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  • 101.
    Bjelland, Elisabeth Krefting
    et al.
    Akershus Univ Hosp, Hlth Serv Res Unit, Lorenskog, Norway.;Norwegian Inst Publ Hlth, Dept Hlth & Aging, Oslo, Norway.;Akershus Univ Hosp, Dept Obstet & Gynecol, Lorenskog, Norway..
    Owe, Katrine Mari
    Natl Hosp Norway, Oslo Univ Hosp, Norwegian Natl Advisory Unit Womens Hlth, Oslo, Norway.;Norwegian Inst Publ Hlth, Dept Child Hlth, Oslo, Norway..
    Nordeng, Hedvig Marie Egeland
    Norwegian Inst Publ Hlth, Dept Child Hlth, Oslo, Norway.;Univ Oslo, Sch Pharm, PharmacoEpidemiol & Drug Safety Res Grp, Oslo, Norway..
    Engdahl, Bo Lars
    Norwegian Inst Publ Hlth, Dept Hlth & Aging, Oslo, Norway..
    Kristiansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Vangen, Siri
    Natl Hosp Norway, Oslo Univ Hosp, Norwegian Natl Advisory Unit Womens Hlth, Oslo, Norway..
    Eberhard-Gran, Malin
    Akershus Univ Hosp, Hlth Serv Res Unit, Lorenskog, Norway.;Norwegian Inst Publ Hlth, Dept Child Hlth, Oslo, Norway.;Univ Oslo, Inst Clin Med, Campus Ahus, Lorenskog, Norway..
    Does progestin-only contraceptive use after pregnancy affect recovery from pelvic girdle pain?: A prospective population study2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 9, artikel-id e0184071Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To estimate associations of progestin-only contraceptives with persistent pelvic girdle pain 18 months after delivery.

    Methods: Prospective population based cohort study during the years 2003-2011. We included 20,493 women enrolled in the Norwegian Mother and Child Cohort Study who reported pelvic girdle pain in pregnancy week 30. Data were obtained by 3 self-administered questionnaires and the exposure was obtained by linkage to the Prescription Database of Norway. The outcome was pelvic girdle pain 18 months after delivery.

    Results: Pelvic girdle pain 18 months after delivery was reported by 9.7% (957/9830) of women with dispense of a progestin-only contraceptive and by 10.5% (1114/10,663) of women without dispense (adjusted odds ratio 0.93; 95% CI 0.84-1.02). In sub-analyses, long duration of exposure to a progestin intrauterine device or progestin-only oral contraceptives was associated with reduced odds of persistent pelvic girdle pain (P-trend = 0.021 and P-trend = 0.005). Conversely, long duration of exposure to progestin injections and/or a progestin implant was associated with modest increased odds of persistent pelvic girdle pain (P-trend = 0.046). Early timing of progestin-only contraceptive dispense following delivery (<= 3 months) was not significantly associated with persistent pelvic girdle pain.

    Conclusions: Our findings suggest a small beneficial effect of progestin intrauterine devices and progestin-only oral contraceptives on recovery from pelvic girdle pain. We cannot completely rule out an opposing adverse effect of exposure to progestin injections and/or progestin implants. However, the modest increased odds of persistent pelvic girdle pain among these users could be a result of unmeasured confounding.

  • 102. Bjerg, Anders
    et al.
    Ekerljung, Linda
    Eriksson, Jonas
    Olafsdottir, Inga Sif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Middelveld, Roelinde
    Franklin, Karl A.
    Forsberg, Bertil
    Larsson, Kjell
    Lotvall, Jan
    Toren, Kjell
    Dahlen, Sven-Erik
    Lundback, Bo
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Higher Risk of Wheeze in Female than Male Smokers. Results from the Swedish GA(2)LEN Study2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 1, s. e54137-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Women who smoke have higher risk of lung function impairment, COPD and lung cancer than smoking men. An influence of sex hormones has been demonstrated, but the mechanisms are unclear and the associations often subject to confounding. This was a study of wheeze in relation to smoking and sex with adjustment for important confounders. Methods: In 2008 the Global Allergy and Asthma European Network (GA(2)LEN) questionnaire was mailed to 45.000 Swedes (age 16-75 years), and 26.851 (60%) participated. "Any wheeze'': any wheeze during the last 12 months. "Asthmatic wheeze'': wheeze with breathlessness apart from colds. Results: Any wheeze and asthmatic wheeze was reported by 17.3% and 7.1% of women, vs. 15.8% and 6.1% of men (both p<0.001). Although smoking prevalence was similar in both sexes, men had greater cumulative exposure, 16.2 pack-years vs. 12.8 in women (p<0.001). Most other exposures and characteristics associated with wheeze were significantly overrepresented in men. Adjusted for these potential confounders and pack-years, current smoking was a stronger risk factor for any wheeze in women aged <53 years, adjusted odds ratio (aOR) 1.85 (1.56-2.19) vs. 1.60 (1.30-1.96) in men. Cumulative smoke exposure and current smoking each interacted significantly with female sex, aOR 1.02 per pack-year (p<0.01) and aOR 1.28 (p = 0.04) respectively. Female compared to male current smokers also had greater risk of asthmatic wheeze, aOR 1.53 vs. 1.03, interaction aOR 1.52 (p = 0.02). These interactions were not seen in age >= 53 years. Discussion: In addition to the increased risk of COPD and lung cancer female, compared to male, smokers are at greater risk of significant wheezing symptoms in younger age. This became clearer after adjustment for important confounders including cumulative smoke exposure. Estrogen has previously been shown to increase the bioactivation of several compounds in tobacco smoke, which may enhance smoke-induced airway inflammation in fertile women.

  • 103.
    Bjersand, Kathrine
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Seidal, Tomas
    Department of Pathology, Halmstad Medical Center Hospital, Halmstad, Sweden.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Åkerud, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Skírnisdottir, Ingiridur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 6, artikel-id e0179363Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: To evaluate the prognostic effect of the Heterogeneous nuclear ribonucleoprotein type M (HNRPM) and Solute carrier 1A5 (SLC1A5) in FIGO-stages I-II epithelial ovarian cancer.

    METHODS: A retrospective cohort study was designed to investigate the prognostic effect of HNRPM and SLC1A5, and the association with clinical-pathologic characteristics in 131 patients with FIGO-stages I-II epithelial ovarian cancer. Tissue microarrays were constructed and protein levels were assessed by immunohistochemistry (IHC).

    RESULTS: Positive HRNPM status was associated with positive staining for PUMA (P = 0.04), concomitant PUMA and p21 staining (P = 0.005), and VEGF-R2 (P = 0.003). Positive SLC1A5 staining was associated with positive staining of p27 (P = 0.030), PUMA (P = 0.039), concomitant PUMA and p27 staining, and VEGF-R2 (P = 0.039). In non-serous tumors (n = 72), the SLC1A5 positivity was associated with recurrent disease (P = 0.01). In a multivariable logistic regression analysis FIGO-stage (OR = 12.4), tumor grade (OR = 5.1) and SLC1A5 positivity (OR = 0.1) were independent predictive factors for recurrent disease. Disease-free survival (DFS) in women with SLC1A5-positive non-serous tumors was 92% compared with of 66% in patients with SLC1A5-negative non-serous tumors (Log-rank = 15.343; P = 0.008). In Cox analysis with DFS as endpoint, FIGO-stage (HR = 4.5) and SLC1A5 status (HR = 0.3) were prognostic factors.

    CONCLUSIONS: As the proteins HRNPM and SLC1A5 are associated with the cell cycle regulators p21 or p27, the apoptosis regulators PTEN and PUMA, and the VEGF-R2 it is concluded that both proteins have role in the pathogenesis of ovarian cancer. In patients with non-serous ovarian cancer SLC1A5 protects from recurrent disease, presumably by means of biological mechanisms that are unrelated to cytotoxic drug sensitivity.

  • 104. Bjorkenstam, Charlotte
    et al.
    Moller, Jette
    Ringback, Gunilla
    Salmi, Peter
    Hallqvist, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Ljung, Rickard
    An Association between Initiation of Selective Serotonin Reuptake Inhibitors and Suicide - A Nationwide Register-Based Case-Crossover Study2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 9, s. e73973-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Treatment with selective serotonin reuptake inhibitors (SSRI) is one of the most common treatments for depression. It is however not clear whether or not there is an increased short-term suicide risk during initiation with SSRI. Methods: A register-based nationwide case-crossover study including 5,866 suicides, 1,698 women and 4,168 men, from the Death Register 2007-2010 in Sweden. SSRI initiation was defined as a dispensed prescription of SSRI within 28 days prior to the date of suicide with no previous dispensed prescription of SSRI within 4 months prior that prescription. The control period took place one year earlier. Odds ratio (OR) was estimated using conditional logistic regression. Result: During the 28 day period prior to suicide 48 women and 138 men were exposed to SSRI initiation (while not being exposed in the control period) and 22 women and 43 men were exposed in the control period (while not being exposed in the case period). The OR for suicide after initiation with SSRI was 2.7 (95% CI: 1.6-44) for women, and 4.3 (95% CI: 3.0-6.1) for men. The highest OR was found 8-11 days after initiation with SSRI 9.7 (95% CI: 3.0-31.7) for women and men combined. Conclusion: The main limitation in this study is confounding by indication, but the descriptive question is however not confounded by indication. Together with plausible biological mechanisms and previous clinical and epidemiological observations our findings, linking initiation of SSRI to increased short-term suicide risk, deserve further attention specifically in the clinical setting.

  • 105.
    Björk, Anne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Mellström, Dan
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Geriatr Med, Gothenburg, Sweden.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden.
    Karlsson, Magnus
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped Surg, Malmo, Sweden.
    Mallmin, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Johansson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Ljunggren, Östen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Kindmark, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Haplotypes in the CYP2R1 gene are associated with levels of 25(OH)D and bone mineral density, but not with other markers of bone metabolism (MrOS Sweden)2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 12, artikel-id e0209268Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Polymorphisms in the CYP2R1 gene encoding Vitamin D 25-hydroxylase have been reported to correlate with circulating levels of 25-OH vitamin D3 (25(OH)D). It is unknown whether these variations also affect overall bone metabolism. In order to elucidate the overall associations of polymorphisms in the CYP2R1, we studied haplotype tagging single nucleotide polymorphisms (SNPs) in the gene and serum levels of 25(OH)D, calcium, phosphate, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23), as well as bone mineral density (BMD).

    Methods: Baseline data on serum parameters and BMD from MrOS Sweden, a prospective population-based cohort study of elderly men (mean age 75 years, range 69-81), were analyzed. Genotyping was performed for eight SNPs covering the CYP2R1 gene in 2868 men with available samples of DNA. Subjects were followed up concerning incidence of fracture during five years.

    Results: There was a significant genetic association with circulating levels of 25(OH)D (4.6-18.5% difference in mean values between SNP alleles), but there were no correlations with levels of calcium, phosphate, PTH or FGF23 for any genetic variant. No differences were found in fracture incidence between the variants. There was an inverse relationship between lower BMD and concomitant higher 25(OH)D for three of the haplotypes (p < 0.005).

    Conclusions: Common variants in the CYP2R1 gene encoding Vitamin D 25-hydroxylase correlate with levels of circulating 25(OH)D but do not otherwise associate with measures of calcium and phosphate homeostasis. Presence of the specific haplotypes may be an indicator of risk for low 25(OH)D levels, and may in addition be correlated to bone mineral density.

  • 106.
    Björkelund, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Gedda, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Barta, Pavel
    Malmqvist, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Gefitinib Induces Epidermal Growth Factor Receptor Dimers Which Alters the Interaction Characteristics with (125)I-EGF2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 9, s. e24739-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The tyrosine kinase inhibitor gefitinib inhibits growth in some tumor types by targeting the epidermal growth factor receptor (EGFR). Previous studies show that the affinity of the EGF-EGFR interaction varies between hosting cell line, and that gefitinib increases the affinity for some cell lines. In this paper, we investigate possible mechanisms behind these observations. Real-time interaction analysis in LigandTracer (R) Grey revealed that the HER2 dimerization preventing antibody pertuzumab clearly modified the binding of (125)I-EGF to EGFR on HER2 overexpressing SKOV3 cells in the presence of gefitinib. Pertuzumab did not affect the binding on A431 cells, which express low levels of HER2. Cross-linking measurements showed that gefitinib increased the amount of EGFR dimers 3.0-3.8 times in A431 cells in the absence of EGF. In EGF stimulated SKOV3 cells the amount of EGFR dimers increased 1.8-2.2 times by gefitinib, but this effect was cancelled by pertuzumab. Gefitinib treatment did not alter the number of EGFR or HER2 expressed in tumor cell lines A431, U343, SKOV3 and SKBR3. Real-time binding traces were further analyzed in a novel tool, Interaction Map, which deciphered the different components of the measured interaction and supports EGF binding to multiple binding sites. EGFR and HER2 expression affect the levels of EGFR monomers, homodimers and heterodimers and EGF binds to the various monomeric/dimeric forms of EGFR with unique binding properties. Taken together, we conclude that dimerization explains the varying affinity of EGF - EGFR in different cells, and we propose that gefitinib induces EGFR dimmers, which alters the interaction characteristics with (125)I-EGF.

  • 107. Björkenstam, E.
    et al.
    Hjern, A.
    Mittendorfer-Rutz, E.
    Vinnerljung, B.
    Hallqvist, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Ljung, R.
    Multi-Exposure and Clustering of Adverse Childhood Experiences, Socioeconomic Differences and Psychotropic Medication in Young Adults2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 1, s. e53551-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: Stressful childhood experiences have negative long-term health consequences. The present study examines the association between adverse childhood experiences, socioeconomic position, and risk of psychotropic medication in young adulthood. Methods: This register-based cohort study comprises the birth cohorts between 1985 and 1988 in Sweden. We followed 362 663 individuals for use of psychotropic medication from January 2006 until December 2008. Adverse childhood experiences were severe criminality among parents, parental alcohol or drug abuse, social assistance recipiency, parental separation or single household, child welfare intervention before the age of 12, mentally ill or suicidal parents, familial death, and number of changes in place of residency. Estimates of risk of psychotropic medication were calculated as odds ratio (OR) with 95% confidence intervals (CIs) using logistic regression analysis. Results: Adverse childhood experiences were associated with increased risks of psychotropic medication. The OR for more than three adverse childhood experiences and risk of psychotropic medication was for women 2.4 (95% CI 2.3-2.5) and for men 3.1 (95% CI 2.9-3.2). The risk of psychotropic medication increased with a higher rate of adverse childhood experiences, a relationship similar in all socioeconomic groups. Conclusions: Accumulation of adverse childhood experiences increases the risk of psychotropic medication in young adults. Parental educational level is of less importance when adjusting for adverse childhood experiences. The higher risk for future mental health problems among children from lower socioeconomic groups, compared to peers from more advantaged backgrounds, seems to be linked to a higher rate of exposure to adverse childhood experiences.

  • 108.
    Björkstrand, Johannes
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Ågren, Thomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Frick, Andreas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Engman, Jonas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Disruption of Memory Reconsolidation Erases a Fear Memory Trace in the Human Amygdala: An 18-Month Follow-Up.2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 7, s. e0129393-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fear memories can be attenuated by reactivation followed by disrupted reconsolidation. Using functional magnetic resonance imaging we recently showed that reactivation and reconsolidation of a conditioned fear memory trace in the basolateral amygdala predicts subsequent fear expression over two days, while reactivation followed by disrupted reconsolidation abolishes the memory trace and suppresses fear. In this follow-up study we demonstrate that the behavioral effect persists over 18 months reflected in superior reacquisition after undisrupted, as compared to disrupted reconsolidation, and that neural activity in the basolateral amygdala representing the initial fear memory predicts return of fear. We conclude that disrupting reconsolidation have long lasting behavioral effects and may permanently erase the fear component of an amygdala-dependent memory.

  • 109. Black, Karen H.
    et al.
    Travouillon, Kenny J.
    Den Boer, Wendy
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Geovetenskapliga sektionen, Institutionen för geovetenskaper, Paleobiologi.
    Kear, Benjamin P.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Geovetenskapliga sektionen, Institutionen för geovetenskaper, Paleobiologi.
    Cooke, Bernard N.
    Archer, Michael
    A New Species of the Basal "Kangaroo'' Balbaroo and a Re-Evaluation of Stem Macropodiform Interrelationships2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, s. e112705-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exceptionally well-preserved skulls and postcranial elements of a new species of the plesiomorphic stem macropodiform Balbaroo have been recovered from middle Miocene freshwater limestone deposits in the Riversleigh World Heritage Area of northwestern Queensland, Australia. This constitutes the richest intraspecific sample for any currently known basal "kangaroo'', and, along with additional material referred to Balbaroo fangaroo, provides new insights into structural variability within the most prolific archaic macropodiform clade - Balbaridae. Qualitative and metric evaluations of taxonomic boundaries demonstrate that the previously distinct species Nambaroo bullockensis is a junior synonym of B. camfieldensis. Furthermore, coupled Maximum Parsimony and Bayesian phylogenetic analyses reveal that our new Balbaroo remains represent the most derived member of the Balbaroo lineage, and are closely related to the middle Miocene B. camfieldensis, which like most named balbarid species is identifiable only from isolated jaws. The postcranial elements of Balbaroo concur with earlier finds of the stratigraphically oldest balbarid skeleton, Nambaroo gillespieae, and suggest that quadrupedal progression was a primary gait mode as opposed to bipedal saltation. All Balbaroo spp. have low-crowned bilophodont molars, which are typical for browsing herbivores inhabiting the densely forested environments envisaged for middle Miocene northeastern Australia.

  • 110.
    Blacklock, Claire
    et al.
    Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom.
    Gonçalves Bradley, Daniela C
    Nuffield Department of Population Health, University of Oxford, United Kingdom.
    Mickan, Sharon
    Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom.
    Willcox, Merlin
    Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom.
    Roberts, Nia
    Nuffield Department of Population Health and Bodleian Healthcare Library, Knowledge Centre, University of Oxford, United Kingdom.
    Bergström, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Mant, David
    Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom.
    Impact of Contextual Factors on the Effect of Interventions to Improve Health Worker Performance in Sub-Saharan Africa: Review of Randomised Clinical Trials2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 1, artikel-id e0145206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Africa bears 24% of the global burden of disease but has only 3% of the world's health workers. Substantial variation in health worker performance adds to the negative impact of this significant shortfall. We therefore sought to identify interventions implemented in sub-Saharan African aiming to improve health worker performance and the contextual factors likely to influence local effectiveness.

    METHODS AND FINDINGS: A systematic search for randomised controlled trials of interventions to improve health worker performance undertaken in sub-Saharan Africa identified 41 eligible trials. Data were extracted to define the interventions' components, calculate the absolute improvement in performance achieved, and document the likelihood of bias. Within-study variability in effect was extracted where reported. Statements about contextual factors likely to have modified effect were subjected to thematic analysis. Interventions to improve health worker performance can be very effective. Two of the three trials assessing mortality impact showed significant reductions in death rates (age<5 case fatality 5% versus 10%, p<0.01; maternal in-hospital mortality 6.8/1000 versus 10.3/1000; p<0.05). Eight of twelve trials focusing on prescribing had a statistically significant positive effect, achieving an absolute improvement varying from 9% to 48%. However, reported range of improvement between centres within trials varied substantially, in many cases exceeding the mean effect. Nine contextual themes were identified as modifiers of intervention effect across studies; most frequently cited were supply-line failures, inadequate supervision or management, and failure to follow-up training interventions with ongoing support, in addition to staff turnover.

    CONCLUSIONS: Interventions to improve performance of existing staff and service quality have the potential to improve patient care in underserved settings. But in order to implement interventions effectively, policy makers need to understand and address the contextual factors which can contribute to differences in local effect. Researchers therefore must recognise the importance of reporting how context may modify effect size.

  • 111. Blair, M. W.
    et al.
    Soler, A.
    Cortés, Andrés J.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Växtekologi och evolution.
    Diversification and Population Structure in Common Beans (Phaseolus vulgaris L.)2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 11, s. e49488-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wild accessions of crops and landraces are valuable genetic resources for plant breeding and for conserving alleles and gene combinations in planta. The primary genepool of cultivated common beans includes wild accessions of Phaseolus vulgaris. These are of the same species as the domesticates and therefore are easily crossable with cultivated accessions. Molecular marker assessment of wild beans and landraces is important for the proper utilization and conservation of these important genetic resources. The goal of this research was to evaluate a collection of wild beans with fluorescent microsatellite or simple sequence repeat markers and to determine the population structure in combination with cultivated beans of all known races. Marker diversity in terms of average number of alleles per marker was high (13) for the combination of 36 markers and 104 wild genotypes that was similar to the average of 14 alleles per marker found for the 606 cultivated genotypes. Diversity in wild beans appears to be somewhat higher than in cultivated beans on a per genotype basis. Five populations or genepools were identified in structure analysis of the wild beans corresponding to segments of the geographical range, including Mesoamerican (Mexican), Guatemalan, Colombian, Ecuadorian-northern Peruvian and Andean (Argentina, Bolivia and Southern Peru). The combined analysis of wild and cultivated accessions showed that the first and last of these genepools were related to the cultivated genepools of the same names and the penultimate was found to be distinct but not ancestral to the others. The Guatemalan genepool was very novel and perhaps related to cultivars of race Guatemala, while the Colombian population was also distinct. Results suggest geographic isolation, founder effects or natural selection could have created the different semi-discrete populations of wild beans and that multiple domestications and introgression were involved in creating the diversity of cultivated beans.

  • 112.
    Blokzijl, Andries
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Chen, Lei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gustafsdottir, Sigrun M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Vuu, Jimmy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ullenhag, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet.
    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, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Hedstrand, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Elevated Levels of SOX10 in Serum from Vitiligo and Melanoma Patients, Analyzed by Proximity Ligation Assay2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 4, artikel-id e0154214Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    The diagnosis of malignant melanoma currently relies on clinical inspection of the skin surface and on the histopathological status of the excised tumor. The serum marker S100B is used for prognostic estimates at later stages of the disease, but analyses are marred by false positives and inadequate sensitivity in predicting relapsing disorder.

    Objectives

    To investigate SOX10 as a potential biomarker for melanoma and vitiligo.

    Methods

    In this study we have applied proximity ligation assay (PLA) to detect the transcription factor SOX10 as a possible serum marker for melanoma. We studied a cohort of 110 melanoma patients. We further investigated a second cohort of 85 patients with vitiligo, which is a disease that also affects melanocytes.

    Results

    The specificity of the SOX10 assay in serum was high, with only 1% of healthy blood donors being positive. In contrast, elevated serum SOX10 was found with high frequency among vitiligo and melanoma patients. In patients with metastases, lack of SOX10 detection was associated with treatment benefit. In two responding patients, a change from SOX10 positivity to undetectable levels was seen before the response was evident clinically.

    Conclusions

    We show for the first time that SOX10 represents a promising new serum melanoma marker for detection of early stage disease, complementing the established S100B marker. Our findings imply that SOX10 can be used to monitor responses to treatment and to assess if the treatment is of benefit at stages earlier than what is possible radiologically.

  • 113.
    Blomqvist, Björn R. H.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Matematiska institutionen, Tillämpad matematik och statistik.
    Mann, Richard P.
    Univ Leeds, Sch Math, Leeds, W Yorkshire, England.
    Sumpter, David J. T.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Matematiska institutionen, Tillämpad matematik och statistik.
    Using Bayesian dynamical systems, model averaging and neural networks to determine interactions between socio-economic indicators2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 5, artikel-id e0196355Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Social and economic systems produce complex and nonlinear relationships in the indicator variables that describe them. We present a Bayesian methodology to analyze the dynamical relationships between indicator variables by identifying the nonlinear functions that best describe their interactions. We search for the 'best' explicit functions by fitting data using Bayesian linear regression on a vast number of models and then comparing their Bayes factors. The model with the highest Bayes factor, having the best trade-off between explanatory power and interpretability, is chosen as the 'best' model. To be able to compare a vast number of models, we use conjugate priors, resulting in fast computation times. We check the robustness of our approach by comparison with more prediction oriented approaches such as model averaging and neural networks. Our modelling approach is illustrated using the classical example of how democracy and economic growth relate to each other. We find that the best dynamical model for democracy suggests that long term democratic increase is only possible if the economic situation gets better. No robust model explaining economic development using these two variables was found.

  • 114.
    Blystad, Ida
    et al.
    Department of Radiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden, Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
    Warntjes, J B Marcel
    Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden, Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden .
    Smedby, Örjan
    Department of Radiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden, Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden, School of Technology and Health, KTH Royal Institute of Technology, Stockholm, Sweden.
    Lundberg, Peter
    Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden, Department of Radiation Physics and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden .
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
    Tisell, Anders
    Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden, Department of Radiation Physics and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden .
    Quantitative MRI for analysis of peritumoral edema in malignant gliomas.2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 5, artikel-id e0177135Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND PURPOSE: Damage to the blood-brain barrier with subsequent contrast enhancement is a hallmark of glioblastoma. Non-enhancing tumor invasion into the peritumoral edema is, however, not usually visible on conventional magnetic resonance imaging. New quantitative techniques using relaxometry offer additional information about tissue properties. The aim of this study was to evaluate longitudinal relaxation R1, transverse relaxation R2, and proton density in the peritumoral edema in a group of patients with malignant glioma before surgery to assess whether relaxometry can detect changes not visible on conventional images.

    METHODS: In a prospective study, 24 patients with suspected malignant glioma were examined before surgery. A standard MRI protocol was used with the addition of a quantitative MR method (MAGIC), which measured R1, R2, and proton density. The diagnosis of malignant glioma was confirmed after biopsy/surgery. In 19 patients synthetic MR images were then created from the MAGIC scan, and ROIs were placed in the peritumoral edema to obtain the quantitative values. Dynamic susceptibility contrast perfusion was used to obtain cerebral blood volume (rCBV) data of the peritumoral edema. Voxel-based statistical analysis was performed using a mixed linear model.

    RESULTS: R1, R2, and rCBV decrease with increasing distance from the contrast-enhancing part of the tumor. There is a significant increase in R1 gradient after contrast agent injection (P < .0001). There is a heterogeneous pattern of relaxation values in the peritumoral edema adjacent to the contrast-enhancing part of the tumor.

    CONCLUSION: Quantitative analysis with relaxometry of peritumoral edema in malignant gliomas detects tissue changes not visualized on conventional MR images. The finding of decreasing R1 and R2 means shorter relaxation times closer to the tumor, which could reflect tumor invasion into the peritumoral edema. However, these findings need to be validated in the future.

  • 115. Bogaerts, Eliene
    et al.
    Heindryckx, Femke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Devisscher, Lindsey
    Paridaens, Annelies
    Vandewynckel, Yves-Paul
    Van den Bussche, Anja
    Verhelst, Xavier
    Libbrecht, Louis
    van Grunsven, Leo A.
    Geerts, Anja
    Van Vlierberghe, Hans
    Time-Dependent Effect of Hypoxia on Tumor Progression and Liver Progenitor Cell Markers in Primary Liver Tumors2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 3, artikel-id e0119555Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background & Aims Expression of liver progenitor cell (LPC) characteristics has been proposed as a negative prognostic marker in primary liver tumors. Hypoxia has been linked to activation of the Notch pathway which is responsible for activation and proliferation of LPCs and hypoxia- induced LPC activation has been shown in hepatocellular carcinoma. Our aim was to elucidate the time-dependent effects of hypoxia on the LPC niche in hepatocellular carcinoma which could aid in determining a safe time frame for use of hypoxia inducing therapies. Methods We used dimethyloxaloylglycine to mimic a hypoxic reaction in mice by stabilizing hypoxia-inducible factor 1 alpha at three distinct time points in diethylnitrosamine induced hepatocarcinogenesis. LPC, metastasis and Notch pathway markers were determined by quantitative PCR and (immune) histochemistry (heamatoxillin-eosin, reticulin, Sirius red and cytokeratin 19 staining). Results Activating the hypoxia inducible pathway early in hepatocarcinogenesis resulted in an increased incidence of both cholangioma and hepatocellular lesions, associated with high expression of LPC, metastatic and Notch pathway markers. Adversely, activating the hypoxic response during tumor development resulted in decreased incidence of hepatocellular lesions and increased cholangioma incidence, with an unaltered gene expression profile of LPC-, Notch pathway-and metastatic markers. A hypoxic insult at advanced stages of hepatocarcinogenesis severely increased the expression of LPC characteristics, however without increased expression of actors of the Notch pathway and metastatic markers and minor changes in incidence of hepatocellular and cholangioma lesions. Conclusion Our results indicate that increased hypoxia at the onset of tumor development has detrimental effects on tumor progression; patients with HCC developed in a background of fibrosis/cirrhosis might therefore represent a more difficult treatment group. In contrast, hypoxia during tumor development appears to favor tumor outcome, highlighting the importance of early detection. Finally, hypoxia in advanced stages resulted in increased expression of LPC characteristics indicating poor outcome.

  • 116.
    Bohman, Anton
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Juodakis, Julius
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Obstet & Gynecol, Gothenburg, Sweden.
    Oscarsson, Martin
    Skaraborg Hosp, Dept Otorhinolaryngol, Skovde, Sweden.
    Bacelis, Jonas
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Obstet & Gynecol, Gothenburg, Sweden.
    Bende, Mats
    Skaraborg Hosp, Dept Otorhinolaryngol, Skovde, Sweden.
    Naluai, Asa Torinsson
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Microbiol & Immunol, Gothenburg, Sweden.
    A family-based genome-wide association study of chronic rhinosinusitis with nasal polyps implicates several genes in the disease pathogenesis2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 12, artikel-id e0185244Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The pathogenesis of chronic rhinosinusitis with nasal polyps is largely unknown. Previous studies have given valuable information about genetic variants associated with this disease but much is still unexplained. Our goal was to identify genetic markers and genes associated with susceptibility to chronic rhinosinusitis with nasal polyps using a family-based genome-wide association study.

    Methods: 427 patients (293 males and 134 females) with CRSwNP and 393 controls (175 males and 218 females) were recruited from several Swedish hospitals. SNP association values were generated using DFAM (implemented in PLINK) and Efficient Mixed Model Association eXpedited (EMMAX). Analyses of pathway enrichment, gene expression levels and expression quantitative trait loci were then performed in turn.

    Results: None of the analysed SNPs reached genome wide significant association of 5.0 x 10-(8). Pathway analyses using our top 1000 markers with the most significant association p-values resulted in 138 target genes. A comparison between our target genes and gene expression data from the NCBI Gene Expression Omnibus database showed significant overlap for 36 of these genes. Comparisons with data from expression quantitative trait loci showed the most skewed allelic distributions in cases with chronic rhinosinusitis with nasal polyps compared with controls for the genes HLCS, HLA-DRA, BICD2, VSIR and SLC5A1.

    Conclusion: Our study indicates that HLCS, HLA-DRA, BICD2, VSIR and SLC5A1 could be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. HLA-DRA has been associated with chronic rhinosinusitis with nasal polyps in previous studies and HLCS, BICD2, VSIR and SLC5A1 may be new targets for future research.

  • 117. Bohmer, Sylvia-Annette
    et al.
    Weibrecht, Irene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Söderberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bohmer, Frank-D.
    Association of the Protein-Tyrosine Phosphatase DEP-1 with Its Substrate FLT3 Visualized by In Situ Proximity Ligation Assay2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, s. e62871-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein-tyrosine phosphatases (PTPs) are important regulators of signal transduction processes. Essential for the functional characterization of PTPs is the identification of their physiological substrates, and an important step towards this goal is the demonstration of a physical interaction. The association of PTPs with their cellular substrates is, however, often transient and difficult to detect with unmodified proteins at endogenous levels. Density-enhanced phosphatase-1 (DEP-1/PTPRJ) is a regulator of hematopoietic cell functions, and a candidate tumor suppressor. However, association of DEP-1 with any of its proposed substrates at endogenous levels has not yet been shown. We have previously obtained functional and biochemical evidence for a direct interaction of DEP-1 with the hematopoietic receptor-tyrosine kinase Fms-like tyrosine kinase-3 (FLT3). In the current study we have used the method of in situ proximity ligation assay (in situ PLA) to validate this interaction at endogenous levels, and to further characterize it. In situ PLA readily detected association of endogenous DEP1 and FLT3 in the human acute monocytic leukemia cell line THP-1, which was enhanced by FLT3 ligand (FL) stimulation in a time-dependent manner. Association peaked between 10 and 20 min of stimulation and returned to basal levels at 30 min. This time course was similar to the time course of FLT3 autophosphorylation. FLT3 kinase inhibition and DEP-1 oxidation abrogated association. Consistent with a functional role of DEP-1-FLT3 interaction, stable knockdown of DEP-1 in THP-1 cells enhanced FL-induced ERK1/2 activation. These findings support that FLT3 is a bona fide substrate of DEP-1 and that interaction occurs mainly via an enzyme-substrate complex formation triggered by FLT3 ligand stimulation.

  • 118.
    Boije, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Harun-Or-Rashid, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Lee, Yu-Jen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Imsland, Freyja
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Bruneau, Nicolas
    Vieaud, Agathe
    Gourichon, David
    Tixier-Boichard, Michèle
    Bed’hom, Bertrand
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hallböök, Finn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Sonic Hedgehog-Signalling Patterns the Developing Chicken Comb as Revealed by Exploration of the Pea-comb Mutation2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 12, s. e50890-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The genetic basis and mechanisms behind the morphological variation observed throughout the animal kingdom is stillrelatively unknown. In the present work we have focused on the establishment of the chicken comb-morphology byexploring the Pea-comb mutant. The wild-type single-comb is reduced in size and distorted in the Pea-comb mutant. Peacombis formed by a lateral expansion of the central comb anlage into three ridges and is caused by a mutation in SOX5,which induces ectopic expression of the SOX5 transcription factor in mesenchyme under the developing comb. Analysis ofdifferential gene expression identified decreased Sonic hedgehog (SHH) receptor expression in Pea-comb mesenchyme. Byexperimentally blocking SHH with cyclopamine, the wild-type single-comb was transformed into a Pea-comb-likephenotype. The results show that the patterning of the chicken comb is under the control of SHH and suggest that ectopicSOX5 expression in the Pea-comb change the response of mesenchyme to SHH signalling with altered combmorphogenesis as a result. A role for the mesenchyme during comb morphogenesis is further supported by the recentfinding that another comb-mutant (Rose-comb), is caused by ectopic expression of a transcription factor in combmesenchyme. The present study does not only give knowledge about how the chicken comb is formed, it also adds to ourunderstanding how mutations or genetic polymorphisms may contribute to inherited variations in the human face.

  • 119.
    Bolin, Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Zickert, Agneta
    Jönsen, Andreas
    Sjöwall, Christopher
    Svenungsson, Elisabet
    Bengtsson, Anders A
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gunnarsson, Iva
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e84450-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK.

    Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7×10−9, OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (p <0.0001). An additional six genes showed an association with lupus nephritis with p <0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6×10−3 and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.

  • 120. Boman, Krister K
    Impact of prior traumatic life events on parental early stage reactions following a child's cancer2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, ISSN 1932-6203, Vol. 8, nr 3Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Background: In pediatric oncology, effective clinic–based management of acute and long–term distress in families calls forinvestigation of determinants of parents’ psychological response to the child’s cancer. We examined the relationshipbetween parents’ prior exposure to traumatic life events (TLE) and the occurrence of posttraumatic stress symptoms (PTSS)following their child’s cancer diagnosis. Factors mediating the TLE–PTSS relationship were analyzed.Methodology: The study comprised 169 parents (97 mothers, 72 fathers) of 103 cancer diagnosed children (median age: 5,9years; range 0.1–19.7 years). Thirty five parents were of immigrant origin (20.7%). Prior TLE were collated using astandardized questionnaire, PTSS was assessed using the Impact of Events–Revised (IES–R) questionnaire covering intrusion,avoidance and hyperarousal symptoms. The predictive significance of prior TLE on PTSS was tested in adjusted regressionmodels.Results: Mothers demonstrated more severe PTSS across all symptom dimensions. TLE were associated with significantlyincreased hyperarousal symptoms. Parents’ gender, age and immigrant status did not significantly influence the TLE–PTSSrelationship.Conclusions: Prior traumatic life–events aggravate posttraumatic hyperarousal symptoms. In clinic–based psychologicalcare of parents of high–risk pediatric patients, attention needs to be paid to life history, and to heightened vulnerability toPTSS associated with female gender.

  • 121.
    Bonnedahl, Jonas
    et al.
    Linnaeus Univ, Sch Nat Sci, Ctr Ecol & Evolut Microbial Model Syst, SE-39182 Kalmar, Sweden.;Kalmar Cty Hosp, Dept Infect Dis, SE-39185 Kalmar, Sweden..
    Stedt, Johan
    Linnaeus Univ, Sch Nat Sci, Ctr Ecol & Evolut Microbial Model Syst, SE-39182 Kalmar, Sweden..
    Waldenstrom, Jonas
    Linnaeus Univ, Sch Nat Sci, Ctr Ecol & Evolut Microbial Model Syst, SE-39182 Kalmar, Sweden..
    Svensson, Lovisa
    Linnaeus Univ, Sch Nat Sci, Ctr Ecol & Evolut Microbial Model Syst, SE-39182 Kalmar, Sweden..
    Drobni, Mirva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin.
    Olsen, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Comparison of Extended-Spectrum beta-Lactamase (ESBL) CTX-M Genotypes in Franklin Gulls from Canada and Chile2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 10, artikel-id e0141315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Migratory birds have been suggested to contribute to long-distance dispersal of antimicrobial resistant bacteria, but tests of this hypothesis are lacking. In this study we determined resistance profiles and genotypes of ESBL-producing bacteria in randomly selected Escherichia coli from Franklin's gulls (Leucophaeus pipixcan) at breeding sites in Canada and compared with similar data from the gulls' wintering grounds in Chile. Resistant E. coli phenotypes were common, most notably to ampicillin (30.1%) and cefadroxil (15.1%). Furthermore, 17.0% of the gulls in Canada carried ESBL producing bacteria, which is higher than reported from human datasets from the same country. However, compared to gulls sampled in Chile (30.1%) the prevalence of ESBL was much lower. The dominant ESBL variants in Canada were bla(CTX-M-14) and bla(CTX-M-15) and differed in proportions to the data from Chile. We hypothesize that the observed differences in ESBL variants are more likely linked to recent exposure to bacteria from anthropogenic sources, suggesting high local dissemination of resistant bacteria both at breeding and non-breeding times rather than a significant trans-hemispheric exchange through migrating birds.

  • 122. Bonnet, Cecilia
    et al.
    Rusz, Jan
    Megrelishvili, Marika
    Sieger, Tomas
    Matouskova, Olga
    Okujava, Michael
    Brozova, Hana
    Nikolai, Tomas
    Hanuska, Jaromir
    Kapianidze, Mariam
    Mikeladze, Nina
    Botchorishvili, Nazi
    Khatiashvili, Irine
    Janelidze, Marina
    Serranova, Tereza
    Fiala, Ondrej
    Roth, Jan
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Jech, Robert
    Rivaud-Pechoux, Sophie
    Gaymard, Bertrand
    Ruzicka, Evzen
    Eye Movements in Ephedrone-Induced Parkinsonism2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 8, s. e104784-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro-and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system.

  • 123. Borena, Wegene
    et al.
    Edlinger, Michael
    Bjørge, Tone
    Häggström, Christel
    Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
    Lindkvist, Björn
    Nagel, Gabriele
    Engeland, Anders
    Stocks, Tanja
    Strohmaier, Susanne
    Manjer, Jonas
    Selmer, Randi
    Tretli, Steinar
    Concin, Hans
    Hallmans, Goran
    Jonsson, Håkan
    Stattin, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Ulmer, Hanno
    A prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (Me-Can) collaborative study2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 2, s. e89368-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE:

    To investigate the association between metabolic risk factors (individually and in combination) and risk of gallbladder cancer (GBC).

    METHODS:

    The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden with data on 578,700 men and women. We used Cox proportional hazard regression models to calculate relative risks of GBC by body mass index (BMI), blood pressure, and plasma levels of glucose, cholesterol, and triglycerides as continuous standardised variables and their standardised sum of metabolic syndrome (MetS) z-score. The risk estimates were corrected for random error in measurements.

    RESULTS:

    During an average follow-up of 12.0 years (SD = 7.8), 184 primary gallbladder cancers were diagnosed. Relative risk of gallbladder cancer per unit increment of z-score adjusted for age, smoking status and BMI (except for BMI itself) and stratified by birth year, sex and sub-cohorts, was for BMI 1.31 (95% confidence interval 1.11, 1.57) and blood glucose 1.76 (1.10, 2.85). Further analysis showed that the effect of BMI on GBC risk is larger among women in the premenopausal age group (1.84 (1.23, 2.78)) compared to those in the postmenopausal age group (1.29 (0.93, 1.79)). For the other metabolic factors no significant association was found (mid blood pressure 0.96 (0.71, 1.31), cholesterol 0.84 (0.66, 1.06) and serum triglycerides 1.16 (0.82, 1.64)). The relative risk per one unit increment of the MetS z-score was 1.37 (1.07, 1.73).

    CONCLUSION:

    This study showed that increasing BMI and impaired glucose metabolism pose a possible risk for gallbladder cancer. Beyond the individual factors, the results also showed that the metabolic syndrome as an entity presents a risk constellation for the occurrence of gallbladder cancer.

  • 124.
    Bornelöv, Susanne
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Saaf, Annika
    Melen, Erik
    Bergstrom, Anna
    Moghadam, Behrooz Torabi
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pulkkinen, Ville
    Acevedo, Nathalie
    Pietras, Christina Orsmark
    Ege, Markus
    Braun-Fahrlaender, Charlotte
    Riedler, Josef
    Doekes, Gert
    Kabesch, Michael
    van Hage, Marianne
    Kere, Juha
    Scheynius, Annika
    Soderhall, Cilla
    Pershagen, Goran
    Komorowski, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 11, s. e80080-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Both genetic and environmental factors are important for the development of allergic diseases. However, a detailed understanding of how such factors act together is lacking. To elucidate the interplay between genetic and environmental factors in allergic diseases, we used a novel bioinformatics approach that combines feature selection and machine learning. In two materials, PARSIFAL (a European cross-sectional study of 3113 children) and BAMSE (a Swedish birth-cohort including 2033 children), genetic variants as well as environmental and lifestyle factors were evaluated for their contribution to allergic phenotypes. Monte Carlo feature selection and rule based models were used to identify and rank rules describing how combinations of genetic and environmental factors affect the risk of allergic diseases. Novel interactions between genes were suggested and replicated, such as between ORMDL3 and RORA, where certain genotype combinations gave odds ratios for current asthma of 2.1 (95% CI 1.2-3.6) and 3.2 (95% CI 2.0-5.0) in the BAMSE and PARSIFAL children, respectively. Several combinations of environmental factors appeared to be important for the development of allergic disease in children. For example, use of baby formula and antibiotics early in life was associated with an odds ratio of 7.4 (95% CI 4.5-12.0) of developing asthma. Furthermore, genetic variants together with environmental factors seemed to play a role for allergic diseases, such as the use of antibiotics early in life and COL29A1 variants for asthma, and farm living and NPSR1 variants for allergic eczema. Overall, combinations of environmental and life style factors appeared more frequently in the models than combinations solely involving genes. In conclusion, a new bioinformatics approach is described for analyzing complex data, including extensive genetic and environmental information. Interactions identified with this approach could provide useful hints for further in-depth studies of etiological mechanisms and may also strengthen the basis for risk assessment and prevention.

  • 125. Borte, Stephan
    et al.
    Janzi, Magdalena
    Pan-Hammarstrom, Qiang
    von Döbeln, Ulrika
    Nordvall, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Winiarski, Jacek
    Fasth, Anders
    Hammarström, Lennart
    Placental Transfer of Maternally-Derived IgA Precludes the Use of Guthrie Card Eluates as a Screening Tool for Primary Immunodeficiency Diseases2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 8, s. e43419-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is a need for neonatal screening tools to improve the long-term clinical outcome of patients with primary immunodeficiency diseases (PID). Recently, a PCR-based screening method for both TRECs and KRECs using Guthrie card samples has been developed. However, the applicability of these excision circle assays is limited to patients with severe T or B cell lymphopenia (SCID, XLA and A-T), whereas the most common forms of PID are not detected. Absence of serum IgA is seen in a major fraction of patients with immunological defects. As serum IgA in newborns is considered to be of fetal origin, eluates from routinely collected dried blood spot samples might thus be suitable for identification of children with PID. To assess the applicability of such screening assays, stored Guthrie card samples were obtained from 47 patients with various forms of primary immunodeficiency diseases (SCID, XLA, A-T, HIGM and IgAD), 20 individuals with normal serum IgA levels born to IgA-deficient mothers and 51 matched healthy newborns. Surprisingly, normal serum IgA levels were found in all SCID, XLA, A-T and HIGM patients and, additionally, in all those IgAD patients born to IgA-sufficient mothers. Conversely, no serum IgA was found in any of the 16 IgAD patients born by IgA-deficient mothers. Moreover, half of the IgA-sufficient individuals born by IgA-deficient mothers also lacked IgA at birth whereas no IgA-deficient individuals were found among the controls. IgA in neonatal dried blood samples thus appears to be of both maternal and fetal origin and precludes its use as a reliable marker for neonatal screening of primary immunodeficiency diseases.

  • 126. Bosiger, Yolly J.
    et al.
    Lönnstedt, Oona M.
    McCormick, Mark I.
    Ferrari, Maud C.O.
    Learning Temporal Patterns of Risk in a Predator-Diverse Environment2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 4, s. e34535-Artikel i tidskrift (Refereegranskat)
  • 127.
    Boström, Jannika E.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi.
    Dimitrova, Marina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi. Stockholm Univ, Dept Zool, S-10691 Stockholm, Sweden..
    Canton, Cindy
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi.
    Hastad, Olle
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Box 7011, S-75007 Uppsala, Sweden..
    Qvarnstrom, Anna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi.
    Ödeen, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Zooekologi. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Box 7011, S-75007 Uppsala, Sweden..
    Ultra-Rapid Vision in Birds2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 3, artikel-id e0151099Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Flying animals need to accurately detect, identify and track fast-moving objects and these behavioral requirements are likely to strongly select for abilities to resolve visual detail in time. However, evidence of highly elevated temporal acuity relative to non-flying animals has so far been confined to insects while it has been missing in birds. With behavioral experiments on three wild passerine species, blue tits, collared and pied flycatchers, we demonstrate temporal acuities of vision far exceeding predictions based on the sizes and metabolic rates of these birds. This implies a history of strong natural selection on temporal resolution. These birds can resolve alternating light-dark cycles at up to 145 Hz (average: 129, 127 and 137, respectively), which is ca. 50 Hz over the highest frequency shown in any other vertebrate. We argue that rapid vision should confer a selective advantage in many bird species that are ecologically similar to the three species examined in our study. Thus, rapid vision may be a more typical avian trait than the famously sharp vision found in birds of prey.

  • 128.
    Braenne, Ingrid
    et al.
    Univ Lubeck, Inst Cardiogenet, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany.;Univ Heart Ctr Lubeck, Lubeck, Germany..
    Zeng, Lingyao
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany..
    Willenborg, Christina
    Univ Lubeck, Inst Cardiogenet, Lubeck, Germany..
    Tragante, Vinicius
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands..
    Kessler, Thorsten
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany..
    Willer, Cristen J.
    Univ Michigan, Dept Biostat, 1415 Washington Hts, Ann Arbor, MI USA..
    Laakso, Markku
    Univ Eastern Finland, Internal Med, Inst Clin Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Franks, Paul W.
    Lund Univ, Skane Univ Hosp Malmo, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden..
    Salomaa, Veikko
    THL Natl Inst Hlth & Welf, POB 30,Mannerheimintie 166, Helsinki, Finland..
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, Ca Rotterdam, Netherlands..
    Meitinger, Thomas
    Helmholtz Zentrum Munchen, Inst Human Genet, German Res Ctr Environm Hlth, Neuherberg, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Asselbergs, Folkert W.
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.;Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands.;UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England..
    Erdmann, Jeanette
    Univ Lubeck, Inst Cardiogenet, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany.;Univ Heart Ctr Lubeck, Lubeck, Germany..
    Schunkert, Heribert
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 8, artikel-id e0182999Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10−12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10−10 and 2.21 × 10−6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.

  • 129. Brandariz-Fontes, Claudia
    et al.
    Leonard, Jennifer A.
    Luis Vega-Pla, Jose
    Backström, Niclas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Lindgren, Gabriella
    Lippold, Sebastian
    Rico, Ciro
    Y-Chromosome Analysis in Retuertas Horses2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, s. e64985-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several studies based on a variety of genetic markers have attempted to establish the origins of horse domestication. Thus far a discrepancy between the results of mitochondrial DNA analysis, which show high levels of diversity, and results from the Y-chromosome, with almost no genetic variability, has been identified. Most previous work on the horse Y-chromosome has focused on widespread, popular breeds or local Asian breeds. It is possible that these breeds represent a reduced set of the genetic variation present in the species. Additional genetic variation may be present in local breeds and ancient feral populations, such as the Retuertas horse in Spain. In this study we analyzed the Y-chromosome of the Retuertas horse, a feral horse population on the Iberian Peninsula that is at least several hundred years old, and whose genetic diversity and morphology suggests that it has been reproductively isolated for a long time. Data from the Retuertas horse was compared to another 11 breeds from the region (Portugal, Spain and France) or likely of Iberian origin, and then to data from 15 more breeds from around the globe. We sequenced 31 introns, Zinc finger Y-chromosomal protein (ZFY) and anonymous Y-linked fragments and genotyped 6 microsatellite loci found on the Y-chromosome. We found no sequence variation among all individuals and all breeds studied. However, fifteen differences were discovered between our data set and reference sequences in GenBank. We show that these likely represent errors within the deposited sequences, and suggest that they should not be used as comparative data for future projects.

  • 130. Breed, Andrew C.
    et al.
    Breed, Martin F.
    Australian Centre for Evolutionary Biology and Biodiversity (ACEBB), and School of Earth and Environmental Sciences, University of Adelaide.
    Meers, Joanne
    Field, Hume E.
    Evidence of endemic Hendra virus infection in flying-foxes (Pteropus conspicillatus): implications for disease risk management2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, s. e28816-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study investigated the seroepidemiology of Hendra virus in a spectacled flying-fox (Pteropus conspicillatus) population in northern Australia, near the location of an equine and associated human Hendra virus infection in late 2004. The pattern of infection in the population was investigated using a serial cross-sectional serological study over a 25-month period, with blood sampled from 521 individuals over six sampling sessions. Antibody titres to the virus were determined by virus neutralisation test. In contrast to the expected episodic infection pattern, we observed that seroprevalence gradually increased over the two years suggesting infection was endemic in the population over the study period. Our results suggested age, pregnancy and lactation were significant risk factors for a detectable neutralizing antibody response. Antibody titres were significantly higher in females than males, with the highest titres occurring in pregnant animals. Temporal variation in antibody titres suggests that herd immunity to the virus may wax and wane on a seasonal basis. These findings support an endemic infection pattern of henipaviruses in bat populations suggesting their infection dynamics may differ significantly from the acute, self limiting episodic pattern observed with related viruses (e.g. measles virus, phocine distemper virus, rinderpest virus) hence requiring a much smaller critical host population size to sustain the virus. These findings help inform predictive modelling of henipavirus infection in bat populations, and indicate that the life cycle of the reservoir species should be taken into account when developing risk management strategies for henipaviruses.

  • 131.
    Brindefalk, Björn
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ettema, Thijs J. G.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Viklund, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Thollesson, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Andersson, Siv G. E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    A Phylometagenomic Exploration of Oceanic Alphaproteobacteria Reveals Mitochondrial Relatives Unrelated to the SAR11 Clade2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 9, s. e24457-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: According to the endosymbiont hypothesis, the mitochondrial system for aerobic respiration was derived from an ancestral Alphaproteobacterium. Phylogenetic studies indicate that the mitochondrial ancestor is most closely related to the Rickettsiales. Recently, it was suggested that Candidatus Pelagibacter ubique, a member of the SAR11 clade that is highly abundant in the oceans, is a sister taxon to the mitochondrial-Rickettsiales clade. The availability of ocean metagenome data substantially increases the sampling of Alphaproteobacteria inhabiting the oxygen-containing waters of the oceans that likely resemble the originating environment of mitochondria.

    Methodology/Principal Findings: We present a phylogenetic study of the origin of mitochondria that incorporates metagenome data from the Global Ocean Sampling (GOS) expedition. We identify mitochondrially related sequences in the GOS dataset that represent a rare group of Alphaproteobacteria, designated OMAC (Oceanic Mitochondria Affiliated Clade) as the closest free-living relatives to mitochondria in the oceans. In addition, our analyses reject the hypothesis that the mitochondrial system for aerobic respiration is affiliated with that of the SAR11 clade.

    Conclusions/Significance: Our results allude to the existence of an alphaproteobacterial clade in the oxygen-rich surface waters of the oceans that represents the closest free-living relative to mitochondria identified thus far. In addition, our findings underscore the importance of expanding the taxonomic diversity in phylogenetic analyses beyond that represented by cultivated bacteria to study the origin of mitochondria.

  • 132. Brolin Ribacke, Kim J
    et al.
    van Duinen, Alex J
    Nordenstedt, Helena
    Höijer, Jonas
    Molnes, Ragnhild
    Froseth, Torunn Wigum
    Koroma, A P
    Darj, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell kvinno- och mödrahälsovård och migration.
    Bolkan, Håkon Angel
    Ekström, AnnaMia
    The Impact of the West Africa Ebola Outbreak on Obstetric Health Care in Sierra Leone.2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 2, artikel-id e0150080Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: As Sierra Leone celebrates the end of the Ebola Virus Disease (EVD) outbreak, we can begin to fully grasp its impact on already weak health systems. The EVD outbreak in West Africa forced many hospitals to close down or reduce their activity, either to prevent nosocomial transmission or because of staff shortages. The aim of this study is to assess the potential impact of EVD on nationwide access to obstetric care in Sierra Leone.

    METHODS AND FINDINGS: Community health officers collected weekly data between January 2014-May 2015 on in-hospital deliveries and caesarean sections (C-sections) from all open facilities (public, private for-profit and private non-profit sectors) offering emergency obstetrics in Sierra Leone. This was compared to official data of EVD cases per district. Logistic and Poisson regression analyses were used to compute risk and rate estimates. Nationwide, the number of in-hospital deliveries and C-sections decreased by over 20% during the EVD outbreak. The decline occurred early on in the EVD outbreak and was mainly attributable to the closing of private not-for-profit hospitals rather than government facilities. Due to difficulties in collecting data in the midst of an epidemic, limitations of this study include some missing data points.

    CONCLUSIONS: Both the number of in-hospital deliveries and C-sections substantially declined shortly after the onset of the EVD outbreak. Since access to emergency obstetric care, like C-sections, is associated with decreased maternal mortality, many women are likely to have died due to the reduced access to appropriate care during childbirth. Future research on indirect health effects of health system breakdown should ideally be nationwide and continue also into the recovery phase. It is also important to understand the mechanisms behind the deterioration so that important health services can be reestablished.

  • 133. Brolund, Alma
    et al.
    Franzen, Oscar
    Melefors, Ojar
    Tegmark-Wisell, Karin
    Sandegren, Linus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Plasmidome-Analysis of ESBL-Producing Escherichia coli Using Conventional Typing and High-Throughput Sequencing2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e65793-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Infections caused by Extended spectrum beta-lactamase (ESBL)-producing E. coli are an emerging global problem, threatening the effectiveness of the extensively used beta-lactam antibiotics. ESBL dissemination is facilitated by plasmids, transposons, and other mobile elements. We have characterized the plasmid content of ESBL-producing E. coli from human urinary tract infections. Ten diverse isolates were selected; they had unrelated pulsed-field gel electrophoresis (PFGE) types (<90% similarity), were from geographically dispersed locations and had diverging antibiotic resistance profiles. Three isolates belonged to the globally disseminated sequence type ST131. ESBL-genes of the CTX-M-1 and CTX-M-9 phylogroups were identified in all ten isolates. The plasmid content (plasmidome) of each strain was analyzed using a combination of molecular methods and high-throughput sequencing. Hidden Markov Model-based analysis of unassembled sequencing reads was used to analyze the genetic diversity of the plasmid samples and to detect resistance genes. Each isolate contained between two and eight distinct plasmids, and at least 22 large plasmids were identified overall. The plasmids were variants of pUTI89, pKF3-70, pEK499, pKF3-140, pKF3-70, p1ESCUM, pEK204, pHK17a, p083CORR, R64, pLF82, pSFO157, and R721. In addition, small cryptic high copy-number plasmids were frequent, containing one to seven open reading frames per plasmid. Three clustered groups of such small cryptic plasmids could be distinguished based on sequence similarity. Extrachromosomal prophages were found in three isolates. Two of them resembled the E. coli P1 phage and one was previously unknown. The present study confirms plasmid multiplicity in multi-resistant E. coli. We conclude that high-throughput sequencing successfully provides information on the extrachromosomal gene content and can be used to generate a genetic fingerprint of possible use in epidemiology. This could be a valuable tool for tracing plasmids in outbreaks.

  • 134.
    Brooks, Samantha J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Cedernaes, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Increased prefrontal and parahippocampal activation with reduced dorsolateral prefrontal and insular cortex activation to food images in obesity: a meta-analysis of fMRI studies.2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 4, s. e60393-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Obesity is emerging as the most significant health concern of the twenty-first century. A wealth of neuroimaging data suggest that weight gain might be related to aberrant brain function, particularly in prefrontal cortical regions modulating mesolimbic addictive responses to food. Nevertheless, food addiction is currently a model hotly debated. Here, we conduct a meta-analysis of neuroimaging data, examining the most common functional differences between normal-weight and obese participants in response to food stimuli.

    DATA SOURCE: We conducted a search using several journal databases and adhered to the 'Preferred Reporting Items for Systematic Reviews and Meta-analyses' (PRISMA) method. To this aim, 10 studies were found with a total of 126 obese participants, 129 healthy controls, equaling 184 foci (146 increased, 38 decreased activation) using the Activation Likelihood Estimation (ALE) technique. Out of the 10 studies, 7 investigated neural responses to food versus non-food images.

    RESULTS: In response to food images, obese in comparison to healthy weight subjects had increased activation in the left dorsomedial prefrontal cortex, right parahippocampal gyrus, right precentral gyrus and right anterior cingulate cortex, and reduced activation in the left dorsolateral prefrontal cortex and left insular cortex.

    CONCLUSIONS: Prefrontal cortex areas linked to cognitive evaluation processes, such as evaluation of rewarding stimuli, as well as explicit memory regions, appear most consistently activated in response to images of food in those who are obese. Conversely, a reduced activation in brain regions associated with cognitive control and interoceptive awareness of sensations in the body might indicate a weakened control system, combined with hypo-sensitivity to satiety and discomfort signals after eating in those who are prone to overeat.

  • 135.
    Brooks, Samantha J
    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.
    Jacobsson, Josefin A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Stein, Dan J
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    BDNF polymorphisms are linked to poorer working memory performance, reduced cerebellar and hippocampal volumes and differences in prefrontal cortex in a Swedish elderly population2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 1, s. e82707-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Brain-derived neurotrophic factor (BDNF) links learning, memory and cognitive decline in elderly, but evidence linking BDNF allele variation, cognition and brain structural differences is lacking.

    METHODS: 367 elderly Swedish men (n = 181) and women (n = 186) from Prospective Investigation of the Vasculature in Uppsala seniors (PIVUS) were genotyped and the BDNF functional rs6265 SNP was further examined in subjects who completed the Trail Making Task (TMT), verbal fluency task, and had a magnetic resonance imaging (MRI) scan. Voxel-based morphometry (VBM) examined brain structure, cognition and links with BDNF.

    RESULTS: The functional BDNF SNP (rs6265,) predicted better working memory performance on the TMT with positive association of the Met rs6265, and was linked with greater cerebellar, precuneus, left superior frontal gyrus and bilateral hippocampal volume, and reduced brainstem and bilateral posterior cingulate volumes.

    CONCLUSIONS: The functional BDNF polymorphism influences brain volume in regions associated with memory and regulation of sensorimotor control, with the Met rs6265 allele potentially being more beneficial to these functions in the elderly.

  • 136.
    Brooks, Samantha J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    O'Daly, Owen G.
    Uher, Rudolf
    Friederich, Hans-Christoph
    Giampietro, Vincent
    Brammer, Michael
    Williams, Steven C. R.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Treasure, Janet
    Campbell, Iain C.
    Differential Neural Responses to Food Images in Women with Bulimia versus Anorexia Nervosa2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 7, s. e22259-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Previous fMRI studies show that women with eating disorders (ED) have differential neural activation to viewing food images. However, despite clinical differences in their responses to food, differential neural activation to thinking about eating food, between women with anorexia nervosa (AN) and bulimia nervosa (BN) is not known. Methods: We compare 50 women (8 with BN, 18 with AN and 24 age-matched healthy controls [HC]) while they view food images during functional Magnetic Resonance Imaging (fMRI). Results: In response to food (vs non-food) images, women with BN showed greater neural activation in the visual cortex, right dorsolateral prefrontal cortex, right insular cortex and precentral gyrus, women with AN showed greater activation in the right dorsolateral prefrontal cortex, cerebellum and right precuneus. HC women activated the cerebellum, right insular cortex, right medial temporal lobe and left caudate. Direct comparisons revealed that compared to HC, the BN group showed relative deactivation in the bilateral superior temporal gyrus/insula, and visual cortex, and compared to AN had relative deactivation in the parietal lobe and dorsal posterior cingulate cortex, but greater activation in the caudate, superior temporal gyrus, right insula and supplementary motor area. Conclusions: Women with AN and BN activate top-down cognitive control in response to food images, yet women with BN have increased activation in reward and somatosensory regions, which might impinge on cognitive control over food consumption and binge eating.

  • 137.
    Brooks, Samantha J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    O'Daly, Owen
    Uher, Rudolf
    Friederich, Hans-Christoph
    Giampietro, Vincent
    Brammer, Michael
    Williams, Steven C. R.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Treasure, Janet
    Campbell, Iain C.
    Thinking about Eating Food Activates Visual Cortex with Reduced Bilateral Cerebellar Activation in Females with Anorexia Nervosa: An fMRI Study2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 3, s. e34000-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Women with anorexia nervosa (AN) have aberrant cognitions about food and altered activity in prefrontal cortical and somatosensory regions to food images. However, differential effects on the brain when thinking about eating food between healthy women and those with AN is unknown.

    Methods: Functional magnetic resonance imaging (fMRI) examined neural activation when 42 women thought about eating the food shown in images: 18 with AN (11 RAN, 7 BPAN) and 24 age-matched controls (HC).

    Results: Group contrasts between HC and AN revealed reduced activation in AN in the bilateral cerebellar vermis, and increased activation in the right visual cortex. Preliminary comparisons between AN subtypes and healthy controls suggest differences in cortical and limbic regions.

    Conclusions: These preliminary data suggest that thinking about eating food shown in images increases visual and prefrontal cortical neural responses in females with AN, which may underlie cognitive biases towards food stimuli and ruminations about controlling food intake. Future studies are needed to explicitly test how thinking about eating activates restraint cognitions, specifically in those with restricting vs. binge-purging AN subtypes.

  • 138.
    Brousseau, Louise
    et al.
    INRA, Domaine St Paul, URFM Ecol Forets Mediterraneennes UR629, Site Agroparc CS,Site Agroparc CS 40509, F-84914 Avignon 9, France.;Natl Res Council IBBR CNR, Div Florence, Inst Biosci & BioResources, Via Madonna Piano 10, I-50019 Sesto Fiorentino, FI, France..
    Postolache, Dragos
    Natl Res Council IBBR CNR, Div Florence, Inst Biosci & BioResources, Via Madonna Piano 10, I-50019 Sesto Fiorentino, FI, France.;Scuola Super Sant Anna, Piazza Martiri Liberta 33, I-56127 Pisa, Italy.;Natl Inst Forest Res & Dev INCDS, Res Stn Simeria, Str Biscaria 1, Simeria 335900, Romania..
    Lascoux, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Växtekologi och evolution.
    Drouzas, Andreas D.
    Aristotle Univ Thessaloniki, Sch Biol, GR-54124 Thessaloniki, Greece..
    Källman, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Leonarduzzi, Cristina
    Natl Res Council IBBR CNR, Div Florence, Inst Biosci & BioResources, Via Madonna Piano 10, I-50019 Sesto Fiorentino, FI, France.;Natl 3 Res Council Corso Calatafimi, Div Palermo, Inst Biosci & BioResources, Natl Res Council IBBR CNR, I-90129 Palermo, PA, Italy..
    Liepelt, Sascha
    Univ Marburg, Fac Biol, Conservat Biol, Karl von Frisch Str, D-35032 Marburg, Germany..
    Piotti, Andrea
    Natl Res Council IBBR CNR, Div Florence, Inst Biosci & BioResources, Via Madonna Piano 10, I-50019 Sesto Fiorentino, FI, France..
    Popescu, Flaviu
    Natl Inst Forest Res & Dev INCDS, Res Stn Simeria, Str Biscaria 1, Simeria 335900, Romania..
    Roschanski, Anna M.
    Univ Marburg, Fac Biol, Conservat Biol, Karl von Frisch Str, D-35032 Marburg, Germany.;Leibniz Inst Plant Genet & Crop Plant Res IPK, Genebank Collect North, Inselstr 9, D-23999 Malchow Poel, Germany..
    Zhelev, Peter
    Univ Forestry, 10 Kl Ohridsky Blvd, Sofia 1797, Bulgaria..
    Fady, Bruno
    INRA, Domaine St Paul, URFM Ecol Forets Mediterraneennes UR629, Site Agroparc CS,Site Agroparc CS 40509, F-84914 Avignon 9, France..
    Vendramin, Giovanni Giuseppe
    Natl Res Council IBBR CNR, Div Florence, Inst Biosci & BioResources, Via Madonna Piano 10, I-50019 Sesto Fiorentino, FI, France..
    Local Adaptation in European Firs Assessed through Extensive Sampling across Altitudinal Gradients in Southern Europe2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 7, artikel-id e0158216Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Local adaptation is a key driver of phenotypic and genetic divergence at loci responsible for adaptive traits variations in forest tree populations. Its experimental assessment requires rigorous sampling strategies such as those involving population pairs replicated across broad spatial scales. Methods A hierarchical Bayesian model of selection (HBM) that explicitly considers both the replication of the environmental contrast and the hierarchical genetic structure among replicated study sites is introduced. Its power was assessed through simulations and compared to classical 'within-site' approaches (FDIST, BAYESCAN) and a simplified, within-site, version of the model introduced here (SBM). Results HBM demonstrates that hierarchical approaches are very powerful to detect replicated patterns of adaptive divergence with low false-discovery (FDR) and false-non-discovery (FNR) rates compared to the analysis of different sites separately through within-site approaches. The hypothesis of local adaptation to altitude was further addressed by analyzing replicated Abies alba population pairs (low and high elevations) across the species' southern distribution range, where the effects of climatic selection are expected to be the strongest. For comparison, a single population pair from the closely related species A. cephalonica was also analyzed. The hierarchical model did not detect any pattern of adaptive divergence to altitude replicated in the different study sites. Instead, idiosyncratic patterns of local adaptation among sites were detected by within-site approaches. Conclusion Hierarchical approaches may miss idiosyncratic patterns of adaptation among sites, and we strongly recommend the use of both hierarchical (multi-site) and classical (within-site) approaches when addressing the question of adaptation across broad spatial scales.

  • 139. Brunberg, Emma
    et al.
    Jensen, Per
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Keeling, Linda J.
    Behavioural and Brain Gene Expression Profiling in Pigs during Tail Biting Outbreaks - Evidence of a Tail Biting Resistant Phenotype2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e66513-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Abnormal tail biting behaviour is a major welfare problem for pigs receiving the behaviour, as well as an indication of decreased welfare in the pigs performing it. However, not all pigs in a pen perform or receive tail biting behaviour and it has recently been shown that these 'neutral' pigs not only differ in their behaviour, but also in their gene expression compared to performers and receivers of tail biting in the same pen. To investigate whether this difference was linked to the cause or a consequence of them not being involved in the outbreak of tail biting, behaviour and brain gene expression was compared with 'control' pigs housed in pens with no tail biting. It was shown that the pigs housed in control pens performed a wider variety of pig-directed abnormal behaviour (belly nosing 0.95 +/- 1.59, tail in mouth 0.31 +/- 0.60 and 'other' abnormal 1.53 +/- 4.26; mean +/- S.D) compared to the neutral pigs (belly nosing 0.30 +/- 0.62, tail in mouth 0.13 +/- 0.50 and "other" abnormal 0.42 +/- 1.06). With Affymetrix gene expression arrays, 107 transcripts were identified as differently expressed (p < 0.05) between these two categories of pigs. Several of these transcripts had already been shown to be differently expressed in the neutral pigs when they were compared to performers and receivers of tail biting in the same pen in an earlier study. Hence, the different expression of these genes cannot be a consequence of the neutral pigs not being involved in tail biting behaviour, but rather linked to the cause contributing to why they were not involved in tail biting interactions. These neutral pigs seem to have a genetic and behavioural profile that somehow contributes to them being resistant to performing or receiving pig-directed abnormal behaviour, such as tail biting, even when housed in an environment that elicits that behaviour in other pigs.

  • 140. Brändstedt, Jenny
    et al.
    Wangefjord, Sakarias
    Nodin, Bjorn
    Eberhard, Jakob
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Manjer, Jonas
    Jirstrom, Karin
    Associations of Anthropometric Factors with KRAS and BRAF Mutation Status of Primary Colorectal Cancer in Men and Women: A Cohort Study2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 6, s. e98964-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Obesity is a well-established risk factor for colorectal cancer (CRC), and accumulating evidence suggests a differential influence of sex and anthropometric factors on the molecular carcinogenesis of the disease. The aim of the present study was to investigate the relationship between height, weight, bodyfat percentage, waist-and hip circumference, waist-hip ratio (WHR), body mass index (BMI) and CRC risk according to KRAS and BRAF mutation status of the tumours, with particular reference to potential sex differences. KRAS and BRAF mutations were analysed by pyrosequencing in tumours from 494 incident CRC cases in the Malmo Diet and Cancer Study. Hazard ratios of CRC risk according to anthropometric factors and mutation status were calculated using multivariate Cox regression models. While all anthropometric measures except height were associated with an increased risk of KRAS-mutated tumours, only BMI was associated with an increased risk of KRAS wild type tumours overall. High weight, hip, waist, WHR and BMI were associated with an increased risk of BRAF wild type tumours, but none of the anthropometric factors were associated with risk of BRAF-mutated CRC, neither in the overall nor in the sex-stratified analysis. In men, several anthropometric measures were associated with both KRAS-mutated and KRAS wild type tumours. In women, only a high WHR was significantly associated with an increased risk of KRA-Smutated CRC. A significant interaction was found between sex and BMI with respect to risk of KRAS-mutated tumours. In men, all anthropometric factors except height were associated with an increased risk of BRAF wild type tumours, whereas in women, only bodyfat percentage was associated with an increased risk of BRAF wild type tumours. The results from this prospective cohort study further support an influence of sex and lifestyle factors on different pathways of colorectal carcinogenesis, defined by KRAS and BRAF mutation status of the tumours.

  • 141.
    Brännström, Kristoffer
    et al.
    Umeå universitet, Institutionen för medicinsk kemi och biofysik.
    Lindhagen-Persson, Malin
    Umeå universitet, Institutionen för medicinsk kemi och biofysik.
    Gharibyan, Anna L.
    Umeå universitet, Institutionen för medicinsk kemi och biofysik.
    Iakovleva, Irina
    Umeå universitet, Institutionen för medicinsk kemi och biofysik.
    Vestling, Monika
    Umeå universitet, Institutionen för medicinsk kemi och biofysik.
    Sellin, Mikael E.
    Umeå universitet, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Brännström, Thomas
    Umeå universitet, Patologi.
    Morozova-Roche, Ludmilla
    Umeå universitet, Institutionen för medicinsk kemi och biofysik.
    Forsgren, Lars
    Umeå universitet, Klinisk neurovetenskap.
    Olofsson, Anders
    Umeå universitet, Institutionen för medicinsk kemi och biofysik.
    A Generic Method for Design of Oligomer-Specific Antibodies2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 3, artikel-id e90857Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specific antibodies. The method takes a two-step approach where discrimination between oligomers and fibrils is first accomplished through identification of cryptic epitopes exclusively buried within the structure of the fibrillar form. The second step discriminates between monomers and oligomers based on differences in avidity. We show here that a simple divalent mode of interaction, as within e. g. the IgG isotype, can increase the binding strength of the antibody up to 1500 times compared to its monovalent counterpart. We expose how the ability to bind oligomers is affected by the monovalent affinity and the turnover rate of the binding and, importantly, also how oligomer specificity is only valid within a specific concentration range. We provide an example of the method by creating and characterising a spectrum of different monoclonal antibodies against both the A beta peptide and alpha-synuclein that are associated with Alzheimer's and Parkinson's diseases, respectively. The approach is however generic, does not require identification of oligomer-specific architectures, and is, in essence, applicable to all polypeptides that form oligomeric and fibrillar assemblies.

  • 142.
    Buchner, Denise Lynn
    et al.
    Univ Calgary, Cumming Sch Med, Dept Community Hlth Sci, Calgary, AB, Canada.
    Kitutu, Freddy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH). Makerere Univ, Pharm Dept, Kampala, Uganda.
    Cross, Donall Eoin
    Aberystwyth Univ, Inst Biol Environm & Rural Sci, Aberystwyth, Dyfed, Wales.
    Nakamoga, Esther
    Makerere Univ, Sch Publ Hlth, Kampala, Uganda.
    Awor, Phyllis
    Makerere Univ, Sch Publ Hlth, Kampala, Uganda.
    A cross-sectional study to identify the distribution and characteristics of licensed and unlicensed private drug shops in rural Eastern Uganda to inform an iCCM intervention to improve health outcomes for children under five years2019Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 1, artikel-id e0209641Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Malaria, pneumonia and diarrhea are leading causes of death in young children in Uganda. Between 50-60% of sick children receive treatment from the private sector, especially drug shops. There is an urgent need to improve quality of care and regulation of private drug shops in Uganda. This study was conducted to determine the distribution, the licensing status and characteristics of drug shops in four sub-districts of Kamuli district.

    Methods: This study was part of a pre-post cross sectional study that examined the implementation of an integrated Community Case Management (iCCM) intervention for common childhood illness in rural private drug shops in Kamuli District in Eastern Uganda. This mapping exercise used a snowball sampling technique to identify licensed and unlicensed drug shops and collect information about their characteristics. Data were collected using a questionnaire. GPS data were collected for all drug shops.

    Analysis: Quantitative data were analyzed using SPSS for descriptive statistics. Open ended questions were entered into NVivo 10 and analyzed using thematic analysis strategies.

    Results: In total, 215 drug shops in 284 villages were located. Of these, 123 (57%) were open and consented to an interview. Only 12 (10%) drug shops were licensed, 93 (76%) were unlicensed, and the licensing status of 18 (15%) was unknown. Most respondents were the owner of the drug shop (88%); most drug sellers reported their qualification as nursing assistants (70%). Drug sellers reported licensing fees and costs of contracting an "in-charge" as barriers to licensing. Nearly all drug shops sold drugs for malaria (91%) and antibiotics (79%).

  • 143.
    Byass, Peter
    et al.
    Department of Public Health and Clinical Medicine, Umeå Centre for Global Health Research, Umeå University, Swede.
    Sankoh, Osman
    INDEPTH Network, Accra, Ghana.
    Tollman, Stephen M.
    Department of Public Health and Clinical Medicine, Umeå Centre for Global Health Research, Umeå University, Sweden.
    Högberg, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Wall, Stig
    Department of Public Health and Clinical Medicine, Umeå Centre for Global Health Research, Umeå University, Sweden.
    Lessons from History for Designing and Validating Epidemiological Surveillance in Uncounted Populations2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 8, s. e22897-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Due to scanty individual health data in low- and middle-income countries (LMICs), health planners often use imperfect data sources. Frequent national-level data are considered essential, even if their depth and quality are questionable. However, quality in-depth data from local sentinel populations may be better than scanty national data, if such local data can be considered as nationally representative. The difficulty is the lack of any theoretical or empirical basis for demonstrating that local data are representative where data on the wider population are unavailable. Thus these issues can only be explored empirically in a complete individual dataset at national and local levels, relating to a LMIC population profile. Methods and Findings: Swedish national data for 1925 were used, characterised by relatively high mortality, a low proportion of older people and substantial mortality due to infectious causes. Demographic and socioeconomic characteristics of Sweden then and LMICs now are very similar. Rates of livebirths, stillbirths, infant and cause-specific mortality were calculated at national and county levels. Results for six million people in 24 counties showed that most counties had overall mortality rates within 10% of the national level. Other rates by county were mostly within 20% of national levels. Maternal mortality represented too rare an event to give stable results at the county level. Conclusions: After excluding obviously outlying counties (capital city, island, remote areas), any one of the remaining 80% closely reflected the national situation in terms of key demographic and mortality parameters, each county representing approximately 5% of the national population. We conclude that this scenario would probably translate directly to about 40 LMICs with populations under 10 million, and to individual states or provinces within about 40 larger LMICs. Unsubstantiated claims that local sub-national population data are "unrepresentative" or "only local" should not therefore predominate over likely representativity.

  • 144. Cadenas, José Oswaldo
    et al.
    Megson, Graham M.
    Luengo Hendriks, Cris L.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Preconditioning 2D integer data for fast convex hull computations2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 3, artikel-id e0149860Artikel i tidskrift (Refereegranskat)
  • 145. Caffrey, Brian E.
    et al.
    Williams, Tom A.
    Jiang, Xiaowei
    Toft, Christina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Hokamp, Karsten
    Fares, Mario A.
    Proteome-Wide Analysis of Functional Divergence in Bacteria: Exploring a Host of Ecological Adaptations2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 4, s. e35659-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Functional divergence is the process by which new genes and functions originate through the modification of existing ones. Both genetic and environmental factors influence the evolution of new functions, including gene duplication or changes in the ecological requirements of an organism. Novel functions emerge at the expense of ancestral ones and are generally accompanied by changes in the selective forces at constrained protein regions. We present software capable of analyzing whole proteomes, identifying putative amino acid replacements leading to functional change in each protein and performing statistical tests on all tabulated data. We apply this method to 750 complete bacterial proteomes to identify high-level patterns of functional divergence and link these patterns to ecological adaptations. Proteome-wide analyses of functional divergence in bacteria with different ecologies reveal a separation between proteins involved in information processing (Ribosome biogenesis etc.) and those which are dependent on the environment (energy metabolism, defense etc.). We show that the evolution of pathogenic and symbiotic bacteria is constrained by their association with the host, and also identify unusual events of functional divergence even in well-studied bacteria such as Escherichia coli. We present a description of the roles of phylogeny and ecology in functional divergence at the level of entire proteomes in bacteria.

  • 146.
    Cai, Yanling
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Welch, Ken
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Photocatalytic Antibacterial Effects Are Maintained on Resin-Based TiO2 Nanocomposites after Cessation of UV Irradiation2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 10, s. e75929-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Photocatalysis induced by TiO2 and UV light constitutes a decontamination and antibacterial strategy utilized in many applications including self-cleaning environmental surfaces, water and air treatment. The present work reveals that antibacterial effects induced by photocatalysis can be maintained even after the cessation of UV irradiation. We show that resin-based composites containing 20% TiO2 nanoparticles continue to provide a pronounced antibacterial effect against the pathogens Escherichia coli, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus mutans and Enterococcus faecalis for up to two hours post UV. For biomaterials or implant coatings, where direct UV illumination is not feasible, a prolonged antibacterial effect after the cessation of the illumination would offer new unexplored treatment possibilities.

  • 147.
    Calciano, Lucia
    et al.
    Univ Verona, Dept Diagnost & Publ Hlth, Unit Epidemiol & Med Stat, Verona, Italy..
    Corsico, Angelo Guido
    Univ Pavia, IRCCS, Div Resp Dis, San Matteo & Hosp Fdn, Pavia, Italy..
    Pirina, Pietro
    Univ Sassari, Inst Resp Dis, Sassari, Italy..
    Trucco, Giulia
    Univ Turin, Dept Publ Hlth & Pediat, Turin, Italy..
    Jarvis, Deborah
    Imperial Coll, Natl Heart & Lung Inst, London, England..
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Accordini, Simone
    Univ Verona, Dept Diagnost & Publ Hlth, Unit Epidemiol & Med Stat, Verona, Italy..
    Assessment of asthma severity in adults with ever asthma: A continuous score2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 5, artikel-id e0177538Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In epidemiological studies, continuous measures of asthma severity should be used to catch the heterogeneity of phenotypes. This study aimed at developing and validating continuous measures of asthma severity in adult patients with ever asthma from the general population, to be used in epidemiological studies.

    Methods: Respiratory symptoms, anti-asthmatic treatment and lung function were measured on 520 patients with ever asthma aged 20-64 years from the general Italian population (GEIRD study; 2007/2010). The variables that represent the same dimension of asthma severity were identified through an exploratory factor analysis and were summarized through a multiple factor analysis.

    Results: Only respiratory symptoms and anti-asthmatic treatment were summarized in a continuous score (STS). STS ranges from 0 (no symptoms/treatment) to 10 (maximum symptom frequency and treatment intensity). STS was positively correlated with the Global Initiative for Asthma classification of asthma severity computed on the 137 cases with a doctor's diagnosis (Spearman's coefficient = 0.61, p-value<0.0001) (concurrent validity). Furthermore, using a cohort of 1,097 European asthmatics (ECRHS II study; 1999/2002), increasing STS levels at baseline (1991/1993) were positively associated with long-term outcomes (hospitalization and lost workdays for breathing problems, asthma attack frequency and use of asthma controllers) (predictive validity). Finally, the STS scores computed from the GEIRD and ECRHS II data were comparable (Lin's coefficient = 0.95, p-value<0.0001) (replication analysis).

    Conclusions: STS is a valid and replicable measure of asthma severity in adults, which could be used in association studies.

  • 148.
    Calounova, Gabriela
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Livera, Gabriel
    INSERM/CEA/paris Diderot-Paris 7.
    Zhang, X-Q
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Liu, Kui
    Umeå Universitet.
    Gosden, Roger G
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    The Src homology 2 domain-containing adapter protein B (SHB) regulates mouse oocyte maturation2010Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, nr 6, s. e11155-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    SHB (Src homology 2 domain-containing adapter protein B) is involved in receptor tyrosine kinase signaling. Mice deficient in the Shb gene have been found to exhibit a transmission ratio distortion with respect to inheritance of the Shb null allele among offspring and this phenomenon was linked to female gamete production. Consequently, we postulated that Shb plays a role for oocyte biology and thus decided to investigate oocyte formation, meiotic maturation, and early embryo development in relation to absence of the Shb gene. Oogenesis was apparently accelerated judging from the stages of oocyte development on fetal day 18.5 and one week postnatally in Shb -/- mice; but in adulthood ovarian follicle maturation was impaired in these mice. Completion of meiosis I (first polar body extrusion) was less synchronized, with a fraction of oocytes showing premature polar body extrusion in the absence of Shb. In vitro fertilization of mature oocytes isolated from Shb +/+, +/- and -/- mice revealed impaired early embryo development in the -/- embryos. Moreover, the absence of Shb enhanced ERK (extracellular-signal regulated kinase) and RSK (ribosomal S6 kinase) signaling in oocytes and these effects were paralleled by an increased ribosomal protein S6 phosphorylation and activation. It is concluded that SHB regulates normal oocyte and follicle development and that perturbation of SHB signaling causes defective meiosis I and early embryo development.

  • 149.
    Campione, Nicolas E.
    et al.
    Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, Ontario, Canada.
    Evans, David C.
    Royal Ontario Museum.
    Cranial Growth and Variation in Edmontosaurs (Dinosauria: Hadrosauridae): Implications for Latest Cretaceous Megaherbivore Diversity in North America2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 9, s. e25186-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The well-sampled Late Cretaceous fossil record of North America remains the only high-resolution dataset for evaluating patterns of dinosaur diversity leading up to the terminal Cretaceous extinction event. Hadrosaurine hadrosaurids (Dinosauria: Ornithopoda) closely related to Edmontosaurus are among the most common megaherbivores in latest Campanian and Maastrichtian deposits of western North America. However, interpretations of edmontosaur species richness and biostratigraphy have been in constant flux for almost three decades, although the clade is generally thought to have undergone a radiation in the late Maastrichtian. We address the issue of edmontosaur diversity for the first time using rigorous morphometric analyses of virtually all known complete edmontosaur skulls. Results suggest only two valid species, Edmontosaurus regalis from the late Campanian, and E. annectens from the late Maastrichtian, with previously named taxa, including the controversial Anatotitan copei, erected on hypothesized transitional morphologies associated with ontogenetic size increase and allometric growth. A revision of North American hadrosaurid taxa suggests a decrease in both hadrosaurid diversity and disparity from the early to late Maastrichtian, a pattern likely also present in ceratopsid dinosaurs. A decline in the disparity of dominant megaherbivores in the latest Maastrichtian interval supports the hypothesis that dinosaur diversity decreased immediately preceding the end Cretaceous extinction event.

  • 150.
    Cardemil, Carina
    et al.
    University of Gothenburg.
    Elgali, Ibrahim
    University of Gothenburg.
    Xia, Wei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Emanuelsson, Lena
    Gothenburg University.
    Norlindh, Birgitta
    University of Gothenburg.
    Omar, Omar
    University of Gothenburg.
    Thomsen, Peter
    Gothenburg University.
    Strontium-Doped Calcium Phosphate and Hydroxyapatite Granules Promote Different Inflammatory and Bone Remodelling Responses in Normal and Ovariectomised Rats2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e84932-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The healing of bone defects may be hindered by systemic conditions such as osteoporosis. Calcium phosphates, with or without ion substitutions, may provide advantages for bone augmentation. However, the mechanism of bone formation with these materials is unclear. The aim of this study was to evaluate the healing process in bone defects implanted with hydroxyapatite (HA) or strontium-doped calcium phosphate (SCP) granules, in non-ovariectomised (non-OVX) and ovariectomised (OVX) rats. After 0 (baseline), six and 28d, bone samples were harvested for gene expression analysis, histology and histomorphometry. Tumour necrosis factor-alpha (TNF-alpha), at six days, was higher in the HA, in non-OVX and OVX, whereas interleukin-6 (IL-6), at six and 28d, was higher in SCP, but only in non-OVX. Both materials produced a similar expression of the receptor activator of nuclear factor kappa-B ligand (RANKL). Higher expression of osteoclastic markers, calcitonin receptor (CR) and cathepsin K (CatK), were detected in the HA group, irrespective of non-OVX or OVX. The overall bone formation was comparable between HA and SCP, but with topological differences. The bone area was higher in the defect centre of the HA group, mainly in the OVX, and in the defect periphery of the SCP group, in both non-OVX and OVX. It is concluded that HA and SCP granules result in comparable bone formation in trabecular bone defects. As judged by gene expression and histological analyses, the two materials induced different inflammatory and bone remodelling responses. The modulatory effects are associated with differences in the spatial distribution of the newly formed bone.

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