jaworowska, Ewa
    Lubiński, Jan
    Boccia, Stefania
    Rajkumar, Thangarajan
    Samant, Tanuja A
    Mahimkar, Manoj B
    Matsuo, Keitaro
    Franceschi, Silvia
    Byrnes, Graham
    Brennan, Paul
    McKay, James D
    The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0117639Article in journal (Refereed)
    Abstract [en]

    Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

  • 130.
    Delhomme, Nicolas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Sundström, Görel
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, Uppsala, Sweden.
    Zamani, Neda
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, Uppsala, Sweden.
    Lantz, Henrik
    Lin, Yao-Cheng
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Norwegian Univ Life Sci, Dept Chem Biotechnol & Food Sci, As, Norway.
    Hoppner, Marc P.
    Jern, Patric
    Van de Peer, Yves
    Lundeberg, Joakim
    Grabherr, Manfred G.
    Street, Nathaniel R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Serendipitous Meta-Transcriptomics: The Fungal Community of Norway Spruce (Picea abies)2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0139080Article in journal (Refereed)
    Abstract [en]

    After performing de novo transcript assembly of >1 billion RNA-Sequencing reads obtained from 22 samples of different Norway spruce (Picea abies) tissues that were not surface sterilized, we found that assembled sequences captured a mix of plant, lichen, and fungal transcripts. The latter were likely expressed by endophytic and epiphytic symbionts, indicating that these organisms were present, alive, and metabolically active. Here, we show that these serendipitously sequenced transcripts need not be considered merely as contamination, as is common, but that they provide insight into the plant's phyllosphere. Notably, we could classify these transcripts as originating predominantly from Dothideomycetes and Leotiomycetes species, with functional annotation of gene families indicating active growth and metabolism, with particular regards to glucose intake and processing, as well as gene regulation.

  • 131. Desai, Meghna
    et al.
    Buff, Ann M
    Khagayi, Sammy
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Amek, Nyaguara
    van Eijk, Annemieke
    Slutsker, Laurence
    Vulule, John
    Odhiambo, Frank O
    Phillips-Howard, Penelope A
    Lindblade, Kimberly A
    Laserson, Kayla F
    Hamel, Mary J
    Age-specific malaria mortality rates in the KEMRI/CDC health and demographic surveillance system in western Kenya, 2003-20102014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e106197Article in journal (Refereed)
    Abstract [en]

    Recent global malaria burden modeling efforts have produced significantly different estimates, particularly in adult malaria mortality. To measure malaria control progress, accurate malaria burden estimates across age groups are necessary. We determined age-specific malaria mortality rates in western Kenya to compare with recent global estimates. We collected data from 148,000 persons in a health and demographic surveillance system from 2003-2010. Standardized verbal autopsies were conducted for all deaths; probable cause of death was assigned using the InterVA-4 model. Annual malaria mortality rates per 1,000 person-years were generated by age group. Trends were analyzed using Poisson regression. From 2003-2010, in children <5 years the malaria mortality rate decreased from 13.2 to 3.7 per 1,000 person-years; the declines were greatest in the first three years of life. In children 5-14 years, the malaria mortality rate remained stable at 0.5 per 1,000 person-years. In persons ≥15 years, the malaria mortality rate decreased from 1.5 to 0.4 per 1,000 person-years. The malaria mortality rates in young children and persons aged ≥15 years decreased dramatically from 2003-2010 in western Kenya, but rates in older children have not declined. Sharp declines in some age groups likely reflect the national scale up of malaria control interventions and rapid expansion of HIV prevention services. These data highlight the importance of age-specific malaria mortality ascertainment and support current strategies to include all age groups in malaria control interventions.

  • 132. Dhillon, Sundeep S.
    et al.
    Torell, Frida
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Accelerator Lab (ACL), Karlsruhe Institute of Technology, Karlsruhe, Germany; AcureOmics, Umeå, Sweden.
    Donten, Magdalena
    Lundstedt-Enkel, Katrin
    Bennett, Kate
    Raennar, Stefan
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. AcureOmics, Umeå, Sweden.
    Lundstedt, Torbjorn
    Metabolic profiling of zebrafish embryo development from blastula period to early larval stages2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0213661Article in journal (Refereed)
    Abstract [en]

    The zebrafish embryo is a popular model for drug screening, disease modelling and molecular genetics. In this study, samples were obtained from zebrafish at different developmental stages. The stages that were chosen were 3/4, 4/5, 24, 48, 72 and 96 hours post fertilization (hpf). Each sample included fifty embryos. The samples were analysed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Principle component analysis (PCA) was applied to get an overview of the data and orthogonal projection to latent structure discriminant analysis (OPLS-DA) was utilised to discriminate between the developmental stages. In this way, changes in metabolite profiles during vertebrate development could be identified. Using a GC-TOF-MS metabolomics approach it was found that nucleotides and metabolic fuel (glucose) were elevated at early stages of embryogenesis, whereas at later stages amino acids and intermediates in the Krebs cycle were abundant. This agrees with zebrafish developmental biology, as organs such as the liver and pancreas develop at later stages. Thus, metabolomics of zebrafish embryos offers a unique opportunity to investigate large scale changes in metabolic processes during important developmental stages in vertebrate development. In terms of stability of the metabolic profile and viability of the embryos, it was concluded at 72 hpf was a suitable time point for the use of zebrafish as a model system in numerous scientific applications.

  • 133. Dicks, Matthew DJ
    et al.
    Spencer, Alexandra J
    Edwards, Nick J
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bojang, Kalifa
    Gilbert, Sarah C
    Hill, Adrian VS
    Cottingham, Matthew G
    A novel chimpanzee adenovirus vector with low human seroprevalence: improved systems for vector derivation and comparative immunogenicity2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e40385-Article in journal (Refereed)
    Abstract [en]

    Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less exposed in order to circumvent preexisting anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1:200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.

  • 134. Diekstra, Frank P.
    et al.
    Saris, Christiaan G. J.
    van Rheenen, Wouter
    Franke, Lude
    Jansen, Ritsert C.
    van Es, Michael A.
    van Vught, Paul W. J.
    Blauw, Hylke M.
    Groen, Ewout J. N.
    Horvath, Steve
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G.
    Robberecht, Wim
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Melki, Judith
    Meininger, Vincent
    Hardiman, Orla
    Landers, John E.
    Brown, Robert H., Jr.
    Shatunov, Aleksey
    Shaw, Christopher E.
    Leigh, P. Nigel
    Al-Chalabi, Ammar
    Ophoff, Roel A.
    van den Berg, Leonard H.
    Veldink, Jan H.
    Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e35333-Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 x 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.

  • 135. Drotz, Marcus K
    et al.
    Brodin, Tomas
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Nilsson, Anders N
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Changing Names with Changed Address: Integrated Taxonomy and Species Delimitation in the Holarctic Colymbetes paykulli Group (Coleoptera: Dytiscidae)2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143577Article in journal (Refereed)
    Abstract [en]

    Species delimitation of geographically isolated forms is a long-standing problem in less studied insect groups. Often taxonomic decisions are based directly on morphologic variation, and lack a discussion regarding sample size and the efficiency of migration barriers or dispersal/migration capacity of the studied species. These problems are here exemplified in a water beetle complex from the Bering Sea region that separates North America from Eurasia. Only a few sampled specimens occur from this particular area and they are mostly found in museum and private collections. Here we utilize the theory of integrated taxonomy to discuss the speciation of the Holarctic Colymbetes paykulli water beetle complex, which historically has included up to five species of which today only two are recognized. Three delimitation methods are used; landmark based morphometry of body shape, variation in reticulation patterns of the pronotum exo-skeleton and sequence variation of the partial mitochondrial gene Cyt b. Our conclusion is that the Palearctic and Nearctic populations of C. paykulli are given the status of separate species, based on the fact that all methods showed significant separation between populations. As a consequence the name of the Palearctic species is C. paykulli Erichson and the Nearctic species should be known as C. longulus LeConte. There is no clear support for delineation between Palearctic and Nearctic populations of C. dahuricus based on mtDNA. However, significant difference in size and reticulation patterns from the two regions is shown. The combined conclusion is that the C. dahuricus complex needs a more thorough investigation to fully disentangle its taxonomic status. Therefore it is here still regarded as a Holarctic species. This study highlights the importance to study several diagnosable characters that has the potential to discriminate evolutionary lineage during speciation.

  • 136. Drotz, Marcus K.
    et al.
    Brodin, Tomas
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Saura, Anssi
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Giles, Barbara E.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Ecotype Differentiation in the Face of Gene Flow within the Diving Beetle Agabus bipustulatus (Linnaeus, 1767) in Northern Scandinavia2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, p. e31381-Article in journal (Refereed)
    Abstract [en]

    The repeated occurrence of habitat-specific polyphyletic evolved ecotypes throughout the ranges of widely distributed species implies that multiple, independent and parallel selection events have taken place. Ecological transitions across altitudinal gradients over short geographical distances are often associated with variation in habitat-related fitness, these patterns suggest the action of strong selective forces. Genetic markers will therefore contribute differently to differences between ecotypes in local hybrid zones. Here we have studied the adaptive divergence between ecotypes of the water beetle Agabus bipustulatus along several parallel altitudinal gradients in northern Scandinavia. This water beetle is well known for its remarkable morphological variation associated with mountain regions throughout the western Palaearctic. Two morphological ecotypes are recognised: a montane type with reduced flight muscles and a lowland type with fully developed muscles. Using a multilocus survey of allozyme variation and a morphological analysis with landmark-based morphometrics, across thirty-three populations and seven altitudinal gradients, we studied the local adaptive process of gene flow and selection in detail. Populations were sampled at three different elevations: below, at and above the tree line. The results indicate that the levels of divergence observed between ecotypes in morphology and allele frequencies at alpha-Glycerophosphate dehydrogenase relative to those shown by neutral molecular markers reflects local diversifying selection in situ. Four main lines of evidence are shown here: (1) A repeated morphological pattern of differentiation is observed across all altitudinal transects, with high reclassification probabilities. (2) Allele and genotype frequencies at the alpha-Gpdh locus are strongly correlated with altitude, in sharp contrast to the presumable neutral markers. (3) Genetic differentiation is two to three times higher among populations across the tree line than among populations at or below. (4) Genetic differentiation between ecotypes within independent mountain areas is reflected by different sets of allozymes.

  • 137.
    Druzin, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Malinina, Evgenya
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Grimsholm, Ola
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Johansson, Staffan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Mechanism of estradiol-induced block of voltage-gated K+ currents in rat medial preoptic neurons.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 5, p. e20213-Article in journal (Refereed)
    Abstract [en]

    The present study was conducted to characterize possible rapid effects of 17-β-estradiol on voltage-gated K(+) channels in preoptic neurons and, in particular, to identify the mechanisms by which 17-β-estradiol affects the K(+) channels. Whole-cell currents from dissociated rat preoptic neurons were studied by perforated-patch recording. 17-β-Estradiol rapidly (within seconds) and reversibly reduced the K(+) currents, showing an EC(50) value of 9.7 µM. The effect was slightly voltage dependent, but independent of external Ca(2+), and not sensitive to an estrogen-receptor blocker. Although 17-α-estradiol also significantly reduced the K(+) currents, membrane-impermeant forms of estradiol did not reduce the K(+) currents and other estrogens, testosterone and cholesterol were considerably less effective. The reduction induced by estradiol was overlapping with that of the K(V)-2-channel blocker r-stromatoxin-1. The time course of K(+) current in 17-β-estradiol, with a time-dependent inhibition and a slight dependence on external K(+), suggested an open-channel block mechanism. The properties of block were predicted from a computational model where 17-β-estradiol binds to open K(+) channels. It was concluded that 17-β-estradiol rapidly reduces voltage-gated K(+) currents in a way consistent with an open-channel block mechanism. This suggests a new mechanism for steroid action on ion channels.

  • 138.
    Dupont, Chris L.
    et al.
    J. Craig Venter Institute, USA.
    Larsson, John
    Stockholm University.
    Yooseph, Shibu
    J. Craig Venter Institute, USA.
    Ininbergs, Karolina
    Stockholm University.
    Goll, Johannes
    J. Craig Venter Institute, USA.
    Asplund-Samuelsson, Johannes
    Stockholm University.
    McCrow, John P.
    J. Craig Venter Institute, USA.
    Celepli, Narin
    Stockholm University.
    Allen, Lisa Zeigler
    J. Craig Venter Institute, USA.
    Ekman, Martin
    Stockholm University.
    Lucas, Andrew J.
    Hagström, Åke
    University of Gothenburg.
    Thiagarajan, Mathangi
    Brindefalk, Bjorn
    Richter, Alexander R.
    Andersson, Anders F.
    Tenney, Aaron
    Lundin, Daniel
    KTH Royal Institute of Technology.
    Tovchigrechko, Andrey
    Nylander, Johan A. A.
    Brami, Daniel
    Badger, Jonathan H.
    Allen, Andrew E.
    Rusch, Douglas B.
    Hoffman, Jeff
    Norrby, Erling
    Friedman, Robert
    Pinhassi, Jarone
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Venter, J. Craig
    Bergman, Birgitta
    Functional Tradeoffs Underpin Salinity-Driven Divergence in Microbial Community Composition2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, article id e89549Article in journal (Refereed)
    Abstract [en]

    Bacterial community composition and functional potential change subtly across gradients in the surface ocean. In contrast, while there are significant phylogenetic divergences between communities from freshwater and marine habitats, the underlying mechanisms to this phylogenetic structuring yet remain unknown. We hypothesized that the functional potential of natural bacterial communities is linked to this striking divide between microbiomes. To test this hypothesis, metagenomic sequencing of microbial communities along a 1,800 km transect in the Baltic Sea area, encompassing a continuous natural salinity gradient from limnic to fully marine conditions, was explored. Multivariate statistical analyses showed that salinity is the main determinant of dramatic changes in microbial community composition, but also of large scale changes in core metabolic functions of bacteria. Strikingly, genetically and metabolically different pathways for key metabolic processes, such as respiration, biosynthesis of quinones and isoprenoids, glycolysis and osmolyte transport, were differentially abundant at high and low salinities. These shifts in functional capacities were observed at multiple taxonomic levels and within dominant bacterial phyla, while bacteria, such as SAR11, were able to adapt to the entire salinity gradient. We propose that the large differences in central metabolism required at high and low salinities dictate the striking divide between freshwater and marine microbiomes, and that the ability to inhabit different salinity regimes evolved early during bacterial phylogenetic differentiation. These findings significantly advance our understanding of microbial distributions and stress the need to incorporate salinity in future climate change models that predict increased levels of precipitation and a reduction in salinity.

  • 139.
    Dynesius, Mats
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Gibb, Heloise
    Department of Zoology, La Trobe University, Melbourne, Australia.
    Hjältén, Joakim
    Department of Wildlife, Fish, and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Surface covering of downed logs: Drivers of a neglected process in dead wood ecology2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 10, p. e13237-Article in journal (Refereed)
    Abstract [en]

    Many species use coarse woody debris (CWD) and are disadvantaged by the forestry-induced loss of this resource. A neglected process affecting CWD is the covering of the surfaces of downed logs caused by sinking into the ground (increasing soil contact, mostly covering the underside of the log), and dense overgrowth by ground vegetation. Such cover is likely to profoundly influence the quality and accessibility of CWD for wood-inhabiting organisms, but the factors affecting covering are largely unknown. In a five-year experiment we determined predictors of covering rate of fresh logs in boreal forests and clear-cuts. Logs with branches were little covered because they had low longitudinal ground contact. For branchless logs, longitudinal ground contact was most strongly related to estimated peat depth (positive relation). The strongest predictor for total cover of branchless logs was longitudinal ground contact. To evaluate the effect on cover of factors other than longitudinal ground contact, we separately analyzed data from only those log sections that were in contact with the ground. Four factors were prominent predictors of percentage cover of such log sections: estimated peat depth, canopy shade (both increasing cover), potential solar radiation calculated from slope and slope aspect, and diameter of the log (both reducing cover). Peat increased cover directly through its low resistance, which allowed logs to sink and soil contact to increase. High moisture and low temperatures in pole-ward facing slopes and under a canopy favor peat formation through lowered decomposition and enhanced growth of peat-forming mosses, which also proved to rapidly overgrow logs. We found that in some boreal forests, peat and fast-growing mosses can rapidly cover logs lying on the ground. When actively introducing CWD for conservation purposes, we recommend that such rapid covering is avoided, thereby most likely improving the CWD’s longevity as habitat for many species.

  • 140.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47045-Article in journal (Refereed)
    Abstract [en]

    High macrophage infiltration has been correlated to improved survival in colorectal cancer (CRC). Tumor associated macrophages (TAMs) play complex roles in tumorigenesis since they are believed to hold both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we have applied an immunohistochemical approach to determine the degree of infiltrating macrophages with a M1 or M2 phenotype in clinical specimens of CRC in relation to prognosis, both in CRC in general but also in subgroups of CRC defined by microsatellite instability (MSI) screening status and the CpG island methylator phenotype (CIMP). A total of 485 consecutive CRC specimens were stained for nitric oxide synthase 2 (NOS2) (also denoted iNOS) as a marker for the M1 macrophage phenotype and the scavenger receptor CD163 as a marker for the M2 macrophage phenotype. The average infiltration of NOS2 and CD163 expressing macrophages along the invasive tumor front was semi-quantitatively evaluated using a four-graded scale. Two subtypes of macrophages, displaying M1 (NOS2(+)) or M2 (CD163(+)) phenotypes, were recognized. We observed a significant correlation between the amount of NOS2(+) and CD163(+) cells (P<0.0001). A strong inverse correlation to tumor stage was found for both NOS2 (P<0.0001) and CD163 (P<0.0001) infiltration. Furthermore, patients harbouring tumors highly infiltrated by NOS2+ cells had a significantly better prognosis than those infiltrated by few NOS2+ cells, and this was found to be independent of MSI screening status and CIMP status. No significant difference was found on cancer-specific survival in groups of CRC with different NOS2/CD163 ratios. In conclusion, an increased infiltration of macrophages with a M1 phenotype at the tumor front is accompanied by a concomitant increase in macrophages with a M2 phenotype, and in a stage dependent manner correlated to a better prognosis in patients with CRC.

  • 141.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74982-Article in journal (Refereed)
    Abstract [en]

    Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a "mixed" M1/M2 phenotype, which in turn could contribute to a "good inflammatory response". This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer.

  • 142.
    Ehlers, Ina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Betson, Tatiana R.
    Vetter, Walter
    Schleucher, Jürgen
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Elucidating Turnover Pathways of Bioactive Small Molecules by Isotopomer Analysis: The Persistent Organic Pollutant DDT2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e110648-Article in journal (Refereed)
    Abstract [en]

    The persistent organic pollutant DDT (1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane) is still indispensable in the fight againstmalaria, although DDT and related compounds  pose toxicological  hazards. Technical DDT contains the dichloro congenerDDD (1-chloro-4-[2,2-dichloro-1-(4-chlorophenyl)ethyl]benzene)   as by-product, but  DDD is also formed by  reductive degradation of DDT in the environment. To differentiate between DDD formation pathways, we applied deuterium NMR spectroscopy to measure intramolecular deuterium distributions (2H isotopomer abundances) of DDT and DDD. DDD formed in the technical  DDT synthesis was strongly deuterium-enriched at one intramolecular position, which we traced back to 2H/1H fractionation of a chlorination step in the technical synthesis.  In contrast, DDD formed by reductive degradation was strongly depleted at the same position, which was due to the incorporation of 2H-depleted hydride equivalents during reductive degradation. Thus, intramolecular isotope distributions give mechanistic information on reaction pathways, and explain a puzzling difference in the whole-molecule 2H/1H ratio between DDT and DDD. In general, our results highlight that intramolecular isotope distributions are essential to interpret whole-molecule isotope ratios. Intramolecular isotope information allows distinguishing pathways of DDD formation, which is important to identify polluters or to assess  DDT turnover in the environment. Because  intramolecular isotope data directly reflect isotope fractionation of individual chemical reactions, they are broadly applicable to elucidate transformation pathways of smallbioactive molecules in chemistry, physiology and environmental science.

  • 143.
    Elcadi, Guilherme H
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Högskolan Gävle.
    Forsman, Mikael
    Högskolan Gävle; Karolinska institutet Stockholm.
    Hallman, David M
    Högskolan Gävle.
    Aasa, Ulrika
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Fahlstrom, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Professionell Development. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Crenshaw, Albert G
    Högskolan Gävle.
    Oxygenation and hemodynamics do not underlie early muscle fatigue for patients with work-related muscle pain.2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, article id e95582Article in journal (Refereed)
    Abstract [en]

    Patients suffering from work-related muscle pain (WRMP) fatigue earlier during exercise than healthy controls. Inadequate oxygen consumption and/or inadequate blood supply can influence the ability of the muscles to withstand fatigue. However, it remains unknown if oxygenation and hemodynamics are associated with early fatigue in muscles of WRMP patients. In the present study we applied near-infrared spectroscopy (NIRS) on the extensor carpi radialis (ECR) and trapezius (TD) muscles of patients with WRMP (n = 18) and healthy controls (n = 17). Our objective was to determine if there were group differences in endurance times for a low-level contraction of 15% maximal voluntary contraction (MVC)--sustained for 12-13 min, and to see if these differences were associated with differences in muscle oxygenation and hemodynamics. At baseline, oxygen saturation (StO2%) was similar between groups for the ECR, but StO2% was significantly lower for TD for the WRMP patients (76%) compared to controls (85%) (P<0.01). Also, baseline ECR blood flow was similar in the two groups. For both muscles there were a larger number of patients, compared to controls, that did not maintain the 15% MVC for the allotted time. Consequently, the endurance times were significantly shorter for the WRMP patients than controls (medians, ECR: 347 s vs. 582 s; TD: 430 s vs. 723 s respectively). Responses in StO2% during the contractions were not significantly different between groups for either muscle, i.e. no apparent difference in oxygen consumption. Overall, we interpret our findings to indicate that the early fatigue for our WRMP patients was not associated with muscle oxygenation and hemodynamics.

  • 144. Elfving, Karin
    et al.
    Olsen, Björn
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Waldenström, Jonas
    Lundkvist, Åke
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Mejlon, Hans
    Nilsson, Kenneth
    Dissemination of spotted fever rickettsia agents in Europe by migrating birds2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, p. e8572-Article in journal (Refereed)
    Abstract [en]

    Migratory birds are known to play a role as long-distance vectors for many microorganisms. To investigate whether this is true of rickettsial agents as well, we characterized tick infestation and gathered ticks from 13,260 migratory passerine birds in Sweden. A total of 1127 Ixodes spp. ticks were removed from these birds and the extracted DNA from 957 of them was available for analyses. The DNA was assayed for detection of Rickettsia spp. using real-time PCR, followed by DNA sequencing for species identification. Rickettsia spp. organisms were detected in 108 (11.3%) of the ticks. Rickettsia helvetica, a spotted fever rickettsia associated with human infections, was predominant among the PCR-positive samples. In 9 (0.8%) of the ticks, the partial sequences of 17kDa and ompB genes showed the greatest similarity to Rickettsia monacensis, an etiologic agent of Mediterranean spotted fever-like illness, previously described in southern Europe as well as to the Rickettsia sp.IrITA3 strain. For 15 (1.4%) of the ticks, the 17kDa, ompB, gltA and ompA genes showed the greatest similarity to Rickettsia sp. strain Davousti, Rickettsia japonica and Rickettsia heilongjiangensis, all closely phylogenetically related, the former previously found in Amblyomma tholloni ticks in Africa and previously not detected in Ixodes spp. ticks. The infestation prevalence of ticks infected with rickettsial organisms was four times higher among ground foraging birds than among other bird species, but the two groups were equally competent in transmitting Rickettsia species. The birds did not seem to serve as reservoir hosts for Rickettsia spp., but in one case it seems likely that the bird was rickettsiemic and that the ticks had acquired the bacteria from the blood of the bird. In conclusion, migratory passerine birds host epidemiologically important vector ticks and Rickettsia species and contribute to the geographic distribution of spotted fever rickettsial agents and their diseases.

  • 145.
    Elluri, Sridhar
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Division of Pathophysiology, National Institute of Cholera and Enteric Diseases, Kolkata, West Bengal, India.
    Enow Oben Ayuk, Constance
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vdovikova, Svitlana
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rompikuntal, Pramod K
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Dongre, Mitesh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Carlsson, Sven
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pal, Amit
    Division of Pathophysiology, National Institute of Cholera and Enteric Diseases, Kolkata, West Bengal, India.
    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).
    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).
    Outer membrane vesicles mediate transport of biologically active Vibrio cholerae cytolysin (VCC) from V. cholerae strains2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e106731Article in journal (Refereed)
    Abstract [en]

    Background Outer membrane vesicles (OMVs) released from Gram-negative bacteria can serve as vehicles for the translocation of virulence factors. Vibrio cholerae produce OMVs but their putative role in translocation of effectors involved in pathogenesis has not been well elucidated. The V. cholerae cytolysin (VCC), is a pore-forming toxin that lyses target eukaryotic cells by forming transmembrane oligomeric β-barrel channels. It is considered a potent toxin that contributes to V. cholerae pathogenesis. The mechanisms involved in the secretion and delivery of the VCC have not been extensively studied.

    Methodology/Principal Findings OMVs from V. cholerae strains were isolated and purified using a differential centrifugation procedure and Optiprep centrifugation. The ultrastructure and the contents of OMVs were examined under the electron microscope and by immunoblot analyses respectively. We demonstrated that VCC from V. cholerae strain V:5/04 was secreted in association with OMVs and the release of VCC via OMVs is a common feature among V. cholerae strains. The biological activity of OMV-associated VCC was investigated using contact hemolytic assay and epithelial cell cytotoxicity test. It showed toxic activity on both red blood cells and epithelial cells. Our results indicate that the OMVs architecture might play a role in stability of VCC and thereby can enhance its biological activities in comparison with the free secreted VCC. Furthermore, we tested the role of OMV-associated VCC in host cell autophagy signalling using confocal microscopy and immunoblot analysis. We observed that OMV-associated VCC triggered an autophagy response in the target cell and our findings demonstrated for the first time that autophagy may operate as a cellular defence mechanism against an OMV-associated bacterial virulence factor.

    Conclusion/Significance Biological assays of OMVs from the V. cholerae strain V:5/04 demonstrated that OMV-associated VCC is indeed biologically active and induces toxicity on mammalian cells and furthermore can induce autophagy.

  • 146.
    Elwér, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Harryson, Lisa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine. Umeå University, Faculty of Social Sciences, Umeå Centre for Gender Studies (UCGS).
    Bolin, Malin
    Department of Social Sciences, Mid Sweden University.
    Hammarström, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Patterns of gender equality at workplaces and psychological distress2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, article id e53246Article in journal (Refereed)
    Abstract [en]

    Research in the field of occupational health often uses a risk factor approach which has been criticized by feminist researchers for not considering the combination of many different variables that are at play simultaneously. To overcome this shortcoming this study aims to identify patterns of gender equality at workplaces and to investigate how these patterns are associated with psychological distress. Questionnaire data from the Northern Swedish Cohort (n=715) have been analysed and supplemented with register data about the participants’ workplaces. The register data were used to create gender equality indicators of women/men ratios of number of employees, educational level, salary and parental leave. Cluster analysis was used to identify patterns of gender equality at the workplaces. Differences in psychological distress between the clusters were analysed by chi-square test and logistic regression analyses, adjusting for individual socio-demographics and previous psychological distress. The cluster analysis resulted in six distinctive clusters with different patterns of gender equality at the workplaces that were associated to psychological distress for women but not for men. For women the highest odds of psychological distress was found on traditionally gender unequal workplaces. The lowest overall occurrence of psychological distress as well as same occurrence for women and men was found on the most gender equal workplaces. The results from this study support the convergence hypothesis as gender equality at the workplace does not only relate to better mental health for women, but also more similar occurrence of mental ill-health between women and men. This study highlights the importance of utilizing a multidimensional view of gender equality to understand its association to health outcomes. Health policies need to consider gender equality at the workplace level as a social determinant of health that is of importance for reducing differences in health outcomes for women and men.

  • 147. Emma, Rosalia
    et al.
    Bansal, Aruna T.
    Kolmert, Johan
    Wheelock, Craig E.
    Dahlen, Swen-Erik
    Loza, Matthew J.
    De Meulder, Bertrand
    Lefaudeux, Diane
    Auffray, Charles
    Dahlen, Barbro
    Bakke, Per S.
    Chanez, Pascal
    Fowler, Stephen J.
    Horvath, Ildiko
    Montuschi, Paolo
    Krug, Norbert
    Sanak, Marek
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Shaw, Dominick E.
    Fleming, Louise J.
    Djukanovic, Ratko
    Howarth, Peter H.
    Singer, Florian
    Sousa, Ana R.
    Sterk, Peter J.
    Cortield, Julie
    Pandis, Ioannis
    Chung, Kian F.
    Adcock, Ian M.
    Lutter, Rene
    Fabbella, Lorena
    Caruso, Massimo
    Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 9, article id e0203874Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF(2 alpha) and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF(2 alpha); IS-transcriptomics; BB-transcriptomics; BBrtranscriptomics). Urinary 8-iso-PGF(2 alpha) was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF(2 alpha) was increased in SAs/ex, median (IQR) = 31.7 (24.5 +/- 44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6 +/- 36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4 +/- 47.7), vs. ESA, median (IQR) = 29.4 (22.3 +/- 40.5), and NSA, median (IQR) = 26.5 (19.6 +/- 16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF(2 alpha) in the smokers/ex-smokers group.

  • 148.
    Eneslätt, Kjell
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Normark, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Björk, Rafael
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rietz, Cecilia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wolfraim, Lawrence A
    Stöven, Svenja
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Signatures of T cells as correlates of immunity to Francisella tularensis2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e32367-Article in journal (Refereed)
    Abstract [en]

    Tularemia or vaccination with the live vaccine strain (LVS) of Francisella tularensis confers long-lived cell-mediated immunity. We hypothesized that this immunity depends on polyfunctional memory T cells, i.e., CD4(+) and/or CD8(+) T cells with the capability to simultaneously express several functional markers. Multiparametric flow cytometry, measurement of secreted cytokines, and analysis of lymphocyte proliferation were used to characterize in vitro recall responses of peripheral blood mononuclear cells (PBMC) to killed F. tularensis antigens from the LVS or Schu S4 strains. PBMC responses were compared between individuals who had contracted tularemia, had been vaccinated, or had not been exposed to F. tularensis (naive). Significant differences were detected between either of the immune donor groups and naive individuals for secreted levels of IL-5, IL-6, IL-10, IL-12, IL-13, IFN-gamma, MCP-1, and MIP-1 beta. Expression of IFN-gamma, MIP-1 beta, and CD107a by CD4(+)CD45RO(+) or CD8(+) CD45RO(+) T cells correlated to antigen concentrations. In particular, IFN-gamma and MIP-1 beta strongly discriminated between immune and naive individuals. Only one cytokine, IL-6, discriminated between the two groups of immune individuals. Notably, IL-2- or TNF-alpha-secretion was low. Our results identify functional signatures of T cells that may serve as correlates of immunity and protection against F. tularensis.

  • 149.
    Engdahl, Cecilia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Knutsson, Sofie
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fredriksson, Sten-Åke
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bucht, Göran
    Ekström, Fredrik
    Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, article id e0138598Article in journal (Refereed)
    Abstract [en]

    Mosquitoes of the Anopheles (An.) and Aedes (Ae.) genus are principal vectors of human diseases including malaria, dengue and yellow fever. Insecticide-based vector control is an established and important way of preventing transmission of such infections. Currently used insecticides can efficiently control mosquito populations, but there are growing concerns about emerging resistance, off-target toxicity and their ability to alter ecosystems. A potential target for the development of insecticides with reduced off-target toxicity is the cholinergic enzyme acetylcholinesterase (AChE). Herein, we report cloning, baculoviral expression and functional characterization of the wild-type AChE genes (ace-1) from An. gambiae and Ae. aegypti, including a naturally occurring insecticide-resistant (G119S) mutant of An. gambiae. Using enzymatic digestion and liquid chromatography-tandem mass spectrometry we found that the secreted proteins were post-translationally modified. The Michaelis-Menten constants and turnover numbers of the mosquito enzymes were lower than those of the orthologous AChEs from Mus musculus and Homo sapiens. We also found that the G119S substitution reduced the turnover rate of substrates and the potency of selected covalent inhibitors. Furthermore, non-covalent inhibitors were less sensitive to the G119S substitution and differentiate the mosquito enzymes from corresponding vertebrate enzymes. Our findings indicate that it may be possible to develop selective non-covalent inhibitors that effectively target both the wild-type and insecticide resistant mutants of mosquito AChE.

  • 150. Engvall, Gunn
    et al.
    Ångström-Brännström, Charlotte
    Umeå University, Faculty of Medicine, Department of Nursing.
    Mullaney, Tara
    Umeå University, Faculty of Science and Technology, Umeå Institute of Design.
    Nilsson, Kristina
    Wickart-Johansson, Gun
    Svärd, Anna-Maja
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lindh, Jack
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lindh, Viveca
    Umeå University, Faculty of Medicine, Department of Nursing.
    It Is Tough and Tiring but It Works - Children's Experiences of Undergoing Radiotherapy2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153029Article in journal (Refereed)
    Abstract [en]

    Approximately 300 children ages 0 to 18 are diagnosed with cancer in Sweden every year, and 80 to 90 of them undergo radiotherapy treatment. The aim was to describe children's experiences of preparing for and undergoing radiotherapy, and furthermore to describe children's suggestions for improvement. Thirteen children between the ages of 5 and 15 with various cancer diagnoses were interviewed. Data was analyzed using qualitative content analysis. The findings revealed five categories: positive and negative experiences with hospital stays and practical arrangements; age-appropriate information, communication, and guidance to various degrees; struggle with emotions; use of distraction and other suitable coping strategies; and children's suggestions for improvement during radiotherapy. An overarching theme emerged: "It is tough and tiring but it works". Some key areas were: explanatory visits, the need for information and communication, being afraid, discomfort and suffering, the need for media distraction, dealing with emotions, and the need for support. A systematic, family-centered preparation program could possible help families prepare and individualized distraction during radiotherapy could contribute to reducing distress. Further studies with interventions could clarify successful programs.

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  • text
  • asciidoc
  • rtf