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  • Public defence: 2018-02-22 09:30 B/C4:305, Uppsala
    Mao, Guanzhong
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Investigation of RNase P active site residues and catalytic domain interaction2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    RNase P is an essential endoribonuclease responsible for the maturation of the tRNA 5’end. The RNase P family encompasses the ribozyme based, RNase P RNP, and proteinaceous RNase P (PRORP). The ribozyme based RNase P is widely distributed in most species while PRORP has so far mainly been found in some eukaryotic cells.

    The RNase P RNP contains one RNA subunit (RPR), which is the catalytic moiety, and one or more protein subunits. The structural topology of the RPR is crucial for RNase P RNP to correctly and efficiently maintain its function. The RPR is composed of domains such as the specificity (S) and catalytic (C) domains, and structural elements that connect these.

    The objectives of my thesis were to study the importance of structural elements in the C-domain of the RPR with respect to substrate interaction and catalysis. Another objective was to study substrate interaction in PRORP-mediated catalysis, and to compare RNase P RNP- and PRORP-mediated cleavage. To achieve this I have studied cleavage of both pre-tRNA and model hairpin loop substrates with RPR variants carrying deletions and base substitutions, and PRORP1 from Arabidopsis thaliana.

    My data provide evidence for an intra domain interaction, referred to as the P6-mimic, in the RPR C-domain. The P6-mimic forms when the S-domain of the RPR is deleted and it contributes to catalysis. The inter domain P8/P18 interaction, which connects the S- and the C-domains, plays an important role for catalysis. My data suggest that, in the absence of the S-domain, P18 does not contribute to catalysis raising the possibility that the P8/ P18-interaction acts as a structural mediator between the TSL/ TBS-interaction site in the S-domain and the active center that ensures correct and efficient cleavage. This is consistent with that RNase P RNP operates through an induced fit mechanism.  

    Furthermore, on the basis of biochemical and genetic data the well-conserved A248 in the RPR has been proposed to form a cis Watson-Crick/Watson-Crick (cis WC/WC) pair with the residue immediately 5' of the cleavage site, N-1, in the substrate. My data does not support this cis WC/WC pairing. Rather, the data are consistent with a model where the structural topology of the active site varies and depends on the identity of the nucleobases at, and in proximity to, the cleavage site and their potential to interact. As a consequence, this affects the positioning of Mg2+ that activates the water that acts as the nucleophile resulting in efficient and correct cleavage. In this scenario it is suggested that the role of A248 is to exclude bulk water from accessing the amino acid acceptor stem and thereby prevent non-specific hydrolysis of the pre-tRNA. In a broader perspective, base stacking might be a way to prevent access of water to functionally important base pairing interactions, and thereby ensuring high fidelity during RNA processing and decoding of mRNA.

    As for RNase P RNP, my studies on PRORP1 indicate the importance of the identity of N-1 and the N-1: N+73 base pair in the substrate for efficient and correct cleavage. Although, the data indicate similarities they also provide key differences in substrate recognition by RNase P RNP and PRORP1 where the RNP form appears to require more recognition determinants for cleavage site selection.

    List of papers
    1. Impact of the P6- and P8/ P18-interactions in cleavage of model substrates by RNase P RNA with and without the specificity domain
    Open this publication in new window or tab >>Impact of the P6- and P8/ P18-interactions in cleavage of model substrates by RNase P RNA with and without the specificity domain
    (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    Abstract The natural trans-acting ribozyme RNase P RNA (RPR) is composed of two domains in which the catalytic (C-) domain mediates cleavage of various substrates. The C-domain alone, after removal of the second specificity (S-) domain, catalyzes this reaction as well, albeit with reduced efficiency. Here we provide experimental evidence indicating that efficient cleavage mediated by the Escherichia coli C-domain (Eco CP RPR) with and without the C5 protein likely depends on an interaction referred to as the "P6-mimic". Moreover, the P18 helix connects the C- and S-domains between its loop and the P8 helix in the S-domain (the P8/ P18-interaction). In contrast to the "P6-mimic", the presence of P18 does not contribute to the catalytic performance by the C-domain lacking the S-domain in cleavage of an all ribo model hairpin loop substrate while deletion or disruption of the P8/ P18-interaction in full-size RPR lowers the catalytic efficiency in cleavage of the same model hairpin loop substrate in keeping with previously reported data using precursor tRNAs. Consistent with that P18 is not required for cleavage mediated by the C-domain we show that the archaeal Pyrococcus furiosus RPR C-domain, which lacks the P18 helix, is catalytically active in trans without S-domain and any protein. Our data also suggest that the S-domain has a larger impact on catalysis for E. coli RPR compared to P. furiosus RPR. Finally, we provide data indicating that the absence8 of the S-domain and P18, or the P8/ P18-interaction in full-length RPR influences the charge distribution near the cleavage site in the RPR-substrate complex to a small but reproducible extent.

    Place, publisher, year, edition, pages
    Uppsala universitet
    Keyword
    RNase P/ Ribozyme/ Model substrates/ Divalent metal ions/ tRNA precursors/ RNA processing.
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biology with specialization in Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-339604 (URN)
    Available from: 2018-01-21 Created: 2018-01-21 Last updated: 2018-01-22
    2. Role of residue 248 in Escherichia coli RNase P RNA mediated cleavage
    Open this publication in new window or tab >>Role of residue 248 in Escherichia coli RNase P RNA mediated cleavage
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Abstract tRNA genes are transcribed as precursors and ribonuclease P (RNase P) generates the 5' end of tRNAs in the cell. It has been suggested that residue -1 (the residue immediately 5' of the scissile bond) in the substrate interacts with the well-conserved RNase P RNA (RPR) residue A248 (Escherichia coli numbering). The way A248 interacts with residue -1 is not clear. To gain insight into the role of A248, we analyzed cleavage as a function of A248 substitutions and N-1 nucleobase identity by using pre-tRNA and three all-ribo model substrates. Our findings are consistent with a model where the structural topology of the active site varies and depends on the identity of the nucleobases at, and in proximity to, the cleavage site and their potential to interact. This leads to positioning of Mg2+ that activates the water that acts as the nucleophile resulting in efficient and correct cleavage. Furthermore, we propose that the role of A248 is to exclude bulk water from access to the amino acid acceptor stem, thereby preventing non-specific hydrolysis of the pre-tRNA. Finally, base stacking is discussed as a way to protect functionally important base-pairing interactions from non-specific hydrolysis, thereby ensuring high fidelity during RNA processing and the decoding of mRNA.

    Keyword
    RNase P/Ribozyme/Divalent metal ions/tRNA precursors/ tRNA processing.
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biology with specialization in Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-339605 (URN)
    Available from: 2018-01-21 Created: 2018-01-21 Last updated: 2018-01-22
    3. Cleavage of Model Substrates by Arabidopsis thaliana PRORP1 Reveals New Insights into Its Substrate Requirements
    Open this publication in new window or tab >>Cleavage of Model Substrates by Arabidopsis thaliana PRORP1 Reveals New Insights into Its Substrate Requirements
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    2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160246Article in journal (Refereed) Published
    Abstract [en]

    Two broad classes of RNase P trim the 5' leader of precursor tRNAs (pre-tRNAs): ribonucleoprotein (RNP)- and proteinaceous (PRORP)-variants. These two RNase P types, which use different scaffolds for catalysis, reflect independent evolutionary paths. While the catalytic RNA-based RNP form is present in all three domains of life, the PRORP family is restricted to eukaryotes. To obtain insights on substrate recognition by PRORPs, we examined the 5' processing ability of recombinant Arabidopsis thaliana PRORP1 (AtPRORP1) using a panel of pre-tRNA(Ser) variants and model hairpin-loop derivatives (pATSer type) that consist of the acceptor-T-stem stack and the T-/D-loop. Our data indicate the importance of the identity of N-1 (the residue immediately 5' to the cleavage site) and the N-1: N+73 base pair for cleavage rate and site selection of pre-tRNA(Ser) and pATSer. The nucleobase preferences that we observed mirror the frequency of occurrence in the complete suite of organellar pre-tRNAs in eight algae/plants that we analyzed. The importance of the T-/D-loop in pre-tRNA(Ser) for tight binding to AtPRORP1 is indicated by the 200-fold weaker binding of pATSer compared to pre-tRNA(Ser), while the essentiality of the T-loop for cleavage is reflected by the near-complete loss of activity when a GAAA-tetraloop replaced the T-loop in pATSer. Substituting the 2'-OH at N-1 with 2'-H also resulted in no detectable cleavage, hinting at the possible role of this 2'-OH in coordinating Mg2+ ions critical for catalysis. Collectively, our results indicate similarities but also key differences in substrate recognition by the bacterial RNase P RNP and AtPRORP1: while both forms exploit the acceptor-T-stem stack and the elbow region in the pre-tRNA, the RNP form appears to require more recognition determinants for cleavage-site selection.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-307895 (URN)10.1371/journal.pone.0160246 (DOI)000381369500026 ()
    Funder
    Swedish Research Council, Dnr 349-2006-267 Dnr 621-2011-5848Carl Tryggers foundation
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2018-01-22Bibliographically approved
  • Public defence: 2018-02-23 09:15 Å4001, Uppsala
    Åberg Lindell, Matilda
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Nuclear safeguards evaluation and analysis techniques for application to nuclear fuel material in Generation IV nuclear energy systems2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A new generation of nuclear energy systems called Generation IV is under development to ensure that nuclear power will be a safe, reliable and sustainable energy source for the future. This thesis addresses the challenge of making future nuclear energy systems increasingly resistant to nuclear material diversion attempts.

    Several tools have been developed for structured evaluation of a system's resistance to nuclear proliferation, in order to identify areas where nuclear energy systems are the most inherently vulnerable. In this thesis, the TOPS methodology has been applied to three different fuel cycles involving a fast reactor with fuel recycling and fuel fabrication capabilities. The recycling facility, where the fuel is dissolved and undergoes chemical separation, is identified as being particularly vulnerable. Nondestructive measurements for verification of fuel assemblies in the receipt area of the recycling facility are essential, since it is the last opportunity to verify intact fuel items. Moreover, iterative evaluation of proliferation resistance by using two different assessment methodologies – TOPS and PR&PP – as suggested in this thesis, may act as an aid in facility design and for proposing safeguards implementation.

    Based on the identified need to measure irradiated fuel assemblies prior to dissolution in the recycling facility, new methods used for analyzing gamma-ray spectroscopy data using multivariate analysis methods have been investigated. Fuel parameters of modeled nuclear fuel have been determined without any reliance on operator-declared data. Nonlinear classifiers, e.g. support vector machines (SVM), have successfully been used for discrimination between uranium oxide fuels and mixed oxide fuels. Cooling time, burnup and initial fissile content have been determined using decision tree and SVM regression. The results are promising and indicate that the nuclear safeguards regime may benefit from using multivariate techniques for data analysis. It must be emphasized, however, that experimental verification of the multivariate analysis techniques is necessary.

    List of papers
    1. Assessment of proliferation resistances of aqueous reprocessing techniques using the TOPS methodology
    Open this publication in new window or tab >>Assessment of proliferation resistances of aqueous reprocessing techniques using the TOPS methodology
    2013 (English)In: Annals of Nuclear Energy, ISSN 0306-4549, E-ISSN 1873-2100, Vol. 62, p. 390-397Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study is to assess and compare the proliferation resistances (PR) of three possible Generation IV lead-cooled fast reactor fuel cycles, involving the reprocessing techniques Purex, Ganex and a combination of Purex, Diamex and Sanex, respectively. The examined fuel cycle stages are reactor operation, reprocessing and fuel fabrication. The TOPS methodology has been chosen for the PR assessment, and the only threat studied is the case where a technically advanced state diverts nuclear material covertly.

    According to the TOPS methodology, the facilities have been divided into segments, here roughly representing the different forms of nuclear material occurring in each examined fuel cycle stage. For each segment, various proliferation barriers have been assessed.

    The results make it possible to pinpoint where the facilities can be improved. The results show that the proliferation resistance of a fuel cycle involving recycling of minor actinides is higher than for the traditional Purex reprocessing cycle. Furthermore, for the purpose of nuclear safeguards, group actinide extraction should be preferred over reprocessing options where pure plutonium streams occur. This is due to the fact that a solution containing minor actinides is less attractive to a proliferator than a pure Pu solution. Thus, the safeguards analysis speaks in favor of Ganex as opposed to the Purex process.

    Place, publisher, year, edition, pages
    Elsevier, 2013
    Keyword
    proliferation resistance, reprocessing, Generation IV, lead-cooled fast reactor
    National Category
    Other Physics Topics
    Research subject
    Physics
    Identifiers
    urn:nbn:se:uu:diva-205579 (URN)10.1016/j.anucene.2013.06.040 (DOI)000327170800046 ()
    Note

    Erratum in Annals of Nuclear Energy, 2014:66, pp 61-62, doi: 10.1016/j.anucene.2013.11.044

    Available from: 2013-08-20 Created: 2013-08-20 Last updated: 2018-01-15Bibliographically approved
    2. Schematic design and safeguards instrumentation of a Gen IV fuel recycling facility.
    Open this publication in new window or tab >>Schematic design and safeguards instrumentation of a Gen IV fuel recycling facility.
    2013 (English)Conference paper, Published paper (Other academic)
    Abstract [en]

    The sustainability criterion for Gen IV systems, inherently presumes the availability of efficient fuel recycling capabilities. Research activities concerning advanced fuel recycling are currently pursued, and one area for such research concerns safeguards aspects of recycling facilities. Since a recycling facility may be considered as sensitive from a non-proliferation perspective, it is important to address these issues early in the design process, according to the principle of Safeguards By Design.

    Presented in this paper is a suggested safeguards approach for a fuel recycling facility belonging to a small Gen IV lead-cooled fast reactor system that is under study in Sweden. A schematic design of a small-scale recycling facility, where actinides are separated using group actinide solvent extraction, is put forward. Measurement points are suggested based on available information on the recycling process activities and calculated material flows.

    Based on the identified need for measurements in the facility, possible techniques and instrumentation for measurements have been identified with the purpose to provide both inspecting parties and facility operators with necessary information for their respective needs. More generally, this type of analysis may be used to support Safeguards By Design in the planning of new recycling facilities.

    Keyword
    Gen IV, recycling, group actinide extraction, instrumentation, Safeguards By Design
    National Category
    Other Physics Topics
    Research subject
    Applied Nuclear Physics
    Identifiers
    urn:nbn:se:uu:diva-204141 (URN)
    Conference
    The 35th ESARDA Annual Meeting
    Available from: 2013-07-22 Created: 2013-07-22 Last updated: 2018-01-15
    3. Proliferation resistance assessments during the design phase of a fuel recycling facility as a means of reducing proliferation risks
    Open this publication in new window or tab >>Proliferation resistance assessments during the design phase of a fuel recycling facility as a means of reducing proliferation risks
    2013 (English)Conference paper, Published paper (Refereed)
    Abstract [en]

    The sustainability criterion for Gen IV nuclear energy systems inherently presumes the availability of efficient fuel recycling capabilities. One area for research on advanced fuel recycling concerns safeguards aspects of this type of facilities. Since a recycling facility may be considered as sensitive from a non-proliferation perspective, it is important to address these issues early in the design process, according to the principle of Safeguards By Design.

    Presented in this paper is a mode of procedure, where assessments of the proliferation resistance (PR) of a recycling facility for fast reactor fuel have been performed so as to identify the weakest barriers to proliferation of nuclear material. Two supplementing established methodologies have been applied; TOPS and PR&PP. The chosen fuel recycling facility belongs to a small Gen IV lead-cooled fast reactor system that is under study in Sweden. A schematic design of the recycling facility, where actinides are separated using solvent extraction, has been examined.

    The PR assessment methodologies make it possible to pinpoint areas in which the facility can be improved in order to reduce the risk of diversion. The initial facility design may then be slightly modified and/or safeguards measures may be introduced to reduce the total identified proliferation risk. After each modification of design and/or safeguards implementation, a new PR assessment of the revised system can been carried out. This way, each modification can be evaluated and new ways to further enhance the proliferation resistance can be identified.

    This type of iterative procedure may support Safeguards By Design in the planning of new recycling plants and other nuclear facilities.

    Keyword
    Proliferation resistance, safeguards by design, reprocessing, Generation IV
    National Category
    Other Physics Topics
    Research subject
    Physics
    Identifiers
    urn:nbn:se:uu:diva-205866 (URN)
    Conference
    GLOBAL 2013: International Nuclear Fuel Cycle Conference
    Available from: 2013-08-23 Created: 2013-08-23 Last updated: 2018-01-15Bibliographically approved
    4. Discrimination of irradiated MOX fuel from UOX fuel by multivariate statistical analysis of simulated activities of gamma-emitting isotopes
    Open this publication in new window or tab >>Discrimination of irradiated MOX fuel from UOX fuel by multivariate statistical analysis of simulated activities of gamma-emitting isotopes
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    2018 (English)In: Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, ISSN 0168-9002, E-ISSN 1872-9576, Vol. 885Article in journal (Refereed) In press
    Abstract [en]

    Abstract This paper investigates how concentrations of certain fission products and their related gamma-ray emissions can be used to discriminate between uranium oxide (UOX) and mixed oxide (MOX) type fuel. Discrimination of irradiated MOX fuel from irradiated UOX fuel is important in nuclear facilities and for transport of nuclear fuel, for purposes of both criticality safety and nuclear safeguards. Although facility operators keep records on the identity and properties of each fuel, tools for nuclear safeguards inspectors that enable independent verification of the fuel are critical in the recovery of continuity of knowledge, should it be lost. A discrimination methodology for classification of UOX and MOX fuel, based on passive gamma-ray spectroscopy data and multivariate analysis methods, is presented. Nuclear fuels and their gamma-ray emissions were simulated in the Monte Carlo code Serpent, and the resulting data was used as input to train seven different multivariate classification techniques. The trained classifiers were subsequently implemented and evaluated with respect to their capabilities to correctly predict the classes of unknown fuel items. The best results concerning successful discrimination of UOX and MOX-fuel were acquired when using non-linear classification techniques, such as the k nearest neighbors method and the Gaussian kernel support vector machine. For fuel with cooling times up to 20 years, when it is considered that gamma-rays from the isotope  134Cs can still be efficiently measured, success rates of 100% were obtained. A sensitivity analysis indicated that these methods were also robust.

    Keyword
    Spent nuclear fuel, MOX, Gamma spectroscopy, Multivariate analysis, Classification
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-337676 (URN)10.1016/j.nima.2017.12.020 (DOI)
    Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-01-15
    5. Determination of irradiated nuclear fuel characteristics by nonlinear multivariate regression of simulated gamma-ray emissions
    Open this publication in new window or tab >>Determination of irradiated nuclear fuel characteristics by nonlinear multivariate regression of simulated gamma-ray emissions
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    2017 (English)In: Article in journal (Refereed) Submitted
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-337677 (URN)
    Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-01-15
  • Public defence: 2018-02-23 09:15 Häggsalen, Ang/10132, Uppsala
    Liang, Feiyan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Engineering cyanobacteria for increased growth and productivity2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Increasing the photosynthetic efficiency is one of the strategies to increase the crop yields to meet the requirement of 50% more food by 2050. Due to the similarity on photosynthesis between crops and cyanobacteria, cyanobacteria are ideal alternatives to study photosynthesis since cyanobacteria are prokaryotes, easier to engineer and have shorter life cycle. On the other hand, cyanobacteria are promising cell factories for food additives, biofuels, and other products. To get the desired products from cyanobacteria directly will consume atmospheric CO2 and avoid additional releasing of CO2 from the usage of fossil resources.

    In this thesis, four CBB cycle enzymes were overexpressed individually in the model cyanobacterium Synechocystis PCC 6803. To get ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) overexpressed, two methods were used. One was to introduce another copy of the carboxysome protein CcmM gene into the cells since CcmM is essential for packing RuBisCO into the carboxysome. Another way was to tag the RuBisCO gene either on the N terminus of the large subunit or on the C terminus of the small subunit by FLAG. Even though the RuBisCO level increased, the specific RuBisCO activity did not change. Fructose-1,6-/sedoheptulose-1,7-bisphosphatase (FBP/SBPase), aldolase (FBA) and transketolase (TK) were overexpressed by introducing a second copy of corresponding gene. The engineered strains with increased levels of RuBisCO, FBP/SBPase, and FBA grew faster, had higher maximum net oxygen evolution rate and accumulated more biomass when cultivated under 100µmol photons m-2 s-1 light intensity. The strain carrying more TK showed a chlorotic phenotype but still accumulated more biomass under the same light condition. Four strains with one of the CBB cycle enzymes overexpressed were selected to investigate the effects on ethanol production. Increased ethanol production and ethanol to total biomass rate were observed in the CBB cycle engineered strains. The best strain produced almost 50% ethanol out of the total biomass.

    This work shows that overexpressing selected enzymes of the CBB cycle in cyanobacteria resulted in enhanced total biomass accumulation and increased compound (exampled as ethanol) production under certain growth conditions.

    List of papers
    1. Effects of overexpressing photosynthetic carbon flux control enzymes in the cyanobacterium Synechocystis PCC 6803
    Open this publication in new window or tab >>Effects of overexpressing photosynthetic carbon flux control enzymes in the cyanobacterium Synechocystis PCC 6803
    2016 (English)In: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184, Vol. 38, p. 56-64Article in journal (Refereed) Published
    Abstract [en]

    Synechocystis PCC 6803 is a model unicellular cyanobacterium used in e.g. photosynthesis and CO2 assimilation research. In the present study we examined the effects of overexpressing Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), sedoheptulose 1,7-biphosphatase (SBPase), fructose-bisphosphate aldolase (FBA) and transketolase (TK), confirmed carbon flux control enzymes of the Calvin-Bassham-Benson (CBB) cycle in higher plants, in Synechocystis PCC 6803. Overexpressing RuBisCO, SBPase and FBA resulted in increased in vivo oxygen evolution (maximal 115%), growth rate and biomass accumulation (maximal 52%) under 100μmolphotonsm(-2)s(-1) light condition. Cells overexpressing TK showed a chlorotic phenotype but increased biomass by approximately 42% under 100μmolphotonsm(-2)s(-1) light condition. Under 15μmolphotonsm(-2)s(-1) light condition, cells overexpressing TK showed enhanced in vivo oxygen evolution. This study demonstrates increased growth and biomass accumulation when overexpressing selected enzymes of the CBB cycle. RuBisCO, SBPase, FBA and TK are identified as four potential targets to improve growth and subsequently also yield of valuable products from Synechocystis PCC 6803.

    Keyword
    RuBisCO, CcmM, SBPase, FBA, TK, Synechocystis PCC 6803
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-306885 (URN)10.1016/j.ymben.2016.06.005 (DOI)000387984600007 ()27328433 (PubMedID)
    Funder
    Knut and Alice Wallenberg Foundation, 2011.0067Swedish Energy Agency, 11674-5
    Available from: 2016-11-04 Created: 2016-11-04 Last updated: 2018-01-07Bibliographically approved
    2. Synechocystis PCC 6803 overexpressing RuBisCO grow faster withincreased photosynthesis
    Open this publication in new window or tab >>Synechocystis PCC 6803 overexpressing RuBisCO grow faster withincreased photosynthesis
    2017 (English)In: Metabolic Engineering Communications, ISSN 2214-0301Article in journal (Refereed) Published
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-338075 (URN)
    Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-01-07
    3. Evaluation of promoters and ribosome binding sites for biotechnological applications in the unicellular cyanobacterium Synechocystis sp. PCC 6803
    Open this publication in new window or tab >>Evaluation of promoters and ribosome binding sites for biotechnological applications in the unicellular cyanobacterium Synechocystis sp. PCC 6803
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36640Article in journal (Refereed) Published
    Abstract [en]

    For effective metabolic engineering, a toolbox of genetic components that enables predictable control of gene expression is needed. Here we present a systematic study of promoters and ribosome binding sites in the unicellular cyanobacterium Synechocystis sp. PCC 6803. A set of metal ion inducible promoters from Synechocystis were compared to commonly used constitutive promoters, by measuring fluorescence of a reporter protein in a standardized setting to allow for accurate comparisons of promoter activity. The most versatile and useful promoter was found to be PnrsB, which from a relatively silent expression could be induced almost 40-fold, nearly up to the activity of the strong psbA2 promoter. By varying the concentrations of the two metal ion inducers Ni(2+) and Co(2+), expression from the promoter was highly tunable, results that were reproduced with PnrsB driving ethanol production. The activities of several ribosomal binding sites were also measured, and tested in parallel in Synechocystis and Escherichia coli. The results of the study add useful information to the Synechocystis genetic toolbox for biotechnological applications.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-308074 (URN)10.1038/srep36640 (DOI)000388069200002 ()27857166 (PubMedID)
    Funder
    Swedish Energy Agency, 38334-1
    Available from: 2016-11-23 Created: 2016-11-23 Last updated: 2018-01-07Bibliographically approved
    4. Engineered cyanobacteria with enhanced growth show increased ethanol production and higher biofuel to biomass ratio
    Open this publication in new window or tab >>Engineered cyanobacteria with enhanced growth show increased ethanol production and higher biofuel to biomass ratio
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-338077 (URN)
    Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-01-14
    5. Engineering Cyanobacteria for Biofuel Production
    Open this publication in new window or tab >>Engineering Cyanobacteria for Biofuel Production
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    2017 (English)In: Modern Topics in the Phototrophic Prokaryotes: Environmental and Applied Aspects / [ed] Hallenbeck, Patrick, USA: Springer, 2017, p. 351-393Chapter in book (Refereed)
    Place, publisher, year, edition, pages
    USA: Springer, 2017
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-338078 (URN)978-3-319-46259-2 (ISBN)978-3-319-46261-5 (ISBN)
    Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-02-01Bibliographically approved
  • Public defence: 2018-02-23 13:00 B42, Uppsala
    Shahidi Dadras, Mahsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Regulation of cell polarity and invasion by TGF-β and BMP signaling2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways are involved in many physiological processes during embryonic and adult life. TGF-β promotes epithelial to mesenchymal transition (EMT). We identified a gene target of TGF-β signaling, encoding the salt-inducible kinase 1 (SIK1). A potential substrate of this kinase, the polarity protein Par3, is an established regulator of tight junction assembly. SIK1 associates with Par3, can potentially phosphorylate Par3 and leads to its degradation, contributing to tight junction disassembly.

    Glioblastoma multiforme (GBM) is a common malignancy in the central nervous system, characterized by high heterogeneity, invasiveness, and resistance to therapy. One of the causes of heterogeneity and therapy-resistance is the existence of glioblastoma stem cells (GSCs). TGF-β signaling promotes self-renewal while BMP signaling induces differentiation of GSCs. Snail is a potent inducer of the EMT in carcinomas. However, in the context of GBM, Snail induces BMP signaling and represses TGF-β signaling through interaction with SMADs, the signaling mediators of TGF-β and BMP. In conclusion, Snail differentially regulates the activity of the opposing BMP and TGF-β pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

    Although profound changes in cell polarity is a hallmark of invasive malignancies, little is known about the role of the polarity machinery in tumor suppression. Patient transcriptomic data suggested low Par3 expression, correlating with poor survival of the GBM patients. Par3 silencing decreased the GSC self-renewal capacity and enhanced their invasiveness. Transcriptomic analysis indicates that loss of Par3 leads to downregulation of genes encoding mitochondrial enzymes that generate ATP. These results support a novel role of Par3 in GBM, beyond its contribution to junctional contacts between cells.

    Another regulator of TGF-β and BMP signaling is the liver kinase B1 (LKB1). According to GBM patient mRNA analysis, high levels of LKB1 correlate with poor prognosis. Silencing of LKB1 in GSCs impairs invasion and self-renewal capacity due to downregulation of genes involved in these processes. Moreover, loss of LKB1 induces mitochondrial dysfunction, leading to decreased ATP levels. Collectively, this thesis has delivered a group of novel regulatory pathways that control critical aspects of cancer cell polarity, invasion and stemness.

    List of papers
    1. The protein kinase SIK downregulates the polarity protein Par3
    Open this publication in new window or tab >>The protein kinase SIK downregulates the polarity protein Par3
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-334429 (URN)
    Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-11-28
    2. Snail regulates BMP and TGF-β pathways to control the differentiation status of glioma initiating cells
    Open this publication in new window or tab >>Snail regulates BMP and TGF-β pathways to control the differentiation status of glioma initiating cells
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    (English)Manuscript (preprint) (Other academic)
    Abstract
    National Category
    Biochemistry and Molecular Biology Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-334439 (URN)
    Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-01-17
    3. Par3 promotes glioblastoma stem cell self-renewal while inhibiting cell invasion
    Open this publication in new window or tab >>Par3 promotes glioblastoma stem cell self-renewal while inhibiting cell invasion
    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-334454 (URN)
    Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-11-28
    4. The protein kinase LKB1 takes oncogenic actions in glioblastoma promoting self-renewal and invasiveness
    Open this publication in new window or tab >>The protein kinase LKB1 takes oncogenic actions in glioblastoma promoting self-renewal and invasiveness
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Biochemistry and Molecular Biology Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-334464 (URN)
    Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-12-04
  • Public defence: 2018-02-27 09:00 80127, Uppsala
    Hettiarachchi, Pasan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Electricity.
    Measurements of X-Ray Emission from Laboratory Sparks and Upward Initiated Lightning2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In 1925 Nobel laureate R. C. Wilson predicted that high electric fields of thunderstorms could accelerate electrons to relativistic energies which are capable of generating high energetic radiation. The first detection of X-rays from lightning was made in 2001 and from long sparks in 2005. Still there are gaps in our knowledge concerning the production of X-rays from lightning and long sparks, and the motivation of this thesis was to rectify this situation by performing new experiments to gather data in this subject.

    The first problem that we addressed in this thesis was to understand how the electrode geometry influences the generation of X-rays. The results showed that the electrode geometry affects the X-ray generation and this dependency could be explained using a model developed previously by scientists at Uppsala University. The other missing information was the distribution of energy. Using a series of attenuators, we observed how the X-ray photons were attenuated as a function of barrier thickness and using a simple model we obtained the average and the maximum energy of X-rays. 

    All the studies conducted previously was based on the lightning impulses, but in switching impulses, the voltage waveform rises very slowly compared to lightning impulses, and according to some scientists the rate of rise is an important parameter in X-ray development. Our study showed that the switching impulses were as efficient as lightning impulses in generating X-rays even though the rate of rise of voltage in switching impulses was hundreds of times slower.

    All the observations on X-ray generation from lightning by other scientists were based on either natural downward lightning flashes or triggered lightning in Florida. The first experiments to study the X-ray generation from upward lightning flashes systematically was conducted within this thesis work at Gaisberg Tower in Austria. The results showed that the X-ray emissions from these flashes were much weaker than the ones produced by either natural downward or triggered lightning. An attempt was made to explain this observation by invoking the possible differences in the charge distribution of leaders associated with the triggered lightning flashes in Florida and upward initiated lightning flashes at Gaisberg tower.

    List of papers
    1. X-rays from negative laboratory sparks in air: Influence of the anode geometry
    Open this publication in new window or tab >>X-rays from negative laboratory sparks in air: Influence of the anode geometry
    2017 (English)In: Journal of Atmospheric and Solar-Terrestrial Physics, ISSN 1364-6826, E-ISSN 1879-1824, Vol. 154, p. 190-194Article in journal (Refereed) Published
    Abstract [en]

    In this experimental work, the influence of the grounded anode geometry is studied on the X-ray production from the laboratory sparks in air at atmospheric pressure when a negative impulse voltage is applied to a high voltage rod which served as a cathode. The result shows that the smaller the diameter of the anode, the higher the energy of X-ray bursts. This observation can be explained by the mechanism that the encounter of negative and positive streamer fronts just before the final breakdown is the event that accelerates electrons to X-ray generating energies, but may not be the only mechanism that generates X-rays.

    Keyword
    X-rays, laboratory sparks, electrodes, runaway electrons
    National Category
    Meteorology and Atmospheric Sciences Engineering and Technology
    Research subject
    Engineering Science with specialization in Atmospheric Discharges
    Identifiers
    urn:nbn:se:uu:diva-268859 (URN)10.1016/j.jastp.2016.07.012 (DOI)000395952000019 ()
    Funder
    Swedish Research Council, 621-2012-3300
    Available from: 2015-12-10 Created: 2015-12-10 Last updated: 2018-01-08Bibliographically approved
    2. Energy Distribution of X-rays Produced by Meter-long Negative Discharges in Air
    Open this publication in new window or tab >>Energy Distribution of X-rays Produced by Meter-long Negative Discharges in Air
    2017 (English)In: Atmosphere, ISSN 2073-4433, E-ISSN 2073-4433, Vol. 8, no 12, article id 244Article in journal (Refereed) Published
    Abstract [en]

    The energy deposited from X-rays generated by 1 m long laboratory sparks in air created by 950 kV negative lightning impulses on scintillated detectors was measured. Assuming the X-ray energy detected in such sparks results from the accumulation of multiple photons at the detector having a certain energy distribution, an experiment was designed in such a way to characterize their distribution parameters. The detector was screened by a copper shield, and eight series of fifteen impulses were applied by stepwise increasing the copper shield thickness. The average deposited energy was calculated in each series and compared with the results from a model consisting of the attenuation of photons along their path and probable photon distributions. The results show that the energy distribution of X-ray bursts can be approximated by a bremsstrahlung spectrum of photons, having a maximum energy of 200 keV to 250 keV and a mean photon energy around 52 keV to 55 keV.

    National Category
    Meteorology and Atmospheric Sciences Engineering and Technology
    Research subject
    Engineering Science with specialization in Atmospheric Discharges
    Identifiers
    urn:nbn:se:uu:diva-335142 (URN)10.3390/atmos8120244 (DOI)000419179200014 ()
    Available from: 2017-11-30 Created: 2017-11-30 Last updated: 2018-02-14Bibliographically approved
    3. X-ray observations at Gaisberg Tower
    Open this publication in new window or tab >>X-ray observations at Gaisberg Tower
    Show others...
    2018 (English)In: Atmosphere, ISSN 2073-4433, E-ISSN 2073-4433, Vol. 9, no 1, article id 20Article in journal (Refereed) Published
    Abstract [en]

    We report the occurrence of X-rays at ground level due to cloud-to-ground flashes of upward initiated lightning from Gaisberg Tower in Austria which is located at a 1300 m altitude.  This is the first time that the X-rays from upward lightning from a tower top located in high altitude is observed. Measurement was carried out using scintillation detectors installed close to the tower top in two phases from 2011 to 2015. X-rays were recorded in three subsequent strokes of three flashes out of the total of 108 flashes recorded in the system during both phases. In contrast to the observations from downward natural or triggered lightning, X-rays were observed only within 10 µs before the subsequent return stroke. This shows that X-rays were emitted when the dart leader is in the vicinity of the tower top and hence during the most intense phase of the dart leader. Both the detected energy and the fluence of X-rays are far lower compared to X-rays from downward natural or rocket-triggered lightning. In addition to above 108 flashes, an interesting observation of X-rays produced by a nearby downward flash is also presented. The shorter dart-leader channels length in Gaisberg is suggested as a possible cause of this apparently weaker X-ray production.

    National Category
    Meteorology and Atmospheric Sciences
    Research subject
    Engineering Science with specialization in Atmospheric Discharges
    Identifiers
    urn:nbn:se:uu:diva-338132 (URN)10.3390/atmos9010020 (DOI)
    Funder
    Swedish Research Council, 2015-05026
    Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-01-26Bibliographically approved
    4. X-ray observations from laboratory sparks in air at atmospheric pressure under negative switching impulse voltages
    Open this publication in new window or tab >>X-ray observations from laboratory sparks in air at atmospheric pressure under negative switching impulse voltages
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We present for the first time detection of X-rays from laboratory sparks created in air at atmospheric pressure by applying an impulse voltage with slow rise time. X-ray production from three different electrode configurations were studied. The results confirm, for the first time, the production of X-rays in gaps excited by switching impulses. Results also show that the slow rate of rise of the voltage from switching impulses does not have a significant influence on the production of X-rays. Additionally, the timing of the X-ray occurrence strengthens the possibility that the mechanism of X-ray production is related to the encounter between streamers of opposite polarity.

    National Category
    Meteorology and Atmospheric Sciences
    Research subject
    Engineering Science with specialization in Atmospheric Discharges
    Identifiers
    urn:nbn:se:uu:diva-338135 (URN)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2004-2031Swedish Research Council, 621-2009-2697Swedish Research Council, 621-2006-4299Swedish Research Council, 621-2012-3300
    Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-01-08
  • Public defence: 2018-02-28 09:00 Rosénsalen, Uppsala
    Nazir, Madiha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Drug Repositioning for Cancer Treatment: Novel Candidate Identification Strategies2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Regardless of the enormous investments in cancer research and drug development, the proportion of approved drugs in oncology is low compared to other indications, and new avenues are needed. One attractive approach in this regard is drug repositioning where new uses outside the scope of the original medical indications for existing drugs are identified. It offers the advantages of reduced development risks, time and cost over de novo drug discovery pathways.

    The main focus of this thesis was to explore and employ different strategies to identify repurposable drug candidates for treatment of cancer. Aiming for this, in the first project we followed a bioinformatics approach to evaluate PDE3A as a drug target and biomarker. We showed that subgroups of tumors, within many different cancer types, overexpress PDE3A (mRNA and protein) and that PDE3A can predict sensitivity to the clinically tested phosphodiesterase inhibitors zardaverine and quazinone (Paper I). In the second project, a novel automated image based microscopy assay was developed and used for detection of apoptotic cells. In a screen the method was successfully used to identify apoptosis inducing compounds. Two of these apoptosis inducers were found to have repurposing potential (Paper II). Moreover, high-throughput combination screening was performed using different cell models. In paper III, monolayer cell cultures were used as cell model to search for combination partners for the anti-parasitic compound mebendazole (a repurposing candidate). As a result, the antipsychotic drug thioridazine was found to have synergistic effect when combined with mebendazol. Finally, a novel drug-combination platform for three-dimensional cell culture based screening, in 384 well formats, was developed. This assay was used to search for combination partners to the anti-parasitic compound nitazoxanide (a repurposing candidate), which was previously reported to specifically target quiescent cancer cells. The screen identified the antifungal agent ketoconazole as selectively toxic to hypoxic and nutrient deprived cancer cells when combined with nitazoxanide (Paper IV). Thus, we have developed/explored several methodological approaches and identified drugs that potentially can be repurposed for treatment of cancer. 

    List of papers
    1. Targeting tumor cells based on phosphodiesterase 3A expression
    Open this publication in new window or tab >>Targeting tumor cells based on phosphodiesterase 3A expression
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    2017 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 361, p. 308-315Article in journal, Meeting abstract (Refereed) Published
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-338321 (URN)
    Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-01-09
    2. Label free high throughput screening for apoptosis inducing chemicals using time-lapse microscopy signal processing
    Open this publication in new window or tab >>Label free high throughput screening for apoptosis inducing chemicals using time-lapse microscopy signal processing
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    2014 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 19, no 9, p. 1411-1418Article in journal (Refereed) Published
    Abstract [en]

    Label free time-lapse microscopy has opened a new avenue to the study of time evolving events in living cells. When combined with automated image analysis it provides a powerful tool that enables automated large-scale spatiotemporal quantification at the cell population level. Very few attempts, however, have been reported regarding the design of image analysis algorithms dedicated to the detection of apoptotic cells in such time-lapse microscopy images. In particular, none of the reported attempts is based on sufficiently fast signal processing algorithms to enable large-scale detection of apoptosis within hours/days without access to high-end computers. Here we show that it is indeed possible to successfully detect chemically induced apoptosis by applying a two-dimensional linear matched filter tailored to the detection of objects with the typical features of an apoptotic cell in phase-contrast images. First a set of recorded computational detections of apoptosis was validated by comparison with apoptosis specific caspase activity readouts obtained via a fluorescence based assay. Then a large screen encompassing 2,866 drug like compounds was performed using the human colorectal carcinoma cell line HCT116. In addition to many well known inducers (positive controls) the screening resulted in the detection of two compounds here reported for the first time to induce apoptosis.

    Keyword
    Apoptosis, high throughput screening, cancer
    National Category
    Cancer and Oncology
    Research subject
    Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-229069 (URN)10.1007/s10495-014-1009-9 (DOI)000340518000010 ()
    Funder
    Swedish Society for Medical Research (SSMF)
    Available from: 2014-07-29 Created: 2014-07-29 Last updated: 2018-01-09Bibliographically approved
    3. Drug combination screening for mebendazole for the treatment of colorectal cancer
    Open this publication in new window or tab >>Drug combination screening for mebendazole for the treatment of colorectal cancer
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Research subject
    Clinical Pharmacology
    Identifiers
    urn:nbn:se:uu:diva-336682 (URN)
    Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2018-01-09
    4. Drug combination screening in multicellular tumor spheroids identifies synthetic lethalities in quiescent cancer cells
    Open this publication in new window or tab >>Drug combination screening in multicellular tumor spheroids identifies synthetic lethalities in quiescent cancer cells
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-336689 (URN)
    Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2018-01-09
  • Public defence: 2018-03-01 13:15 Rosénsalen, Uppsala
    Al-Mashhadi, Ammar Nadhom Farman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    High Blood Pressure in Children with Hydronephrosis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The most common cause of secondary hypertension is intrinsic renal disease, but little is known about the influence of hydronephrosis on blood pressure. In this thesis, the risk of development of hypertension in children with hydronephrosis was studied.

    Experimental and clinical studies were combined in order to investigate the risk of developing elevated blood pressure following conservative treatment of hydronephrosis, and to further explore underlying mechanisms. We started with a clinical study in children (study I), which in agreement with previous experimental studies, showed that blood pressure was lowered by surgical management of hydronephrosis. In parallel, an experimental study was conducted (study II) to investigate the involvement of renal sympathetic nerve activity in development of hypertension following induction of hydronephrosis caused by pelvo-ureteric junction obstruction. Renal denervation of the obstructed kidney attenuated hypertension and restored the renal excretion pattern, effects that were associated with reduced activity of both renal NADPH oxidase derived oxidative stress and components of the renin-angiotensin-aldosterone system.

    Based on the findings in studies I and II, we continued our studies in children with hydronephrosis, and including two control groups as comparisons with the hydronephrotic group (study III). In the same study, we further investigated potential mechanism(s) of hypertension by analyzing markers of oxidative stress and nitric oxide homeostasis in both urine and blood samples. We demonstrated increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which was restored to normal levels by surgical correction of the obstruction. Finally, in a retrospective cohort study, blood pressure of adult patients undergoing surgical management of hydronephrosis due to pelvo-ureteric junction obstruction was assessed (study IV). Similar to that demonstrated in the pediatric hydronephrotic population, blood pressure was significantly reduced by relief of the obstruction. In addition, blood pressure was increased again if the hydronephrosis recurred, and was reduced again following re-operation.

    It is concluded that conservative management of hydronephrosis in children is associated with a risk for development of high blood pressure, which can be reduced or even normalized by relief of the obstruction. The mechanism(s), at least in part, is coupled to increased oxidative stress.

    List of papers
    1. Surgical treatment reduces blood pressure in children with unilateral congenital hydronephrosis
    Open this publication in new window or tab >>Surgical treatment reduces blood pressure in children with unilateral congenital hydronephrosis
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    2015 (English)In: Journal of Pediatric Urology, ISSN 1477-5131, E-ISSN 1873-4898, Vol. 11, no 2, p. 91.e1-91.e6Article in journal (Refereed) Published
    Abstract [en]

    Objective Renal disorders can cause hypertension, but less is known about the influence of hydronephrosis on blood pressure. Hydronephrosis due to pelvo-ureteric junction obstruction (PUJO) is a fairly common condition (incidence in newborns of 0.5-1%). Although hypertensive effects of hydronephrosis have been suggested, this has not been substantiated by prospective studies in humans [1-3]. Experimental studies with PUJO have shown that animals with induced hydronephrosis develop salt-sensitive hypertension, which strongly correlate to the degree of obstruction [4-7]. Moreover, relief of the obstruction normalized blood pressure [8]. In this first prospective study our aim was to study the blood pressure pattern in pediatric patients with hydronephrosis before and after surgical correction of the ureteral obstruction. Specifically, we investigated if preoperative blood pressure is reduced after surgery and if split renal function and renographic excretion curves provide any prognostic information. Patients and methods Twelve patients with unilateral congenital hydronephrosis were included in this prospective study. Ambulatory blood pressure (24 h) was measured preoperatively and six months after surgery. Preoperative evaluations of bilateral renal function by Tc99m-MAG3 scintigraphy, and renography curves, classified according to O'Reilly, were also performed. Results As shown in the summary figure, postoperative systolic (103 +/- 2 mmHg) and diastolic (62 +/- 2 mmHg) blood pressure were significantly lower than those obtained preoperatively (110 +/- 4 and 69 +/- 2 mmHg, respectively), whereas no changes in circadian variation or pulse pressure were observed. Renal functional share of the hydronephrotic kidney ranged from 11 to 55%. There was no correlation between the degree of renal function impairment and the preoperative excretory pattern, or between the preoperative excretory pattern and the blood pressure reduction postoperatively. However, preoperative MAG3 function of the affected kidney correlated with the magnitude of blood pressure change after surgery. Discussion Correction of the obstruction lowered blood pressure, and the reduction in blood pressure appeared to correlate with the degree of renal functional impairment, but not with the excretory pattern. Thus, in the setting of hypertension, it appears that the functional share of the hydronephrotic kidney should be considered an indicator of the need for surgery, whereas the renography curve is less reliable. The strength of the present study is the prospective nature and that ambulatory blood pressure monitoring was used. Future longitudinal prolonged follow-up studies are warranted to confirm the present findings, and to understand if a real nephrogenic hypertension with potential necessity of treatment will develop. Conclusion This novel prospective study in patients with congenital hydronephrosis demonstrates a reduction in blood pressure following relief of the obstruction. Based on the present results, we propose that the blood pressure level should also be taken into account when deciding whether to correct hydronephrosis surgically or not.

    Keyword
    Hydronephrosis, Hypertension, Pelvo-ureteric junction obstruction, Pyeloplasty, Renal function
    National Category
    Pediatrics Urology and Nephrology
    Identifiers
    urn:nbn:se:uu:diva-257044 (URN)10.1016/j.jpurol.2015.01.008 (DOI)000355333400035 ()
    Available from: 2015-06-29 Created: 2015-06-29 Last updated: 2018-01-11
    2. Renal denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension in rats with hydronephrosis
    Open this publication in new window or tab >>Renal denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension in rats with hydronephrosis
    Show others...
    2016 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 310, no 1, p. F43-F56Article in journal (Refereed) Published
    Abstract [en]

    Hydronephrosis is associated with development of salt-sensitive hypertension. Studies suggest that increased sympathetic nerve activity (SNA) and oxidative stress play important roles in renovascular hypertension. This study aimed to investigate the link between renal SNA and NADPH oxidase (NOX) regulation in the development of hypertension in rats with hydronephrosis. Hydronephrosis was induced by partial unilateral ureteral obstruction (PUUO) in young rats. Sham surgery or renal denervation was performed at the same time. Blood pressure was measured during normal, high and low salt diets. Renal excretion pattern, NOX activity and expression, as well as components of RAAS were characterized. On normal salt diet, PUUO rats had elevated blood pressure compared with controls (115±3 vs 87±1 mmHg), and displayed increased urine production and lower urine osmolality. Blood pressure change in response to salt loading (salt-sensitivity) was more pronounced in the PUUO group compared with controls (15±2 vs 5±1mmHg). Renal denervation in PUUO rats attenuated hypertension (97±3mmHg) and salt-sensitivity (5±1mmHg), and normalized renal excretion pattern, whereas the degree of renal fibrosis and inflammation was not changed. NOX activity and expression, as well as renin and AT1A receptor expression, were increased in renal cortex from PUUO rats, and normalized by denervation. Plasma sodium and potassium levels were elevated in PUUO rats and normalized after renal denervation. Denervation in PUUO rats was also associated with reduced NOX expression, superoxide production and fibrosis in the heart. This study emphasizes a link between renal nerves, NOX function, and development of hypertension.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-267780 (URN)10.1152/ajprenal.00345.2015 (DOI)000366593500007 ()26538440 (PubMedID)
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2018-01-22Bibliographically approved
    3. Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative stress following surgical correction of hydronephrosis in children
    Open this publication in new window or tab >>Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative stress following surgical correction of hydronephrosis in children
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    2017 (English)In: Pediatric nephrology (Berlin, West), ISSN 0931-041X, E-ISSN 1432-198XArticle in journal (Refereed) Published
    Abstract [en]

    Objective Recent clinical studies have suggested an increased risk of elevated arterial pressure in patients with hydronephrosis. Animals with experimentally induced hydronephrosis develop hypertension, which is correlated to the degree of obstruction and increased oxidative stress. In this prospective study we investigated changes in arterial pressure, oxidative stress, and nitric oxide (NO) homeostasis following correction of hydronephrosis.

    Methods Ambulatory arterial pressure (24 h) was monitored in pediatric patients with hydronephrosis (n = 15) before and after surgical correction, and the measurements were compared with arterial pressure measurements in two control groups, i.e. healthy controls (n = 8) and operated controls (n = 8). Markers of oxidative stress and NO homeostasis were analyzed in matched urine and plasma samples.

    Results The preoperative mean arterial pressure was significantly higher in hydronephrotic patients [83 mmHg; 95% confidence interval (CI) 80–88 mmHg] than in healthy controls (74 mmHg; 95% CI 68–80 mmHg; p < 0.05), and surgical correction of ureteral obstruction reduced arterial pressure (76 mmHg; 95% CI 74–79 mmHg; p < 0.05). Markers of oxidative stress (i.e., 11- dehydroTXB2, PGF2α, 8-iso-PGF2α, 8,12-iso-iPF2α-VI) were significantly increased (p < 0.05) in patients with hydronephrosis compared with both control groups, and these were reduced following surgery (p < 0.05). Interestingly, there was a trend for increased NO synthase activity and signaling in hydronephrosis, which may indicate compensatory mechanism(s).

    Conclusion This study demonstrates increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which can be restored to normal levels by surgical correction of the obstruction. Once reference data on ambulatory blood pressure in this young age group become available, we hope cut-off values can be defined for deciding whether or not to correct hydronephrosis surgically.

    Keywords Blood pressure . Hydronephrosis . Hypertension . Nitric oxide . Oxidative stress . Ureteral obstruction 

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-337796 (URN)10.1007/s00467-017-3848-4 (DOI)
    Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-01-18Bibliographically approved
    4. Reduction of arterial pressure following relief of obstruction in patients with hydronephrosis
    Open this publication in new window or tab >>Reduction of arterial pressure following relief of obstruction in patients with hydronephrosis
    (English)Manuscript (preprint) (Other academic)
    Keyword
    blood pressure, hydronephrosis, hypertension, kidney, renal function, ureteral obstruction
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-338672 (URN)
    Available from: 2018-01-11 Created: 2018-01-11 Last updated: 2018-01-22
  • Public defence: 2018-03-02 09:00 A1:107a, Uppsala
    Kovachev, Petar Stefanov
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    The role of RNA in prion aggregation and disease2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    As humanity evolved to witness an exceptionally high standard of living, Alzheimer’s, cancer and diabetes gradually replaced infections as the main limiting factors in longevity. It is both disturbing and captivating that such degenerative conditions are caused by the most ubiquitous biomolecule – the protein. Indeed, proteins are not only the most functional, but also the least understood of the cellular biopolymers. It is then not surprising that many severe human ailments are associated with aberrant proteostasis. The key, causative mechanism of proteinopathy is protein aggregation. Naturally occurring and sometimes functional, aggregation is an auxiliary pathway in protein folding. In the context of a crowded cellular environment, folding and aggregation are the least and one of the least understood molecular processes, respectively. Unravelling one can help deconstruct the other and vice versa, but also can provide mechanistic insight on degenerative proteinopathies. A special class of proteins, which appear to propagate their own aggregation, occupy center-stage in the scientific field devoted to this goal. These proteins known as prions, can exist in at least two distinct forms. With the human prion, one of those is functional and benign and the other is infectious, aggregation prone, self-replicating and fatally pathogenic. As it happens, prion disease shares many of the descriptive features of other proteinaceous neuropathies. That, and the seductive idea that prions dwell in the twilight zone between folding and aggregation, have made the prion phenomenon a fixation for many molecular biologists. This thesis, although not the product of fixation, deals with one aspect of the prion process – the involvement of a molecular cofactor.

    Of all plausible adjuvants, RNAs have been proposed as likely participants in the prion process. Their prominent secondary structures and attractive polyanionic surfaces allow RNAs to freely engage in interactions, at times transmitting conformational information through induced fit effects. The present work summarizes the influence of various RNAs on the aggregation profiles of three prionogenic model systems. The produced results indicate a generic role for RNA in the molecular processes prion propagation and aggregation. Altogether, this study illustrates a previously overlooked RNA function, of potential relevance for protein-based disease. 

    List of papers
    1. Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain.
    Open this publication in new window or tab >>Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain.
    Show others...
    2017 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 22, p. 9345-9357Article in journal (Refereed) Published
    Abstract [en]

    Inactivation of the tumor suppressor protein p53 by mutagenesis, chemical modification, protein-protein interaction, or aggregation has been associated with different human cancers. Although DNA is the typical substrate of p53, numerous studies have reported p53 interactions with RNA. Here, we have examined the effects of RNA of varied sequence, length, and origin on the mechanism of aggregation of the core domain of p53 (p53C) using light scattering, intrinsic fluorescence, transmission electron microscopy, thioflavin-T binding, seeding, and immunoblot assays. Our results are the first to demonstrate that RNA can modulate the aggregation of p53C and full-length p53. We found bimodal behavior of RNA in p53C aggregation. A low RNA:protein ratio (∼1:50) facilitates the accumulation of large amorphous aggregates of p53C. By contrast, at a high RNA:protein ratio (≥1:8), the amorphous aggregation of p53C is clearly suppressed. Instead, amyloid p53C oligomers are formed that can act as seeds nucleating de novo aggregation of p53C. We propose that structured RNAs prevent p53C aggregation through surface interaction and play a significant role in the regulation of the tumor suppressor protein.

    Place, publisher, year, edition, pages
    American Society for Biochemistry and Molecular Biology, 2017
    Keyword
    RNA, amyloid, domain V of 23S rRNA, fluorescence, kinetics, p53, p53C, prion, protein aggregation, protein folding
    National Category
    Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-327976 (URN)10.1074/jbc.M116.762096 (DOI)000402538900028 ()28420731 (PubMedID)
    Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2018-01-14
    2. Direct involvement of RNA in mammalian prion protein aggregation: Involvement of RNA in rPrP aggregation
    Open this publication in new window or tab >>Direct involvement of RNA in mammalian prion protein aggregation: Involvement of RNA in rPrP aggregation
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    (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351XArticle in journal (Other academic) Submitted
    Abstract [en]

    Whether nucleic acids act as cofactors in the aggregation of prion proteins is still under debate. By employing RNAs of various source and size, we have studied the role of RNA in the aggregation of murine recombinant prion protein (rPrP23-231) using Rayleigh light scattering, dynamic light scattering, sedimentation, transmission electron microscopy, circular dichroism and isothermal titration calorimetry. We find that RNA modulates rPrP23-231 aggregation in a concentration dependent manner, affecting both the extent and rate of the process; the latter evident from fast kinetics measurements of rPrP23-231 aggregation using stopped-flow technique. At lower concentration, RNA stimulates amorphous aggregation of rPrP23-231, and at higher concentration it, instead, facilitates formation of oligomeric species capable of seeding de novo aggregation of rPrP23-231. Furthermore, RNA co-sediments with rPrP23-231. This leads to partial RNase resistance of RNA and secondary structure alterations in the protein, indicating a direct interaction between the two. Sequence analysis of the RNA co-aggregated with rPrP23-231 suggests that the interaction is not specific to RNA sequence. Alternatively, rPrP23-231 interaction with RNA appears site-specific and mediated by the N-terminus. Our study demonstrates the effective modulation of rPrP23-231 aggregation by RNA and puts forward the idea of the potential role of RNA in protein aggregation as a whole.

    Keyword
    prion, RNA, cofactor, RNA-protein interaction, aggregation, kinetics
    National Category
    Biochemistry and Molecular Biology
    Research subject
    Molecular Cellbiology
    Identifiers
    urn:nbn:se:uu:diva-338856 (URN)
    Available from: 2018-01-14 Created: 2018-01-14 Last updated: 2018-01-14
    3. Intervention of ribosomal RNA in HET-s prion aggregation Intervention of ribosomal RNA in HET-s prion aggregation
    Open this publication in new window or tab >>Intervention of ribosomal RNA in HET-s prion aggregation Intervention of ribosomal RNA in HET-s prion aggregation
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The role of nucleic acids in prion aggregation / disaggregation has remained unclear. Here, using HET-s prion from Podospora anserina as a model system, we have studied the role of RNA, particularly different domains of ribosomal RNA, in its aggregation process. Our results show that domain V rRNA, from the large subunit of the ribosome, substantially prevents amyloid aggregation of the HET-s prion in a concentration dependent manner. Instead, it promotes the formation of oligomeric seeds, which facilitate de novo HET-s aggregation. The interaction sites for the HET-s prion on domain V rRNA were also identified and shown to overlap with the sites previously found to responsible for the protein folding activity of the ribosome (PFAR). This study provides a missing link between the role of rRNA-based PFAR and prion propagation.

    National Category
    Biochemistry and Molecular Biology
    Research subject
    Molecular Cellbiology
    Identifiers
    urn:nbn:se:uu:diva-338605 (URN)
    Available from: 2018-01-14 Created: 2018-01-14 Last updated: 2018-01-14
  • Public defence: 2018-03-02 09:15 Häggsalen, Uppsala
    Östman, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Physics.
    Collective properties of magnetic mesospins2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mesoscopic spin systems consist of an ensemble of lithographically patterned nanomagnetic elements - mesospins. The interactions between the mesospins, can be designed at will by altering their lateral arrangement, enabling the study of collective magnetic order in a wide range of systems.          

      The spin dimensionality of a mesospin is controlled by its shape and form. Thin elongated elements are Ising-like, with only two possible magnetization directions. Disc shaped elements can be single domain and behave XY-like, with a magnetization direction free to rotate in the plane of the disc. Larger disc sizes result in magnetic vortices. Tuning the material parameters of the elements enables mesospin dynamics at and below room temperature. Combining all of the above, the magnetic state of a lattice is then defined by the mesospins lateral arrangement, their spin dimensionality, and the temperature.          

      In this Thesis we investigate the magnetic order and dynamic properties in a series of different configurations, where the nano-magnetic elements are in the vortex state, Ising-like mesospins or of mixed mesospin dimensionality. Chains of Ising-mesospins were investigated and shown to be successfully described by the Ising model. A lossless transition between the magnetic vortex state and the collinear state, was found in square arrays of magnetic discs. In a more complicated interaction regime, square artificial spin ice, the dynamical range of the Ising-like mesospins in the lattice was probed, in terms of magnetization relaxation studies.          

      Utilizing the configurational freedom in mesoscopic spin systems, together with the possibility to alter the spin dimensionality of the elements, it is possible to create a lattice with no naturally occurring analogue. In such a lattice, where XY mesospins were added to square artificial spin ice, it was found that the degeneracy of the square ice model was restored. Furthermore, using a reciprocal space analysis tool, the magnetic spin structure factor, the system was shown to possess the characteristic features of a Coulomb spin liquid with strong local correlations and absence of long range order. Increasing the interaction between the elements, results in an emergent magnetic order on a large length-scale.

    List of papers
    1. Ising like behaviour of mesoscopic magnetic chains
    Open this publication in new window or tab >>Ising like behaviour of mesoscopic magnetic chains
    (English)Manuscript (preprint) (Other academic)
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-338704 (URN)
    Available from: 2018-01-11 Created: 2018-01-11 Last updated: 2018-01-12
    2. Hysteresis-free switching between vortex and collinear magnetic states
    Open this publication in new window or tab >>Hysteresis-free switching between vortex and collinear magnetic states
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    2014 (English)In: New Journal of Physics, ISSN 1367-2630, E-ISSN 1367-2630, Vol. 16, p. 053002-Article in journal (Refereed) Published
    Abstract [en]

    We demonstrate a lossless switching between vortex and collinear magnetic states in circular FePd disks arranged in a square lattice. Above a bifurcation temperature (Te) we show that thermal fluctuations are enough to facilitate flipping between the two distinctly different magnetic states. We find that the temperature dependence of the vortex annihilation and nucleation fields can be described by a simple power law relating them to the saturation magnetization.

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-224245 (URN)10.1088/1367-2630/16/5/053002 (DOI)000335383800002 ()
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research Council
    Available from: 2014-05-07 Created: 2014-05-07 Last updated: 2018-01-12Bibliographically approved
    3. Thermally induced magnetic relaxation in square artificial spin ice
    Open this publication in new window or tab >>Thermally induced magnetic relaxation in square artificial spin ice
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    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 37097Article in journal (Refereed) Published
    Abstract [en]

    The properties of natural and artificial assemblies of interacting elements, ranging from Quarks to Galaxies, are at the heart of Physics. The collective response and dynamics of such assemblies are dictated by the intrinsic dynamical properties of the building blocks, the nature of their interactions and topological constraints. Here we report on the relaxation dynamics of the magnetization of artificial assemblies of mesoscopic spins. In our model nano-magnetic system - square artificial spin ice - we are able to control the geometrical arrangement and interaction strength between the magnetically interacting building blocks by means of nano-lithography. Using time resolved magnetometry we show that the relaxation process can be described using the Kohlrausch law and that the extracted temperature dependent relaxation times of the assemblies follow the Vogel-Fulcher law. The results provide insight into the relaxation dynamics of mesoscopic nano-magnetic model systems, with adjustable energy and time scales, and demonstrates that these can serve as an ideal playground for the studies of collective dynamics and relaxations.

    National Category
    Physical Sciences Materials Engineering
    Identifiers
    urn:nbn:se:uu:diva-315927 (URN)10.1038/srep37097 (DOI)000392061500001 ()27883013 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research CouncilGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2018-01-12Bibliographically approved
    4. Interaction modiers in articial spin ices
    Open this publication in new window or tab >>Interaction modiers in articial spin ices
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Condensed Matter Physics Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-328864 (URN)
    Available from: 2017-10-10 Created: 2017-10-10 Last updated: 2018-01-12
  • Public defence: 2018-03-02 10:00 ITC/2446, Uppsala
    Zafari, Afshin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Advances in Task-Based Parallel Programming for Distributed Memory Architectures2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    It has become common knowledge that parallel programming is needed for scientific applications, particularly for running large scale simulations. Different programming models are introduced for simplifying parallel programming, while enabling an application to use the full computational capacity of the hardware. In task-based programming, all the variables in the program are abstractly viewed as data. Parallelism is provided by partitioning the data. A task is a collection of operations performed on input data to generate output data. In distributed memory environments, the data is distributed over the computational nodes (or processes), and is communicated when a task needs remote data.

    This thesis discusses advanced techniques in distributed task-based parallel programming, implemented in the DuctTeip software library. DuctTeip uses MPI (Message Passing Interface) for asynchronous inter-process communication and Pthreads for shared memory parallelization within the processes. The data dependencies that determine which subsets of tasks can be executed in parallel are extracted from information about the data accesses (input or output) of the tasks. A versioning system is used internally to represent the task-data dependencies efficiently. A hierarchical partitioning of tasks and data allows for independent optimization of the size of computational tasks and the size of communicated data. A data listener technique is used to manage communication efficiently.

    DuctTeip provides an algorithm independent dynamic load balancing functionality. Redistributing tasks from busy processes to idle processes dynamically can provide an overall shorter execution time. A random search method with high probability of success is employed for locating idle/busy nodes.

    The advantage of the abstract view of tasks and data is exploited in a unified programming interface, which provides a standard for task-based frameworks to decouple framework development from application development. The interface can be used for collaboration between different frameworks in running an application program efficiently on different hardware.

    To evaluate the DuctTeip programming model, applications such as Cholesky factorization, a time-dependent PDE solver for the shallow water equations, and the fast multipole method have been implemented using DuctTeip. Experiments show that DuctTeip provides both scalability and performance. Comparisons with similar frameworks such as StarPU, OmpSs, and PaRSEC show competitive results.

    List of papers
    1. Programming models based on data versioning for dependency-aware task-based parallelisation
    Open this publication in new window or tab >>Programming models based on data versioning for dependency-aware task-based parallelisation
    2012 (English)In: Proc. 15th International Conference on Computational Science and Engineering, Los Alamitos, CA: IEEE Computer Society, 2012, p. 275-280Conference paper, Published paper (Refereed)
    Place, publisher, year, edition, pages
    Los Alamitos, CA: IEEE Computer Society, 2012
    National Category
    Software Engineering
    Identifiers
    urn:nbn:se:uu:diva-187446 (URN)10.1109/ICCSE.2012.45 (DOI)000317475000038 ()978-1-4673-5165-2 (ISBN)
    Conference
    CSE 2012
    Projects
    eSSENCEUPMARC
    Available from: 2013-01-24 Created: 2012-12-06 Last updated: 2018-01-16Bibliographically approved
    2. DuctTeip: An efficient programming model for distributed task based parallel computing
    Open this publication in new window or tab >>DuctTeip: An efficient programming model for distributed task based parallel computing
    (English)Manuscript (preprint) (Other academic)
    National Category
    Software Engineering
    Identifiers
    urn:nbn:se:uu:diva-338832 (URN)
    Projects
    UPMARCeSSENCE
    Available from: 2018-01-14 Created: 2018-01-14 Last updated: 2018-01-24Bibliographically approved
    3. TaskUniVerse: A Task-Based Unified Interface for Versatile Parallel Execution
    Open this publication in new window or tab >>TaskUniVerse: A Task-Based Unified Interface for Versatile Parallel Execution
    2018 (English)In: Parallel Processing and Applied Mathematics, Springer, 2018Conference paper, Published paper (Refereed)
    Place, publisher, year, edition, pages
    Springer, 2018
    Series
    Lecture Notes in Computer Science
    National Category
    Software Engineering
    Identifiers
    urn:nbn:se:uu:diva-338836 (URN)
    Conference
    PPAM 2017
    Projects
    eSSENCE
    Note

    to appear

    Available from: 2018-01-14 Created: 2018-01-14 Last updated: 2018-01-24Bibliographically approved
    4. Task parallel implementation of a solver for electromagnetic scattering problems
    Open this publication in new window or tab >>Task parallel implementation of a solver for electromagnetic scattering problems
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Computer Sciences Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-338833 (URN)
    Projects
    eSSENCE
    Available from: 2018-01-14 Created: 2018-01-14 Last updated: 2018-01-24Bibliographically approved
    5. Distributed dynamic load balancing for task parallel programming
    Open this publication in new window or tab >>Distributed dynamic load balancing for task parallel programming
    (English)Manuscript (preprint) (Other academic)
    National Category
    Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-338835 (URN)
    Projects
    UPMARCeSSENCE
    Available from: 2018-01-14 Created: 2018-01-14 Last updated: 2018-01-24Bibliographically approved
  • Public defence: 2018-03-02 13:00 Enghoffsalen, Uppsala
    Bagge, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Surgical ablation for the treatment of atrial fibrillation in different patient populations: A study of clinical outcomes including rhythm, quality of life, atrial function and safety2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with atrial fibrillation (AF) have markedly reduced quality of life (QoL) and catheter ablation has become a useful tool in the rhythm control therapy. However, because of the poor outcome for patients with persistent AF, new surgical ablation strategies for rhythm control are emerging.

    The aims of this thesis were to evaluate QoL, the main indication for rhythm control, after three different types of surgical ablation for AF, two stand-alone epicardial AF ablation procedures and one concomitant procedure during mitral valve surgery (MVS), and to perform a long-term follow-up of one of the techniques with regard to rhythm outcome, left atrial function, exercise capacity and safety.

    As the first center in the Nordic countries to adopt the video-assisted epicardial pulmonary vein isolation and ganglionated plexi ablation combined with left atrial appendage excision (LAA), the  freedom from AF at one year follow-up was found to be 71% and associated with improved exercise capacity, QoL and symptoms as well as preserved left atrial function and size. The most common complication was bleeding events (14%). After 10 years, the improved symptoms and QoL remained, reaching comparable levels of the general Swedish population, despite a marked decline in the rate of freedom from AF (36%). 4 strokes appeared during follow-up despite LAA excision in 3 of these patients.

    In order to improve the rhythm outcome for patients with longstanding persistent AF a box-lesion was added to the procedure. At one year follow-up, both symptoms and QoL improved and was indistinguishable from those in the Swedish general population.

    Finally, concomitant AF ablation during MVS did not improve QoL compared to MVS alone in a double blinded randomized controlled trial. Moreover, no difference was seen between patients in AF or sinus rhythm at one year follow-up, irrespective of the allocated therapy, indicating that their preoperative symptoms were mainly related to their valve disease.

    In conclusion, the stand-alone procedures using surgical ablation was found to be effective but at the expense of procedural complications. In contrast, the concomitant surgical AF ablation did not improve QoL, a finding that raises concerns regarding current recommendations for this procedure. 

    List of papers
    1. Epicardial off-pump pulmonary vein isolation and vagal denervation improve long-term outcome and quality of life in patients with atrial fibrillation
    Open this publication in new window or tab >>Epicardial off-pump pulmonary vein isolation and vagal denervation improve long-term outcome and quality of life in patients with atrial fibrillation
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    2009 (English)In: Journal of Thoracic and Cardiovascular Surgery, ISSN 0022-5223, E-ISSN 1097-685X, Vol. 137, no 5, p. 1265-1271Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: The limited information available on thoracoscopic pulmonary vein isolation combined with ganglionated plexi ablation and the lack of studies regarding its effect on quality of life and physical capacity urged us to study its acute and long-term results in patients with atrial fibrillation. METHODS: Forty-three patients (mean age 57.1 years) with symptomatic atrial fibrillation referred for thoracoscopic off-pump epicardial pulmonary vein isolation and ganglionated plexi ablation using radiofrequency energy were included. RESULTS: The physical capacity improved significantly at 6-month follow-up compared with baseline (mean +/- standard deviation, 165.2 +/- 65 Watt versus 155.9 +/- 57 Watt, P = .02). Quality of life (Short Form-36 health survey) significantly improved 12 months after surgery compared with baseline in all subscales except for bodily pain. The symptom severity questionnaire score decreased significantly from mean 15.2 +/- 4.0 points to 10.7 +/- 4.8 points (P = .02). Overall, 25 of 33 patients (76%) followed up for 12 months had no symptomatic atrial fibrillation recurrences or atrial fibrillation episodes on 24-hour Holter recordings. The corresponding figures were 79% (19/24) for patients with paroxysmal atrial fibrillation, 100% (2/2) for persistent atrial fibrillation, and 57% (4/7) for permanent atrial fibrillation. The most common complication was bleeding events (9%) during pulmonary vein dissection. CONCLUSIONS: Epicardial off-pump pulmonary vein isolation combined with ganglionated plexi ablation improved quality of life, symptoms, and exercise capacity and therefore may be considered for patients with atrial fibrillation who fail endocardial pulmonary vein ablation or as a first-line procedure if left atrial appendage exclusion is warranted.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-103119 (URN)10.1016/j.jtcvs.2008.12.017 (DOI)000265299000034 ()19380002 (PubMedID)
    Available from: 2009-05-14 Created: 2009-05-14 Last updated: 2018-01-14Bibliographically approved
    2. Left atrial function after epicardial pulmonary vein isolation in patients with atrial fibrillation.
    Open this publication in new window or tab >>Left atrial function after epicardial pulmonary vein isolation in patients with atrial fibrillation.
    Show others...
    2017 (English)In: Journal of interventional cardiac electrophysiology (Print), ISSN 1383-875X, E-ISSN 1572-8595, Vol. 50, no 2, p. 195-201Article in journal (Refereed) Published
    Keyword
    left atrial function; epicardial; atrial fibrillation; left atrial size; minimally invasive; pulmonary vein isolation; vagal denervation; ganglionated plexi
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-338090 (URN)10.1007/s10840-017-0290-2 (DOI)000416448400007 ()29127542 (PubMedID)
    Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-02-08Bibliographically approved
    3. Quality of life is not improved after mitral valve surgery combined with epicardial left atrial cryoablation as compared with mitral valve surgery alone: a substudy of the double blind randomized SWEDish Multicentre Atrial Fibrillation study (SWEDMAF)
    Open this publication in new window or tab >>Quality of life is not improved after mitral valve surgery combined with epicardial left atrial cryoablation as compared with mitral valve surgery alone: a substudy of the double blind randomized SWEDish Multicentre Atrial Fibrillation study (SWEDMAF)
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    2017 (English)In: Europace, ISSN 1099-5129, E-ISSN 1532-2092Article in journal (Refereed) Epub ahead of print
    Keyword
    concomitant surgical ablation; mitral valve surgery; atrial fibrillation; quality of life; ablation;
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-338091 (URN)10.1093/europace/eux253 (DOI)
    Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-02-14Bibliographically approved
    4. 10 years follow-up of video-assisted epicardial pulmonary vein isolation and vagal denervation in patients with atrial fibrillation
    Open this publication in new window or tab >>10 years follow-up of video-assisted epicardial pulmonary vein isolation and vagal denervation in patients with atrial fibrillation
    (English)In: Article in journal (Other academic) Submitted
    Keyword
    Atrial fibrillation; epicardial; pulmonary vein isolation; qualiy of life; minimally invasive; vagal denervation; ganglionated plexi
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-338092 (URN)
    Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-02-14
    5. A Prospective Study of the Effects of Thoracoscopic Epicardial Left Atrial Ablation on Symptoms and Quality of Life: A comparison with the normal Swedish population and other severe disease states
    Open this publication in new window or tab >>A Prospective Study of the Effects of Thoracoscopic Epicardial Left Atrial Ablation on Symptoms and Quality of Life: A comparison with the normal Swedish population and other severe disease states
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Atrial fibrillation; quality of life; thoracoscopic; epicardial; left atrial ablation;
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-338093 (URN)
    Available from: 2018-01-07 Created: 2018-01-07 Last updated: 2018-01-15
  • Public defence: 2018-03-02 13:15 Humanistiska Teatern, Uppsala
    Sköld, Olle
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of ALM.
    Documenting Videogame Communities: A Study of Community Production of Information in Social-Media Environments and its Implications for Videogame Preservation2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Drawing on the disciplines of library and information studies and archival studies, this study seeks to explore the production of information in online videogame communities and to elucidate how such insights can offer practical and conceptual support to the knotty issue of how to preserve those sociocultural aspects of videogames that exist 'beyond' the code and audiovisual data resources of the videogame itself. This is accomplished in two principal moves: (i) by delving into the current state of socioculturally-focused videogame preservation and; (ii) by inquiring into the production of information carried out by videogame communities in what arguably is one of their most important interfaces of interaction—discussion forums, wikis, and other social-media services. The study is based on four papers (I–IV). Paper I develops the theoretical framework of the study on the basis of practice theory and document theory. Papers II and III report on field-studies of videogame-community information production in the context of two processes of importance in community social life: memory-making (II) and knowledge production (III). Paper IV offers a qualitative systematic review of videogame-archiving literature, allowing Papers I–III to be situated in an archival context. The study employs multiple methods and encompasses several empirical sites of inquiry and was inspired by the framework of exploratory research and of 'bricolage' research strategies.

    The results of the study add to the present state of knowledge on how information in the social-media environments of the large and influential present-day videogaming domain emerges as a result of community practices of production, and how videogame-community social life is entangled with information production in such spaces. The study also furthers archival inquiry on the topic of videogame preservation by providing a description and analysis of what information objects videogame-related social media plausibly hold, and by what communal practices and processes they have been brought into existence. Furthermore, the study examines the consequences of collecting community-produced social media and framing it as documentation of the sociocultural aspects of videogames—a key issue in videogames preservation.

    List of papers
    1. Tracing Traces: A Document-Centred Approach to the Preservation of Virtual World Communities
    Open this publication in new window or tab >>Tracing Traces: A Document-Centred Approach to the Preservation of Virtual World Communities
    2013 (English)In: Information research, ISSN 1368-1613, E-ISSN 1368-1613, Vol. 18, no 3Article in journal (Refereed) Published
    Abstract [en]

    Introduction. The aim of this paper is to form a framework capable of theorizing how virtual communities are entangled with their new media environments, thereby contributing to the understanding of present-day virtual communities and how to preserve them.

    Method. An extensive bibliography on virtual worlds, virtual world preservation, document- and practice theory, and virtual communities forms the conceptual basis of the paper.

    Analysis. The proposed framework was formed by the way of qualitative and synthetic conceptual analysis of the collected literature. Results. Virtual world communities can be fruitfully conceptualized as distinct domains with specialized documentary practices. In each domain of practice, the virtual world’s related new media ecology functions as a central hub where the configuration of shared routinized sayings, doings, and knowings specific to that virtual world are negotiated. 

    Conclusion. By theorizing the activities of virtual communities in new media environments as documentary practices, and blog posts, comments, and tweets as documents, the framework accentuates new media as infrastructures that do not solely carry informative traces of the activities of virtual communities, but in effect are an active and formative part of them. As such, they merit high preservational priority.

    Keyword
    Documents, Practices, New Media, Digital cultural heritage preservation, Virtual worlds
    National Category
    Information Studies
    Research subject
    Library and Information Science
    Identifiers
    urn:nbn:se:uu:diva-213410 (URN)000329310400018 ()
    Conference
    Proceedings of the Eighth International Conference on Conceptions of Library and Information Science, Copenhagen, Denmark, 19-22 August, 2013
    Available from: 2013-12-20 Created: 2013-12-20 Last updated: 2018-01-14
    2. Documenting Virtual World Cultures: Memory-Making and Documentary Practices in the City of Heroes Community
    Open this publication in new window or tab >>Documenting Virtual World Cultures: Memory-Making and Documentary Practices in the City of Heroes Community
    2015 (English)In: Journal of Documentation, ISSN 0022-0418, E-ISSN 1758-7379, Vol. 71, no 2, p. 294-316Article in journal (Refereed) Published
    Abstract [en]

    Purpose. The purpose of this paper is to explore how virtual world communities employ new media as a repository to record information about their past.

    Design/methodology/approach. Using the notions of documentary practice and memory-making as a framework, a case study of MMORPGCity of Heroes’ (CoH) virtual community on Reddit discussion board “/r/cityofheroes” was conducted. The study consists of an interpretative analysis of posts, comments, images, and other materials submitted to /r/cityofheroes during a period of approximately seven months.

    Findings. The principal finding of the study is that the CoH community, with varying levels of intentionality, documented a range of pasts on /r/cityofheroes, relating to CoH as a game world, a site of personal experience, a product, a nexus of narratives, and a game. The analysis also lays bare the community’s memory-making processes, in which the documented conceptions of CoH’s past were put to work in the present, informing community action and viewpoints.

    Originality/value. Games and gaming practices are increasingly prevalent in leisure and professional settings. This trend, which makes virtual environments and online media proxies for or augmentations of “real life”, makes it necessary for information scholars to understand how the full range of human information behaviours, including documenting, and memory-making, emerge or are replicated online. Additionally, few studies have examined the interplay between new media affordances, documentary practices, and memory-making in the context of virtual world communities.

    Place, publisher, year, edition, pages
    Emerald Group Publishing Limited, 2015
    National Category
    Information Studies
    Research subject
    Library and Information Science
    Identifiers
    urn:nbn:se:uu:diva-247471 (URN)10.1108/JD-11-2013-0146 (DOI)000352716700007 ()
    Available from: 2015-03-18 Created: 2015-03-18 Last updated: 2018-01-14
    3. Getting-to-Know: Inquiries, Sources, Methods, and the Production of Knowledge on a Videogame Wiki
    Open this publication in new window or tab >>Getting-to-Know: Inquiries, Sources, Methods, and the Production of Knowledge on a Videogame Wiki
    2017 (English)In: Journal of Documentation, ISSN 0022-0418, E-ISSN 1758-7379, Vol. 73, no 6, p. 1299-1321Article in journal (Refereed) Published
    Abstract [en]

    Purpose. The purpose of this paper is to investigate the sociocultural underpinnings of wiki-based knowledge production in the videogame domain, and to elucidate how these underpinnings relate to the formation of wikis as resources of videogame documentation.

    Design/methodology/approach. The paper is based on a three-month ethnographic investigation of knowledge practices on the Dark Souls Wiki (DSW). In focus of the analysis were the boundaries and knowledge aims of the DSW, together with how its contributors organized inquiries and used various sources, methods of investigation, and ways of warranting knowledge claims.

    Findings. The principal result of the paper is an empirical account of how the DSW functions as a culture of knowledge production, and how the content and structure of the wiki connects to the knowledge practices of its contributors. Four major factors that influenced knowledge practices on the wiki were identified: the structures and practices established by the community’s earlier wiki efforts; principles and priorities that informed wiki knowledge practices; the characteristics of the videogame in focus of the site’s knowledge-building work; the extent and types of relevant documentation provided by videogame industry, the videogaming press included.

    Originality/value. Previous research has shown interest in investigating the mechanisms by which community-created knowledge and online resources of documentation emerge, and how these are utilized in play. There is, however, little research seeking to elucidate the sociocultural structures and practices that determine and sustain collaborative online videogame knowledge production.

    Keyword
    Wikis, Knowledge production, Ethnography, Social media, Practices, Videogames
    National Category
    Information Studies
    Research subject
    Library and Information Science
    Identifiers
    urn:nbn:se:uu:diva-336745 (URN)10.1108/JD-11-2016-0145 (DOI)
    Available from: 2017-12-16 Created: 2017-12-16 Last updated: 2018-01-14
    4. Understanding the “Expanded Notion” of Videogames as Archival Objects: A Review of Priorities, Methods, and Conceptions
    Open this publication in new window or tab >>Understanding the “Expanded Notion” of Videogames as Archival Objects: A Review of Priorities, Methods, and Conceptions
    2018 (English)In: Journal of the Association for Information Science and Technology, ISSN 2330-1635, E-ISSN 2330-1643, Vol. 69, no 1, p. 134-145Article in journal (Refereed) Published
    Abstract [en]

    This paper aims to show how videogames are construed as archival objects in the videogame-preservation literature by investigating drivers and motivations, selection of material, and methods of preservation. The review focuses on the expanded notion of videogames (“the EN”), a concept this paper introduces to collectively refer to the cultural and social aspects of videogames—for example, game culture, experiences, play, and community life and activity. The study's research aims are pursued on the basis of a critical systematic literature review of 42 publications originating from academic research and videogame-archiving projects. The study's main finding is that the archiving literature construes the EN of videogames in three principal ways: i) as an essential part of the videogame as an archival object; ii) as a useful resource in archiving videogames, able to provide documentation of game culture and social context; and iii) as a useful resource in inquiries focused on the current state and recent history of society and culture from a sociotechnical viewpoint. The study suggests videogame community dynamics, videogame ontology, the development of archival theory, and videogame-archive studies as rewarding directions for further research.

    National Category
    Information Studies
    Research subject
    Library and Information Science
    Identifiers
    urn:nbn:se:uu:diva-336747 (URN)10.1002/asi.23875 (DOI)
    Available from: 2017-12-16 Created: 2017-12-16 Last updated: 2018-01-14
  • Public defence: 2018-03-08 13:00 Rosen, Uppsala
    Santos, Arnoldo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Hemodynamic Effects of Lung Function Optimization in Experimental Acute Respiratory Distress Syndrome2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute Respiratory Distress Syndrome (ARDS) is a severe pulmonary inflammation affecting thousands of patients every year in Sweden and has a mortality of 30-50%. Mechanical ventilation (MV) is usually necessary, but could per se augment the inflammation and contribute to mortality. MV strategies protective for the lung parenchyma have been developed but without considering the pulmonary circulation or the right heart ventricle (RV) that also are affected in ARDS. MV should ideally be optimized to protect both the lung parenchyma and the RV/pulmonary vasculature. My hypothesis was that MV that prevents alveolar collapse and overdistension, i.e., the “open lung approach (OLA)” would be optimal. The aims of this project were 1) to carefully describe the pulmonary vascular mechanics (PVM) in ARDS compared with healthy lungs, 2) to assess how different ventilatory methods influence PVM, and 3) to propose a ventilatory method that protects both lung parenchyma and circulation.

    In a porcine model, high fidelity pressure and flow sensors were applied directly on the main pulmonary artery to evaluate steady and oscillatory components of PVM.  In this way a complete PVM description was obtained for normal and injured lungs at different MV. In particular, the effects of OLA were compared with standard MV and, in addition, with MV methods where overdistension or collapse were present.

    Results: 1) Compared with collapse or overdistension, OLA provided better PVM. 2) The effects on PVM of OLA and the standard protective MV were similar. 3) Early ARDS augmented the effects of pulse wave reflection on PVM leading to a situation in which the RV had to increase its work to maintain adequate blood flow. Thus, a part of this work was wasted by the effect of wave reflections, making the RV/pulmonary vasculature inefficient. 4) Tidal breathing affected PVM cyclically and this effect was enhanced in ARDS compared with healthy lungs.

    In conclusion, ARDS and different ventilatory methods, as well as tidal ventilation per se, affected PVM. OLA improved PVM compared with other MV settings where significant collapse and overdistension were allowed. However, OLA was not superior to standard protective MV.

    List of papers
    1. The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome
    Open this publication in new window or tab >>The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome
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    2017 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, no 3, p. e298-e305Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To test whether positive end-expiratory pressure consistent with an open lung approach improves pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressures in experimental acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: Animal research laboratory.

    SUBJECTS: Ten pigs, 35 ± 5.2 kg.

    INTERVENTIONS: Acute respiratory distress syndrome was induced combining saline lung lavages with injurious mechanical ventilation. The positive end-expiratory pressure level resulting in highest compliance during a decremental positive end-expiratory pressure trial after lung recruitment was determined. Thereafter, three positive end-expiratory pressure levels were applied in a random order: hyperinflation, 6 cm H2O above; open lung approach, 2 cm H2O above; and collapse, 6 cm H2O below the highest compliance level. High fidelity pressure and flow sensors were placed at the main pulmonary artery for measuring pulmonary artery resistance (Z0), effective arterial elastance, compliance, and reflected pressure waves.

    MEASUREMENTS AND MAIN RESULTS: After inducing acute respiratory distress syndrome, Z0 and effective arterial elastance increased (from 218 ± 94 to 444 ± 115 dyn.s.cm and from 0.27 ± 0.14 to 0.62 ± 0.22 mm Hg/mL, respectively; p < 0.001), vascular compliance decreased (from 2.76 ± 0.86 to 1.48 ± 0.32 mL/mm Hg; p = 0.003), and reflected waves arrived earlier (0.23 ± 0.07 vs 0.14 ± 0.05, arbitrary unit; p = 0.002) compared with baseline. Comparing the three positive end-expiratory pressure levels, open lung approach resulted in the lowest: 1) Z0 (297 ± 83 vs 378 ± 79 dyn.s.cm, p = 0.033, and vs 450 ± 119 dyn.s.cm, p = 0.002); 2) effective arterial elastance (0.37 ± 0.08 vs 0.50 ± 0.15 mm Hg/mL, p = 0.04, and vs 0.61 ± 0.12 mm Hg/mL, p < 0.001), and 3) reflection coefficient (0.35 ± 0.17 vs 0.48 ± 0.10, p = 0.024, and vs 0.53 ± 0.19, p = 0.005), comparisons with hyperinflation and collapse, respectively.

    CONCLUSIONS: In this experimental setting, positive end-expiratory pressure consistent with the open lung approach resulted in the best pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressure settings.

    Keyword
    Fluid responsiveness, Spontaneous breathing, Head-up tilt, Pulse pressure variation, Stroke volume variation, Systolic pressure variation
    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-307915 (URN)10.1097/CCM.0000000000002082 (DOI)27763913 (PubMedID)
    Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2018-01-12Bibliographically approved
    2. Effects on Pulmonary Vascular Mechanics of Two Different Lung-Protective Ventilation Strategies in an Experimental Model of Acute Respiratory Distress Syndrome.
    Open this publication in new window or tab >>Effects on Pulmonary Vascular Mechanics of Two Different Lung-Protective Ventilation Strategies in an Experimental Model of Acute Respiratory Distress Syndrome.
    Show others...
    2017 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, no 11, p. e1157-e1164Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: To compare the effects of two lung-protective ventilation strategies on pulmonary vascular mechanics in early acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: University animal research laboratory.

    SUBJECTS: Twelve pigs (30.8 ± 2.5 kg).

    INTERVENTIONS: Acute respiratory distress syndrome was induced by repeated lung lavages and injurious mechanical ventilation. Thereafter, animals were randomized to 4 hours ventilation according to the Acute Respiratory Distress Syndrome Network protocol or to an open lung approach strategy. Pressure and flow sensors placed at the pulmonary artery trunk allowed continuous assessment of pulmonary artery resistance, effective elastance, compliance, and reflected pressure waves. Respiratory mechanics and gas exchange data were collected.

    MEASUREMENTS AND MAIN RESULTS: Acute respiratory distress syndrome led to pulmonary vascular mechanics deterioration. Four hours after randomization, pulmonary vascular mechanics was similar in Acute Respiratory Distress Syndrome Network and open lung approach: resistance (578 ± 252 vs 626 ± 153 dyn.s/cm; p = 0.714), effective elastance, (0.63 ± 0.22 vs 0.58 ± 0.17 mm Hg/mL; p = 0.710), compliance (1.19 ± 0.8 vs 1.50 ± 0.27 mL/mm Hg; p = 0.437), and reflection index (0.36 ± 0.04 vs 0.34 ± 0.09; p = 0.680). Open lung approach as compared to Acute Respiratory Distress Syndrome Network was associated with improved dynamic respiratory compliance (17.3 ± 2.6 vs 10.5 ± 1.3 mL/cm H2O; p < 0.001), driving pressure (9.6 ± 1.3 vs 19.3 ± 2.7 cm H2O; p < 0.001), and venous admixture (0.05 ± 0.01 vs 0.22 ± 0.03, p < 0.001) and lower mean pulmonary artery pressure (26 ± 3 vs 34 ± 7 mm Hg; p = 0.045) despite of using a higher positive end-expiratory pressure (17.4 ± 0.7 vs 9.5 ± 2.4 cm H2O; p < 0.001). Cardiac index, however, was lower in open lung approach (1.42 ± 0.16 vs 2.27 ± 0.48 L/min; p = 0.005).

    CONCLUSIONS: In this experimental model, Acute Respiratory Distress Syndrome Network and open lung approach affected pulmonary vascular mechanics similarly. The use of higher positive end-expiratory pressures in the open lung approach strategy did not worsen pulmonary vascular mechanics, improved lung mechanics, and gas exchange but at the expense of a lower cardiac index.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-334177 (URN)10.1097/CCM.0000000000002701 (DOI)28872540 (PubMedID)
    Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2018-01-12
    3. Acute Respiratory Distress Syndrome deteriorates pulmonary vascular efficiency and increases cardiac energy wasting in a porcine model.
    Open this publication in new window or tab >>Acute Respiratory Distress Syndrome deteriorates pulmonary vascular efficiency and increases cardiac energy wasting in a porcine model.
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Right ventricle failure worsen outcomes in acute respiratory distress syndrome (ARDS). However, the pathophysiology of right ventricle failure and vascular dysfunction in ARDS is not completely understood. In this study we aim to evaluate the effects of early ARDS on pulmonary vascular efficiency for transmission of flow and pressure in an experimental animal model.  

    Methods: ARDS was induced in 10 pigs (32.5±4.3 kg) combining saline lung-lavages with injurious mechanical ventilation. Pressure and flow sensors were placed at the main pulmonary artery for pulmonary vascular function evaluation, including arterial load parameters, cardiac power and energy transmission ratio.

    Results: Compared to baseline healthy conditions, ARDS increased pulmonary vascular resistance (199±62 versus 524±154 dyn.s.cm-5, p <0.001), effective arterial elastance (0.65±0.26 versus 1.13±0.36 mmHg/ml, p <0.001) and total hydraulic power (195±60 to 266±87 mW, p =0.015), decreased pulmonary arterial compliance (from 2.34±0.86 to 1.00±0.25 ml/mmHg, p <0.001) and energy transmission ratio (68±15 versus 55±14%, p = 0.014), whereas oscillatory power did not change (17±6 versus 16±6%, p = 0.359).

    Conclusions: In this experimental ARDS model, an increase in pulmonary arterial load was associated with a higher cardiac power and a decrease in the energy transmission ratio. These results suggest that right ventricle energy consumption is increased and part of this energy is wasted in pulmonary circulation worsening pulmonary vascular efficiency in the early course of ARDS. These findings may help to explain primary mechanisms leading to right ventricle dysfunction in ARDS.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-337402 (URN)
    Available from: 2017-12-25 Created: 2017-12-25 Last updated: 2018-01-12
    4. Cyclic Changes of Pulmonary Vascular Mechanics During mechanical ventilation in acute respiratory distress syndrome. A porcine experimental model.
    Open this publication in new window or tab >>Cyclic Changes of Pulmonary Vascular Mechanics During mechanical ventilation in acute respiratory distress syndrome. A porcine experimental model.
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Objective: To test the hypothesis that acute respiratory syndrome (ARDS) worsens pulmonary vascular mechanics during the respiratory cycle under mechanical ventilation in an animal model.  

    Design: Experimental study.

    Setting: Animal research laboratory.

    Subjects: 6 pigs, 31.7 ± 5.4 kg.

    Interventions: ARDS was induced by combining saline lung-lavages with injurious mechanical ventilation. Pressure and flow sensors were placed at the main pulmonary artery (PA) and signals were collected simultaneously with airway pressure and flow. Pulmonary vascular mechanics and cardiac function parameters were calculates beat by beat during 2-3 minutes. We designed a novel method to quantify how the calculated variables behave during the whole respiratory cycle, i.e., during expiration and during inspiration. Results are expressed as the mean value during the corresponding phase of the respiratory cycle.

    Measurements and Main Results: During the whole respiratory cycle and at expiration ARDS decreased SV and arterial compliance while increased mean and pulse PA pressure, effective arterial elastance and Dp/Dtmax when compared to baseline. At baseline and after ARDS, inspiration in positive pressure ventilation caused a decrease in stroke volume (-3±1ml, p<0.001 and -3±1ml, p<0.001), pulmonary mean (-0.5±0.3, p=0.007 and -0.7±0.3mmHg, p=0.002) and pulse pressure (-0.8±0.4, p=0.003 and -1,5±0.7mmHg, p=0.003) and compliance (-0.07±0.04 and -0.04±0.00ml/mmHg, p<0.001) and an increase in resistance (34±13, p=0.001 and 50±32dyn.s.cm-5, p=0.012) and in effective arterial elastance (0.04±0.01, p=0.001 and 0.08±0.04mmHg/ml, p=0.003). ARDS produced a more pronounced inspiratory increase in effective arterial elastance (p=0.041) when compared to baseline. Positive pressure ventilation caused a decrease in Dp/Dtmax at baseline (-15±9mmHg/s, p=0.010) but this was not significant during ARDS (-27±28mmHg/s, p=0.068).  

    Conclusions: We found in this experimental model that MV induced tidal increase in arterial load and that this effect was higher during ARDS. This finding if transferred to patients, might partly explain the high rate of right heart failure clinically in ARDS.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-337405 (URN)
    Available from: 2017-12-25 Created: 2017-12-25 Last updated: 2018-01-12
  • Public defence: 2018-03-09 09:15 Sal X, Uppsala
    Salih Joelsson, Lana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lifestyle and Reproductive Health among Women prior to Conception2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Health and lifestyle is of great importance when women intend to become pregnant, as well as during pregnancy. It is crucial that people seeking for infertility are aware of which lifestyle changes they can undertake to enhance the likelihood of treatment success. The overall aim of this project was to investigate the extent to which women comply with recommendations for lifestyle changes during the time they try to conceive and during early pregnancy and the impact of lifestyle risk factors on treatment results in sub-fertile women. Lifestyle factors and mental health at baseline and lifestyle changes women made while they were trying to conceive were assessed by a study-specific questionnaire. Both pregnant women and non-pregnant sub-fertile women in the mid-Sweden region were included. The level of pregnancy planning was associated with planning behavior. Only one-third of all pregnant women took folic acid one month prior to conception, 17% used tobacco daily and 11% used alcohol weekly three months before conception. In the sub-fertile non-pregnant women cohort, 13.2% used tobacco daily, 13.6% drank more than three cups of coffee per day, and 11.6% consumed more than two glasses of alcohol weekly. Among sub-fertile women, one-third were overweight or obese. Pregnant women who conceived with Assisted Reproductive Technology (ART) reported lower rates of anxiety and depression symptoms compared to sub-fertile women. They also showed no difference in depression and anxiety symptoms compared to women who conceived naturally. Among sub-fertile women undergoing their first IVF treatment cycle, an independent as well as a cumulative effect of smoking and BMI on the number of aspirated oocytes and the proportion of mature oocytes was observed, especially among women with low ovarian reserve. In conclusion, approximately half of the women in our studies retained habits with negative effects on fertility. This is worrying because the harmful consequences of negative lifestyle factors are well established. These negative lifestyle factors are easy to detect and adjust at an early stage in the assessment process and might allow for optimization of fertility treatment and pregnancy outcomes.

    List of papers
    1. Is pregnancy planning associated with background characteristics and pregnancy planning behavior?
    Open this publication in new window or tab >>Is pregnancy planning associated with background characteristics and pregnancy planning behavior?
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    2016 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 95, no 2, p. 182-189Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Prevalence of planned pregnancies varies between countries but is often measured in a dichotomous manner. The aim of this study was to investigate to what level pregnant women had planned their pregnancies and whether pregnancy planning was associated with background characteristics and pregnancy planning behavior.

    MATERIAL AND METHODS: A cross-sectional study that utilized the baseline measurements from the Swedish Pregnancy Planning (SWEPP) study. Pregnant women (n= 3390) recruited at antenatal clinics answered a questionnaire. Data were analyzed with multinomial logistic regression, Kruskal-Wallis H and χ(2) tests.

    RESULTS: Three out of four pregnancies were very or fairly planned and 12 % fairly or very unplanned. Of women with very unplanned pregnancies, 32 % had considered an induced abortion. Women with planned pregnancies were more likely to have a higher level of education, higher household income, to be currently working ≥50 %, and to have longer relationships than women with unplanned pregnancies. The level of pregnancy planning was associated with planning behavior, such as information seeking and intake of folic acid, but without a reduction in alcohol consumption. One third of all women took folic acid one month prior to conception, 17 % used tobacco daily and 11 % used alcohol weekly three months before conception.

    CONCLUSIONS: A majority rated their pregnancy as very or fairly planned, with socio-economic factors as explanatory variables. The level of pregnancy planning should be queried routinely to enable individualized counselling, especially for women with unplanned pregnancies. Preconception recommendations need to be established and communicated to the public to increase health promoting planning behavior.

    Keyword
    Planned pregnancy; unplanned pregnancy; preconception care; folic acid; health behavior
    National Category
    Nursing
    Identifiers
    urn:nbn:se:uu:diva-270500 (URN)10.1111/aogs.12816 (DOI)000368004300007 ()26566076 (PubMedID)
    Available from: 2015-12-29 Created: 2015-12-29 Last updated: 2018-01-19Bibliographically approved
    2. Do subfertile women adjust their habits when trying to conceive?
    Open this publication in new window or tab >>Do subfertile women adjust their habits when trying to conceive?
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    2016 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 3, p. 184-191Article in journal (Refereed) Published
    Abstract [en]

    AbstractAIM:

    The aim of this study was to investigate lifestyle habits and lifestyle adjustments among subfertile women trying to conceive.

    MATERIALS AND METHODS:

    Women (n = 747) were recruited consecutively at their first visit to fertility clinics in mid-Sweden. Participants completed a questionnaire. Data were analyzed using logistic regression, t tests, and chi-square tests.

    RESULTS:

    The response rate was 62% (n = 466). Mean duration of infertility was 1.9 years. During this time 13.2% used tobacco daily, 13.6% drank more than three cups of coffee per day, and 11.6% consumed more than two glasses of alcohol weekly. In this sample, 23.9% of the women were overweight (body mass index, BMI 25-29.9 kg/m(2)), and 12.5% were obese (BMI ≥30 kg/m(2)). Obese women exercised more and changed to healthy diets more frequently than normal-weight women (odds ratio 7.43; 95% confidence interval 3.7-14.9). Six out of ten women (n = 266) took folic acid when they started trying to conceive, but 11% stopped taking folic acid after some time. Taking folic acid was associated with a higher level of education (p < 0.001).

    CONCLUSIONS:

    Among subfertile women, one-third were overweight or obese, and some had other lifestyle factors with known adverse effects on fertility such as use of tobacco. Overweight and obese women adjusted their habits but did not reduce their body mass index. Women of fertile age would benefit from preconception counseling, and the treatment of infertility should routinely offer interventions for lifestyle changes.

    KEYWORDS:

    Alcohol consumption; assisted reproduction; diet; infertility; lifestyle; obesity; pregnancy; tobacco use

    Keyword
    Alcohol consumption; assisted reproduction; diet; infertility; lifestyle; obesity; pregnancy; tobacco use
    National Category
    Obstetrics, Gynecology and Reproductive Medicine Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-301385 (URN)10.1080/03009734.2016.1176094 (DOI)000381958400006 ()
    Available from: 2016-08-22 Created: 2016-08-22 Last updated: 2018-01-18Bibliographically approved
    3. Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women
    Open this publication in new window or tab >>Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women
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    2017 (English)In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 45, p. 212-219Article in journal (Refereed) Published
    Abstract [en]

    Background

    Infertility has been associated with psychological distress, but whether these symptoms persist after achieving pregnancy via assisted reproductive technology (ART) remains unclear. We compared the prevalence of anxiety and depressive symptoms between women seeking for infertility treatment and women who conceived after ART or naturally.

    Methods

    Four hundred and sixty-eight sub-fertile non-pregnant women, 2972 naturally pregnant women and 143 women pregnant after ART completed a questionnaire in this cross-sectional study. The Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A≥8) and Edinburgh Postnatal Depression Scale (EPDS≥12) were used for assessing anxiety and depressive symptoms, respectively. Multivariate Poisson regression models with robust variance were applied to explore associations with anxiety and depressive symptoms.

    Results

    The prevalence of anxiety and depressive symptoms among sub-fertile, non-pregnant women (57.6% and 15.7%, respectively) were significantly higher compared to women pregnant after ART (21.1% and 8.5%, respectively) and naturally pregnant women (18.8% and 10.3%, respectively). History of psychiatric diagnosis was identified as an independent risk factor for both anxiety and depressive symptoms. The presence of at least one unhealthy lifestyle behavior (daily tobacco smoking, weekly alcohol consumption, BMI≥25, and regular physical exercise < 2 h/week) was also associated with anxiety (Prevalence Ratio, PR: 1.24; 95%CI: 1.09–1.40) and depressive symptoms (PR: 1.25; 95%CI: 1.04–1.49).

    Conclusions

    Women pregnant after ART showed no difference in anxiety and depressive symptoms compared to naturally pregnant women. However, early psychological counseling and management of unhealthy lifestyle behaviors for sub-fertile women may be advisable, particularly for women with a previous history of psychiatric diagnosis.

    Keyword
    anxiety, depression, infertility, assisted reproductive technology, pregnancy
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-338378 (URN)10.1016/j.eurpsy.2017.07.004 (DOI)000414461300029 ()28957789 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-02-12Bibliographically approved
    4. Investigating the effect of lifestyle risk factors upon the number of aspirated and mature oocytes in in vitro fertilization cycles: interaction with antral follicle count
    Open this publication in new window or tab >>Investigating the effect of lifestyle risk factors upon the number of aspirated and mature oocytes in in vitro fertilization cycles: interaction with antral follicle count
    (English)Manuscript (preprint) (Other academic)
    Keyword
    infertility, oocytes, lifestyle, obesity, alcohol, in vitro fertilization, nicotine use, smoking
    National Category
    Clinical Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-338379 (URN)
    Available from: 2018-01-08 Created: 2018-01-08 Last updated: 2018-01-18
  • Public defence: 2018-03-09 10:00 Hamberg, Uppsala
    den Boer, Wendy
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Evolutionary Progression of the Iconic Australasian Kangaroos, Rat-Kangaroos, and their Fossil Relatives (Marsupialia: Macropodiformes)2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The exceptionally diverse macropodiform’s (kangaroos, rat-kangaroos and their fossil allies) currently have a fossil record that spans from the late Oligocene to the Holocene with an Australasian widespread fossil occurence. The origins of the macropodiforms are believed to have been during the Eocene possibly having split from the Phalangeridae. This is largely based on molecular data as there is a complete lack of macropodiform fossil material prior to the late Oligocene leaving the origins of the macropodiforms to be largely speculative. Thus, late Oligocene rat-kangaroo dental fossil elements associated with Palaeopotorous priscus (which shares characteristics observed in both phalangerid and macropodiforms) were examined to get a better insight into the potential origins of the macropodiforms. The results obtained suggested that P. priscus is currently the most basal macropodiform known. Furthermore, due to the absence of adequate macropodiform post-cranial material, the functional eco-morphological interpretation of various macropodiform fossil taxa has been based largely on cranial and dental characteristics. Consequently, the examination of Miocene Balbaridae kangaroo’s (Balbaroo nalima and an untaxonomised balbarid) post-cranial elements was undertaken, suggesting an array of locomotion types (similar to living macropodiforms) and a likely persistent arboreal and quadrupedal lifestyle. In addition, the Pleistocene Protemnodon anak’s post-cranial material are examined, proposing a probable combination of quadrupedal bounding and a slow walking gait alternative to the eminent fast bipedal saltation seen in almost all extant macropodiforms.

    List of papers
    1. A New Species of the Basal "Kangaroo'' Balbaroo and a Re-Evaluation of Stem Macropodiform Interrelationships
    Open this publication in new window or tab >>A New Species of the Basal "Kangaroo'' Balbaroo and a Re-Evaluation of Stem Macropodiform Interrelationships
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    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112705-Article in journal (Refereed) Published
    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.

    National Category
    Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-240097 (URN)10.1371/journal.pone.0112705 (DOI)000345533200034 ()25409233 (PubMedID)
    Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2018-01-22Bibliographically approved
    2. Is the Fossil Rat-Kangaroo Palaeopotorous pricus the Most Basally Branching Macropodiform?
    Open this publication in new window or tab >>Is the Fossil Rat-Kangaroo Palaeopotorous pricus the Most Basally Branching Macropodiform?
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Earth and Related Environmental Sciences
    Research subject
    Earth Science with specialization in Historical Geology and Palaeontology
    Identifiers
    urn:nbn:se:uu:diva-339580 (URN)
    Available from: 2018-01-21 Created: 2018-01-21 Last updated: 2018-01-31Bibliographically approved
    3. Autopodial Anatomy Elucidate Climbing Ability in Miocene Balbarid 'kangaroos' (Marsupialia, Macropodifromes)
    Open this publication in new window or tab >>Autopodial Anatomy Elucidate Climbing Ability in Miocene Balbarid 'kangaroos' (Marsupialia, Macropodifromes)
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Earth and Related Environmental Sciences
    Research subject
    Earth Science with specialization in Historical Geology and Palaeontology
    Identifiers
    urn:nbn:se:uu:diva-339581 (URN)
    Available from: 2018-01-21 Created: 2018-01-21 Last updated: 2018-01-31Bibliographically approved
    4. Functional Eco-Morphology of the 'Giant Extinct Wallaby' Protemnodon anak from Morwell Local Fauna, Victoria, Australia
    Open this publication in new window or tab >>Functional Eco-Morphology of the 'Giant Extinct Wallaby' Protemnodon anak from Morwell Local Fauna, Victoria, Australia
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Earth and Related Environmental Sciences
    Research subject
    Earth Science with specialization in Historical Geology and Palaeontology
    Identifiers
    urn:nbn:se:uu:diva-339582 (URN)
    Available from: 2018-01-21 Created: 2018-01-21 Last updated: 2018-01-31Bibliographically approved
    5. Systematic Review of the Fossil Macropodiformes (Kangaroo, Rat-Kangaroos, and their Allies)
    Open this publication in new window or tab >>Systematic Review of the Fossil Macropodiformes (Kangaroo, Rat-Kangaroos, and their Allies)
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Earth and Related Environmental Sciences
    Research subject
    Earth Science with specialization in Historical Geology and Palaeontology
    Identifiers
    urn:nbn:se:uu:diva-339583 (URN)
    Available from: 2018-01-21 Created: 2018-01-21 Last updated: 2018-01-31Bibliographically approved
  • Public defence: 2018-03-09 13:00 Rudbecksalen, Rudbecklaboratoriet, Uppsala
    Georganaki, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vascular targeting for enhanced cancer immunotherapy2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Induced angiogenesis and chronic inflammation are major components of tumor immunosuppression. The scope of this thesis is to understand the role of the vasculature in anti-tumor immunity and thereby to improve cancer immunotherapy.

    The anti-tumor effects of anti-angiogenic therapies range from vessel normalization to directly affecting immune responses. In Paper I, we demonstrate that VEGF, a major pro-angiogenic factor, inhibits TNFα-induced endothelial activation via interfering with the NF-κB pathway and suppressing T-cell chemoattractants. Sunitinib, an anti-angiogenic tyrosine kinase inhibitor targeting VEGFR2 signaling, enhanced T-cell recruitment and reverted endothelial cell anergy by upregulating pro-inflammatory cytokines in murine melanomas. Therefore, in Paper II, we study the anti-tumor potential of combining sunitinib treatment with CD40-stimulating immunotherapy. CD40 activation leads to increased anti-tumor T-cell responses. The combination therapy was superior in restricting tumor growth and enhancing survival, associated with decreased immunosuppression and increased endothelial activation leading to improved T-cell recruitment. In Paper III, RNA-sequencing reveals that tumor endothelial cells are capable of acquiring negative feedback mechanisms secondary to CD40 immunotherapy by upregulating immunosuppressive genes such as IDO1. Co-administration of agonistic CD40 antibody treatment with an IDO1 inhibitor delayed tumor growth, associated with increased intratumoral T-cell activation.

    In Paper IV, we investigate ELTD1, an orphan adhesion G protein-coupled receptor, which is upregulated in high-grade glioma vessels. ELTD1 deficiency did not affect developmental angiogenesis in mice but increased tumor growth. Interestingly, ELTD1 loss improved glioma vessel perfusion and reduced permeability and hypoxia. Thus, ELTD1 targeting may normalize tumor vessels, potentially enhancing drug delivery.

    In Paper V, we demonstrate that ectopic expression of specific cytokines in murine gliomas induces tertiary lymphoid organ- (TLO-) TLO-like structures in the brain. TLOs, mainly composed of T- and B-cell clusters and high endothelial venules, are onsite preservers of robust immune responses. In line with this, increased survival of mice with gliomas overexpressing either LT-αβ or LIGHT was associated with alleviated tumor immunosuppresion. This suggests that TLO-inducing agents may improve cancer immunotherapy for glioma treatment.

    Collectively, this thesis demonstrates that the tumor vasculature is crucial for anti-tumor immune responses and that vascular targeting can enhance cancer immunotherapy.

    List of papers
    1. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
    Open this publication in new window or tab >>VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
    Show others...
    2015 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 1, p. 227-238Article in journal (Refereed) Published
    Abstract [en]

    Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) signaling pathway is in clinical use, but its effect on vascular function and the tumor microenvironment is poorly understood. Here, we investigate cross-talk between VEGF and proinflammatory TNF-α signaling in endothelial cells and its impact on leukocyte recruitment. We found that cotreatment with VEGF decreased TNF-α-induced Jurkat cell adhesion to human microvascular endothelial cells by 40%. This was associated with inhibition of TNF-α-mediated regulation of 86 genes, including 2 T-lymphocyte-attracting chemokines, CXCL10 and CXCL11 [TNF-α concentration 1 ng/ml; 50% inhibition/inhibitory concentration (IC50) VEGF, 3 ng/ml]. Notably, VEGF directly suppressed TNF-α-induced gene expression through negative cross-talk with the NF-κB-signaling pathway, leading to an early decrease in IFN regulatory factor 1 (IRF-1) expression and reduced phosphorylation of signal transducer and activator of transcription 1 (p-Stat1) at later times. Inhibition of VEGF signaling in B16 melanoma tumor-bearing mice by sunitinib treatment resulted in up-regulation of CXCL10 and CXCL11 in tumor vessels, accompanied by up to 18-fold increased infiltration of CD3(+) T-lymphocytes in B16 tumors. Our results demonstrate a novel role of VEGF in negative regulation of NF-κB signaling and endothelial activation in the tumor microenvironment and provide evidence that pharmacological inhibition of VEGF signaling enhances T-lymphocyte recruitment through up-regulation of chemokines CXCL10 and CXCL11.-Huang, H., Langenkamp, E., Georganaki, M., Loskog, A., Fuchs, P. F., Dieterich, L. C., Kreuger, J., Dimberg, A. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation.

    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-239496 (URN)10.1096/fj.14-250985 (DOI)000347378600022 ()25361735 (PubMedID)
    Note

    Författare två och tre delar andraförfattarskapet.

    Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2018-01-17Bibliographically approved
    2. Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
    Open this publication in new window or tab >>Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
    Show others...
    2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 31, p. 50277-50289Article in journal (Refereed) Published
    Abstract [en]

    CD40-activating immunotherapy has potent antitumor effects due to its ability to activate dendritic cells and induce cytotoxic T-cell responses. However, its efficacy is limited by immunosuppressive cells in the tumor and by endothelial anergy inhibiting recruitment of T-cells. Here, we show that combining agonistic CD40 monoclonal antibody (mAb) therapy with vascular targeting using the tyrosine kinase inhibitor sunitinib decreased tumor growth and improved survival in B16.F10 melanoma and T241 fibrosarcoma. Treatment of tumor-bearing mice with anti-CD40 mAb led to increased activation of CD11c(+) dendritic cells in the tumor draining lymph node, while sunitinib treatment reduced vessel density and decreased accumulation of CD11b(+)Gr1(+) myeloid derived suppressor cells. The expression of ICAM-1 and VCAM-1 adhesion molecules was up-regulated on tumor endothelial cells only when anti-CD40 mAb treatment was combined with sunitinib. This was associated with enhanced intratumoral infiltration of CD8(+) cytotoxic T-cells. Our results show that combining CD40-stimulating immunotherapy with sunitinib treatment exerts potent complementary antitumor effects mediated by dendritic cell activation, a reduction in myeloid derived suppressor cells and increased endothelial activation, resulting in enhanced recruitment of cytotoxic T-cells.

    Keyword
    CD40, sunitinib, MDSC, endothelial activation, T-cell
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-308035 (URN)10.18632/oncotarget.10364 (DOI)000385422000111 ()
    Funder
    EU, FP7, Seventh Framework Programme, 317445Swedish Childhood Cancer FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
    Available from: 2016-11-24 Created: 2016-11-23 Last updated: 2018-01-17Bibliographically approved
    3. Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapy
    Open this publication in new window or tab >>Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapy
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-339104 (URN)
    Available from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-01-17
    4. Loss of tumor vessel marker ELTD1 (ADGRL4) reduces vascular abnormality and enhances tumor growth
    Open this publication in new window or tab >>Loss of tumor vessel marker ELTD1 (ADGRL4) reduces vascular abnormality and enhances tumor growth