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  • 1051.
    Wiren, Sara
    et al.
    Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden..
    Drevin, Linda
    Univ Uppsala Hosp, Reg Canc Ctr, Uppsala, Sweden..
    Akre, Olof
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Robinson, David
    Ryhov Cty Hosp, Dept Urol, Jonkoping, Sweden..
    Stattin, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi. Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden..
    Fathering of Dizygotic Twins and Risk of Prostate Cancer: Nationwide, Population-Based Case-Control Study2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 10, artikel-id e110506Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: An association between male fertility and risk of prostate cancer has been suggested, possibly through lower androgen levels in subfertile men. We evaluated male fertility in relation to risk of prostate cancer by assessing the frequency of fathering of dizygotic twins, a marker of high fertility, among cases of prostate cancer and controls. Methods: We performed a case-control study in Prostate Cancer data Base Sweden (PCBaSe), a nationwide, population-based cohort. PCBaSe was linked to the Swedish twin register for information on zygosity for same-sex twins and to other nationwide health care registers and demographic databases for information on socioeconomic factors, comorbidity, and tumor characteristics for 96 301 prostate cancer cases and 378 583 matched controls. To account for the influence of in vitro fertilization on dizygotic twinning, analyses were restricted to men who had fathered children before 1991, when in vitro fertilization was still uncommon in Sweden. Results: 1 112 cases and 4 538 controls had fathered dizygotic twins. Men with dizygotic twins had no increased risk of prostate cancer compared to fathers of singletons; neither for total prostate cancer odds ratio (OR) 0.95(95% CI 0.89-1.02), nor for any risk category, OR 0.97 (95% CI 0.84-1.12) for low-risk disease, and OR 1.04 (95% CI 0.90-1.22) for metastatic disease. Conclusion: The lack of association between fathering of dizygotic twins and prostate cancer risk give no support for an association between male fertility and prostate cancer risk.

  • 1052.
    Wojciechowski, Bartosz Wojciech
    et al.
    Univ Silesia, Inst Psychol, Katowice, Poland.
    Gräns, Minna
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Juridiska fakulteten.
    Lidén, Moa
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Juridiska fakulteten, Juridiska institutionen.
    A true denial or a false confession?: Assessing veracity of suspects' statements using MASAM and SVA2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 6, artikel-id e0198211Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous research on statement analysis has mainly concerned accounts by witnesses and plaintiffs. In our studies we examined true and false statements as told by offenders. It was hypothesized that SVA and MASAM techniques would enhance the ability to discriminate between true and false offenders' statements. Truthful and deceptive statements (confessions and denials) were collected from Swedish and Polish criminal case files. In Experiment 1, Swedish law students (N = 39) were asked to assess the veracity of statements either after training in and usage of MASAM or without any training and using their own judgements. In Experiment 2, Polish psychology students (N = 34) assessed veracity after training in and usage of either MASAM or SVA or without prior training using their own judgements. The veracity assessments of participants who used MASAM and SVA were significantly more correct than the assessments of participants that used their own judgements. Results show, that trained coders are much better at distinguishing between truths and lies than lay evaluators. There were significant difference between total scores of truthful and false statements for both total SVA and MASAM and it can be concluded that both veracity assessment techniques are useful in assessing veracity. It was also found, that the content criteria most strongly associated with correct assessments were: logical structure, contextual embedding, self depreciation, volume of statement, contextual setting and descriptions of relations. The results are discussed in relation to statement analysis of offenders' accounts.

  • 1053. Woolway, R. Iestyn
    et al.
    Jones, Ian D.
    Maberly, Stephen C.
    French, Jon R.
    Livingstone, David M.
    Monteith, Donald T.
    Simpson, Gavin L.
    Thackeray, Stephen J.
    Andersen, Mikkel R.
    Battarbee, Richard W.
    DeGasperi, Curtis L.
    Evans, Christopher D.
    de Eyto, Elvira
    Feuchtmayr, Heidrun
    Hamilton, David P.
    Kernan, Martin
    Krokowski, Jan
    Rimmer, Alon
    Rose, Kevin C.
    Rusak, James A.
    Ryves, David B.
    Scott, Daniel R.
    Shilland, Ewan M.
    Smyth, Robyn L.
    Staehr, Peter A.
    Thomas, Rhian
    Waldron, Susan
    Weyhenmeyer, Gesa A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Diel Surface Temperature Range Scales with Lake Size2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 3, artikel-id e0152466Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ecological and biogeochemical processes in lakes are strongly dependent upon water temperature. Long-term surface warming of many lakes is unequivocal, but little is known about the comparative magnitude of temperature variation at diel timescales, due to a lack of appropriately resolved data. Here we quantify the pattern and magnitude of diel temperature variability of surface waters using high-frequency data from 100 lakes. We show that the near-surface diel temperature range can be substantial in summer relative to long-term change and, for lakes smaller than 3 km(2), increases sharply and predictably with decreasing lake area. Most small lakes included in this study experience average summer diel ranges in their near-surface temperatures of between 4 and 7 degrees C. Large diel temperature fluctuations in the majority of lakes undoubtedly influence their structure, function and role in biogeochemical cycles, but the full implications remain largely unexplored.

  • 1054.
    Wulaningsih, Wahyu
    et al.
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London WC2R 2LS, England.;Univ Gadjah Mada, Div Haematol Oncol, Yogyakarta, Indonesia..
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London WC2R 2LS, England..
    Abeler-Doner, Lucie
    Kings Coll London, Dept Immunobiol, London WC2R 2LS, England..
    Ng, Tony
    Kings Coll London, Richard Dimbleby Dept Canc Res, Randall Div, London WC2R 2LS, England.;Kings Coll London, Div Canc Studies, London WC2R 2LS, England.;UCL, Dept Med Oncol, Inst Canc, London, England..
    Rohrmann, Sabine
    Univ Zurich, Inst Social & Prevent Med, CH-8006 Zurich, Switzerland..
    Van Hemelrijck, Mieke
    Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London WC2R 2LS, England..
    Associations of C-Reactive Protein, Granulocytes and Granulocyte-to-Lymphocyte Ratio with Mortality from Breast Cancer in Non-Institutionalized American Women2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 6, artikel-id e0157482Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inflammation may play a role in breast cancer, but evidence in the general population is lacking. We investigated the association between serum inflammatory markers (C-reactive protein (CRP), absolute granulocyte count (AGC) and granulocyte-to-lymphocyte (G/L) ratio) and breast cancer (BCa) mortality in American women while accounting for adiposity. From the Third National Health and Nutrition Examination Survey (NHANES III) we selected all women aged 20+ without any known history of cancer (n = 7,780). Multivariable Cox regression models were used to assess CRP, AGC and G/L ratio in relation to mortality from BCa, all cancer, cardiovascular disease and all causes. Stratification analyses by body mass index (BMI) and waist circumference were performed to investigate the effect of adiposity on this association. During a mean follow-up of 167 months, 44 women died from BCa. After adjustments for BMI and waist circumference, only G/L ratio was associated to risk of BCa death (e.g. HR: 2.35, 95% CI: 1.36-4.06 for the 3rd compared to the 1st tertile, P-trend = 0.01). Except for a borderline interaction between CRP categories and obesity by BMI, no statistically significant interaction between markers and categories of BMI or waist circumference was observed. All three markers were associated with mortality from cardiovascular disease and all causes. Our findings support a role of inflammation in BCa mortality which may involve mechanisms apart from obesity, and potential usefulness of GLR as a marker in assessing inflammation and cancer.

  • 1055. Wulaningsih, Wahyu
    et al.
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Garmo, Hans
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Wigertz, Annette
    Carroll, Paul
    Lambe, Mats
    Hammar, Niklas
    Walldius, Goeran
    Jungner, Ingmar
    Van Hemelrijck, Mieke
    Serum Glucose and Fructosamine in Relation to Risk of Cancer2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 1, s. e54944-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Impaired glucose metabolism has been linked with increased cancer risk, but the association between serum glucose and cancer risk remains unclear. We used repeated measurements of glucose and fructosamine to get more insight into the association between the glucose metabolism and risk of cancer. Methods: We selected 11,998 persons (>20 years old) with four prospectively collected serum glucose and fructosamine measurements from the Apolipoprotein Mortality Risk (AMORIS) study. Multivariate Cox proportional hazards regression was used to assess standardized log of overall mean glucose and fructosamine in relation to cancer risk. Similar analyses were performed for tertiles of glucose and fructosamine and for different types of cancer. Results: A positive trend was observed between standardized log overall mean glucose and overall cancer risk (HR = 1.08; 95% CI: 1.02-1.14). Including standardized log fructosamine in the model resulted in a stronger association between glucose and cancer risk and aninverse association between fructosamine and cancer risk (HR = 1.17; 95% CI: 1.08-1.26 and HR: 0.89; 95% CI: 0.82-0.96, respectively). Cancer risks were highest among those in the highest tertile of glucose and lowest tertile of fructosamine. Similar findings were observed for prostate, lung, and colorectal cancer while none observed for breast cancer. Conclusion: The contrasting effect between glucose, fructosamine, and cancer risk suggests the existence of distinct groups among those with impaired glucose metabolism, resulting in different cancer risks based on individual metabolic profiles. Further studies are needed to clarify whether glucose is a proxy of other lifestyle-related or metabolic factors.

  • 1056. Xavier, Miguel J
    et al.
    Williams, Michael J
    The Rho-family GTPase Rac1 regulates integrin localization in Drosophila immunosurveillance cells2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 5, s. e19504-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: When the parasitoid wasp Leptopilina boulardi lays an egg in a Drosophila larva, phagocytic cells called plasmatocytes and specialized cells known as lamellocytes encapsulate the egg. The Drosophila β-integrin Myospheroid (Mys) is necessary for lamellocytes to adhere to the cellular capsule surrounding L. boulardi eggs. Integrins are heterodimeric adhesion receptors consisting of α and β subunits, and similar to other plasma membrane receptors undergo ligand-dependent endocytosis. In mammalian cells it is known that integrin binding to the extracellular matrix induces the activation of Rac GTPases, and we have previously shown that Rac1 and Rac2 are necessary for a proper encapsulation response in Drosophila larvae. We wanted to test the possibility that Myospheroid and Rac GTPases interact during the Drosophila anti-parasitoid immune response.

    RESULTS: In the current study we demonstrate that Rac1 is required for the proper localization of Myospheroid to the cell periphery of haemocytes after parasitization. Interestingly, the mislocalization of Myospheroid in Rac1 mutants is rescued by hyperthermia, involving the heat shock protein Hsp83. From these results we conclude that Rac1 and Hsp83 are required for the proper localization of Mys after parasitization.

    SIGNIFICANCE: We show for the first time that the small GTPase Rac1 is required for Mysopheroid localization. Interestingly, the necessity of Rac1 in Mys localization was negated by hyperthermia. This presents a problem, in Drosophila we quite often raise larvae at 29°C when using the GAL4/UAS misexpression system. If hyperthermia rescues receptor endosomal recycling defects, raising larvae in hyperthermic conditions may mask potentially interesting phenotypes.

  • 1057. Xiao, Zhijie
    et al.
    Rodriguez, Patricia Q.
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Tryggvason, Karl
    Patrakka, Jaakko
    Wtip- and Gadd45a-Interacting Protein Dendrin Is Not Crucial for the Development or Maintenance of the Glomerular Filtration Barrier2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e83133-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glomerular podocyte cells are critical for the function of the renal ultrafiltration barrier. Especially, the highly specialized cell cell junction of podocytes, the slit diaphragm, has a central role in the filtration barrier. This is highlighted by the fact that mutations in molecular components of the slit diaphragm, inclucling nephrin and Cd2-associated protein (Cd2ap), result in proteinuric diseases in man. Dendrin is a poorly characterized cytosalic component of the slit diaphragm in where it interact h nephrin and Cd2ap. Dendrin is highly specific for the podocyte slit diaphragm, suggesting that it has a dedicated role in glomerular filtration barrier. In this study, we have generated a dendrin knockout mouse line and explored the molecular interactions of dendrin. Dendrin-deficient mice were viable, fertile, and had a normal life span. Morphologically, the glomerulogenesis proceeded normally and adult dendrin-deficient mice showed normal glomerular histology. No significant protainuria was observed. Fallowing glomerular injury, lack of dendrin did not affect the severity of the damage or h recovery process. Yeast two-hybrid screen and co-immunoprecipitation experiments showed that dendrin binds to interacting protein (Wtip) and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a). Wtip and Gadd45a mediate gene transcription in the nucleus, suggesting that dendrin may have similar functions in podacytes In line with this, we observed he relocation of dendrin to nucleus in adriamycin nephropathy model. Our results indicate that dendrin is dispensable forth unction of the normal glomerular filtration barrier and that dendrin interacts with Wtip and Gadd45a.

  • 1058. Xu, Weiping
    et al.
    Morris, Ulrika
    Aydin-Schmidt, Berit
    Msellem, Mwinyi I.
    Shakely, Deler
    Petzold, Max
    Bjorkman, Anders
    Mårtensson, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    SYBR Green Real-Time PCR-RFLP Assay Targeting the Plasmodium Cytochrome B Gene - A Highly Sensitive Molecular Tool for Malaria Parasite Detection and Species Determination2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 3, artikel-id e0120210Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A prerequisite for reliable detection of low-density Plasmodium infections in malaria pre-elimination settings is the availability of ultra-sensitive and high-throughput molecular tools. We developed a SYBR Green real-time PCR restriction fragment length polymorphism assay (cytb-qPCR) targeting the cytochrome b gene of the four major human Plasmodium species (P. falciparum, P. vivax, P. malariae, and P. ovale) for parasite detection and species determination with DNA extracted from dried blood spots collected on filter paper. The performance of cytb-qPCR was first compared against four reference PCR methods using serially diluted Plasmodium samples. The detection limit of the cytb-qPCR was 1 parasite/mu l (p/mu l) for P. falciparum and P. ovale, and 2 p/mu l for P. vivax and P. malariae, while the reference PCRs had detection limits of 0.5-10 p/mu l. The ability of the PCR methods to detect low-density Plasmodium infections was then assessed using 2977 filter paper samples collected during a cross-sectional survey in Zanzibar, a malaria pre-elimination setting in sub-Saharan Africa. Field samples were defined as 'final positive' if positive in at least two of the five PCR methods. Cytb-qPCR preformed equal to or better than the reference PCRs with a sensitivity of 100% (65/65; 95% CI 94.5-100%) and a specificity of 99.9%(2910/2912; 95% CI 99.7-100%) when compared against 'final positive' samples. The results indicate that the cytb-qPCR may represent an opportunity for improved molecular surveillance of low-density Plasmodium infections in malaria pre-elimination settings.

  • 1059. Yamane, Takashi
    et al.
    Goenaga, Julieta
    Rönn, Johanna Liljestrand
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi.
    Arnqvist, Göran
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi.
    Male Seminal Fluid Substances Affect Sperm Competition Success and Female Reproductive Behavior in a Seed Beetle2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 4, artikel-id e0123770Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Male seminal fluid proteins are known to affect female reproductive behavior and physiology by reducing mating receptivity and by increasing egg production rates. Such substances are also though to increase the competitive fertilization success of males, but the empirical foundation for this tenet is restricted. Here, we examined the effects of injections of size-fractioned protein extracts from male reproductive organs on both male competitive fertilization success (i.e., P2 in double mating experiments) and female reproduction in the seed beetle Callosobruchus maculatus. We found that extracts of male seminal vesicles and ejaculatory ducts increased competitive fertilization success when males mated with females 1 day after the females' initial mating, while extracts from accessory glands and testes increased competitive fertilization success when males mated with females 2 days after the females' initial mating. Moreover, different size fractions of seminal fluid proteins had distinct and partly antagonistic effects on male competitive fertilization success. Collectively, our experiments show that several different seminal fluid proteins, deriving from different parts in the male reproductive tract and of different molecular weight, affect male competitive fertilization success in C. maculatus. Our results highlight the diverse effects of seminal fluid proteins and show that the function of such proteins can be contingent upon female mating status. We also document effects of different size fractions on female mating receptivity and egg laying rates, which can serve as a basis for future efforts to identify the molecular identity of seminal fluid proteins and their function in this model species.

  • 1060.
    Yan, Junhong
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gu, Gucci Jijuan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Jost, Christian
    Hammond, Maria
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Plueckthun, Andreas
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    A Universal Approach to Prepare Reagents for DNA-Assisted Protein Analysis2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 9, s. e108061-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The quality of DNA-labeled affinity probes is critical in DNA-assisted protein analyses, such as proximity ligation and extension assays, immuno-PCR, and immuno-rolling circle amplification reactions. Efficient, high-performance methods are therefore required for isolation of pure conjugates from reactions where DNA strands have been coupled to antibodies or recombinant affinity reagents. Here we describe a universal, scalable approach for preparing high-quality oligonucleotide-protein conjugates by sequentially removing any unconjugated affinity reagents and remaining free oligonucleotides from conjugation reactions. We applied the approach to generate high-quality probes using either antibodies or recombinant affinity reagents. The purified high-grade probes were used in proximity ligation assays in solution and in situ, demonstrating both augmented assay sensitivity and improved signal-to-noise ratios.

  • 1061. Yang, Dong
    et al.
    James, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    de Faire, Ulf
    Alfredsson, Lars
    Jernberg, Tomas
    Moradi, Tahereh
    Likelihood of Treatment in a Coronary Care Unit for a First-Time Myocardial Infarction in Relation to Sex, Country of Birth and Socioeconomic Position in Sweden2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 4, s. e62316-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To examine the relationship between sex, country of birth, level of education as an indicator of socioeconomic position, and the likelihood of treatment in a coronary care unit (CCU) for a first-time myocardial infarction. Design: Nationwide register based study. Setting: Sweden. Patients: 199 906 patients (114 387 men and 85,519 women) of all ages who were admitted to hospital for first-time myocardial infarction between 2001 and 2009. Main outcome measures: Admission to a coronary care unit due to myocardial infarction. Results: Despite the observed increasing access to coronary care units over time, the proportion of women treated in a coronary care unit was 13% less than for men. As compared with men, the multivariable adjusted odds ratio among women was 0.80 (95% confidence interval 0.77 to 0.82). This lower proportion of women treated in a CCU varied by age and year of diagnosis and country of birth. Overall, there was no evidence of a difference in likelihood of treatment in a coronary care unit between Sweden-born and foreign-born patients. As compared with patients with high education, the adjusted odds ratio among patients with a low level of education was 0.93 (95% confidence interval 0.89 to 0.96). Conclusions: Foreign-born and Sweden-born first-time myocardial infarction patients had equal opportunity of being treated in a coronary care unit in Sweden; this is in contrast to the situation in many other countries with large immigrant populations. However, the apparent lower rate of coronary care unit admission after first-time myocardial infarction among women and patients with low socioeconomic position warrants further investigation.

  • 1062.
    Yeo, Astrid
    et al.
    GlaxoSmithKline Med Res Ctr, Dept Genet, Stevenage, Herts, England..
    Li, Li
    GlaxoSmithKline Med Res Ctr, Dept Genet, Res Triangle Pk, NC USA.;PAREXEL Int, Genom Med, Durham, NC USA..
    Warren, Liling
    GlaxoSmithKline Med Res Ctr, Dept Genet, Res Triangle Pk, NC USA.;Teva Pharmaceut, Raleigh, NC USA..
    Aponte, Jennifer
    GlaxoSmithKline Med Res Ctr, Dept Genet, Res Triangle Pk, NC USA.;PAREXEL Int, Genom Med, Durham, NC USA..
    Fraser, Dana
    GlaxoSmithKline Med Res Ctr, Dept Genet, Res Triangle Pk, NC USA.;PAREXEL Int, Genom Med, Durham, NC USA..
    King, Karen
    GlaxoSmithKline Med Res Ctr, Dept Genet, Res Triangle Pk, NC USA.;PAREXEL Int, Genom Med, Durham, NC USA..
    Johansson, Kelley
    GlaxoSmithKline Med Res Ctr, Dept Genet, Res Triangle Pk, NC USA.;PAREXEL Int, Genom Med, Durham, NC USA..
    Barnes, Allison
    GlaxoSmithKline Med Res Ctr, Clin Stat, Res Triangle Pk, NC USA.;PAREXEL Int, Biostat, Durham, NC USA..
    MacPhee, Colin
    GlaxoSmithKline Med Res Ctr, Dept Vasc Biol & Thrombosis, King Of Prussia, PA USA..
    Davies, Richard
    GlaxoSmithKline Med Res Ctr, Metab Pathways & Cardiovasc Therapeut Area, King Of Prussia, PA USA..
    Chissoe, Stephanie
    GlaxoSmithKline Med Res Ctr, Dept Genet, Res Triangle Pk, NC USA.;GlaxoSmithKline, Elliott Ave, Seattle, WA USA..
    Tarka, Elizabeth
    GlaxoSmithKline Med Res Ctr, Metab Pathways & Cardiovasc Therapeut Area, King Of Prussia, PA USA.;Janssen Pharmaceut, Spring House, PA USA..
    O'Donoghue, Michelle L.
    Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA..
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand.;Univ Auckland, Auckland, New Zealand..
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Waterworth, Dawn
    GlaxoSmithKline Med Res Ctr, Dept Genet, Philadelphia, PA USA..
    Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 7, artikel-id e0182115Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA(2)) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA(2) activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genomewide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA(2) activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P <= 5E-08. Review of the PLA2G7 gene (encoding Lp-PLA(2)) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA(2) activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11-1.33, but was protective in darapladib subjects, HR 0.79 ( 95% CI 0.71-0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA(2) levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials.

  • 1063.
    Yeo, Sara K.
    et al.
    University of Hawaii.
    Huggett, Megan J.
    University of Hawaii.
    Eiler, Alexander
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Rappé, Michael S.
    University of Hawaii.
    Coastal Bacterioplankton Community Dynamics in Response to a Natural Disturbance2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 2, s. e56207-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In order to characterize how disturbances to microbial communities are propagated over temporal and spatial scales in aquatic environments, the dynamics of bacterial assemblages throughout a subtropical coastal embayment were investigated via SSU rRNA gene analyses over an 8-month period, which encompassed a large storm event. During non-perturbed conditions, sampling sites clustered into three groups based on their microbial community composition: an offshore oceanic group, a freshwater group, and a distinct and persistent coastal group. Significant differences in measured environmental parameters or in the bacterial community due to the storm event were found only within the coastal cluster of sampling sites, and only at 5 of 12 locations; three of these sites showed a significant response in both environmental and bacterial community characteristics. These responses were most pronounced at sites close to the shoreline. During the storm event, otherwise common bacterioplankton community members such as marine Synechococcus sp. and members of the SAR11 clade of Alphaproteobacteria decreased in relative abundance in the affected coastal zone, whereas several lineages of GammaproteobacteriaBetaproteobacteria, and members of the Roseobacter clade of Alphaproteobacteria increased. The complex spatial patterns in both environmental conditions and microbial community structure related to freshwater runoff and wind convection during the perturbation event leads us to conclude that spatial heterogeneity was an important factor influencing both the dynamics and the resistance of the bacterioplankton communities to disturbances throughout this complex subtropical coastal system. This heterogeneity may play a role in facilitating a rapid rebound of regions harboring distinctly coastal bacterioplankton communities to their pre-disturbed taxonomic composition.

  • 1064. Yin, Lan
    et al.
    Fristedt, Rikard
    Herdean, Andrei
    Solymosi, Katalin
    Bertrand, Martine
    Andersson, Mats X.
    Mamedov, Fikret
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Vener, Alexander V.
    Schoefs, Benoit
    Spetea, Cornelia
    Photosystem II Function and Dynamics in Three Widely Used Arabidopsis thaliana Accessions2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 9, s. e46206-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Columbia-0 (Col-0), Wassilewskija-4 (Ws-4), and Landsberg erecta-0 (Ler-0) are used as background lines for many public Arabidopsis mutant collections, and for investigation in laboratory conditions of plant processes, including photosynthesis and response to high-intensity light (HL). The photosystem II (PSII) complex is sensitive to HL and requires repair to sustain its function. PSII repair is a multistep process controlled by numerous factors, including protein phosphorylation and thylakoid membrane stacking. Here we have characterized the function and dynamics of PSII complex under growth-light and HL conditions. Ws-4 displayed 30% more thylakoid lipids per chlorophyll and 40% less chlorophyll per carotenoid than Col-0 and Ler-0. There were no large differences in thylakoid stacking, photoprotection and relative levels of photosynthetic complexes among the three accessions. An increased efficiency of PSII closure was found in Ws-4 following illumination with saturation flashes or continuous light. Phosphorylation of the PSII D1/D2 proteins was reduced by 50% in Ws-4 as compared to Col-0 and Ler-0. An increase in abundance of the responsible STN8 kinase in response to HL treatment was found in all three accessions, but Ws-4 displayed 50% lower levels than Col-0 and Ler-0. Despite this, the HL treatment caused in Ws-4 the lagest extent of PSII inactivation, disassembly, D1 protein degradation, and the largest decrease in the size of stacked thylakoids. The dilution of chlorophyll-protein complexes with additional lipids and carotenoids in Ws-4 may represent a mechanism to facilitate lateral protein traffic in the membrane, thus compensating for the lack of a full complement of STN8 kinase. Nevertheless, additional PSII damage occurs in Ws-4, which exceeds the D1 protein synthesis capacity, thus leading to enhanced photoinhibition. Our findings are valuable for selection of appropriate background line for PSII characterization in Arabidopsis mutants, and also provide the first insights into natural variation of PSII protein phosphorylation.

  • 1065.
    Yrttiaho, Santeri
    et al.
    University of Tampere.
    Forssman, Linda
    Kaatiala, Jussi
    Leppänen, Jukka M
    Developmental precursors of social brain networks: the emergence of attentional and cortical sensitivity to facial expressions in 5 to 7 months old infants.2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Biases in attention towards facial cues during infancy may have an important role in the development of social brain networks. The current study used a longitudinal design to examine the stability of infants' attentional biases towards facial expressions and to elucidate how these biases relate to emerging cortical sensitivity to facial expressions. Event-related potential (ERP) and attention disengagement data were acquired in response to the presentation of fearful, happy, neutral, and phase-scrambled face stimuli from the same infants at 5 and 7 months of age. The tendency to disengage from faces was highly consistent across both ages. However, the modulation of this behavior by fearful facial expressions was uncorrelated between 5 and 7 months. In the ERP data, fear-sensitive activity was observed over posterior scalp regions, starting at the latency of the N290 wave. The scalp distribution of this sensitivity to fear in ERPs was dissociable from the topography of face-sensitive modulation within the same latency range. While attentional bias scores were independent of co-registered ERPs, attention bias towards fearful faces at 5 months of age predicted the fear-sensitivity in ERPs at 7 months of age. The current results suggest that the attention bias towards fear could be involved in the developmental tuning of cortical networks for social signals of emotion.

  • 1066.
    Yu, Di
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Jin, Chuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ramachandran, Mohanraj
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Xu, Jing
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nilsson, Berith
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Le Blanc, Katarina
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Forsberg-Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Adamson, Rachel
    Maitland, Norman
    Fan, Xiaolong
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Adenovirus Serotype 5 Vectors with Tat-PTD Modified Hexon and Serotype 35 Fiber Show Greatly Enhanced Transduction Capacity of Primary Cell Cultures2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 1, s. e54952-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recombinant adenovirus serotype 5 (Ad5) vectors represent one of the most efficient gene delivery vectors in life sciences. However, Ad5 is dependent on expression of the coxsackievirus-adenovirus- receptor (CAR) on the surface of target cell for efficient transduction, which limits it's utility for certain cell types. Herein we present a new vector, Ad5PTDf35, which is an Ad5 vector having serotype 35 fiber-specificity and Tat-PTD hexon-modification. This vector shows dramatically increased transduction capacity of primary human cell cultures including T cells, monocytes, macrophages, dendritic cells, pancreatic islets and exocrine cells, mesenchymal stem cells and tumor initiating cells. Biodistribution in mice following systemic administration (tail-vein injection) show significantly reduced uptake in the liver and spleen of Ad5PTDf35 compared to unmodified Ad5. Therefore, replication-competent viruses with these modifications may be further developed as oncolytic agents for cancer therapy. User-friendly backbone plasmids containing these modifications were developed for compatibility to the AdEasy-system to facilitate the development of surface-modified adenoviruses for gene delivery to difficult-to-transduce cells in basic, pre-clinical and clinical research.

  • 1067. Zajmi, Asdren
    et al.
    Hashim, Najihah Mohd
    Noordin, Mohamed Ibrahim
    Khalifa, Shaden A. M.
    Ramli, Faiqah
    Ali, Hapipah Mohd
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Ultrastructural Study on the Antibacterial Activity of Artonin E versus Streptomycin against Staphylococcus aureus Strains2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 6, artikel-id e0128157Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Staphylococci are facultative anaerobes, perfectly spherical un-encapsulated cocci, with a diameter not exceeding 1 micrometer in diameter. Staphylococcus aureus are generally harmless and remain confined to the skin unless they burrow deep into the body, causing life-threatening infections in bones, joints, bloodstream, heart valves and lungs. Among the 20 medically important staphylococci species, Staphylococcus aureus is one of the emerging human pathogens. Streptomycin had its highest potency against Staphylococcus infections despite the likelihood of getting a resistant type of staphylococcus strains. Methicillin-resistant S. aureus (MRSA) is the persister type of Staphylococcus aureus and was evolved after decades of antibiotic misuse. Inadequate penetration of the antibiotic is one of the principal factors related to success/failure of the therapy. The active drug needs to reach the bacteria at concentrations necessary to kill or suppress the pathogen's growth. In turn the effectiveness of the treatment relied on the physical properties of Staphylococcus aureus. Thus understanding the cell integrity, shape and roughness is crucial to the overall influence of the therapeutic agent on S. aureus of different origins. Hence our experiments were designed to clarify ultrastructural changes of S. aureus treated with streptomycin (synthetic compound) in comparison to artonin E (natural compound). In addition to the standard in vitro microbial techniques, we used transmission electron microscopy to study the disrupted cell architecture under antibacterial regimen and we correlate this with scanning electron microscopy (SEM) to compare results of both techniques.

  • 1068.
    Zaremba-Niedzwiedzka, Katarzyna
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Andersson, Siv G. E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    No Ancient DNA Damage in Actinobacteria from the Neanderthal Bone2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, s. e62799-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The Neanderthal genome was recently sequenced using DNA extracted from a 38,000-year-old fossil. At the start of the project, the fraction of mammalian and bacterial DNA in the sample was estimated to be <6% and 9%, respectively. Treatment with restriction enzymes prior to sequencing increased the relative proportion of mammalian DNA to 15%, but the large majority of sequences remain uncharacterized. Principal Findings: Our taxonomic profiling of 3.95 Gb of Neanderthal DNA isolated from the Vindija Neanderthal Vi33.16 fossil showed that 90% of about 50,000 rRNA gene sequence reads were of bacterial origin, of which Actinobacteria accounted for more than 75%. Actinobacteria also represented more than 80% of the PCR-amplified 16S rRNA gene sequences from a cave sediment sample taken from the same G layer as the Neanderthal bone. However, phylogenetic analyses did not identify any sediment clones that were closely related to the bone-derived sequences. We analysed the patterns of nucleotide differences in the individual sequence reads compared to the assembled consensus sequences of the rRNA gene sequences. The typical ancient nucleotide substitution pattern with a majority of C to T changes indicative of DNA damage was observed for the Neanderthal rRNA gene sequences, but not for the Streptomyces-like rRNA gene sequences. Conclusions/Significance: Our analyses suggest that the Actinobacteria, and especially members of the Streptomycetales, contribute the majority of sequences in the DNA extracted from the Neanderthal fossil Vi33.16. The bacterial DNA showed no signs of damage, and we hypothesize that it was derived from bacteria that have been enriched inside the bone. The bioinformatic approach used here paves the way for future studies of microbial compositions and patterns of DNA damage in bacteria from archaeological bones. Such studies can help identify targeted measures to increase the relative amount of endogenous DNA in the sample.

  • 1069. Zatloukal, Bernhard
    et al.
    Kufferath, Iris
    Thueringer, Andrea
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Zatloukal, Kurt
    Haybaeck, Johannes
    Sensitivity and Specificity of In situ Proximity Ligation for Protein Interaction Analysis in a Model of Steatohepatitis with Mallory-Denk Bodies2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 5, s. e96690-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The in situ proximity ligation assay (isPLA) is an increasingly used technology for in situ detection of protein interactions, post-translational modifications, and spatial relationships of antigens in cells and tissues, in general. In order to test its performance we compared isPLA with immunofluorescence microscopy by analyzing protein interactions in cytoplasmic protein aggregates, so-called Mallory Denk bodies (MDBs). These structures represent protein inclusions in hepatocytes typically found in human steatohepatitis and they can be generated in mice by feeding of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). We investigated the colocalization of all three key MDB components, namely keratin 8 (K8), keratin 18 (K18), and p62 (sequestosome 1) by isPLA and immunofluorescence microscopy. Sensitivity and specificity of isPLA was assessed by using Krt8(-/-) and Krt18(-/-) mice as biological controls, along with a series of technical controls. isPLA signal visualization is a robust technology with excellent sensitivity and specificity. The biological relevance of signals generated critically depends on the performance of antibodies used, which requires careful testing of antibodies like in immunofluorescence microscopy. There is a clear advantage of isPLA in visualizing protein co-localization, particularly when antigens are present at markedly different concentrations. Furthermore, isPLA is superior to confocal microscopy with respect to spatial resolution of colocalizing antigens. Disadvantages compared to immunofluorescence are increased costs and longer duration of the laboratory protocol.

  • 1070.
    Zeller, Kathrin Stephanie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Riaz, Anjum
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sarve, Hamid
    SLU, Centrum för bildanalys.
    Li, Jia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Johansson, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    The role of mechanical force and ROS in integrin-dependent signals2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, artikel-id e64897Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cells are exposed to several types of integrin stimuli, which generate responses generally referred to as "integrin signals", but the specific responses to different integrin stimuli are poorly defined. In this study, signals induced byintegrin ligation during cell attachment, mechanical force from intracellular contraction, or cell stretching by external force were compared. The elevated phosphorylation levels of several proteins during the early phase of cell attachment and spreading of fibroblast cell lines were not affected by inhibition ofROCK and myosin II activity, i.e. the reactions occurred independently ofintracellular contractile force acting on the adhesion sites. The contraction-independent phosphorylation sites included ERK1/2 T202/Y204, AKT S473, p130CAS Y410, and cofilin S3. In contrast to cell attachment, cyclic stretching ofthe adherent cells induced a robust phosphorylation only of ERK1/2 and thephosphorylation levels of the other investigated proteins were not or only moderately affected by stretching. No major differences between signaling via alpha 5 beta 1 or alpha v beta 3 integrins were detected. The importance ofmitochondrial ROS for the integrin-induced signaling pathways was investigated using rotenone, a specific inhibitor of complex I in the respiratory chain. While rotenone only moderately reduced ATP levels and hardly affected the signalsinduced by cyclic cell stretching, it abolished the activation of AKT and reduced theactin polymerization rate in response to attachment in both cell lines. In contrast, scavenging of extracellular ROS with catalase or the vitamin C analog Asc-2P did not significantly influence the attachment-derived signaling, but caused a selective and pronounced enhancement of ERK1/2 phosphorylation in response to stretching. In conclusion, the results showed that "integrin signals" are composedof separate sets of reactions triggered by different types of integrin stimulation. Mitochondrial ROS and extracellular ROS had specific and distinct effects on theintegrin signals induced by cell attachment and mechanical stretching.

  • 1071.
    Zetterberg, Camilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin. University of Gävle, Department of Occupational and Public Health Sciences, Centre for Musculoskeletal Research.
    Richter, Hans O.
    Forsman, Mikael
    Temporal Co-Variation between Eye Lens Accommodation and Trapezius Muscle Activity during a Dynamic Near-Far Visual Task2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 5, artikel-id e0126578Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Near work is associated with increased activity in the neck and shoulder muscles, but the underlying mechanismis still unknown. This study was designed to determine whether a dynamic change in focus, alternating between a nearby and a more distant visual target, produces a direct parallel change in trapezius muscle activity. Fourteen healthy controls and 12 patients with a history of visual and neck/shoulder symptoms performed a Near-Far visual task under three different viewing conditions; one neutral condition with no trial lenses, one condition with negative trial lenses to create increased accommodation, and one condition with positive trial lenses to create decreased accommodation. Eye lens accommodation and trapeziusmuscle activity were continuously recorded. The trapezius muscle activity was significantly higher during Near than during Far focusing periods for both groups within the neutral viewing condition, and there was a significant co-variation in time between accommodation and trapezius muscle activity within the neutral and positive viewing conditions for the control group. In conclusion, these results reveal a connection between Near focusing and increased muscle activity during dynamic changes in focus between a nearby and a far target. A direct link, from the accommodation/vergence system to the trapezius muscles cannot be ruled out, but the connection may also be explained by an increased need for eye-neck (head) stabilization when focusing on a nearby target as compared to a more distant target.

  • 1072. Zetterberg, Henrik
    et al.
    Mörtberg, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Song, Linan
    Chang, Lei
    Provuncher, Gail K
    Patel, Purvish P
    Ferrell, Evan
    Fournier, David R
    Kan, Cheuk W
    Campbell, Todd G
    Meyer, Ray
    Rivnak, Andrew J
    Pink, Brian A
    Minnehan, Kaitlin A
    Piech, Tomasz
    Rissin, David M
    Duffy, David C
    Rubertsson, Sten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Wilson, David H
    Blennow, Kaj
    Hypoxia Due to Cardiac Arrest Induces a Time-Dependent Increase in Serum Amyloid β Levels in Humans2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 12, s. e28263-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyloid β (Aβ) peptides are proteolytic products from amyloid precursor protein (APP) and are thought to play a role in Alzheimer disease (AD) pathogenesis. While much is known about molecular mechanisms underlying cerebral Aβ accumulation in familial AD, less is known about the cause(s) of brain amyloidosis in sporadic disease. Animal and postmortem studies suggest that Aβ secretion can be up-regulated in response to hypoxia. We employed a new technology (Single Molecule Arrays, SiMoA) capable of ultrasensitive protein measurements and developed a novel assay to look for changes in serum Aβ42 concentration in 25 resuscitated patients with severe hypoxia due to cardiac arrest. After a lag period of 10 or more hours, very clear serum Aβ42 elevations were observed in all patients. Elevations ranged from approximately 80% to over 70-fold, with most elevations in the range of 3-10-fold (average approximately 7-fold). The magnitude of the increase correlated with clinical outcome. These data provide the first direct evidence in living humans that ischemia acutely increases Aβ levels in blood. The results point to the possibility that hypoxia may play a role in the amyloidogenic process of AD.

  • 1073.
    Zetterling, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Berhane, Luwam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Jakola, Asgeir S
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi. Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Prognostic markers for survival in patients with oligodendroglial tumors; a single-institution review of 214 cases2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 11, artikel-id e0188419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: In the 2016 WHO classification, the diagnosis of oligodendroglioma has been restricted to IDH mutated, 1p19q codeleted tumors (IDHmut-codel). IDHmut oligoastrocytoma is now classified either as oligodendroglioma or astrocytoma based on presence of 1p19q codeletion. There is growing evidence that this molecular classification more closely reflects patient outcome. Due to the strong association between IDHmut-codel with oligodendroglial morphology, the additional impact of these markers on prognostic accuracy is largely unknown. Our aim was to assess the prognostic impact of IDHmut-codel in an unselected cohort of morphologically classified oligodendroglial tumors.

    METHODS: We performed a retrospective chart review of oligodendroglial tumors (WHO grade II and III) operated since 1983. A total of 214 tumors were included, and molecular information was available for 96 tumors. The prognostic impact of IDHmut-codel together with clinical parameters was analyzed by multivariate Cox regression.

    RESULTS: IDHmut-codel was registered in 64 tumors while for 150 tumors the molecular profile was negative for IDHmut-codel, unknown or incomplete. Comparison between the two groups showed that patients with IDHmut-codel tumors were younger (42 vs. 48 years), had more frequent frontal tumor location (48 vs. 33%) and presented more often with seizures (72 vs. 51%) and no signs of neurological impairment (14 vs. 30%) than patients harboring tumors with unknown or incomplete molecular profile. Multivariate survival analysis identified young age (HR 1.78 ≥ 40 years), the absence of neurological deficits or personality changes (HR 0.57), frontal tumor location (HR 0.64) and the presence of IDHmut-codel (HR 0.50) as independent predictors for longer survival, whereas tumor grade was not.

    CONCLUSION: In this unselected single-institution cohort, the presence of IDHmut-codel was associated with more beneficial clinical parameters and was identified as an independent prognostic factor. We conclude that the classical oligodendroglioma genotype provides additional prognostic data beyond clinical characteristics, morphology and tumor grade.

  • 1074.
    Zha, Yinghua
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Berga, Mercè
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Comte, Jérôme
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Langenheder, Silke
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Limnologi.
    Effects of Dispersal and Initial Diversity on the Composition and Functional Performance of Bacterial Communities2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 5, artikel-id e0155239Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Natural communities are open systems and consequently dispersal can play an important role for the diversity, composition and functioning of communities at the local scale. It is, however, still unclear how effects of dispersal differ depending on the initial diversity of local communities. Here we implemented an experiment where we manipulated the initial diversity of natural freshwater bacterioplankton communities using a dilution-to-extinction approach as well as dispersal from a regional species pool. The aim was further to test whether dispersal effects on bacterial abundance and functional parameters (average community growth rates, respiration rates, substrate utilisation ability) differ in dependence of the initial diversity of the communities. First of all, we found that both initial diversity and dispersal rates had an effect on the recruitment of taxa from a regional source, which was higher in communities with low initial diversity and at higher rates of dispersal. Higher initial diversity and dispersal also promoted higher levels of richness and evenness in local communities and affected, both, separately or interactively, the functional performance of communities. Our study therefore suggests that dispersal can influence the diversity, composition and functioning of bacterial communities and that this effect may be enhanced if the initial diversity of communities is depleted.

  • 1075. Zhang, Jian
    et al.
    Xie, Penghui
    Lascoux, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Växtekologi och evolution.
    Meagher, Thomas R.
    Liu, Jianquan
    Rapidly Evolving Genes and Stress Adaptation of Two Desert Poplars, Populus euphratica and P. pruinosa2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e66370-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Understanding which genes have evolved rapidly with the recent tree speciation in arid habitats can provide valuable insights into different adaptation mechanisms. We employed a comparative evolutionary analysis of expressed sequence tags (ESTs) from two desert poplars, Populus pruinosa and P. euphratica, which diverged in the recent past. Following an approach taken previously with P. euphratica, we conducted a deep transcriptomic analysis of P. pruinosa. To maximize representation of conditional transcripts, mRNA was obtained from living tissues of two types of callus and desert-grown trees. De novo assembly generated 114,866 high-quality unique sequences using Solexa sequence data. Following assembly we were able to identify, with high confidence, 2859 orthologous sequence pairs between the two species. Based on the ratio of nonsynonymous (Ka) to synonymous (Ks) substitutions, we identified a total of 84 (2.9%) ortholog pairs exhibiting rapid evolution with signs of strong selection (Ka/Ks>1). Genes homologous to these ortholog pairs in model species are mainly involved in 'responses to stress', 'ubiquitin-dependent protein catabolic processes', and 'biological regulation'. Finally, we examined the expression patterns of candidate genes with rapid evolution in response to salt stress. Only one pair of orthologs up-regulated their expression in both species while three and four genes were found to up-regulated in P. pruinosa and in P. euphratica respectively. Our findings together suggest that the genes at the same category or network but with differentiated expressions or functions may have evolved rapidly during adaptive divergence of the two species to differentiated salty desert habitats.

  • 1076. Zhang, Xin
    et al.
    Li, Fan
    Zhang, Li
    Zhao, Zhuohui
    Norbäck, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    A Longitudinal Study of Sick Building Syndrome (SBS) among Pupils in Relation to SO2, NO2, O-3 and PM10 in Schools in China2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, s. e112933-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There are fewer longitudinal studies from China on symptoms as described for the sick building syndrome (SBS). Here, we performed a two-year prospective study and investigated associations between environmental parameters such as room temperature, relative air humidity (RH), carbon dioxide (CO2), nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O-3), particulate matter (PM10), and health outcomes including prevalence, incidence and remission of SBS symptoms in junior high schools in Taiyuan, China. Totally 2134 pupils participated at baseline, and 1325 stayed in the same classrooms during the study period (2010-2012). The prevalence of mucosal symptoms, general symptoms and symptoms improved when away from school (school-related symptoms) was 22.7%, 20.4% and 39.2%, respectively, at baseline, and the prevalence increased during follow-up (P<0.001). At baseline, both indoor and outdoor SO2 were found positively associated with prevalence of school-related symptoms. Indoor O-3 was shown to be positively associated with prevalence of skin symptoms. At follow-up, indoor PM10 was found to be positively associated with new onset of skin, mucosal and general symptoms. CO2 and RH were positively associated with new onset of mucosal, general and school-related symptoms. Outdoor SO2 was positively associated with new onset of skin symptoms, while outdoor NO2 was positively associated with new onset of skin, general and mucosal symptoms. Outdoor PM10 was found to be positively associated with new onset of skin, general and mucosal symptoms as well as school-related symptoms. In conclusion, symptoms as described for SBS were commonly found in school children in Taiyuan City, China, and increased during the two-year follow-up period. Environmental pollution, including PM10, SO2 and NO2, could increase the prevalence and incidence of SBS and decrease the remission rate. Moreover, parental asthma and allergy (heredity) and pollen or pet allergy (atopy) can be risk factors for SBS.

  • 1077.
    Zheleznyakova, Galina Yu
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Nilsson, Emil K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Kiselev, Anton V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Maretina, Marianna A.
    Tishchenko, Lyudmila I.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Baranov, Vladislav S.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Methylation Levels of SLC23A2 and NCOR2 Genes Correlate with Spinal Muscular Atrophy Severity2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 3, artikel-id e0121964Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinal muscular atrophy (SMA) is a monogenic neurodegenerative disorder subdivided into four different types. Whole genome methylation analysis revealed 40 CpG sites associated with genes that are significantly differentially methylated between SMA patients and healthy individuals of the same age. To investigate the contribution of methylation changes to SMA severity, we compared the methylation level of found CpG sites, designed as "targets", as well as the nearest CpG sites in regulatory regions of ARHGAP22, CDK2AP1, CHML, NCOR2, SLC23A2 and RPL9 in three groups of SMA patients. Of notable interest, compared to type I SMA male patients, the methylation level of a target CpG site and one nearby CpG site belonging to the 5'UTR of SLC23A2 were significantly hypomethylated 19-22% in type III-IV patients. In contrast to type I SMA male patients, type III-IV patients demonstrated a 16% decrease in the methylation levels of a target CpG site, belonging to the 5'UTR of NCOR2. To conclude, this study validates the data of our previous study and confirms significant methylation changes in the SLC23A2 and NCOR2 regulatory regions correlates with SMA severity.

  • 1078. Zhou, Xiaohong
    et al.
    Wang, Ke
    Lv, Dongwen
    Wu, Cheng Jun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Li, Jiarui
    Zhao, Pei
    Lin, Zhishan
    Du, Lipu
    Yan, Yueming
    Ye, Xingguo
    Global Analysis of Differentially Expressed Genes and Proteins in the Wheat Callus Infected by Agrobacterium tumefaciens2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 11, s. e79390-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Agrobacterium-mediated plant transformation is an extremely complex and evolved process involving genetic determinants of both the bacteria and the host plant cells. However, the mechanism of the determinants remains obscure, especially in some cereal crops such as wheat, which is recalcitrant for Agrobacterium-mediated transformation. In this study, differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were analyzed in wheat callus cells co-cultured with Agrobacterium by using RNA sequencing (RNA-seq) and two-dimensional electrophoresis (2-DE) in conjunction with mass spectrometry (MS). A set of 4,889 DEGs and 90 DEPs were identified, respectively. Most of them are related to metabolism, chromatin assembly or disassembly and immune defense. After comparative analysis, 24 of the 90 DEPs were detected in RNA-seq and proteomics datasets simultaneously. In addition, real-time RT-PCR experiments were performed to check the differential expression of the 24 genes, and the results were consistent with the RNA-seq data. According to gene ontology (GO) analysis, we found that a big part of these differentially expressed genes were related to the process of stress or immunity response. Several putative determinants and candidate effectors responsive to Agrobacterium mediated transformation of wheat cells were discussed. We speculate that some of these genes are possibly related to Agrobacterium infection. Our results will help to understand the interaction between Agrobacterium and host cells, and may facilitate developing efficient transformation strategies in cereal crops.

  • 1079. Zhu, Min
    et al.
    Yu, Xiaobo
    Choo, Brian
    Qu, Qingming
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Jia, Liantao
    Zhao, Wenjin
    Qiao, Tuo
    Lu, Jing
    Fossil Fishes from China Provide First Evidence of Dermal Pelvic Girdles in Osteichthyans2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 4, s. e35103-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The pectoral and pelvic girdles support paired fins and limbs, and have transformed significantly in the diversification of gnathostomes or jawed vertebrates (including osteichthyans, chondrichthyans, acanthodians and placoderms). For instance, changes in the pectoral and pelvic girdles accompanied the transition of fins to limbs as some osteichthyans (a clade that contains the vast majority of vertebrates - bony fishes and tetrapods) ventured from aquatic to terrestrial environments. The fossil record shows that the pectoral girdles of early osteichthyans (e. g., Lophosteus, Andreolepis, Psarolepis and Guiyu) retained part of the primitive gnathostome pectoral girdle condition with spines and/or other dermal components. However, very little is known about the condition of the pelvic girdle in the earliest osteichthyans. Living osteichthyans, like chondrichthyans (cartilaginous fishes), have exclusively endoskeletal pelvic girdles, while dermal pelvic girdle components (plates and/or spines) have so far been found only in some extinct placoderms and acanthodians. Consequently, whether the pectoral and pelvic girdles are primitively similar in osteichthyans cannot be adequately evaluated, and phylogeny-based inferences regarding the primitive pelvic girdle condition in osteichthyans cannot be tested against available fossil evidence.

    Methodology/Principal Findings: Here we report the first discovery of spine-bearing dermal pelvic girdles in early osteichthyans, based on a new articulated specimen of Guiyu oneiros from the Late Ludlow (Silurian) Kuanti Formation, Yunnan, as well as a re-examination of the previously described holotype. We also describe disarticulated pelvic girdles of Psarolepis romeri from the Lochkovian (Early Devonian) Xitun Formation, Yunnan, which resemble the previously reported pectoral girdles in having integrated dermal and endoskeletal components with polybasal fin articulation.

    Conclusions/Significance: The new findings reveal hitherto unknown similarity in pectoral and pelvic girdles among early osteichthyans, and provide critical information for studying the evolution of pelvic girdles in osteichthyans and other gnathostomes.

  • 1080.
    Ziaei, Shirin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Frith, Amy Lynn
    thaca Coll, Sch Hlth Sci & Human Performance, Ithaca, NY 14850 USA.
    Ekström, Eva-Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Naved, Ruchira Tabassum
    Int Ctr Diarrhoeal Dis Res ICDDR B, Dhaka, Bangladesh.
    Experiencing Lifetime Domestic Violence: Associations with Mental Health and Stress among Pregnant Women in Rural Bangladesh: The MINIMat Randomized Trial2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 12, artikel-id e0168103Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Experience of domestic violence has negative mental health consequences for women. The association of cumulative and specific forms of domestic violence, particularly emotional violence and controlling behavior, with common mental disorders and stress has rarely been studied in pregnant women. The aim of this study is to evaluate associations of specific and multiple forms of lifetime domestic violence and controlling behavior with distress and cortisol level during pregnancy in rural Bangladeshi women.

    METHODS AND FINDINGS: In this observational sub-study of larger MINIMat trial, 3504 pregnant women were interviewed using a shortened Conflict Tactic Scale about their lifetime experience of domestic violence including physical, sexual, emotional domestic violence and controlling behavior. Women's levels of emotional distress were assessed using the self-reported questionnaire (SRQ-20) developed by WHO, and levels of morning salivary cortisol were measured in a subsample (n = 1300) of women during week 28-32 of pregnancy. Regression analyses were used to estimate the associations of lifetime physical, sexual, emotional domestic violence and controlling behavior with levels of distress and cortisol during pregnancy. The prevalence of lifetime domestic violence was 57% and emotional distress was 35% in these pregnant women. All forms of domestic violence were associated with higher levels of emotional distress. Women who experienced either emotional violence or controlling behavior had the highest levels of emotional distress. There was a dose-response relationship between cumulative number of the different forms of domestic violence and women's levels of emotional distress. There was no association between women's experience of domestic violence and level of morning salivary cortisol.

    CONCLUSION: Including emotional violence and controlling behavior as major types of violence in future research and health interventions is warranted. Furthermore, the extent of the negative impacts of domestic violence on pregnant women, multiple forms of violence and their cumulative effects need to be investigated.

  • 1081.
    Zoerner, Frank
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Wiklund, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Miclescu, Adriana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Martijn, Cecile
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, s. e64792-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34°C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

  • 1082. Zygmunt, Peter M.
    et al.
    Ermund, Anna
    Movahed, Pouya
    Andersson, David A.
    Simonsen, Charlotte
    Jonsson, Bo A. G.
    Blomgren, Anders
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Bevan, Stuart
    Eschalier, Alain
    Mallet, Christophe
    Gomis, Ana
    Hogestatt, Edward D.
    Monoacylglycerols Activate TRPV1-A Link between Phospholipase C and TRPV12013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e81618-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H-1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H-1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage'' compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations. Furthermore, intracerebroventricular injection of JZL184 produced TRPV1-dependent antinociception in the mouse formalin test. Our results show that intact 2-arachidonoylglycerol and 1-arachidonoylglycerol are endogenous TRPV1 activators, contributing to phospholipase C-dependent TRPV1 channel activation and TRPV1-mediated antinociceptive signaling in the brain.

  • 1083.
    Zysk, Marlena
    et al.
    Med Univ Gdansk, Dept Lab Med, Gdansk, Poland.
    Gapys, Beata
    Med Univ Gdansk, Dept Lab Med, Gdansk, Poland.
    Ronowska, Anna
    Med Univ Gdansk, Dept Lab Med, Gdansk, Poland.
    Gul-Hinc, Sylwia
    Med Univ Gdansk, Dept Lab Med, Gdansk, Poland.
    Erlandsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Iwanicki, Adam
    Univ Gdansk, Dept Mol Bacteriol, Gdansk, Poland;Med Univ Gdansk, Gdansk, Poland.
    Sakowicz-Burkiewicz, Monika
    Med Univ Gdansk, Dept Mol Med, Gdansk, Poland.
    Szutowicz, Andrzej
    Med Univ Gdansk, Dept Lab Med, Gdansk, Poland.
    Bielarczyk, Hanna
    Med Univ Gdansk, Dept Lab Med, Gdansk, Poland.
    Protective effects of voltage-gated calcium channel antagonists against zinc toxicity in SN56 neuroblastoma cholinergic cells2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 12, artikel-id e0209363Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of the pathological site effects in excitotoxic activation is Zn2+ overload to postsynaptic neurons. Such an effect is considered to be equivalent to the glutamate component of excitotoxicity. Excessive uptake of Zn2+ by active voltage-dependent transport systems in these neurons may lead to significant neurotoxicity. The aim of this study was to investigate whether and which antagonists of the voltage gated calcium channels (VGCC) might modify this Zn2+-induced neurotoxicity in neuronal cells. Our data demonstrates that depolarized SN56 neuronal cells may take up large amounts of Zn2+ and store these in cytoplasmic and mitochondrial sub-fractions. The mitochondrial Zn2+ excess suppressed pyruvate uptake and oxidation. Such suppression was caused by inhibition of pyruvate dehydrogenase complex, aconitase and NADP-isocitrate dehydrogenase activities, resulting in the yielding of acetyl-CoA and ATP shortages. Moreover, incoming Zn2+ increased both oxidized glutathione and malondialdehyde levels, known parameters of oxidative stress. In depolarized SN56 cells, nifedipine treatment (L-type VGCC antagonist) reduced Zn2+ uptake and oxidative stress. The treatment applied prevented the activities of PDHC, aconitase and NADP-IDH enzymes, and also yielded the maintenance of acetyl-CoA and ATP levels. Apart from suppression of oxidative stress, N- and P/Q-type VGCCs presented a similar, but weaker protective influence. In conclusion, our data shows that in the course of excitotoxity, impairment to calcium homeostasis is tightly linked with an excessive neuronal Zn2+ uptake. Hence, the VGCCs types L, N and P/Q share responsibility for neuronal Zn2+ overload followed by significant energy-dependent neurotoxicity. Moreover, Zn2+ affects the target tricarboxylic acid cycle enzymes, yields acetyl-CoA and energy deficits as well.

  • 1084.
    Åkerström, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Verdugo, Alberto Delgado
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Starker, Lee F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Cupisti, Kenko
    Willenberg, Holger S.
    Knoefel, Wolfram T.
    Saeger, Wolfgang
    Feller, Alfred
    Ip, Julian
    Soon, Patsy
    Anlauf, Martin
    Alesina, Pier F.
    Schmid, Kurt W.
    Decaussin, Myriam
    Levillain, Pierre
    Wangberg, Bo
    Peix, Jean-Louis
    Robinson, Bruce
    Zedenius, Jan
    Backdahl, Martin
    Caramuta, Stefano
    Iwen, K. Alexander
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Kraimps, Jean-Louis
    Dralle, Henning
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Sidhu, Stan
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Lehnert, Hendrik
    Walz, Martin K.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Carling, Tobias
    Choi, Murim
    Lifton, Richard P.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e41926-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.

    Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.

    Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p < 0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p < 0.005).

    Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

  • 1085.
    Ångström-Brännström, Charlotte
    et al.
    Department of Nursing, Umeå University, Umeå, Sweden.
    Engvall, Gunn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Mullaney, Tara
    Umeå Institute of Design, Umeå University, Umeå, Sweden.
    Nilsson, Kristina
    Section of Oncology, Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden.
    Wickart-Johansson, Gun
    Department of Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
    Svärd, Anna-Maja
    Department of Radiation Sciences, Umeå University, Umeå, Sweden.
    Nyholm, Tufve
    Department of Radiation Sciences, Umeå University, Umeå, Sweden.
    Lindh, Jack
    Department of Radiation Sciences, Umeå University, Umeå, Sweden.
    Lindh, Viveca
    Department of Nursing, Umeå University, Umeå, Sweden.
    Children Undergoing Radiotherapy: Swedish Parents' Experiences and Suggestions for Improvement.2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 10, artikel-id e0141086Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Approximately 300 children, from 0 to 18 years old, are diagnosed with cancer in Sweden every year. Of these children, 80-90 of them undergo radiotherapy treatment for their cancer. Although radiotherapy is an encounter with advanced technology, few studies have investigated the child's and the parent's view of the procedure. As part of an ongoing multicenter study aimed to improve patient preparation and the care environment in pediatric radiotherapy, this article reports the findings from interviews with parents at baseline. The aim of the present study was twofold: to describe parents' experience when their child undergoes radiotherapy treatment, and to report parents' suggestions for improvements during radiotherapy for their children. Sixteen mothers and sixteen fathers of children between 2-16 years old with various cancer diagnoses were interviewed. Data were analyzed using content analysis. The findings showed that cancer and treatment turns people's lives upside down, affecting the entire family. Further, the parents experience the child's suffering and must cope with intense feelings. Radiotherapy treatment includes preparation by skilled and empathetic staff. The parents gradually find that they can deal with the process; and lastly, parents have suggestions for improvements during the radiotherapy treatment. An overarching theme emerged: that despair gradually turns to a sense of security, with a sustained focus on and close interaction with the child. In conclusion, an extreme burden was experienced around the start of radiotherapy, though parents gradually coped with the process.

  • 1086.
    Östman, Örjan
    et al.
    epartment of Aquatic Resources, Swedish University of Agricultural Sciences, Öregrund, Sweden.
    Boström, Maria K.
    Bergström, Ulf
    Andersson, Jan
    Lunneryd, Sven-Gunnar
    Estimating Competition between Wildlife and Humans-A Case of Cormorants and Coastal Fisheries in the Baltic Sea2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e83763-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cormorants and other wildlife populations have come in real or perceived conflicts with humans over exploited fish stocks. From gut contents of cormorants, and using an extension of the Catch equation, we estimated the degree of short term competition between great cormorants and coastal fisheries in two areas along the Swedish Baltic Sea. Cormorants consumed 10 and 44%, in respective area, of the fish biomass of six fish species harvested by humans; eel, flounder, herring, perch, pike, and whitefish. On average, cormorants consumed smaller individuals than harvested in fisheries. But for perch, cod and flounder, cormorants consumed harvestable sized fish corresponding >20% of human catches. Our competition model estimated the direct decrease in fisheries catches due to cormorant predation to be <10% for all species except flounder (>30%) and perch (2-20%). When also including the indirect effects of cormorant predation on smaller fish that never reached harvestable size, the estimated decrease in fisheries catches at least doubled for perch (13-34%) and pike (8-19%). Despite large uncertainties, our model indicates that cormorants may locally have a direct impact on human catches of at least flounder, and when incorporating indirect effects also on perch and pike. The study indicates that the degree of competition between cormorants and humans varies substantially between areas. We also included economical values in the model and concluded that for the commercially most important species, eel and cod, the estimated economic impact of cormorants on fisheries was low.

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