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  • Disputation: 2019-10-18 09:15 Häggsalen, Uppsala
    Durall de la Fuente, Claudia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik. Uppsala University.
    Increased Carbon Fixation for Chemical Production in Cyanobacteria2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The combustion of fossil fuels has created many environmental problems, the major one, the greenhouse effect. Thus, we need solutions in order to replace fossil fuels and recycle the CO2 in the atmosphere. Renewable energies have created attention the last decades but electricity is the main energy form obtained. Photosynthetic organisms (including cyanobacteria) can be used as cell factories since they can convert solar energy to chemical energy. In addition, the requisites to grow them are few; light water, CO2 and inorganic nutrients. Cyanobacteria have been genetically engineered in order to produce numerous chemicals and fuels of human interest in direct processes. However, the amount of product obtained is still low. Increased carbon fixation in cyanobacteria results in higher production of carbon-based substances. This thesis focuses on the effects of overexpressing the native phosphoenolpyruvate carboxylase (PEPc) in the model cyanobacterium Synechocystis PCC 6803. PEPc is an essential enzyme and provides oxaloacetate, an intermediate of the tricarboxylic acid cycle (TCA cycle). The TCA cycle is involved in connecting the carbon and nitrogen metabolism in cyanobacteria. The strains were further engineered to produce ethylene and succinate, two examples of interests for the chemical and fuel industry. Strains with additional PEPc produced significantly more ethylene and succinate. Moreover, an in vitro characterization of PEPc from the cyanobacterium Synechococcus PCC 7002 was performed. The focus was on oligomerization state, kinetics and the structure of the carboxylase. This thesis demonstrates that increasing carbon fixation and discovering the bottlenecks in chemical production can lead to higher yields and gives us hope that cyanobacteria can be commercialized.

    Delarbeten
    1. Mechanisms of carbon fixation and engineering for increased carbon fixation in cyanobacteria
    Öppna denna publikation i ny flik eller fönster >>Mechanisms of carbon fixation and engineering for increased carbon fixation in cyanobacteria
    2015 (Engelska)Ingår i: ALGAL RESEARCH-BIOMASS BIOFUELS AND BIOPRODUCTS, ISSN 2211-9264, Vol. 11, s. 263-270Artikel, forskningsöversikt (Refereegranskat) Published
    Abstract [en]

    Cyanobacteria, gram-negative prokaryotic microorganisms, perform oxygenic photosynthesis with a photosynthetic machinery similar to higher plants which includes ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO) as the main CO2-fixing enzyme. Currently, there is a growing interest to use cyanobacteria as photosynthetic microbial cell factories for the direct production of solar fuels or other compounds of human interest. However, rates and efficiencies to produce e.g. biofuels are still very low. The amount of available fixed carbon for the synthesis of desired product(s) may be one of the limiting steps. This contribution reviews CO2-fixation in cyanobacteria with focus on CO2-concentrating mechanisms, RuBisCO, phosphoenolpyruvate carboxylase and other carboxylases, engineering approaches for increased carbon fixation, and finally the synthetic malonyl-CoA-oxaloacetate-glyoxylate pathways.

    Nyckelord
    Carbon fixation, Cyanobacteria, Genetic engineering, MOG pathway, PEPc, RuBisCO, Synechocystis PCC 6803
    Nationell ämneskategori
    Annan biologi Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-267607 (URN)10.1016/j.algal.2015.07.002 (DOI)000363046900033 ()
    Forskningsfinansiär
    VetenskapsrådetKnut och Alice Wallenbergs Stiftelse
    Tillgänglig från: 2015-11-25 Skapad: 2015-11-25 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    2. Enhanced growth at low light intensity in the cyanobacterium Synechocystis PCC 6803 by overexpressing phosphoenolpyruvate carboxylase
    Öppna denna publikation i ny flik eller fönster >>Enhanced growth at low light intensity in the cyanobacterium Synechocystis PCC 6803 by overexpressing phosphoenolpyruvate carboxylase
    2016 (Engelska)Ingår i: ALGAL RESEARCH-BIOMASS BIOFUELS AND BIOPRODUCTS, ISSN 2211-9264, Vol. 16, s. 275-281Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Synechocystis PCC 6803 strains overexpressing pepc, gene encoding the carbon fixing enzyme phosphoenolpyruvate carboxylase (PEPc), were constructed and characterized for growth, PEPc protein content and in vitro PEPc activities. Synechocystis strains WT + Km(r) - one (native) copy of pepc (control), WT + 2xPEPc - native copy of pepc and two additional native copies of pepc (in total three copies of pepc), and WT + PPM - native copies of ppsa (encoding phosphoenolpyruvate synthase), pepc and mdh (encoding malate dehydrogenase) and one additional copy of each gene (in total two copies each of ppsa, pepc and mdh) were analyzed for growth under normal and low light intensities, and in darkness (no growth). No significant differences in the growth rates were observed when the cells were grown under normal light intensity. However, growth under low light intensity (3 mu mol photons.m(-2).sec(-1)) resulted in increased growth rate, in particular in the strain with 3 copies of pepc. SDS-PAGE/Western immunoblots using antibodies directed against PEPc demonstrated an increased level of PEPc protein with increasing number of copies of pepc. This was followed by increased levels of in vitro PEPc activities. A less efficient ribulose 1,5-bisphosphate carboxylase/oxygenase in combination with reduced levels of NADPH and ATP under low light condition may make the relatively more efficient carbon fixing enzyme PEPc the limiting step for growth under this condition.

    Nyckelord
    Genetic engineering, Enhanced growth, pepc, Phosphoenolpyruvate carboxylase, Synechocystis
    Nationell ämneskategori
    Biomaterial
    Identifikatorer
    urn:nbn:se:uu:diva-297764 (URN)10.1016/j.algal.2016.03.027 (DOI)000375610000032 ()
    Forskningsfinansiär
    Knut och Alice Wallenbergs Stiftelse, 2011.0067Energimyndigheten
    Tillgänglig från: 2016-06-28 Skapad: 2016-06-28 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    3. Phosphoenolpyruvate carboxylase in Synechococcus PCC 7002: Oligomerization, structure, and characteristics
    Öppna denna publikation i ny flik eller fönster >>Phosphoenolpyruvate carboxylase in Synechococcus PCC 7002: Oligomerization, structure, and characteristics
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392227 (URN)
    Tillgänglig från: 2019-09-01 Skapad: 2019-09-01 Senast uppdaterad: 2019-09-01
    4. Increased ethylene production by overexpressing phosphoenolpyruvate carboxylase in the cyanobacterium Synechocystis PCC 6803
    Öppna denna publikation i ny flik eller fönster >>Increased ethylene production by overexpressing phosphoenolpyruvate carboxylase in the cyanobacterium Synechocystis PCC 6803
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392232 (URN)
    Tillgänglig från: 2019-09-01 Skapad: 2019-09-01 Senast uppdaterad: 2019-09-01
    5. Increased succinate production by expressing a glyoxylate shunt in the engineered Synechocystis PCC 6803
    Öppna denna publikation i ny flik eller fönster >>Increased succinate production by expressing a glyoxylate shunt in the engineered Synechocystis PCC 6803
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Biologiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392233 (URN)
    Tillgänglig från: 2019-09-01 Skapad: 2019-09-01 Senast uppdaterad: 2019-09-01
    6. Engineering Cyanobacteria for Biofuel Production
    Öppna denna publikation i ny flik eller fönster >>Engineering Cyanobacteria for Biofuel Production
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    2017 (Engelska)Ingår i: Modern Topics in the Phototrophic Prokaryotes: Environmental and Applied Aspects / [ed] Hallenbeck, Patrick, USA: Springer, 2017, s. 351-393Kapitel i bok, del av antologi (Refereegranskat)
    Ort, förlag, år, upplaga, sidor
    USA: Springer, 2017
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-338078 (URN)978-3-319-46259-2 (ISBN)978-3-319-46261-5 (ISBN)
    Tillgänglig från: 2018-01-07 Skapad: 2018-01-07 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
  • Disputation: 2019-10-18 09:15 Room B42, Uppsala
    Vallianatou, Theodosia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Advanced Mass Spectrometry Imaging in Neuropharmacology2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Mass spectrometry imaging (MSI) has emerged as a valuable approach for mapping multiple molecular species in sections of diverse tissues. It enables simultaneous detection of numerous compounds (from neurotransmitters to small proteins) in the brain at relatively high lateral resolution (>5 μm) on a routine basis. Matrix-assisted laser desorption/ionization (MALDI)-MSI and desorption electrospray ionization (DESI)-MSI are the most widely applied MSI techniques in tissue distribution studies. Recent advances in MSI instruments and software allow quantitative analysis of large numbers of compounds with high mass accuracy and high mass resolving power. Thus, in studies this thesis is based upon, MSI technology was used to address several challenging aspects of neuropharmacology. Restricted passage of potentially neuroactive substances into the brain, unpredictable multi-target effects, and the complexity of the central nervous system (CNS) physiology, are major obstacles in the development of efficient drugs. The simultaneous investigation of drugs’ delivery to the brain and potential effects on several CNS pathways in specific brain regions is, therefore, highly important. In addition, localization information is required for more comprehensive insights into CNS responses to both pharmaceutical agents and biological processes such as aging.

    MSI-based analysis of the transport of two selected drugs into the brain demonstrated effects of efflux membrane proteins on their distributions in the brain. The MDR1 substrate loperamide was found to localize specifically in the choroid plexus, indicating low brain entrance. In addition, MSI uncovered drug-drug interactions at the blood-brain barrier involving MDR1 inhibition. The technology was further used to explore neurochemical alterations induced by aging and acetylcholinesterase inhibition. First, MSI revealed that the cholinergic system’s responsivity in the retrosplenial cortex, a post-cingulate cortical area highly involved in cognition, to acetylcholinesterase inhibition significantly declined with age. Subsequently, simultaneous investigation of multiple brain metabolic pathways in specific brain areas with multivariate data analysis techniques demonstrated age-induced alterations in mitochondrial function, lipid signaling, and acetylcholine metabolism. Finally, MSI unveiled age-induced alterations in levels and distributions of the monoaminergic neurotransmitters and their metabolites in particular brain areas such as the ventral pallidum, caudate putamen, hippocampus, and cortical substructures. Age- and region-specific effects of acetylcholinesterase inhibition on the neurotransmitter systems were also detected. In conclusion, the studies provided novel insights into important brain pharmacokinetic and pharmacodynamic phenomena using advanced MSI techniques, as described and discussed in this thesis.

    Delarbeten
    1. A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability
    Öppna denna publikation i ny flik eller fönster >>A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability
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    2018 (Engelska)Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 172, s. 808-816Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    There is a high need to develop quantitative imaging methods capable of providing detailed brain localization information of several molecular species simultaneously. In addition, extensive information on the effect of the blood-brain barrier on the penetration, distribution and efficacy of neuroactive compounds is required. Thus, we have developed a mass spectrometry imaging method to visualize and quantify the brain distribution of drugs with varying blood-brain barrier permeability. With this approach, we were able to determine blood-brain barrier transport of different drugs and define the drug distribution in very small brain structures (e.g., choroid plexus) due to the high spatial resolution provided. Simultaneously, we investigated the effect of drug-drug interactions by inhibiting the membrane transporter multidrug resistance 1 protein. We propose that the described approach can serve as a valuable analytical tool during the development of neuroactive drugs, as it can provide physiologically relevant information often neglected by traditional imaging technologies.

    Nyckelord
    Mass spectrometry imaging, Blood-brain barrier, Drug-drug interactions, Elacridar, Loperamide, Propranolol
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-353358 (URN)10.1016/j.neuroimage.2018.01.013 (DOI)000430364100067 ()29329980 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 2013-3105]Vetenskapsrådet, 2014-6215]Stiftelsen för strategisk forskning (SSF), RIF14-0078]AstraZenecaEU, FP7, Sjunde ramprogrammet, 607517HjärnfondenScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
    Tillgänglig från: 2018-06-12 Skapad: 2018-06-12 Senast uppdaterad: 2019-09-02Bibliografiskt granskad
    2. Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition.
    Öppna denna publikation i ny flik eller fönster >>Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition.
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    2019 (Engelska)Ingår i: Neuropsychopharmacology, ISSN 0893-133X, Vol. 0, s. 1-8Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The neurotransmitter of the cholinergic system, acetylcholine plays a major role in the brain's cognitive function and is involved in neurodegenerative disorders. Here, we present age-related alterations of acetylcholine levels after administration of the acetylcholinesterase inhibitor drug tacrine in normal mice. Using a quantitative, robust and molecular-specific mass spectrometry imaging method we found that tacrine administration significantly raised acetylcholine levels in most areas of sectioned mice brains, inter alia the striatum, hippocampus and cortical areas. However, acetylcholine levels in retrosplenial cortex were significantly lower in 14-month-old than in 12-week-old animals following its administration, indicating that normal aging affects the cholinergic system's responsivity. This small brain region is interconnected with an array of brain networks and is involved in numerous cognitive tasks. Simultaneous visualization of distributions of tacrine and its hydroxylated metabolites in the brain revealed a significant decrease in levels of the metabolites in the 14-month-old mice. The results highlight strengths of the imaging technique to simultaneously investigate multiple molecular species and the drug-target effects in specific regions of the brain. The proposed approach has high potential in studies of neuropathological conditions and responses to neuroactive treatments.

    Nyckelord
    mass spectrometry imaging, acetylcholine, retrosplenial cortex, tacrine, aging
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392312 (URN)10.1038/s41386-019-0397-5 (DOI)
    Tillgänglig från: 2019-09-02 Skapad: 2019-09-02 Senast uppdaterad: 2019-09-02
    3. Imaging age-induced perturbations of mitochondrial function, neurotransmission and lipid signaling in specific brain regions
    Öppna denna publikation i ny flik eller fönster >>Imaging age-induced perturbations of mitochondrial function, neurotransmission and lipid signaling in specific brain regions
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392314 (URN)
    Tillgänglig från: 2019-09-02 Skapad: 2019-09-02 Senast uppdaterad: 2019-09-02
    4. Imaging aging effects on the catecholamine, serotonin, and histamine neurotransmitter systems in specific brain regions
    Öppna denna publikation i ny flik eller fönster >>Imaging aging effects on the catecholamine, serotonin, and histamine neurotransmitter systems in specific brain regions
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392315 (URN)
    Tillgänglig från: 2019-09-02 Skapad: 2019-09-02 Senast uppdaterad: 2019-09-02
  • Disputation: 2019-10-18 10:15 ITC 2446, Uppsala
    Cheng, Gong
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för beräkningsvetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Numerisk analys.
    Numerical ice sheet modeling: Forward and inverse problems2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Ice sheets have strong influence on the climate system. Numerical simulation provides a mathematical tool to study the ice dynamics in the past and to predict their contribution to climate change in the future. Large scale ice sheets behave as incompressible non-Newtonian fluid. The evolution of ice sheet is governed by the conservation laws of mass, momentum and energy, which is formulated as a system of partial differential equations. Improving the efficiency of numerical ice sheet modeling is always a desirable feature since many of the applications have large domain and aim for long time span. With such a goal, the first part of this thesis focuses on developing efficient and accurate numerical methods for ice sheet simulation.

    A large variety of physical processes are involved in ice dynamics, which are described by physical laws with parameters measured from experiments and field work. These parameters are considered as the inputs of the ice sheet simulations. In certain circumstances, some parameters are unavailable or can not be measured directly. Therefore, the second part of this thesis is devoted to reveal these physical parameters by solving inverse problems.

    In the first part, improvements of temporal and spatial discretization methods and a sub-grid boundary treatment are purposed. We developed an adaptive time stepping method in Paper I to automatically adjust the time steps based on stability and accuracy criteria. We introduced an anisotropic Radial Basis Function method for the spatial discretization of continental scale ice sheet simulations in Paper II. We designed a sub-grid method for solving grounding line migration problem with Stokes equations in Paper VI.

    The second part of the thesis consists of analysis and numerical experiments on inverse problems. In Paper IV and V, we conducted sensitivity analysis and numerical examples of the inversion on time dependent ice sheet simulations. In Paper III, we solved an inverse problem for the thermal conductivity of firn pack at Lomonosovfonna, Svalbard, using the subsurface temperature measurements.

    Delarbeten
    1. Accurate and stable time stepping in ice sheet modeling
    Öppna denna publikation i ny flik eller fönster >>Accurate and stable time stepping in ice sheet modeling
    2017 (Engelska)Ingår i: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 329, s. 29-47Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Beräkningsmatematik
    Identifikatorer
    urn:nbn:se:uu:diva-309278 (URN)10.1016/j.jcp.2016.10.060 (DOI)000390511500003 ()
    Projekt
    eSSENCE
    Tillgänglig från: 2016-11-02 Skapad: 2016-12-02 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    2. Anisotropic radial basis function methods for continental size ice sheet simulations
    Öppna denna publikation i ny flik eller fönster >>Anisotropic radial basis function methods for continental size ice sheet simulations
    2018 (Engelska)Ingår i: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 372, s. 161-177Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Beräkningsmatematik
    Identifikatorer
    urn:nbn:se:uu:diva-333469 (URN)10.1016/j.jcp.2018.06.020 (DOI)000443284400008 ()
    Projekt
    eSSENCE
    Tillgänglig från: 2018-06-15 Skapad: 2017-11-14 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    3. Thermal conductivity of firn at Lomonosovfonna, Svalbard, derived from subsurface temperature measurements
    Öppna denna publikation i ny flik eller fönster >>Thermal conductivity of firn at Lomonosovfonna, Svalbard, derived from subsurface temperature measurements
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    2019 (Engelska)Ingår i: The Cryosphere, ISSN 1994-0416, E-ISSN 1994-0424, Vol. 13, s. 1843-1859Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Naturgeografi
    Identifikatorer
    urn:nbn:se:uu:diva-334156 (URN)10.5194/tc-13-1843-2019 (DOI)000474653300002 ()
    Tillgänglig från: 2019-07-09 Skapad: 2017-11-21 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    4. Parameter sensitivity analysis of dynamic ice sheet models
    Öppna denna publikation i ny flik eller fönster >>Parameter sensitivity analysis of dynamic ice sheet models
    2019 (Engelska)Ingår i: Computing Research Repository, nr 1906.08197Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Nationell ämneskategori
    Beräkningsmatematik Multidisciplinär geovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-392198 (URN)
    Tillgänglig från: 2019-06-19 Skapad: 2019-08-30 Senast uppdaterad: 2019-09-03Bibliografiskt granskad
    5. Parameter sensitivity analysis of dynamic ice sheet models: Numerical computations
    Öppna denna publikation i ny flik eller fönster >>Parameter sensitivity analysis of dynamic ice sheet models: Numerical computations
    2019 (Engelska)Ingår i: The Cryosphere Discussions, ISSN 1994-0432, E-ISSN 1994-0440Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Nationell ämneskategori
    Beräkningsmatematik Multidisciplinär geovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-392146 (URN)10.5194/tc-2019-151 (DOI)
    Projekt
    eSSENCE
    Tillgänglig från: 2019-08-12 Skapad: 2019-08-29 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    6. A full Stokes subgrid model for simulation of grounding line migration in ice sheets using Elmer/ICE(v8.3)
    Öppna denna publikation i ny flik eller fönster >>A full Stokes subgrid model for simulation of grounding line migration in ice sheets using Elmer/ICE(v8.3)
    2019 (Engelska)Ingår i: Geoscientific Model Development Discussions, ISSN 1991-9611, E-ISSN 1991-962XArtikel i tidskrift (Övrigt vetenskapligt) Submitted
    Nationell ämneskategori
    Beräkningsmatematik Multidisciplinär geovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-392197 (URN)10.5194/gmd-2019-244 (DOI)
    Projekt
    eSSENCE
    Tillgänglig från: 2019-09-16 Skapad: 2019-08-30 Senast uppdaterad: 2019-10-02Bibliografiskt granskad
  • Disputation: 2019-10-18 10:15 Sydney Alrutz-salen, Uppsala
    Lymeus, Freddie
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Mindfulness training supported by a restorative natural setting: Integrating individual and environmental approaches to the management of adaptive resources2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis integrates restorative environments research and mindfulness research: two disparate but related approaches to managing the demands of modern living. Both offer ways to improve attention regulation by detaching from routine mental contents and engaging with present experience. However, restoration works bottom-up, from supportive environmental features, while mindfulness meditation works top-down, through effortful training. Complementarities between the two are the foundations of restoration skills training (ReST), a five-week mindfulness-based course that uses mindful sensory exploration in a natural setting to build a meditative state effortlessly. As in conventional mindfulness training (CMT), ReST involves a learning structure to teach versatile adaptive skills.

    Data were collected in four rounds, with successively refined versions of ReST given in a botanic garden and formally matched CMT given indoors. Data were collected to test short-term outcomes of practice sessions and long-term course outcomes. Four papers aim to determine whether ReST confers similar health benefits as CMT and has specific advantages related to lower effort and enhanced restoration. Paper I shows that on repeated measurement occasions across the course weeks, attention tests obtained before and after ReST practice sessions showed restorative effects (improved performance) consistently for general attention and increasingly for executive attention. In contrast, CMT practice indoors incurred increasing effort (deteriorated performance) seen in general attention. Despite these different short-term outcomes, ReST and CMT conferred similar generalized improvements over the course weeks. Paper II shows that ReST compared with CMT had higher course completion and better establishment of a regular practice. Compliance was mediated through perceived restorative qualities in the meditation setting and state mindfulness during the classes. Paper III shows that ReST was attended by at least similar benefits for general psychological functioning as CMT. Ratings of dispositional mindfulness and attention problems remained improved six months after ReST. After CMT, only attention problem ratings remained improved. However, chronic stress ratings were not lastingly improved with either course. Paper IV shows that with ReST, participants with higher initial ratings of attention problems subsequently completed more homework practice during the course. Homework practice in turn explained part of the improvement in dispositional mindfulness and attention problems. With CMT, homework practice was unrelated to initial attention problems and improvement. In conclusion, ReST is a promising alternative for people who struggle under heavy attention demands; effortful training is not necessary to improve attention regulation in early stages of mindfulness training. The theoretical and practical integration can guide further exchange between these related research fields.

    Delarbeten
    1. Building mindfulness bottom-up: Meditation in natural settings supports open monitoring and attention restoration
    Öppna denna publikation i ny flik eller fönster >>Building mindfulness bottom-up: Meditation in natural settings supports open monitoring and attention restoration
    2018 (Engelska)Ingår i: Consciousness and Cognition, ISSN 1053-8100, E-ISSN 1090-2376, Vol. 59, s. 40-56Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

     Mindfulness courses conventionally use effortful, focused meditation to train attention. In contrast, natural settings can effortlessly support state mindfulness and restore depleted attention resources, which could facilitate meditation. We performed two studies that compared conventional training with restoration skills training (ReST) that taught low-effort open monitoring meditation in a garden over five weeks. Assessments before and after meditation on multiple occasions showed that ReST meditation increasingly enhanced attention performance. Conventional meditation enhanced attention initially but increasingly incurred effort, reflected in performance decrements toward the course end. With both courses, attentional improvements generalized in the first weeks of training. Against established accounts, the generalized improvements thus occurred before any effort was incurred by the conventional exercises. We propose that restoration rather than attention training can account for early attentional improvements with meditation. ReST holds promise as an undemanding introduction to mindfulness and as a method to enhance restoration in nature contacts.

    Nyckelord
    Attention, Mindfulness, Meditation, Restoration, Training
    Nationell ämneskategori
    Psykologi
    Identifikatorer
    urn:nbn:se:uu:diva-341717 (URN)10.1016/j.concog.2018.01.008 (DOI)000427810400005 ()
    Tillgänglig från: 2018-02-13 Skapad: 2018-02-13 Senast uppdaterad: 2019-08-25Bibliografiskt granskad
    2. A natural meditation setting improves compliance with mindfulness training
    Öppna denna publikation i ny flik eller fönster >>A natural meditation setting improves compliance with mindfulness training
    2019 (Engelska)Ingår i: Journal of Environmental Psychology, ISSN 0272-4944, E-ISSN 1522-9610, Vol. 64, s. 98-106Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The setting matters in meditation, but most research has neglected it. Many mindfulness-based health interventions emphasize effortful attention training exercises in sparsely furnished indoor settings. However, many beginners with attention regulation problems struggle with the exercises and drop out. In contrast, restoration skills training (ReST) – a five-week course set in a garden environment – builds on mindfulness practices adapted to draw on restorative processes stimulated effortlessly in nature contacts. Expecting that the ReST approach will facilitate the introduction to mindfulness, we compared drop-out and homework completion records from four rounds of ReST vs. conventional mindfulness training (N = 139). Randomly assigned ReST participants had lower drop-out and more sustained homework completion over the course weeks. Supporting the theoretical assumptions, higher restorative environmental qualities and state mindfulness mediated the compliance differences. The improved acceptability with ReST means that more people can enjoy the long-term benefits of establishing a meditation practice.

    Nyckelord
    Mindfulness, Nature, Restoration, Environment, Compliance, Acceptability
    Nationell ämneskategori
    Psykologi
    Identifikatorer
    urn:nbn:se:uu:diva-390941 (URN)
    Tillgänglig från: 2019-08-16 Skapad: 2019-08-16 Senast uppdaterad: 2019-08-25
    3. Mindfulnesss-based restoration skills training (ReST) in a natural setting compared to conventional mindfulness training: A randomized trial with six-month follow-up
    Öppna denna publikation i ny flik eller fönster >>Mindfulnesss-based restoration skills training (ReST) in a natural setting compared to conventional mindfulness training: A randomized trial with six-month follow-up
    Visa övriga...
    (Engelska)Ingår i: Frontiers in Psychology, ISSN 1664-1078, E-ISSN 1664-1078Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Abstract [en]

    Restoration skills training (ReST) is a mindfulness-based course that draws on restorative nature experience to facilitate the meditation practice and teach widely applicable adaptation skills. Previous studies comparing ReST against conventional mindfulness training (CMT) show that ReST has several important advantages: ReST supports beginning meditators with stress and concentration problems in effortless meditation practice and in connecting with restorative environmental qualities, restores their attention regulation capabilities, and helps them complete the course and establish a regular meditation habit. However, mindfulness theory indicates that effortful training is central to achieving the well-established health benefits of beginning mindfulness training. Therefore, this study tests whether the more effortless and acceptable ReST approach is attended by any meaningful disadvantage compared to CMT in terms of health benefits. Over four rounds of parallel courses, participants (total initial N = 152) provided ratings of dispositional mindfulness, cognitive functioning, and chronic stress before, directly after, and (in rounds 2 – 4) six months after the course. Round 4 also included a separately recruited passive control condition. ReST and CMT were attended by similar average improvements in the three outcomes, which for dispositional mindfulness and cognitive functioning were sustained at the follow-up. For those who completed the course, over one third enjoyed reliably improved psychological functioning directly after the course and six months later. The risk of experiencing deteriorated functioning was no greater with either ReST or CMT than for passive control group participants. We conclude that ReST is a promising alternative for people with stress or concentration problems who would be less likely to complete more effortful CMT. Theoretically, we indicate how meditation science can inform restorative environments research regarding learning processes involved in repeated restorative encounters. Environmental approaches to health have the advantage over individual, skill-based approaches that they mitigate fatigue and reinstate lost capacities without imposing further demands. Skill-based approaches have the advantage that they can train adaptive capabilities that then can be deployed even in unsupportive contexts. ReST integrates those advantages.

    Nyckelord
    Mindfulness, Restoration, Meditation, Nature, Environment, Training
    Nationell ämneskategori
    Psykologi
    Forskningsämne
    Psykologi
    Identifikatorer
    urn:nbn:se:uu:diva-391656 (URN)
    Tillgänglig från: 2019-08-25 Skapad: 2019-08-25 Senast uppdaterad: 2019-08-25
    4. Mindfulness meditation training in a natural setting particularly helps people with attention problems
    Öppna denna publikation i ny flik eller fönster >>Mindfulness meditation training in a natural setting particularly helps people with attention problems
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    Mindfulness, Restoration, Attention, Meditation, Nature, Environment
    Nationell ämneskategori
    Psykologi
    Forskningsämne
    Psykologi
    Identifikatorer
    urn:nbn:se:uu:diva-391657 (URN)
    Tillgänglig från: 2019-08-25 Skapad: 2019-08-25 Senast uppdaterad: 2019-08-25
  • Disputation: 2019-10-18 13:00 Rudbecksalen, Uppsala
    Arousell, Jonna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Sacred Ideals: Diversity and Equality in Swedish Reproductive Healthcare2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    To promote diversity (mångfald) and equality (jämlikhet) is a key task for a wide range of welfare institutions in Sweden. The two terms appeal to several aspects simultaneously: inclusiveness, moral goodness, awareness and willingness to facilitate a positive social change. Diversity and equality have become, as I suggest in this thesis, two sacred ideals in Swedish society today. In the context of reproductive healthcare, various forms of diversity and equality measures are thought of as solutions to, for instance, inequalities between immigrant groups and others, structural discrimination of minority groups, and difficulties faced by the Swedish healthcare system in caring for patients’ diverse needs and preferences in clinical encounters. In this thesis, diversity and equality are analysed as two important governing mechanisms in the organisation of healthcare in multicultural Sweden. The aim was to explore how these ideals contribute to shape the provision of reproductive healthcare, and its consequences.

    Paper I shows that targeted interventions towards immigrant women in contraceptive counselling risk singling out some women from standard routes of care because they are categorised as “immigrants” or “Muslims”. Paper II shows that demands upon healthcare providers to accommodate Muslim patients’ presumed needs have the potential of also creating needs that were not there from the start. Paper III shows that many religious counsellors who are affiliated with Swedish healthcare as spiritual advisers present ideas on abortion that are less progressive than what is stipulated in Swedish abortion law. Paper IV shows that imperatives to promote gender equality in contraceptive counselling were taken seriously by providers in their encounters with non-Western women, at the possible expense of respect for relationship structures that do not conform to the ideals of gender equality.

    The findings presented in this thesis show that the interventions and initiatives that sought to presumably help disadvantaged groups of people (i.e. Muslims, immigrant women) could, in fact, be obstacles to solving the problems they were meant to address. I argue that the governance of Swedish reproductive healthcare through diversity and equality ideals must be problematised and balanced with regard to their plausible consequences.

    Delarbeten
    1. Are 'low socioeconomic status' and 'religiousness' barriers to minority women's use of contraception? A qualitative exploration and critique of a common argument in reproductive health research
    Öppna denna publikation i ny flik eller fönster >>Are 'low socioeconomic status' and 'religiousness' barriers to minority women's use of contraception? A qualitative exploration and critique of a common argument in reproductive health research
    2019 (Engelska)Ingår i: Midwifery, ISSN 0266-6138, E-ISSN 1532-3099, Vol. 75, s. 59-65Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: 'Low socioeconomic status' and 'religiousness' appear to have gained status as nearly universal explanatory models for why women in minority groups are less likely to use contraception than other women in the Scandinavian countries. Through interviews with pious Muslim women with immigrant background, living in Denmark and Sweden, we wanted to gain empirical insights that could inform a discussion about what 'low socioeconomic status' and 'religiousness' might mean with regard to women's reproductive decisions.

    Design: Semi-structured interviews were conducted in Denmark and Sweden between 2013 and 2016.

    Findings: We found that a low level of education and a low income were not necessarily obstacles for women's use of contraception; rather, these were strong imperatives for women to wait to have children until their life circumstances become more stable. Arguments grounded in Islamic dictates on contraception became powerful tools for women to substantiate how it is religiously appropriate to postpone having children, particularly when their financial and emotional resources were not yet established.

    Conclusion: We have shown that the dominant theory that 'low socioeconomic status' and 'religiousness' are paramount barriers to women's use of contraception must be problematized. When formulating suggestions for how to provide contraceptive counseling to women in ethnic and religious minority groups in Denmark and Sweden, one must also take into account that factors such as low financial security as well as religious convictions can be strong imperatives for women to use contraception.

    Implications for practice: This study can help inform a critical discussion about the difficulties of using broad group-categorizations for understanding individuals' health-related behavior, as well as the validity of targeted interventions towards large heterogeneous minority groups in Scandinavian contraceptive counseling.

    Nyckelord
    Muslim women, Immigrant women, Contraceptive use, Reproductive health, Denmark, Sweden
    Nationell ämneskategori
    Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi Reproduktionsmedicin och gynekologi
    Identifikatorer
    urn:nbn:se:uu:diva-388751 (URN)10.1016/j.midw.2019.03.017 (DOI)000470962400011 ()31005014 (PubMedID)
    Forskningsfinansiär
    Forte, Forskningsrådet för hälsa, arbetsliv och välfärd, 2014-4576
    Tillgänglig från: 2019-08-14 Skapad: 2019-08-14 Senast uppdaterad: 2019-09-05Bibliografiskt granskad
    2. Modes of Governing: A Foucaultian Perspective on Encounters between Healthcare Providers and Muslim Women in Swedish Reproductive Healthcare
    Öppna denna publikation i ny flik eller fönster >>Modes of Governing: A Foucaultian Perspective on Encounters between Healthcare Providers and Muslim Women in Swedish Reproductive Healthcare
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    There are probably few groups of patients in Sweden today that arouse as much associations and thoughts as do Muslims from the Middle East. The core dilemma in much of these discussions is whether healthcare providers should adjust the provision of care to Muslims’ divergent religious preferences, or if they would be better off to treat Muslims in the same way as other patients. These debates are often entangled with both a concern about politics of equality (i.e. ambitions to treat everyone the same) and politics of diversity (i.e. to treatpeople from ethnic and religious minority groups differently). Inspired by Foucault’s concept of governmentality, we in this study intended to explore the principles of ‘equality’ and 'diversity’ as governing tools for the shaping of healthcare providers and patients’ conduct. We found that although these governing tools are presented as non-conflicting in health policies, there seems to be an often-present trade-off between diversity and equality ideals in their practical implementation. When these policies are assigned meaning and implemented inpractice, they appear to generate unforeseeable consequences, both for healthcare providers and for the patients. It thus appears that the policies that were introduced with the intention of improving the structure of multicultural care encounters, in some cases, had an opposite effect.

    Nyckelord
    Muslim, reproductive healthcare, diversity, equality, politics of recognition, Sweden
    Nationell ämneskategori
    Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392207 (URN)
    Tillgänglig från: 2019-08-31 Skapad: 2019-08-31 Senast uppdaterad: 2019-09-05Bibliografiskt granskad
    3. Does Religious Counselling on Abortion Comply with Sweden’s ‘Women‑Friendly’ Abortion Policies?: A Qualitative Exploration Among Religious Counsellors
    Öppna denna publikation i ny flik eller fönster >>Does Religious Counselling on Abortion Comply with Sweden’s ‘Women‑Friendly’ Abortion Policies?: A Qualitative Exploration Among Religious Counsellors
    2019 (Engelska)Ingår i: Sexuality & Culture, ISSN 1095-5143, E-ISSN 1936-4822, s. 1-20Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The abortion discourse in Sweden is marked by historically liberal ideals about women’s inviolable right to make autonomous reproductive decisions. However, to respond to the increase in cultural and religious pluralism building up over several decades, religious organizations have been given opportunities to provide so-called spiritual care in affiliation with Swedish hospitals since the 1980s. In this study we asked: in what ways do religious counsellors, affiliated with Swedish hospitals, construct their ideas on abortion, and how well do their ideas comply with Sweden’s ‘women-friendly’ abortion policies? Through interviews with Protestant, Catho-lic, Muslim, and Buddhist religious counsellors, we wanted to empirically test the presumption underlying the decisions to grant space to religious actors in Swedish healthcare, i.e., that religious counselling serves to complement existing services. We found that it cannot be expected that religious advice on abortion will always comply with Swedish abortion law and with the women-friendly abortion policy that the Swedish state seeks to impose. When policy-makers open up possibilities for diverse norms on abortion to manifest in close affiliation with healthcare institutions, they must be aware that some religious counsellors argue that only God—and not the woman herself—can decide whether a woman can terminate a pregnancy. We argue that the findings in this study speaks to what researchers have referred to as the “diversity-equality paradox”, which highlights the tension between the promotion of religious ideas on abortion on the one hand and the promotion of liberal ideas about women’s reproductive freedom on the other.

    Nyckelord
    Abortion, Women’s rights, Religious counselling, Diversity promotion, The diversity–equality paradox, Healthcare, Sweden
    Nationell ämneskategori
    Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi
    Identifikatorer
    urn:nbn:se:uu:diva-389908 (URN)10.1007/s12119-019-09614-6 (DOI)
    Forskningsfinansiär
    Forte, Forskningsrådet för hälsa, arbetsliv och välfärd
    Tillgänglig från: 2019-07-31 Skapad: 2019-07-31 Senast uppdaterad: 2019-09-05
    4. Unintended Consequences of Gender Equality Promotion in Swedish Multicultural Contraceptive Counseling: A Discourse Analysis.
    Öppna denna publikation i ny flik eller fönster >>Unintended Consequences of Gender Equality Promotion in Swedish Multicultural Contraceptive Counseling: A Discourse Analysis.
    Visa övriga...
    2017 (Engelska)Ingår i: Qualitative Health Research, ISSN 1049-7323, E-ISSN 1552-7557, Vol. 27, nr 10, s. 1518-1528Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In this article, we explore how reproductive health care providers in Sweden, a country often described as one of the most gender-equal countries in the world, incorporate gender equality ideals in multicultural contraceptive counseling. In the tension between gender equality promotion on one hand and respect for cultural diversity and individualized care on the other, we will demonstrate that values of gender equality were often given priority. This is not necessarily undesirable. Nevertheless, our proposal is that the gender equality ideology may inhibit providers' ability to think differently about issues at stake in contraceptive counseling, which may negatively influence women's possibilities to obtain adequate support. At the end of the article, we suggest how health care providers' reflexivity might be used as a working tool for increased awareness about the taken-for-granted cultural norms that exist in their clinical milieu.

    Nyckelord
    Sweden, contraceptive counseling, cultural diversity, discourse analysis, gender equality, qualitative method, reproductive health, women
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-327196 (URN)10.1177/1049732317697099 (DOI)000406057500007 ()28728532 (PubMedID)
    Forskningsfinansiär
    Forte, Forskningsrådet för hälsa, arbetsliv och välfärd
    Tillgänglig från: 2017-08-07 Skapad: 2017-08-07 Senast uppdaterad: 2019-08-31Bibliografiskt granskad
  • Disputation: 2019-10-18 13:15 Ångströmlaboratoriet, Å80101, Uppsala
    Unger, Elisabeth
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Högenergifysik.
    The Extremes of Neutrino Astronomy: From Fermi Bubbles with IceCube to Ice Studies with ARIANNA2019Doktorsavhandling, monografi (Övrigt vetenskapligt)
    Abstract [en]

    The Fermi bubbles are extended regions of hard gamma-ray emission which were discovered with Fermi-LAT data to exist above and below the Galactic Center. In order to explain the origin of the gamma-rays, different theories are proposed. In particular, within hadronic models, highly-accelerated cosmic rays interact with interstellar matter and create the observed gamma-rays and in addition neutrinos. Data from the neutrino detector IceCube was analyzed using a maximum likelihood method. An upper limit on the possible neutrino flux from the Fermi bubbles at energies between 10 GeV and 200 GeV was determined.

    While this analysis is performed with the lowest energies IceCube can reach, the ARIANNA (Antarctic Ross Ice-shelf ANtenna Neutrino Array) experiment has the goal to detect the highest energy neutrinos by measuring radio wave radiation produced by their interaction products in the ice. With ARIANNA the propagation of radio waves in the firn (packed snow) of the Ross Ice Shelf was investigated. According to the classical approach the radio waves, produced in the firn, are supposed to bend down because of the changing density, and therefore changing refractive index, an effect which is called “shadowing”. Evidence that the waves can travel horizontally over a long distance will be presented. The horizontally propagating signals between two boreholes and to the ARIANNA stations were analyzed and characterized. Analyses were performed under two hypotheses to determine attenuation lengths for horizontal propagation signals. The results showed attenuation lengths between 310 m ± 83 m and 651 m ± 270 m, depending on the assumed hypothesis and performed analysis. In addition unexpected signals consistent with radio waves propagating along the firn surface, here called pre-pulses, were observed and characterized.

  • Disputation: 2019-10-23 10:00 Zootissalen, Uppsala
    Linde, Anna-Malin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Växtekologi och evolution.
    Rates and patterns of bryophyte molecular evolution2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Plants have been growing on land for at least 450 million years. The bryophytes comprising the three phyla liverworts, mosses and hornworts, are considered to be the closest extant relatives to the plants that colonized land. Bryophytes has been described as evolutionary “unchanging sphinxes of the past” regarding both morphological and genetic potential. This suggestion has some support in limited studies of molecular evolution within bryophytes, but has also been questioned based on e.g., studies of species diversification rates. To shed more light on this controversy, the overall aim of this thesis is to investigate rates and patterns of bryophyte molecular evolution.

    Our data suggest that the per nucleotide mutation rates in bryophytes are lower than those in angiosperms. Likewise, angiosperms are also more dynamic in terms of genome size, structural rearrangements, genome duplications and transposon activity. However, our data show that mutation rates of bryophytes are higher or at least on par with those of gymnosperms. Genome evolution in bryophytes is actually, in many aspects, similar to that of gymnosperms. Gymnosperms and bryophytes are both characterized by a low speciation rate, a low nucleotide mutation rate, low variation in chromosome numbers and relatively stable genome sizes. Studies have also suggested that macrosynteny is better conserved between conifer species compared with angiosperms, just as this study shows for bryophytes.

    Hybridization and introgression has been suggested to affect speciation and evolution. Recent genomic data shows that hybridization and introgression in angiosperms is more common then previously thought, but the question is less well studied in bryophytes. The present study gave some support to the occurrence of introgression between Marchantia polymorpha subspecies, but refute a previous hypothesis that M. polymorpha subsp. ruderalis is a new stabilized hybrid between M. polymorpha montivagans and polymorpha.

    An additional aspect of genome evolution and complexity is changes in gene regulatory networks. Gene regulatory networks generally appear more complex in angiosperms compared with bryophytes; also reflected in the circadian clock; with more gene components and more duplicated paralogous members, with possibly overlapping function, allowing a more robust and flexible system. Our studies of the plant circadian clock revealed that orthologs of most genes of the A. thaliana clock were present already in charophycean algae. Although gene numbers and complexity have generally increased during plant circadian clock evolution, our results suggest that gene loss has also been important in shaping the circadian clocks in the three bryophyte groups.

    Delarbeten
    1. Evolutionary history of the Marchantia polymorpha complex
    Öppna denna publikation i ny flik eller fönster >>Evolutionary history of the Marchantia polymorpha complex
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392455 (URN)
    Tillgänglig från: 2019-09-04 Skapad: 2019-09-04 Senast uppdaterad: 2019-09-05
    2. Rates and patterns of molecular evolution in liverwort genomes, with focus of Marchantiopsida.
    Öppna denna publikation i ny flik eller fönster >>Rates and patterns of molecular evolution in liverwort genomes, with focus of Marchantiopsida.
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392459 (URN)
    Tillgänglig från: 2019-09-05 Skapad: 2019-09-05 Senast uppdaterad: 2019-09-05
    3. Rates of structural changes in bryophyte genomes; exemplified by Marchantiopsida
    Öppna denna publikation i ny flik eller fönster >>Rates of structural changes in bryophyte genomes; exemplified by Marchantiopsida
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392461 (URN)
    Tillgänglig från: 2019-09-05 Skapad: 2019-09-05 Senast uppdaterad: 2019-09-05
    4. Early evolution of the land plant circadian clock
    Öppna denna publikation i ny flik eller fönster >>Early evolution of the land plant circadian clock
    Visa övriga...
    2017 (Engelska)Ingår i: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 216, nr 2, s. 576-590Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    While angiosperm clocks can be described as an intricate network of interlocked transcriptional feedback loops, clocks of green algae have been modelled as a loop of only two genes. To investigate the transition from a simple clock in algae to a complex one in angiosperms, we performed an inventory of circadian clock genes in bryophytes and charophytes. Additionally, we performed functional characterization of putative core clock genes in the liverwort Marchantia polymorpha and the hornwort Anthoceros agrestis. Phylogenetic construction was combined with studies of spatiotemporal expression patterns and analysis of M. polymorpha clock gene mutants. Homologues to core clock genes identified in Arabidopsis were found not only in bryophytes but also in charophytes, albeit in fewer copies. Circadian rhythms were detected for most identified genes in M. polymorpha and A. agrestis, and mutant analysis supports a role for putative clock genes in M. polymorpha. Our data are in line with a recent hypothesis that adaptation to terrestrial life occurred earlier than previously expected in the evolutionary history of charophyte algae. Both gene duplication and acquisition of new genes was important in the evolution of the plant circadian clock, but gene loss has also contributed to shaping the clock of bryophytes.

    Nyckelord
    Marchantia polymorpha, bryophyte, circadian clock, evolution, transcription factor
    Nationell ämneskategori
    Botanik Evolutionsbiologi Biokemi och molekylärbiologi Utvecklingsbiologi
    Forskningsämne
    Biologi med inriktning mot evolutionär funktionsgenomik
    Identifikatorer
    urn:nbn:se:uu:diva-317912 (URN)10.1111/nph.14487 (DOI)000427294000024 ()28244104 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 2011-5609Vetenskapsrådet, 2014-522
    Tillgänglig från: 2017-03-22 Skapad: 2017-03-22 Senast uppdaterad: 2019-09-05Bibliografiskt granskad
  • Disputation: 2019-10-24 13:15 Häggsalen, Uppsala
    Mussini, Filipe
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Matematiska institutionen, Analys och sannolikhetsteori.
    Selected Topics in Continuum Percolation: Phase Transitions, Cover Times and Random Fractals2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis consists of an introduction and three research papers. The subject is probability theory and in particular concerns the topics of percolation, cover times and random fractals.

    Paper I deals with the Poisson Boolean model in locally compact Polish metric spaces. We prove that if a metric space M1 is mm-quasi-isometric to another metric space M2 and the Poisson Boolean model in M1 features one of the following percolation properties: it has a subcritical phase or it has a supercritical phase, then respectively so does the Poisson Boolean model in M2. In particular, if the process in M1 undergoes a phase transition, then so does the process in M2. We use these results to study phase transitions in a large family of metric spaces, including Riemannian manifolds, Gromov spaces and Caley graphs.

    In Paper II we study the distribution of the time it takes for a Poisson process of cylinders to cover a bounded subset of d-dimensional Euclidean space. The Poisson process of cylinders is invariant under rotations, reflections and translations. Furthermore, we add a time component, so that one can imagine that the cylinders are “raining from the sky” at unit rate. We show that the cover times of a sequence of discrete and well separated sets converge to a Gumbel distribution as the cardinality of the sets grows. For sequences of sets with positive box dimension, we determine the correct speed at which the cover times of the sets An grows.

    In Paper III we consider a semi-scale invariant version of the Poisson cylinder model. This model induces a random fractal set in the vacant region of the process. We establish an existence phase transition for dimensions d ≥ 2 and a connectivity phase transition for dimensions d ≥ 4. An important step when analysing the connectivity phase transition is to consider the restriction of the process onto subspaces. We show that this restriction induces a fractal ellipsoid model in the corresponding subspace. We then present a detailed description of this induced ellipsoid model. Moreover, the almost sure Hausdorff dimension of the fractal set is also determined.

    Delarbeten
    1. Invariance Under Quasi-isometries of Subcritical and Supercritical Behavior in the Boolean Model of Percolation
    Öppna denna publikation i ny flik eller fönster >>Invariance Under Quasi-isometries of Subcritical and Supercritical Behavior in the Boolean Model of Percolation
    2016 (Engelska)Ingår i: Journal of statistical physics, ISSN 0022-4715, E-ISSN 1572-9613, Vol. 162, nr 3, s. 685-700Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In this work we study the Poisson Boolean model of percolation in locally compact Polish metric spaces and we prove the invariance of subcritical and supercritical phases under mm-quasi-isometries. More precisely, we prove that if a metric space M is mm-quasi-isometric to another metric space N and the Poisson Boolean model in M exhibits any of the following: (a) a subcritical phase; (b) a supercritical phase; or (c) a phase transition, then respectively so does the Poisson Boolean model of percolation in N. Then we use these results in order to understand the phase transition phenomenon in a large family of metric spaces. Indeed, we study the Poisson Boolean model of percolation in the context of Riemannian manifolds, in a large family of nilpotent Lie groups and in Cayley graphs. Also, we prove the existence of a subcritical phase in Gromov spaces with bounded growth at some scale.

    Nyckelord
    Poisson point process, Percolation, Boolean model, Quasi-isometries
    Nationell ämneskategori
    Matematik
    Identifikatorer
    urn:nbn:se:uu:diva-282329 (URN)10.1007/s10955-015-1422-7 (DOI)000371086600006 ()
    Tillgänglig från: 2016-04-05 Skapad: 2016-04-05 Senast uppdaterad: 2019-09-05Bibliografiskt granskad
    2. Random cover times using the Poisson cylinder process.
    Öppna denna publikation i ny flik eller fönster >>Random cover times using the Poisson cylinder process.
    (Engelska)Ingår i: Latin American Journal of Probability and Mathematical Statistics, ISSN 1980-0436, E-ISSN 1980-0436Artikel i tidskrift (Refereegranskat) Accepted
    Abstract [en]

    In this paper we deal with the classical problem of random cover times. We investigate the distribution of the time it takes for a Poisson process of cylinders to cover a subset A of the d-dimensional Euclidean space. This Poisson process of cylinders is invariant under rotations, reflections and translations, and in addition we add a time component so that cylinders are “raining from the sky” at unit rate. Our main results concerns the asymptotic of this cover time as the set A grows. If the set A is discrete and well separated, we show convergence of the cover time to a Gumbel distribution. If instead A has positive box dimension (and satisfies a weak additional assumption), we find the correct rate of convergence.

    Nyckelord
    Cover times, Poisson cylinder process
    Nationell ämneskategori
    Sannolikhetsteori och statistik
    Forskningsämne
    Matematik
    Identifikatorer
    urn:nbn:se:uu:diva-392502 (URN)
    Tillgänglig från: 2019-09-05 Skapad: 2019-09-05 Senast uppdaterad: 2019-09-05
    3. The fractal cylinder process: existence and connectivity phase transition
    Öppna denna publikation i ny flik eller fönster >>The fractal cylinder process: existence and connectivity phase transition
    (Engelska)Ingår i: The Annals of Applied Probability, ISSN 1050-5164, E-ISSN 2168-8737Artikel i tidskrift (Refereegranskat) Submitted
    Abstract [en]

    We consider a semi-scale invariant version of the Poisson cylinder model which in a natural way induces a random fractal set. We show that this random fractal exhibits an existence phase transition for any dimension d ≥ 2, and a connectivityphase transition whenever d ≥ 4. We determine the exact value of the critical point of the existence phase transition, and we show that the fractal set is almost surely empty at this critical point.

    A key ingredient when analysing the connectivity phase transition is to consider a restriction of the full process onto a subspace. We show that this restriction results in a fractal ellipsoid model which we describe in detail, as it is key to obtaining our main results.

    In addition we also determine the almost sure Hausdorff dimension of the fractal set.

    Nationell ämneskategori
    Sannolikhetsteori och statistik
    Identifikatorer
    urn:nbn:se:uu:diva-392504 (URN)
    Tillgänglig från: 2019-09-05 Skapad: 2019-09-05 Senast uppdaterad: 2019-09-05
  • Disputation: 2019-10-25 09:00 Enghoffsalen, Uppsala
    Janiec, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Clinically-driven angiography after coronary artery bypass surgery: Results from the SWEDEHEART registry2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The success of coronary artery bypass grafting (CABG) arguably depends on the patency rate of the conduits. The saphenous vein grafts (SVGs) most often used are subject to graft disease and their reduced long-term patency compared to left internal mammary artery (IMA) grafts is well established. Postoperative coronary artery disease (CAD) symptoms, such as angina or myocardial infarction can undoubtedly be linked to graft failure or progression of atherosclerosis in the native coronary vessels, but the contribution from each of these processes is not completely understood.

    The aim of this thesis was to use clinically-driven angiography as the main outcome measure in studying different bypass conduits and surgical techniques. This endpoint has a very low risk of misclassification, and is likely to have a high association with recurrence of CAD symptoms. The SWEDEHEART registry provides extensive data on all patients undergoing cardiac surgery in Sweden as well as records of angiographies and coronary interventions.

    We studied the incidence of postoperative angiography in 46 663 CABG patients operated with IMA and SVGs. Young age, female sex, presence of diabetes, normal left ventricle function, previous PCI, prior MI, emergency surgery and one or two distal anastomoses were associated with a higher risk. We also studied 6 977 CABG operated individuals with three or more grafted vessels that experienced a postoperative angiography and had available records on individual graft patency. Almost one third of catheterized individuals with CAD symptoms did not demonstrate any failed grafts and in 18% of early and 10% of late angiographies the IMA-graft had failed.

    We compared 862 patients operated with bilateral IMA grafts and 1036 cases of IMA and radial artery grafts with 46 343 cases of IMA and SVGs. When adjusted for risk factors no improvement in outcome could be seen for patients operated with multiple arterial grafts. We also compared 1371 patients operated with “no-touch” SVGs with a propensity-matched cohort of patients with conventional SVGs. An improvement in the risk for angiography could be seen for the “no-touch” group but not for the need of repeat intervention or survival.

    Postoperative angiography is a useful endpoint in studying long-term outcome after CABG surgery. It is less sensitive than mortality to variations in the baseline covariates and thereby possibly less susceptible to confounding by indication. The causation behind the return of CAD symptoms after CABG surgery and the relative importance of the individual contributions from vein graft failures, failure of the IMA graft, as well as from progression of atherosclerotic plaques in both grafted and non-grafted coronary arteries, remains to be determined.

    Delarbeten
    1. Graft failure and recurrence of symptoms after coronary artery bypass grafting
    Öppna denna publikation i ny flik eller fönster >>Graft failure and recurrence of symptoms after coronary artery bypass grafting
    Visa övriga...
    2018 (Engelska)Ingår i: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 52, nr 3, s. 113-119Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objectives: Saphenous vein grafts (SVGs) most often used in coronary artery bypass grafting (CABG) are subject to graft disease and have poor long-term patency, however the clinical implication of this is not completely known. We aim to assess the influence of graft failure on the postoperative recurrence of coronary artery disease (CAD) symptoms in relation to the contribution from progression of atherosclerosis in the native coronary vessels.

    Design: Within the SWEDEHEART registry we identified 46,663 CABG cases between 2001 and 2015 with patient age 40-80 years where single internal mammary artery (IMA) anastomosis (IMA), single IMA with one (1SVG) or multiple SVG anastomoses (2+ SVG) had been performed. Clinical characteristics as well as mortality and postoperative incidence of coronary angiography were recorded and multivariable adjusted hazard ratios were calculated. Indications for the angiographies and occurrence of graft failure were also registered.

    Results: The adjusted hazard ratio for death was similar for the three groups. The adjusted hazard ratio for being submitted to angiography as compared to 2+ SVG was (95% CI) 1.24 (1.06-1.46) for IMA and 1.21 (1.15-1.28) for 1SVG. Failed grafts were found at the first postoperative angiography with preceding CAD symptoms in 21.4% of patients in the IMA group, 41.6% in the 1SVG group and 61.1% in the 2+ SVG group.

    Conclusions: A substantial amount of angiographies occur in patients without any graft failure and a large part of postoperative recurrence of CAD symptoms and are likely attributed to IMA failure or progression of atherosclerosis in the native coronary arteries.

    Ort, förlag, år, upplaga, sidor
    TAYLOR & FRANCIS LTD, 2018
    Nyckelord
    Coronary artery bypass grafting, graft failure, registry study
    Nationell ämneskategori
    Kardiologi
    Identifikatorer
    urn:nbn:se:uu:diva-356335 (URN)10.1080/14017431.2018.1442930 (DOI)000432282000002 ()29508655 (PubMedID)
    Tillgänglig från: 2018-07-26 Skapad: 2018-07-26 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    2. No improvements in long-term outcome after coronary artery bypass grafting with arterial grafts as a second conduit: a Swedish nationwide registry study
    Öppna denna publikation i ny flik eller fönster >>No improvements in long-term outcome after coronary artery bypass grafting with arterial grafts as a second conduit: a Swedish nationwide registry study
    Visa övriga...
    2018 (Engelska)Ingår i: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 53, nr 2, s. 448-454Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVES: Coronary artery bypass grafting using saphenous vein grafts (SVGs) in addition to the left internal mammary artery (IMA) graft is vitiated by poor long-term patency of the vein grafts. Hypothetically, the increased use of arterial grafts could confer even better outcomes. Our goal was to evaluate results after coronary artery bypass grafting in Sweden, where arterial grafts were used as a second conduit.

    METHODS: Within the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, we identified patients who had coronary artery bypass grafting from 2001 to 2015 using the IMA and the SVG, the radial artery (RA) or the additional IMA [bilateral IMA (BIMA)] as a second conduit. Deaths, postoperative incidence of coronary angiography and need for reintervention were recorded, and multivariable adjusted hazard ratios were calculated for different types of grafts.

    RESULTS: The study population comprised 45 319 cases of IMA + SVG, 1225 cases of IMA + RA and 1697 cases of BIMA. The mean follow-up time (SD) was 9.2 (4.2) years for IMA + SVG, 11.2 (4.0) years for IMA + RA grafts and 9.2 (5.2) years for the BIMA graft. The adjusted hazard ratio for death was (95% confidence interval) 1.06 (0.95-1.18) for IMA + RA and 1.21 (1.10-1.33) for BIMA grafts compared with IMA + SVG. The adjusted hazard ratio for the first angiographic examination was (95% confidence interval) 0.89 (0.78-1.01) for IMA + RA and 1.07 (0.96-1.20) for BIMA grafts. The adjusted hazard ratio for the need for reintervention was (95% confidence interval) 0.88 (0.74-1.04) for IMA + RA and 1.14 (0.98-1.32) for BIMA grafts.

    CONCLUSIONS: Patients who had arterial grafts as second conduits did not demonstrate a better outcome in any of the studied end-points. Radial artery grafts seem to be preferable to BIMA grafts as an alternative to an SVG.

    Nyckelord
    BIMA, Coronary artery bypass grafting (CABG), Radial artery, Registry study
    Nationell ämneskategori
    Kardiologi
    Identifikatorer
    urn:nbn:se:uu:diva-342951 (URN)10.1093/ejcts/ezx280 (DOI)000424256500023 ()28958083 (PubMedID)
    Anmärkning

    Correction in: European Journal of Cardio-Thoracic Surgery, Volume: 53, Issue: 5, Pages: 1098-1098, DOI: 10.1093/ejcts/ezy123

    Tillgänglig från: 2018-02-23 Skapad: 2018-02-23 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    3. Long-term clinical outcomes after coronary artery bypass grafting with pedicled saphenous vein grafts
    Öppna denna publikation i ny flik eller fönster >>Long-term clinical outcomes after coronary artery bypass grafting with pedicled saphenous vein grafts
    2018 (Engelska)Ingår i: Journal of Cardiothoracic Surgery, ISSN 1749-8090, E-ISSN 1749-8090, Vol. 13, nr 1, artikel-id 122Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Coronary artery bypass grafting (CABG) using saphenous vein grafts (SVG) is vitiated by poor long-term patency of the vein grafts. Pedicled SVG harvested with the "no-touch" (NT) technique have demonstrated improved patency and could confer better outcomes. We aim to compare long-term results after CABG where NT or conventional technique was used for vein graft harvesting in a hypothesis-generating registry-based study.

    METHODS: Two propensity score matched cohorts (1349 patients) undergoing CABG with veins harvested with NT (NTT) or conventional (CT) technique in Sweden over the period 2005-2015 were used to compare long-term outcomes. Mortality, postoperative incidence of coronary angiography and need for reintervention was recorded and multivariable hazard ratios adjusted for risk factors were calculated.

    RESULTS: The mean follow-up time (SD) was 6.8 (3.3) years for NTT and 6.6 (3.2) years for CT. The adjusted hazard ratios for death, first angiography and need for reintervention for NTT patients were (95% CI) 0.97 (0.80-1.19), 0.76 (0.63-0.93), 0.91 (0.78-1.05), and 0.91 (0.71-1.17), respectively. Failed grafts were found in 43.2% of NTT patients and 53.6% of CT patients at angiography.

    CONCLUSIONS: In this study NT grafting was associated with a lower risk for repeat angiography, however no difference could be observed for mortality and need for reintervention. The earlier reported improvements in patency of NT veins could possibly be reflected in an improved clinical outcome during the first 10 years after surgery.

    Nyckelord
    CABG, Coronary artery bypass grafting, No-touch, Pedicled vein grafts
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:uu:diva-369713 (URN)10.1186/s13019-018-0800-z (DOI)000451321400001 ()30477543 (PubMedID)
    Tillgänglig från: 2018-12-17 Skapad: 2018-12-17 Senast uppdaterad: 2019-09-01Bibliografiskt granskad
    4. Long-term outcome after coronary endarterectomy adjunct to coronary artery bypass grafting.
    Öppna denna publikation i ny flik eller fönster >>Long-term outcome after coronary endarterectomy adjunct to coronary artery bypass grafting.
    2019 (Engelska)Ingår i: Interactive Cardiovascular and Thoracic Surgery, ISSN 1569-9293, E-ISSN 1569-9285, Vol. 29, nr 1, s. 22-27Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVES: Coronary endarterectomy (CE) in coronary artery bypass grafting (CABG) is occasionally required to achieve revascularization in diffusely diseased vessels. Its beneficial effect has been questioned because of an increased risk of perioperative mortality and morbidity; however, its influence on the long-term outcome remains uncertain. The purpose of the study was to evaluate the impact of adjunct CE on the incidence of a first postoperative angiogram and the need for repeat intervention and on late deaths after CABG.

    METHODS: Two propensity-matched cohorts of patients undergoing CABG with CE (537 patients) and without adjunct CE (no CE) (537 patients) in Sweden over the period 2000-2015 were used to compare long-term outcomes. Mortality rates, postoperative incidence of coronary angiography and the need for reintervention were determined using the Kaplan-Meier method.

    RESULTS: The mean follow-up time (standard deviation) was 9.9 (4.6) years for CE and 10.0 (4.6) years for no CE. Overall survival, clinically driven angiography and coronary reintervention during follow-up (95% confidence interval) at 10 years were 65.8% (60.8-70.3), 28.2% (23.8-34.3) and 11.6% (8.7-15.3), respectively, for CE and 70.7% (65.9-74.9), 21.7% (17.8-26.3) and 12.7% (9.7-16.6), respectively, for no CE. There was a significant difference in the use of postoperative angiography between the 2 groups (P = 0.02).

    CONCLUSIONS: Although patients are subjected to an increased risk of repeat angiography, CE seems to be an acceptable treatment alternative in patients who have diffuse coronary artery disease that cannot be treated effectively by CABG alone.

    Nyckelord
    Coronary artery bypass grafting, Coronary endarterectomy, Reintervention, Survival
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:uu:diva-390464 (URN)10.1093/icvts/ivy363 (DOI)30698788 (PubMedID)
    Tillgänglig från: 2019-08-10 Skapad: 2019-08-10 Senast uppdaterad: 2019-09-01
    5. Discovery of failed grafts after coronary artery bypass grafting during clinically-driven angiography.
    Öppna denna publikation i ny flik eller fönster >>Discovery of failed grafts after coronary artery bypass grafting during clinically-driven angiography.
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Kirurgi
    Forskningsämne
    Thoraxkirurgi
    Identifikatorer
    urn:nbn:se:uu:diva-390465 (URN)
    Tillgänglig från: 2019-08-10 Skapad: 2019-08-10 Senast uppdaterad: 2019-09-01
  • Disputation: 2019-10-25 09:15 B22, Biomedicinskt centrum (BMC), Uppsala
    Onsbring, Henning
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Novel insights into protist diversity and niche adaptation using single cell transcriptomics2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Protists are a polyphyletic group of microbes that represents the vast majority of eukaryotic diversity. Despite this, most sequencing efforts targeting eukaryotes have been focused on animals, fungi and plants. The sequencing bias towards multicellular organisms can partially be explained by the difficulty in cultivating protists, which is needed in traditional sequencing workflows. In this thesis, single-cell RNA sequencing has been used to generate transcriptome data from environmental protists, without being dependent on establishing a culture. These transcriptome data have been used to discover novel protist diversity, as well as exploring the cell biology of two ciliates.

    In the first chapter, transcriptomes of cell fragments were generated for the ciliate Stentor. This ciliate is well-known for its ability to repair drastic cellular wounds, and the transcriptomes uncovered genes involved in processes such as cell cycle, signaling and microtubule-based movement to be activated during Stentor regeneration.

    Spirostomum semivirescens is another ciliate, whose transcriptome was generated using single-cell RNA sequencing. The transcriptome data suggest that S. semivirescens is using rhodoquinol-dependent fumarate reduction for respiration in environments with low levels of oxygen.

    Single-cell RNA sequencing was further used to target cells smaller than Stentor and Spirostomum. By generating 124 transcriptomes of environmental protists, a high number of novel lineages could be identified. The generated transcriptome data included free-living prokinetoplastids, non-photosynthetic euglenids, metamonads and katablepharids.

    A few modifications to the single-cell RNA sequencing protocol Smart-seq2 were necessary to generate the 124 transcriptomes of small protists cells. The impact of these modifications to Smart-seq2 was benchmarked using Giardia intestinalis. The generated single-cell transcriptomes revealed that addition of freeze-thaw cycles to Smart-seq2 improved transcript recovery. Finally, we propose a protocol that allows identification of failed cDNA reactions, based only on measuring DNA concentration, without compromising on transcript recovery. Reducing the dependency on quality control will be important if single-cell RNA sequencing would be done in a high-throughput workflow.

    In conclusion, single-cell RNA sequencing can be a powerful tool for studying protist diversity and biology. In particular, it has the potential to efficiently uncover protist diversity, provided that a robust and efficient method to isolate single cells from the environment is established.

    Delarbeten
    1. RNA Sequencing of Stentor Cell Fragments Reveals Transcriptional Changes during Cellular Regeneration
    Öppna denna publikation i ny flik eller fönster >>RNA Sequencing of Stentor Cell Fragments Reveals Transcriptional Changes during Cellular Regeneration
    2018 (Engelska)Ingår i: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 28, nr 8, s. 1281-1288.e3Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    While ciliates of the genus Stentor are known for their ability to regenerate when their cells are damaged or even fragmented, the physical and molecular mechanisms underlying this process are poorly understood. To identify genes involved in the regenerative capability of Stentor cells, RNA sequencing of individual Stentor polymorphus cell fragments was performed. After splitting a cell over the anterior-posterior axis, the posterior fragment has to regenerate the oral apparatus, while the anterior part needs to regenerate the hold fast. Altogether, differential expression analysis of both posterior and anterior S. polymorphus cell fragments for four different post-split time points revealed over 10,000 upregulated genes throughout the regeneration process. Among these, genes involved in cell signaling, microtubule-based movement, and cell cycle regulation seemed to be particularly important during cellular regeneration. We identified roughly nine times as many upregulated genes in regenerating S. polymorphus posterior fragments as compared to anterior fragments, indicating that regeneration of the anterior oral apparatus is a complex process that involves many genes. Our analyses identified several expanded groups of genes, such as dual-specific tyrosine-(Y)-phosphorylation-regulated kinases and MORN domain-containing proteins that seemingly act as key regulators of cellular regeneration. In agreement with earlier morphological and cell biological studies [1, 2], our differential expression analyses indicate that cellular regeneration and vegetative division share many similarities.

    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-354956 (URN)10.1016/j.cub.2018.02.055 (DOI)000430694900049 ()29628369 (PubMedID)
    Forskningsfinansiär
    VetenskapsrådetKnut och Alice Wallenbergs StiftelseVetenskapsrådet, 621-2009-4813EU, Europeiska forskningsrådet, 310039-PUZZLE_CELLStiftelsen för strategisk forskning (SSF), SSF-FFL5
    Tillgänglig från: 2018-06-25 Skapad: 2018-06-25 Senast uppdaterad: 2019-09-07Bibliografiskt granskad
    2. Molecular Investigation of the Ciliate Spirostomum semivirescens, with First Transcriptome and New Geographical Records
    Öppna denna publikation i ny flik eller fönster >>Molecular Investigation of the Ciliate Spirostomum semivirescens, with First Transcriptome and New Geographical Records
    2018 (Engelska)Ingår i: Protist, ISSN 1434-4610, E-ISSN 1618-0941, Vol. 169, nr 6, s. 875-886Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The ciliate Spirostomum semivirescens is a large freshwater protist densely packed with endosymbiotic algae and capable of building a protective coating from surrounding particles. The species has been rarely recorded and it lacks any molecular investigations. We obtained such data from S. semivirescens isolated in the UK and Sweden. Using single-cell RNA sequencing of isolates from both countries, the transcriptome of S. semivirescens was generated. A phylogenetic analysis identified S. semivirescens as a close relative to S. minus. Additionally, rRNA sequence analysis of the green algal endosymbiont revealed that it is closely related to Chlorella vulgaris. Along with the molecular species identification, an analysis of the ciliates' stop codons was carried out, which revealed a relationship where TGA stop codon frequency decreased with increasing gene expression levels. The observed codon bias suggests that S. semivirescens could be in an early stage of reassigning the TGA stop codon. Analysis of the transcriptome indicates that S. semivirescens potentially uses rhodoquinol-dependent fumarate reduction to respire in the oxygen-depleted habitats where it lives. The data also shows that despite large geographical distances (over 1,600 km) between the sampling sites investigated, a morphologically-identical species can share an exact molecular signature, suggesting that some ciliate species, even those over 1 mm in size, could have a global biogeographical distribution.

    Nyckelord
    Protist, stop codon, RNA-seq, anaerobic respiration, symbiotic algae, Heterotrich
    Nationell ämneskategori
    Ekologi
    Identifikatorer
    urn:nbn:se:uu:diva-372698 (URN)10.1016/j.protis.2018.08.001 (DOI)000452432800005 ()30447617 (PubMedID)
    Forskningsfinansiär
    VetenskapsrådetKnut och Alice Wallenbergs StiftelseEU, Europeiska forskningsrådet, 310039-PUZZLE_CELLStiftelsen för strategisk forskning (SSF)Vetenskapsrådet, 2015-04959
    Anmärkning

    Hunter N. Hines and Henning Onsbring contributed equally to this work.

    Tillgänglig från: 2019-01-09 Skapad: 2019-01-09 Senast uppdaterad: 2019-09-07Bibliografiskt granskad
    3. Single-cell transcriptomics expands sampled protist diversity and provides insights into niche adaptation
    Öppna denna publikation i ny flik eller fönster >>Single-cell transcriptomics expands sampled protist diversity and provides insights into niche adaptation
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392616 (URN)
    Anmärkning

    The majority of eukaryotic diversity is dominated by microbial species, also referred to as protists. Among this diversity are several taxonomic groups where access to genomic data is sparse. In an effort to provide gene content information about such species and potentially identify new lineages of protists, we sequenced 124 single-cell transcriptomes covering eight of the major clades in the eukaryotic tree. Among those, we generated transcriptome data for free-living prokinetoplastids and osmotrophic euglenids, two groups of protists for which very limited sequence data has been available to date. We also have significantly expanded the known genomic diversity within Metamonada and Katablepharidae. Additionally, we report several new algae and ciliate species that are only distantly related to lineages that have been previously found. The data generated here has both enabled us to confidently place our newly identified, free-living protist lineages in the eukaryotic tree, and to get an insight into their biology and different niche adaptation strategies.

    Tillgänglig från: 2019-09-06 Skapad: 2019-09-06 Senast uppdaterad: 2019-09-10
    4. An efficient single-cell transcriptomics workflow to assess protist diversity and lifestyle
    Öppna denna publikation i ny flik eller fönster >>An efficient single-cell transcriptomics workflow to assess protist diversity and lifestyle
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Most diversity in the eukaryotic tree of life are represented by microbial eukaryotes, which is a polyphyletic group also referred to as protists. Among the protists, currently sequenced genomes and transcriptomes give a biased view of the actual diversity. This biased view is partly caused by the scientific community, which has prioritized certain microbes of biomedical and agricultural importance. Additionally, it is challenging to establish protist cultures, which further influence what has been studied. It is now possible to bypass the time-consuming process of cultivation and directly analyze the gene content of single protist cells. Single-cell genomics was used in the first experiments where individual protists cells were genomically explored. Unfortunately, single-cell genomics for protists are often associated with low genome recovery and the assembly process can be complicated because of repetitive intergenic regions. Sequencing repetitive sequences can be avoided if single-cell transcriptomics is used, which only targets the part of the genome that is transcribed. In this study we test different modifications of Smart-seq2, a single-cell RNA sequencing protocol optimized for mammalian cells, to establish a robust and more cost-efficient workflow for protists. The diplomonad Giardia intestinaliswas used in all experiments and the available genome for this species allowed us to benchmark our results. We could observe increased transcript recovery when freeze-thaw cycles were added as an extra step to the Smart-seq2 protocol. Further we tried reducing the reaction volume and purifying with alternative beads to test different cost-reducing changes of Smart-seq2. Neither did improve the procedure, and cutting the volumes by half actually led to significantly fewer genes detected. We also added a 5’ biotin modification to our primers and reduced the concentration of oligo-dT, to potentially reduce generation of artifacts. Except adding freeze-thaw cycles and reducing the volume, no other modifications lead to a significant change in gene detection. Therefore, we suggest adding freeze-thaw cycles to Smart-seq2 when working with protists and further consider our other modification described to improve cost and time-efficiency.

    Nationell ämneskategori
    Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392617 (URN)
    Tillgänglig från: 2019-09-06 Skapad: 2019-09-06 Senast uppdaterad: 2019-09-16
  • Disputation: 2019-10-25 09:15 Polhemssalen, Uppsala
    von Fieandt, Kristina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Oorganisk kemi.
    Reactive Sputtering of Complex Multi-component Nitride Thin Films2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The ever-increasing demand on improvement of protective nitride thin films has led to an expansion of the research field into multi-element based materials. The work in this thesis has focused on exploring new complex, multi-component nitride thin films based on three different material systems: Al-Ge-N, Hf-Nb-Ti-V-Zr-N and Al-Cr-Nb-Y-Zr-N. All films were synthesised by reactive dc magnetron sputtering and characterised with regard to structure and material properties, in particular the mechanical, optical and corrosion properties.

    The Al-Ge-O-N coatings exhibited amorphisation of the structure upon oxygen addition, via the formation of a crystalline (Al1-xGex)(N1-yOy) solid solution phase for low O contents. The mechanical properties were improved, and hardness values up to 29 GPa were achieved for low O and Ge concentrations, most likely due to nanocomposite hardening. The optical absorption edge was tuneable towards shorter and longer wavelengths with increasing the O and Ge content respectively. Annealing to 850°C showed indications of increased thermal stability for the quaternary Al-Ge-O-N films compared to the ternary Al-Ge-N films.

    Coatings in the Hf-Nb-Ti-V-Zr-N system were found to be highly crystalline featuring a single solid solution phase with NaCl-type structure for low Hf content, whereas an additional, tetragonally distorted, phase appeared for higher Hf contents. The mechanical properties, such as hardness and Young’s modulus increased with increasing Hf content, although the values were relatively low compared to those for transition metal nitrides in general.

    The Al-Cr-Nb-Y-Zr-N films also crystallised in the NaCl-type structure for the films with high nitrogen contents, i.e. between 46 and 51 at.%. However, partial elemental segregation was present, mainly for yttrium, both within the grains and in the column boundaries. XPS results suggested that yttrium was in a metallic state, while the remaining elements were present in a nitrided environment. The partial segregation could possibly explain the observed ductile behaviour of the nitride films. Electrochemical tests showed that the corrosion resistance increased with increased nitrogen content and the films performed in some cases better than a hyper-duplex stainless steel.

    This thesis demonstrates that solid solutions are formed for three relatively different nitride material systems when varying the composition. The solubilities of the solid solution phases were found to be limited as shown by amorphisation, partial elemental segregation or formation of a two-phase material. The limited solubility and the phase changes can be used to design the material properties.

    Delarbeten
    1. Influence of oxygen content on structure and material properties of reactively sputtered Al-Ge-O-N thin films
    Öppna denna publikation i ny flik eller fönster >>Influence of oxygen content on structure and material properties of reactively sputtered Al-Ge-O-N thin films
    2018 (Engelska)Ingår i: Journal of Alloys and Compounds, ISSN 0925-8388, E-ISSN 1873-4669, Vol. 738, s. 515-527Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Ternary Al-Ge-N and quaternary Al-Ge-O-N coatings were deposited by reactive dc magnetron cosputtering of Al and Ge targets in an Ar/N-2 or Ar/N-2/O-2 atmosphere at a substrate temperature of 250 degrees C. The structure and material properties of the coatings were investigated by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), nanoindentation, UV-vis spectroscopy and optical profilometry. In agreement with literature, the ternary Al-Ge-N coatings were found to be nanocomposite materials with nanocrystalline (Al1-xGex) N-y solid solution phase in a Ge3N4-z amorphous matrix. The Al-Ge-O-N coatings consisted of a nanocrystalline wurzite-type (Al1-xGex)( N1-yOy) solid solution phase for low oxygen concentrations with a possible co-existence of an amorphous Ge-N matrix phase. For higher O contents, the coatings became X-ray amorphous. The mechanical properties of the Al-Ge-O-N films were improved for low oxygen content, as compared to the ternary Al-Ge-N samples, showing an increase in hardness up to 29 GPa and Young's modulus to 320 GPa. The oxygen addition also resulted in an additional design parameter of the optical properties compared to the ternary Al-Ge-N films. The optical absorption edge was thus tuneable towards both shorter and longer wavelength by changing the O and Ge content respectively, and ranged from 302 to 373 nm, corresponding to an optical bandgap (E-04) between 4.1 and 3.3 eV. After annealing of the Al-Ge-O-N coatings in ultra-high vacuum at 500 degrees C, indications of increased thermal stability for the coating with high oxygen content were observed. For the annealed Al-Ge-O-N films the mechanical properties were improved upon heat treatment, while the optical properties were only slightly changed. These results suggests that coatings of the Al-Ge-O-N system could be suitable as protective optical coatings at elevated temperatures.

    Ort, förlag, år, upplaga, sidor
    ELSEVIER SCIENCE SA, 2018
    Nyckelord
    Reactive sputtering, Al-Ge-O-N, Optical properties, Hard coatings, Thermal stability
    Nationell ämneskategori
    Oorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-341556 (URN)10.1016/j.jallcom.2017.12.185 (DOI)000419214800062 ()
    Forskningsfinansiär
    Vetenskapsrådet, C0514401Stiftelsen för strategisk forskning (SSF), RIF14-0053
    Tillgänglig från: 2018-02-13 Skapad: 2018-02-13 Senast uppdaterad: 2019-09-08Bibliografiskt granskad
    2. In Situ Formation of Ge Nanoparticles by Annealing of Al-Ge‑N ThinFilms Followed by HAXPES and XRD
    Öppna denna publikation i ny flik eller fönster >>In Situ Formation of Ge Nanoparticles by Annealing of Al-Ge‑N ThinFilms Followed by HAXPES and XRD
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    2019 (Engelska)Ingår i: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 58, nr 16, s. 11100-11109Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Ge nanoparticles embedded in thin films have attracted a lot of attention due to their promising optical and electronic properties that can be tuned by varying the particle size and choice of matrix material. In this study, Ge nanoparticle formation was investigated for Al-Ge-N based thin films by simultaneous measurements of HAXPES and grazing incidence XRD during in situ annealing in vacuum conditions. As-deposited Al-Ge-N thin films, synthesized by reactive dc magnetron sputtering, consisted of a nanocrystalline (Al1–xGex)Ny solid solution and an amorphous tissue phase of Ge3Ny. Upon annealing to 750 °C, elemental Ge was formed shown by both HAXPES and XRD measurements, and N2 gas was released as measured by a mass spectrometer. Postannealed ex situ analysis by SEM and TEM showed that the elemental Ge phase formed spherical nanoparticles on the surface of the film, with an average size of 210 nm. As the annealing temperature increased further to 850 °C, the Ge particles on the film surface evaporated, while the phase segregation of Ge still could be observed within the film. Thus, these results show the possibility for a controlled synthesis of Ge nanoparticles through annealing of Al-Ge-N thin films to produce materials suitable for use in electronic or optoelectronic devices.

    Nationell ämneskategori
    Oorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-392698 (URN)10.1021/acs.inorgchem.9b01631 (DOI)000482173300075 ()31381309 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 2014-6463EU, FP7, Sjunde ramprogrammet, INCA 600398
    Tillgänglig från: 2019-09-08 Skapad: 2019-09-08 Senast uppdaterad: 2019-10-08Bibliografiskt granskad
    3. Multicomponent Hf-Nb-Ti-V-Zr nitride coatings by reactive magnetron sputter deposition
    Öppna denna publikation i ny flik eller fönster >>Multicomponent Hf-Nb-Ti-V-Zr nitride coatings by reactive magnetron sputter deposition
    2018 (Engelska)Ingår i: Surface & Coatings Technology, ISSN 0257-8972, E-ISSN 1879-3347, Vol. 349, s. 529-539Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Multicomponent nitride coatings of the Hf-Nb-Ti-V-Zr system with different Hf content (0-18 at.%) were deposited using reactive dc magnetron sputtering. Coatings with lower Hf content (0-7 at.%) were found to consist of a single solid solution phase with NaCl-type structure (space group Fm-3m). Coatings with higher Hf content (10-18 at.%) showed a two-phase material consisting of cubic Fm-3m and tetragonal I4/m:run solid solution phase. The lattice distortion, estimated by calculating the delta-parameter under the assumption of a single solid solution phase, varied between 3.8 and 4.0% and slightly decreased with increasing Hf content. SEM and TEM cross section images showed a columnar microstructure with columns that were frayed on the surface or throughout the whole column. The column size decreased as Hf content increased. The hardness increased from 8 to 19 GPa with increased Hf content, which most probably is related to the change in microstructure rather than change in lattice distortion. The electrical resistivity for all samples ranged between 231 and 286 mu Omega cm.

    Ort, förlag, år, upplaga, sidor
    ELSEVIER SCIENCE SA, 2018
    Nyckelord
    Multiprincipal element nitride, High-entropy nitride, Two-phase nitride, Transition metal nitride, Tetragonal distortion, Thin films
    Nationell ämneskategori
    Materialkemi Bearbetnings-, yt- och fogningsteknik
    Identifikatorer
    urn:nbn:se:uu:diva-362098 (URN)10.1016/j.surfcoat.2018.06.030 (DOI)000441492600056 ()
    Forskningsfinansiär
    Vetenskapsrådet, C0514401Stiftelsen för strategisk forskning (SSF), RIF14-0053
    Tillgänglig från: 2018-10-01 Skapad: 2018-10-01 Senast uppdaterad: 2019-09-08Bibliografiskt granskad
    4. Multi-component (Al,Cr,Nb,Y,Zr)N thin films by reactive magnetron sputter deposition for increased hardness and corrosion resistance
    Öppna denna publikation i ny flik eller fönster >>Multi-component (Al,Cr,Nb,Y,Zr)N thin films by reactive magnetron sputter deposition for increased hardness and corrosion resistance
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Oorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-392700 (URN)
    Tillgänglig från: 2019-09-08 Skapad: 2019-09-08 Senast uppdaterad: 2019-09-11
    5. Influence of N content on structure and mechanical properties of multi-component Al-Cr-Nb-Y-Zr based thin films by reactive magnetron sputtering
    Öppna denna publikation i ny flik eller fönster >>Influence of N content on structure and mechanical properties of multi-component Al-Cr-Nb-Y-Zr based thin films by reactive magnetron sputtering
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Oorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-392701 (URN)
    Tillgänglig från: 2019-09-08 Skapad: 2019-09-08 Senast uppdaterad: 2019-09-08
    6. Corrosion in Al-Cr-Nb-Y-Zr-N multi-component alloys: What role does the nitrogen content play?
    Öppna denna publikation i ny flik eller fönster >>Corrosion in Al-Cr-Nb-Y-Zr-N multi-component alloys: What role does the nitrogen content play?
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Oorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-392702 (URN)
    Tillgänglig från: 2019-09-08 Skapad: 2019-09-08 Senast uppdaterad: 2019-09-11
  • Disputation: 2019-10-25 13:00 A1:107a, BMC, Uppsala
    Magnúsdóttir, Elín Ingibjörg
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Peripheral Regulation of Pain and Itch2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Pain and itch are diverse sensory modalities, transmitted by the somatosensory nervous system. Stimuli such as heat, cold, mechanical pain and itch can be transmitted by different neuronal populations, which show considerable overlap with regards to sensory activation. Moreover, the immune and nervous systems can be involved in extensive crosstalk in the periphery when reacting to these stimuli. With recent advances in genetic engineering, we now have the possibility to study the contribution of distinct neuron types, neurotransmitters and other mediators in vivo by using gene knock-out mice. The neuropeptide calcitonin gene-related peptide (CGRP) and the ion channel transient receptor potential cation channel subfamily V member 1 (TRPV1) have both been implicated in pain and itch transmission. In Paper I, the Cre-LoxP system was used to specifically remove CGRPα from the primary afferent population that expresses TRPV1. CGRPα-mCherrylx/lx;Trpv1-Cre mice had attenuated responses to visceral pain induced by acid, while mechanosensitivity of the colon and somatic pain sensation remained unaffected.

    Mast cell proteases (MCPs) are stored in high quantities within mast cell (MC) granules and have been linked to both protective and pro-inflammatory properties, but little is known about their exact roles in vivo. In Papers II, IV and V, we used knock-out mice to investigate the contribution of MCs and their MCPs (the chymase mMCP4, tryptase mMCP6 and carboxypeptidase CPA3) in pain resulting from tissue injury, inflammation-induced heat hypersensitivity and different types of itch. Surprisingly, we found that neither MCPs nor MCs were essential for the pain behavior tested (Paper II). Our data indicate that mMCP6 and CPA3 have a protective role in scratching behavior induced by the peptide endothelin-1 (ET-1; Paper IV) and in scratching induced by the MC degranulator compound 48/80 (Paper V), but no differences were observed with the other pruritogens histamine, chloroquine or SLIGRL.

    In Paper III, we saw that a novel single-stranded oligonucleotide (ssON) attenuated compound 48-induced scratching in BALB/c mice by blocking MC degranulation. ssON could also block degranulation in human MC in vitro and we determined that this was due to ssON interfering with Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor involved in non-allergic MC degranulation.

    By better understanding the contribution of individual components of the nervous and immune systems in pain and itch, we hopefully increase the possibilities of developing better treatments for burdensome pain- and itch-related disorders in the future.

    Delarbeten
    1. CGRP alpha within the Trpv1-Cre population contributes to visceral nociception
    Öppna denna publikation i ny flik eller fönster >>CGRP alpha within the Trpv1-Cre population contributes to visceral nociception
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    2018 (Engelska)Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 314, nr 2, s. G188-G200Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRP alpha is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRP alpha from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRP alpha-mCherry(lx/lx); Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRP alpha-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRP alpha- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor potential cation channel subfamily V member 1 (TRPV1)-expressing primary afferent neurons, but the functional role of CGRP alpha specifically in these neurons is unknown in pain processing from visceral and somatic afferents. We used cre-lox recombination to conditionally delete CGRP alpha from TRPV1-expressing neurons in mice. We show that CGRP alpha from within TRPV1-cre population plays an important role in visceral nociception but less so in somatic nociception.

    Ort, förlag, år, upplaga, sidor
    AMER PHYSIOLOGICAL SOC, 2018
    Nyckelord
    calcitonin gene-related peptide, nociception, pain, transient receptor potential cation channel subfamily V member 1, visceral
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-349363 (URN)10.1152/ajpgi.00188.2017 (DOI)000425923800005 ()28971837 (PubMedID)
    Forskningsfinansiär
    VetenskapsrådetRagnar Söderbergs stiftelseÅke Wibergs Stiftelse
    Tillgänglig från: 2018-04-26 Skapad: 2018-04-26 Senast uppdaterad: 2019-09-08Bibliografiskt granskad
    2. Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin
    Öppna denna publikation i ny flik eller fönster >>Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin
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    2018 (Engelska)Ingår i: Molecular Pain, ISSN 1744-8069, E-ISSN 1744-8069, Vol. 14, artikel-id 1744806918808161Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Subcutaneous formalin injections are used as a model for tissue injury-induced pain where formalin induces pain and inflammation indirectly by crosslinking proteins and directly through activation of the transient receptor potential A1 receptor on primary afferents. Activation of primary afferents leads to both central and peripheral release of neurotransmitters. Mast cells are found in close proximity to peripheral sensory nerve endings and express receptors for neurotransmitters released by the primary afferents, contributing to the neuro/immune interface. Mast cell proteases are found in large quantities within mast cell granules and are released continuously in small amounts and upon mast cell activation. They have a wide repertoire of proposed substrates, including Substance P and calcitonin gene-related peptide, but knowledge of their in vivo function is limited. We evaluated the role of mouse mast cell proteases (mMCPs) in tissue injury pain responses induced by formalin, using transgenic mice lacking either mMCP4, mMCP6, or carboxypeptidase A3 (CPA3), or mast cells in their entirety. Further, we investigated the role of mast cells in heat hypersensitivity following a nerve growth factor injection. No statistical difference was observed between the respective mast cell protease knockout lines and wild-type controls in the formalin test. Mast cell deficiency did not have an effect on formalin-induced nociceptive responses nor nerve growth factor-induced heat hypersensitivity. Our data thus show that mMCP4, mMCP6, and CPA3 as well as mast cells as a whole, do not play a significant role in the pain responses associated with acute tissue injury and inflammation in the formalin test. Our data also indicate that mast cells are not essential to heat hypersensitivity induced by nerve growth factor.

    Nyckelord
    Pain formalin, transgenic, mast cell, protease
    Nationell ämneskategori
    Immunologi Immunologi inom det medicinska området
    Identifikatorer
    urn:nbn:se:uu:diva-372455 (URN)10.1177/1744806918808161 (DOI)000451284400001 ()30280636 (PubMedID)
    Forskningsfinansiär
    VetenskapsrådetRagnar Söderbergs stiftelse
    Tillgänglig från: 2019-01-08 Skapad: 2019-01-08 Senast uppdaterad: 2019-09-08Bibliografiskt granskad
    3. Compound 48/80-induced itch is attenuated by mouse mast cell tryptase and carboxypeptidase A3
    Öppna denna publikation i ny flik eller fönster >>Compound 48/80-induced itch is attenuated by mouse mast cell tryptase and carboxypeptidase A3
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392708 (URN)
    Tillgänglig från: 2019-09-08 Skapad: 2019-09-08 Senast uppdaterad: 2019-09-08
    4. Mouse mast cell tryptase and carboxypeptidase A3 play a protective role in itch induced by endothelin-1
    Öppna denna publikation i ny flik eller fönster >>Mouse mast cell tryptase and carboxypeptidase A3 play a protective role in itch induced by endothelin-1
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392707 (URN)
    Tillgänglig från: 2019-09-08 Skapad: 2019-09-08 Senast uppdaterad: 2019-09-08
    5. Amelioration of Mas-related G protein-coupled receptor X2-mediated itch and reduced mast cell degranulation by a single-stranded oligonucleotide
    Öppna denna publikation i ny flik eller fönster >>Amelioration of Mas-related G protein-coupled receptor X2-mediated itch and reduced mast cell degranulation by a single-stranded oligonucleotide
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-392537 (URN)
    Tillgänglig från: 2019-09-08 Skapad: 2019-09-08 Senast uppdaterad: 2019-09-08
  • Disputation: 2019-10-25 13:00 Lindahlsalen, Uppsala
    Tusso Gomez, Sergio Ivan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi. Division of Evolutionary Biology, Faculty of Biology, LMU Munich.
    Adaptive divergence in fission yeast: From experimental evolution to evolutionary genomics2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    How adaptation and population differentiation occur is fundamental to understand the origin of biodiversity. Work in speciation alongside the increased ease of generating genomic data have allowed the exploration of genomic changes relevant to adaptation. However, it remains challenging to infer the underlying mechanisms from genomic patterns of divergence governed by both genomic properties and external selective pressures. The chronological order of genomic changes, evolutionary history and selective forces can rarely be inferred from natural populations.

    Currently, I see two promising ways to tackle the problem of the genomic underpinnings of divergence: (1) evolution experiments simulating adaptation and population divergence and measuring genomic changes as they occur through time; (2) empirical studies of closely related populations in which the extent of divergence varies, allowing us to infer the chronology of the genomic changes. In my Ph.D. research I applied these two approaches, using the fungus Schizosaccharomyces pombe. First, I experimentally tested the potential for ecological divergence with gene flow, and investigated genomic and phenotypic changes associated with this process. Next, I studied genomic data obtained from natural populations sampled worldwide.  In both cases, the genetic inference relied on different sequencing technologies including the Illumina, Pacific Biosciences and Oxford Nanopore platforms.

    The experiment explored the effect of gene flow on phenotype and fitness, and uncovered potential molecular mechanisms underlying adaptive divergence. In paper I we demonstrate the emergence of specialisation under low gene flow, but generalist strategies when gene flow was high. Evolved phenotypes were largely influenced by standing genetic variation subject to opposite antagonistic pleiotropy complemented by new mutations enriched in a subset of genes. In paper II, we show that the experimental selective regime also had an effect on mating strategies, result of temporal ecological heterogeneity and selection for mating efficiency. We found that the evolution of mating strategies was explained by a trade-off between mating efficiency and asexual growth rate dependent on environmental stability. Papers III and IV consider the role of gene flow in natural populations. In paper III, we provide evidence that gene flow also played a predominant role in adaptive divergence in nature. All strains resulted from recent hybridization between two ancestral groups manifested in large phenotypic variation and reproductive isolation.This demographic history of hybridization was confirmed in paper IV focusing on patterns of mitochondrial diversity, adding evidence for the geographic distribution of the ancestral populations and potential for horizontal gene transfer from a distant yeast clade. 

    Delarbeten
    1. Parallelism in adaptive divergence and the modulating effect of gene flow
    Öppna denna publikation i ny flik eller fönster >>Parallelism in adaptive divergence and the modulating effect of gene flow
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    adaptive divergence, gene flow, experimental evolution
    Nationell ämneskategori
    Evolutionsbiologi
    Forskningsämne
    Biologi med inriktning mot evolutionär genetik
    Identifikatorer
    urn:nbn:se:uu:diva-392416 (URN)
    Tillgänglig från: 2019-09-03 Skapad: 2019-09-03 Senast uppdaterad: 2019-09-03
    2. Repeated evolution of self-compatibility for reproductive assurance
    Öppna denna publikation i ny flik eller fönster >>Repeated evolution of self-compatibility for reproductive assurance
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    2018 (Engelska)Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 1639Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Sexual reproduction in eukaryotes requires the fusion of two compatible gametes of opposite sexes or mating types. To meet the challenge of finding a mating partner with compatible gametes, evolutionary mechanisms such as hermaphroditism and self-fertilization have repeatedly evolved. Here, by combining the insights from comparative genomics, computer simulations and experimental evolution in fission yeast, we shed light on the conditions promoting separate mating types or self-compatibility by mating-type switching. Analogous to multiple independent transitions between switchers and non-switchers in natural populations mediated by structural genomic changes, novel switching genotypes readily evolved under selection in the experimental populations. Detailed fitness measurements accompanied by computer simulations show the benefits and costs of switching during sexual and asexual reproduction, governing the occurrence of both strategies in nature. Our findings illuminate the trade-off between the benefits of reproductive assurance and its fitness costs under benign conditions facilitating the evolution of self-compatibility.

    Nationell ämneskategori
    Genetik
    Identifikatorer
    urn:nbn:se:uu:diva-354954 (URN)10.1038/s41467-018-04054-6 (DOI)000430674000028 ()29691402 (PubMedID)
    Forskningsfinansiär
    VetenskapsrådetEU, Europeiska forskningsrådet, HapSelA-336633Carl Tryggers stiftelse för vetenskaplig forskning
    Anmärkning

    These authors jointly supervised this work: Jochen B.W. Wolf, Simone Immler.

    Tillgänglig från: 2018-06-25 Skapad: 2018-06-25 Senast uppdaterad: 2019-09-03Bibliografiskt granskad
    3. Ancestral admixture is the main determinant of global biodiversity in fission yeast
    Öppna denna publikation i ny flik eller fönster >>Ancestral admixture is the main determinant of global biodiversity in fission yeast
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    2019 (Engelska)Ingår i: Molecular Biology and EvolutionArtikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Abstract. Mutation and recombination are key evolutionary processes governing phenotypic variation and reproductive isolation. We here demonstrate that biodive

    Nationell ämneskategori
    Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-390729 (URN)10.1093/molbev/msz126 (DOI)
    Tillgänglig från: 2019-08-14 Skapad: 2019-08-14 Senast uppdaterad: 2019-09-03
    4. Intraspecific diversity of fission yeast mitochondrial genomes
    Öppna denna publikation i ny flik eller fönster >>Intraspecific diversity of fission yeast mitochondrial genomes
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    2019 (Engelska)Ingår i: Genome Biology and EvolutionArtikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Abstract. The fission yeast Schizosaccharomyces pombe is an important model organism, but its natural diversity and evolutionary history remain under-studied.

    Nationell ämneskategori
    Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-390730 (URN)10.1093/gbe/evz165 (DOI)
    Tillgänglig från: 2019-08-14 Skapad: 2019-08-14 Senast uppdaterad: 2019-09-03
  • Disputation: 2019-10-25 13:00 A1:111a, Uppsala
    Kalliokoski, Paul
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Vitamin D, muscle strength, prolonged labour, Caesarean sections and lifestyle: Clinical and intervention studies in pregnant Somali and Swedish women and new mothers2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Long-term severe vitamin D deficiency may cause osteomalacia with muscle weakness, pain, soft bones, cramps and eventually death. In a pilot study, I found many Somali women to be vitamin D deficient and very weak. This raised my interest and resulted in the research questions regarding if and how this weakness was linked to vitamin D deficiency, if it could be treated with simple lifestyle advice and supplementation, and if pronounced deficiency could cause serious birth outcomes due to prolonged labour?

    Study I showed that 90% of pregnant Somali women (n = 52) and new mothers from primary antenatal care suffered from vitamin D deficiency with pronounced muscular weakness and signs of skeletal degradation, compared with 10% of the Swedish women (n = 71). Handgrip strength was predicted by vitamin D levels.

    Study II showed that vitamin D supplementation among those with insufficient levels at baseline reversed deficiency and skeletal degradation. Furthermore, increased strength in hands and legs was predicted by the amount of supplement intake.

    Study III aimed to investigate the vitamin D levels and the birth outcomes of cesarean sections and assisted birth for prolonged labour. A directed acyclic graph was established to adjust for covariates. A causal effect of critically low (unmeasurable) vitamin D levels on the outcomes of caesarean sections, emergency caesarean sections and assisted birth for prolonged labour was found with the increased odds of four, nine and six times to one for the birth outcomes, respectively.

    Lifestyle associated with vitamin D may concern many due to risk of low sun exposure, for example, when working long office hours, engaging in excessive computer gaming, using sunscreen, wearing veiled clothes, or when having special diets like vegan food.

    It is important to monitor individuals in primary- and antenatal care with muscle weakness and risk factors for vitamin D deficiency, especially in the high-risk group of Somali pregnant women and new mothers.         

    Delarbeten
    1. Physical performance and 25-hydroxyvitamin D: a cross-sectional study of pregnant Swedish and Somali immigrant women and new mothers
    Öppna denna publikation i ny flik eller fönster >>Physical performance and 25-hydroxyvitamin D: a cross-sectional study of pregnant Swedish and Somali immigrant women and new mothers
    2013 (Engelska)Ingår i: BMC Pregnancy and Childbirth, ISSN 1471-2393, E-ISSN 1471-2393, Vol. 13, artikel-id 237Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background:

    Severe vitamin D deficiency can impair muscle strength. The study aims were to examine physical performance in the hands and upper legs, and analyze plasma 25-hydroxyvitamin D (25(OH) D) concentrations in women with presumably low (veiled, Somali-born) and high levels (unveiled, Swedish-born).

    Methods:

    Women (n = 123, 58% Swedish) enrolled at a Swedish antenatal clinic, latitude 60 degrees N, were recruited. Plasma 25(OH) D was analyzed, measured as nmol/L, then categorized as <10 = undetectable, 10-24, 25-49, 50-74 or >75. Muscle strength was tested: maximal hand grip strength (in Newtons, N), and upper leg performance (categorized as able/unable to perform squatting, standing on one leg, standing from a chair, and lifting their hips). Social and anthropometric data were collected. Non-parametric statistics tested the data for differences in their ability to perform the tests across 25(OH) D categories. Undetectable values (< 10 nmol/L) were replaced with '9' in the linear correlation statistics. A final main effect model for grip strength (in N) was calculated using stepwise linear regression for independent variables: country of birth, 25(OH) D levels, age, height, weight, physical activity, lactation status, parity, and gestational age.

    Results:

    Somali participants (35%) had 25(OH) D levels of < 10 nmol/L, and 90% had < 25 nmol/L; 10% of Swedish participants had < 25 nmol/L of 25(OH) D, and 54% had < 50 nmol/L. Somali women had a relatively weak grip strength compared with Swedish women: median 202 N (inter-quartile range 167-246) vs. median 316 N (inter-quartile range 278-359), respectively. Somali women were also weak in upper leg performance: 73% were unable to squat, 29% unable to stand on one leg, and 21% could not lift their hips (not significant across 25(OH) D categories); most Swedish women could perform these tests. In the final model, grip strength (N) was significantly associated with 25(OH) D levels (B 0.94, p=0.013) together with Somali birth (B -63.9, p<0.001), age (B 2.5, p=0.02) and height (B 2.6, p=0.01).

    Conclusions:

    Many Somali women had undetectable/severely low 25(OH) D concentrations and pronounced hand and upper leg weakness; grip strength was strongly associated with 25(OH) D. Maternity health care personnel should be aware of this increased frequency and manage care accordingly.

    Nyckelord
    Vitamin D, 25(OH)D, Ultraviolet B radiation, Grip strength, Clinical observation, Physical performance, Primary care, Somalia, Pregnancy
    Nationell ämneskategori
    Allmänmedicin
    Identifikatorer
    urn:nbn:se:uu:diva-217631 (URN)10.1186/1471-2393-13-237 (DOI)000329252000003 ()
    Tillgänglig från: 2014-02-06 Skapad: 2014-02-04 Senast uppdaterad: 2019-09-05Bibliografiskt granskad
    2. Critically low vitamin D may cause emergency caesarean sections:a cohort study of Somali and Swedish women in antenatal primary care
    Öppna denna publikation i ny flik eller fönster >>Critically low vitamin D may cause emergency caesarean sections:a cohort study of Somali and Swedish women in antenatal primary care
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    Caesarean section, dystocia, immigrant, muscle strength, obstetric labour 70 complications, osteomalacia, Somalia, vitamin D
    Nationell ämneskategori
    Reproduktionsmedicin och gynekologi
    Forskningsämne
    Obstetrik och gynekologi
    Identifikatorer
    urn:nbn:se:uu:diva-392423 (URN)
    Tillgänglig från: 2019-09-03 Skapad: 2019-09-03 Senast uppdaterad: 2019-09-05
    3. Long-term adherence and effects on grip strength and upper leg performance of prescribed supplemental vitamin D in pregnant and recently pregnant women of Somali and Swedish birth with 25-hydroxyvitamin D deficiency: a before-and-after treatment study
    Öppna denna publikation i ny flik eller fönster >>Long-term adherence and effects on grip strength and upper leg performance of prescribed supplemental vitamin D in pregnant and recently pregnant women of Somali and Swedish birth with 25-hydroxyvitamin D deficiency: a before-and-after treatment study
    2016 (Engelska)Ingår i: BMC Pregnancy and Childbirth, ISSN 1471-2393, E-ISSN 1471-2393, Vol. 16, artikel-id 353Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Muscular weakness and severe vitamin D deficiency is prevalent in Somali (veiled) pregnant women, Sweden. The study aims here were to explore adherence to prescribed supplemental vitamin D in new mothers with vitamin D deficiency and its effects on grip strength and upper leg performance in Somali (target group TG) and Swedish women (reference group RG) from spring through winter.

    Methods: A before-and after study was designed. A cross-sectional sample of women in antenatal care with serum 25-OHD <= 50 nmol/L were prescribed one or two tablets daily (800 or 1600 IU vitamin D3 with calcium) for 10 months. Reminders were made by Somali nurses (TG) or Swedish doctors (RG). Baseline and 10 month measurements of plasma nmol/L 25-OHD, maximal grip strength held for 10 s (Newton, N) and ability to squat (yes; no) were done. Total tablet intake (n) was calculated. Outcome variables were changes from baseline in grip strength and ability to squat. Predicting variables for change in grip strength and ability to squat were calculated using linear and binary regression in final models. Undetectable 25-OHD values (< 10 nmol/L) were replaced with '9' in statistic calculations.

    Results: Seventy-one women (46 TG, 1/3 with undetectable baseline 25-OHD; 25 RG) participated. At the 10-month follow up, 17% TG and 8% RG women reported having refrained from supplement. Mean 25-OHD increased 16 to 49 nmol/L (TG) and 39 nmol/L to 67 nmol/L (RG), (both p < 0.001). Grip strength had improved from 153 to 188 N (TG) (p < 0.001) and from 257 to 297 N (RG) (p = 0.003) and inability to squat had decreased in TG (35 to 9, p < 0. 001). Intake of number of tablets predicted increased grip strength (B 0.067, 95% CI 0.008-0.127, p = 0.027). One tablet daily (> 300 in total) predicted improved ability to squat (OR 16; 95% CI 1.8-144.6).

    Conclusions: Adherence to supplemental vitamin D and calcium should be encouraged as an even moderate intake was associated to improved grip strength and upper leg performance, which was particularly useful for the women with severe 25-OHD deficiency and poor physical performance at baseline.

    Nyckelord
    Adherence, Multicultural care, Vitamin D, Physical performance, Grip strength, Pregnancy, Somalia
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-309795 (URN)10.1186/s12884-016-1117-3 (DOI)000387608700001 ()27846821 (PubMedID)
    Tillgänglig från: 2016-12-21 Skapad: 2016-12-07 Senast uppdaterad: 2019-09-05Bibliografiskt granskad
    4. Impact on Vitamin D related lifestyle in Somali women with severe deficiency following medical advice by doctor: A mixed method study of before and after treatment
    Öppna denna publikation i ny flik eller fönster >>Impact on Vitamin D related lifestyle in Somali women with severe deficiency following medical advice by doctor: A mixed method study of before and after treatment
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    Clinical trial, Food, Lifestyle, Somalia, Vitamin D, Pregnant
    Nationell ämneskategori
    Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi
    Forskningsämne
    Allmänmedicin
    Identifikatorer
    urn:nbn:se:uu:diva-392424 (URN)
    Tillgänglig från: 2019-09-03 Skapad: 2019-09-03 Senast uppdaterad: 2019-09-05
  • Disputation: 2019-10-30 09:00 Sal IX, Uppsala
    Farisco, Michele
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Brain, consciousness and disorders of consciousness at the intersection of neuroscience and philosophy2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The present dissertation starts from the general claim that neuroscience is not neutral, with regard to theoretical questions like the nature of consciousness, but it needs to be complemented with dedicated conceptual analysis. Specifically, the argument for this thesis is that the combination of empirical and conceptual work is a necessary step for assessing the significant questions raised by the most recent study of the brain. Results emerging from neuroscience are conceptually very relevant in themselves but, notwithstanding its theoretical sophistication, neuroscience is not sufficient to provide a complete interpretation or an appropriate understanding of their impact. Consequently, the present thesis starts from the need for an interdisciplinary and hybrid field of research, i.e. fundamental neuroethics.

    Within this framework, the thesis takes consciousness and related disorders (i.e. Vegetative State/Unresponsive Wakefulness Syndrome, Minimally Conscious State and Coma) and the addicted brain as illustrative cases of the potential fruitful collaboration between empirical and conceptual investigations.

    The general goal of the thesis is to contribute to the overall development of bridging the gap between empirical and conceptual understandings of consciousness. The first paper sets the theoretical framework, providing an empirically-based description of the brain with significant philosophical implications for an understanding of consciousness. The last three papers of the thesis try to apply the theoretical framework to illustrative cases. Papers II and III analyse the possible application of science and technology for an easier detection and clinical care of patients with disorders of consciousness, with particular attention to communication mediated by neurotechnology and the simulation of the conscious brain, respectively; paper IV provides a potentially new ethical analysis of addiction within the elaborated general conceptual framework.

    The conclusion of the thesis is that the impact of neuroscientific results needs that a dedicated conceptual approach reveals and investigates their conceptual meaning. This conceptual analysis is not exclusive but integrative and complementary to the empirical science. The case of consciousness, analysed from both an ethical and conceptual point of view, is highly illustrative in this respect. In the end, a conceptual/linguistic work of clarification is urgently needed.

    Delarbeten
    1. The Intrinsic Activity of the Brain and Its Relation to Levels and Disorders of Consciousness
    Öppna denna publikation i ny flik eller fönster >>The Intrinsic Activity of the Brain and Its Relation to Levels and Disorders of Consciousness
    2017 (Engelska)Ingår i: Mind and Matter, ISSN 1611-8812, E-ISSN 2051-3003, Vol. 15, nr 2, s. 197-219Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Science and philosophy still lack an overarching theory of consciousness. We suggest that a further step toward it requires going beyond the view of the brain as input-output machine and focusing on its intrinsic activity, which may express itself in two distinct modalities, i.e. aware and unaware. We specifically investigate the predisposition of the brain to evaluate and to model the world. These intrinsic activities of the brain retain a deep relation with consciousness. In fact the ability of the brain to evaluate and model the world can develop in two modalities, implicit or explicit, that correspond to what we usually refer to as the unconscious and consciousness, and both are multilevel configurations of the brain along a continuous and dynamic line. Starting from an empirical understanding of the brain as intrinsically active and plastic, we here distinguish between higher cognitive functions and basic phenomenal consciousness, suggesting that the latter might characterize the brain’s intrinsic activity as such, even if at a very basic level. We proceed to explore possible impacts of the notion of intrinsic cerebral phenomenality on our understanding of consciousness and its disorders, particularly on the diagnosis and management of patients with disorders of consciousness.

    Ort, förlag, år, upplaga, sidor
    Imprint Academic, 2017
    Nyckelord
    Brain, Consciousness, Neuroscience, Philosophy
    Nationell ämneskategori
    Filosofi Etik Neurologi
    Forskningsämne
    Filosofi; Neurovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-339292 (URN)
    Forskningsfinansiär
    EU, Horisont 2020, 720270
    Tillgänglig från: 2018-01-17 Skapad: 2018-01-17 Senast uppdaterad: 2019-08-30Bibliografiskt granskad
    2. Externalization of Consciousness: Scientific Possibilities and Clinical Implications
    Öppna denna publikation i ny flik eller fönster >>Externalization of Consciousness: Scientific Possibilities and Clinical Implications
    2015 (Engelska)Ingår i: Ethical Issues in Behavioural Neuroscience / [ed] G. Lee-J. Illes-F Ohl, Springer Berlin/Heidelberg, 2015, s. 205-222Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    The paper starts by analyzing recent advancements in neurotechnological assessment of residual consciousness in patients with disorders of consciousness and in neurotechnology-mediated communication with them. Ethical issues arising from these developments are described, with particular focus on informed consent. Against this background, we argue for the necessity of further scientific efforts and ethical reflection in neurotechnological assessment of consciousness and ‘cerebral communication’ with verbally non-communicative patients.

    Ort, förlag, år, upplaga, sidor
    Springer Berlin/Heidelberg, 2015
    Serie
    Current Topics in Behavioural Neuroscience, ISSN 1866-3370 ; 19
    Nyckelord
    Consciousness Disorders of consciousness Neurotechnology Informed consent
    Nationell ämneskategori
    Neurologi
    Forskningsämne
    Neurovetenskap; Bioetik
    Identifikatorer
    urn:nbn:se:uu:diva-245265 (URN)10.1007/7854_2014_338 (DOI)978-3-662-44866-3 (ISBN)
    Projekt
    Human Brain Project
    Forskningsfinansiär
    EU, FP7, Sjunde ramprogrammet, 604102
    Tillgänglig från: 2015-02-26 Skapad: 2015-02-26 Senast uppdaterad: 2019-08-30
    3. Large-scale brain simulation and disorders of consciousness: Mapping technical and conceptual issues
    Öppna denna publikation i ny flik eller fönster >>Large-scale brain simulation and disorders of consciousness: Mapping technical and conceptual issues
    2018 (Engelska)Ingår i: Frontiers in Psychology, ISSN 1664-1078, E-ISSN 1664-1078, Vol. 9, artikel-id 585Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Modelling and simulations have gained a leading position in contemporary attempts to describe, explain, and quantitatively predict the human brain's operations. Computer models are highly sophisticated tools developed to achieve an integrated knowledge of the brain with the aim of overcoming the actual fragmentation resulting from different neuroscientific approaches. In this paper we investigate plausibility of simulation technologies for emulation of consciousness and the potential clinical impact of large-scale brain simulation on the assessment and care of disorders of consciousness (DOCs), e.g. Coma, Vegetative State/Unresponsive Wakefulness Syndrome, Minimally Conscious State.Notwithstanding their technical limitations, we suggest that simulation technologies may offer new solutions to old practical problems, particularly in clinical contexts. We take DOCs as an illustrative case, arguing that the simulation of neural correlates of consciousness is potentially useful for improving treatments of patients with DOCs.

    Nyckelord
    Consciousness, Consciousness Disorders, brain modeling, Neuroethics, brain simulation
    Nationell ämneskategori
    Datorsystem Etik Filosofi Neurologi Bioinformatik och systembiologi
    Forskningsämne
    Neurovetenskap; Filosofi
    Identifikatorer
    urn:nbn:se:uu:diva-347782 (URN)10.3389/fpsyg.2018.00585 (DOI)000430833800001 ()29740372 (PubMedID)
    Projekt
    The human brain project
    Forskningsfinansiär
    EU, Horisont 2020, 720270
    Tillgänglig från: 2018-04-06 Skapad: 2018-04-06 Senast uppdaterad: 2019-08-30Bibliografiskt granskad
    4. Drug addiction: from neuroscience to ethics
    Öppna denna publikation i ny flik eller fönster >>Drug addiction: from neuroscience to ethics
    2018 (Engelska)Ingår i: Frontiers in Psychiatry, ISSN 1664-0640, E-ISSN 1664-0640, Vol. 9, artikel-id 595Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In the present paper we suggest a potential new ethical analysis of addiction focusing on the relationship between aware and unaware processings in the brain, i.e. on what is consciously and what is non-consciously perceived by the individual. We take the case of the opioids epidemics to argue that a consideration of both aware and unaware processings provides a more comprehensive ethical framework to discuss the ethical issues raised by addiction.Finally, our hypothesis is that in addition to identified Central Nervous System’s neuronal/neurochemical factors contributing to addictive dynamics, the socio-economic status, i.e. the individual background, plays a causal role through epigenetic processes, originating the need for additional reward in the brain. This provides a strong base for a socio-political form of responsibility for preventing and managing addiction crisis.

    Nyckelord
    Addiction, Ethics of addiction, Unaware processing, Opioids Epidemics, Drugs addiction
    Nationell ämneskategori
    Psykiatri Etik
    Identifikatorer
    urn:nbn:se:uu:diva-364429 (URN)10.3389/fpsyt.2018.00595 (DOI)000450456300001 ()30524319 (PubMedID)
    Projekt
    Human Brain Project
    Forskningsfinansiär
    EU, Horisont 2020, 785907
    Tillgänglig från: 2018-10-26 Skapad: 2018-10-26 Senast uppdaterad: 2019-08-30Bibliografiskt granskad
  • Disputation: 2019-10-31 13:15 B:21, Uppsala
    Nissbeck, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    PARN – The Tail End: Function and mechanisms of specificity and processivity2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Poly(A)-specific ribonuclease (PARN) is an exoribonuclease that is processive, poly(A) specific and cap-binding. PARN deadenylates the poly(A) tails present on a subset of mRNAs and non-coding RNAs, including among others certain snoRNAs, miRNAs and precursor rRNAs. 

    Here, we have investigated molecular mechanisms behind PARN’s specificity for adenine and ribose, essential properties for PARN’s ability to degrade poly(A) on RNAs. We have applied enzyme kinetics and used divalent metal ions as mechanistic probes to show that PARN’s poly(A) specificity is tightly linked to a translocation event during the hydrolytic cycle of PARN action. 

    To further understand the mechanism of PARN’s processive mode of action we are developing a kinetic model that allow us to measure the probability of processive action for each round of the hydrolytic cycle. Our kinetic model will be general and applicable to the processive action of any processive enzymatic activity. In conclusion, our study has so far established a mechanistic link between PARN’s processive mode of action, hydrolytic activity and preference for degrading poly(A). 

    Human patients with genetic lesions in PARN suffer from a spectrum of syndromes called telomere biology disorders (TBD), which are associated with short telomeres. PARN is involved in the maturation of the snoRNA telomerase RNA component (TERC) that is used as template during the elongation of the telomer by the telomerase. Point mutations in the gene for PARN have been identified in patients. We show that point mutations in PARN that perturb its deadenylation activity correlated with TBDs and developmental disorders.

    Our mechanistic studies of PARN action will provide a framework for our understanding of PARN’s physiological role and in extension the molecular basis for human diseases caused by perturbed PARN action. Our studies will also be of general interest for our detailed and mechanistic understanding of basic and essential mechanisms of gene expression and RNA biology.

    Delarbeten
    1. Specificity for adenine is established during the hydrolytic cycle of poly(A)-specific ribonuclease (PARN): Mechanism for poly(A) selectivity by PARN
    Öppna denna publikation i ny flik eller fönster >>Specificity for adenine is established during the hydrolytic cycle of poly(A)-specific ribonuclease (PARN): Mechanism for poly(A) selectivity by PARN
    Visa övriga...
    (Engelska)Ingår i: Artikel i tidskrift, Editorial material (Refereegranskat) Submitted
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392781 (URN)
    Tillgänglig från: 2019-09-09 Skapad: 2019-09-09 Senast uppdaterad: 2019-09-12
    2. Mechanisms of PARN action: Specificity and requirement for the 2’OH groups of the substrate
    Öppna denna publikation i ny flik eller fönster >>Mechanisms of PARN action: Specificity and requirement for the 2’OH groups of the substrate
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392970 (URN)
    Tillgänglig från: 2019-09-11 Skapad: 2019-09-11 Senast uppdaterad: 2019-09-12
    3. Mechanisms of PARN action: Kinetic analysis of processive mode of degradation
    Öppna denna publikation i ny flik eller fönster >>Mechanisms of PARN action: Kinetic analysis of processive mode of degradation
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Forskningsämne
    Mikrobiologi
    Identifikatorer
    urn:nbn:se:uu:diva-392971 (URN)
    Tillgänglig från: 2019-09-11 Skapad: 2019-09-11 Senast uppdaterad: 2019-09-12
    4. Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)
    Öppna denna publikation i ny flik eller fönster >>Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)
    Visa övriga...
    2015 (Engelska)Ingår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 52, nr 11, s. 738-748Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN. Methods We identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease. Results We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease. Conclusions Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.

    Nyckelord
    Genetics, Haematology (incl Blood transfusion), Copy-number, Molecular genetics, Neurology
    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-269251 (URN)10.1136/jmedgenet-2015-103292 (DOI)000364633100003 ()26342108 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet
    Tillgänglig från: 2015-12-17 Skapad: 2015-12-15 Senast uppdaterad: 2019-09-12Bibliografiskt granskad
    5. From incomplete penetrance with normal telomere length to severe disease and telomere shortening in a family with monoallelic and biallelic PARN pathogenic variants
    Öppna denna publikation i ny flik eller fönster >>From incomplete penetrance with normal telomere length to severe disease and telomere shortening in a family with monoallelic and biallelic PARN pathogenic variants
    Visa övriga...
    2019 (Engelska)Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-392969 (URN)10.1002/humu.23898 (DOI)
    Tillgänglig från: 2019-09-11 Skapad: 2019-09-11 Senast uppdaterad: 2019-09-12
  • Disputation: 2019-11-01 09:15 Grönwallsalen, Uppsala
    Acosta Ruiz, Vanessa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    CT Guided Ablation of T1 Renal Tumors2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The widespread use of medical imaging contributes to the increased detection of incidentally detected small renal tumors, a majority which are often indolent masses found in elderly patients with preexisting chronic kidney disease. In Sweden, partial nephrectomy with minimal invasive surgical approach is the current standard for removing these tumors, although another option is percutaneous image-guided tumor ablation that allows treatment of elderly patients with comorbidities for who surgery is a risk. Due to the lack of long-term follow-up studies and prospective randomized trials, ablation is still considered an alternative option to surgery in Sweden. The aim of this thesis was to evaluate treatment of T1 renal tumors with CT guided radiofrequency (RFA) and microwave ablation (MWA).

    Factors affecting the efficacy rate of complete tumor ablation with RFA after a single session were evaluated (Paper I). Optimal electrode placement and a long tumor distance to the collecting system were associated with an increased primary efficacy. Renal tumor RFA was compared with laparoscopic partial nephrectomy (LPN: Papers II-III): both methods had comparable secondary efficacy rates, but RFA involved several treatment sessions. Total session times and hospitalization times were shorter and complications less frequent for RFA than for LPN (Paper II). After treatment, renal function impact was assessed by evaluation of both renal function quantity and quality through determination of the split renal function (SRF: Paper III). Standard renal function measurements were assessed and both RFA and LPN were nephron sparing when treating small renal tumors and did not affect creatinine or GFR. However, LPN involved greater SRF reduction in the affected kidney than RFA. Initial experience with microwave ablation was evaluated and this new ablation technique demonstrated high efficacy rates with fewer complications, and was comparable with the mid-term results of now established ablation techniques (Paper IV).

    In conclusion, CT guided RFA and MWA are safe and effective treatments for the removal of T1 renal tumors. This thesis provides further insights into the field of thermal ablation of small renal masses, which can aid future treatment selection and patient management.

    Delarbeten