uu.seUppsala University Publications
1 - 18 of 18
rss atomLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
  • Public defence: 2018-12-14 09:15 Å80127, Uppsala
    Nouhi, Shirin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Structure formation at solid/liquid interfaces: Understanding self-assembly and environmental challenges2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work described in the present dissertation has explored the structure of particles and molecules at solid/liquid interfaces, aiming to understand the physics of self-organizing systems and use this knowledge to address some environmental issues. Surface-sensitive neutron scattering techniques, such as reflectometry and grazing incidence small angle scattering, have been used as the primary tool to investigate structures in proximity to an interface. Some of the challenges in the interpretation of neutron scattering data are discussed, and new methods for analyzing the signal have been proposed.

    It was shown that charged stabilized colloidal particles can self-assemble and form large areas (20 cm2) of crystalline structures, close to a smooth solid surface extending to depths of several micrometers, while orienting themselves into smaller crystallites in the bulk of the suspension. The adsorption of proteins from the seeds of different species of Moringa trees on alumina, silica and polystyrene surfaces was studied, as a means for using proteins from different sources and with different properties, for the water clarification step in the purification process. The seed proteins also showed to enable locking the structure of colloidal particles at the solid/liquid interface, acting as a molecular glue.

    Perfluorinated surfactants (PFASs), widely used in industrial, pharmaceutical and food packing products, have been identified as emerging pollutants, raising a global concern for the environment and wildlife. The present study has shown how PFASs molecules of different fluorocarbon chain length and with different functional groups, create defects in model membranes by partitioning and removing phospholipids from the bilayer, making the bilayer thin and less dense.

    The effect of interface roughness was studied on the lamellar structure of a non-ionic surfactant. Concentrated solutions of the surfactant have been shown to form well-ordered and well-aligned structures at a smooth interface, which could be modified further by simply heating the sample. However it was found that even small roughness, of the same order as the bilayer thickness, can distort the structure to a depth of several micrometers from the interface. Heating the sample could improve the alignment but not as much as that formed at a smooth surface.

    List of papers
    1. Comparative study of flocculation and adsorption behavior of Moringa peregrina and Moringa oleifera seed proteins for water treatment
    Open this publication in new window or tab >>Comparative study of flocculation and adsorption behavior of Moringa peregrina and Moringa oleifera seed proteins for water treatment
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Earth and Related Environmental Sciences Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-362073 (URN)
    Available from: 2018-09-30 Created: 2018-09-30 Last updated: 2018-10-17Bibliographically approved
    2. Grazing-Incidence Small Angle Neutron Scattering from Structures below an Interface
    Open this publication in new window or tab >>Grazing-Incidence Small Angle Neutron Scattering from Structures below an Interface
    2017 (English)In: Journal of applied crystallography, ISSN 0021-8898, E-ISSN 1600-5767, Vol. 50, no 4, p. 1066-1074Article in journal (Refereed) Published
    Abstract [en]

    Changes of scattering are observed as the grazing angle of incidence of an incoming beam increases and probes different depths in samples. A model has been developed to describe the observed intensity in grazing incidence small angle neutron scattering (GISANS) experiments. This includes the significant effects of instrument resolution, the sample transmission, which depends on both absorption and scattering, as well as the sample structure. The calculations are tested with self-organised structures of two colloidal samples with different size particles that were measured on two different instruments. The model allows calculations for various instruments with defined resolution and can be used to design future improved experiments. The possibilities and limits of GISANS for different studies are discussed using the model calculations. 

    Keywords
    GISANS, Solid/liquid interface, colloidal particles
    National Category
    Physical Sciences
    Research subject
    Physics
    Identifiers
    urn:nbn:se:uu:diva-322577 (URN)10.1107/S1600576717007518 (DOI)000407040700011 ()28808432 (PubMedID)
    Funder
    Swedish Research Council, 621-2012-4382
    Available from: 2017-05-26 Created: 2017-05-26 Last updated: 2018-10-13Bibliographically approved
    3. Sticking particles to solid surfaces using Moringa oleifera proteins as a glue
    Open this publication in new window or tab >>Sticking particles to solid surfaces using Moringa oleifera proteins as a glue
    Show others...
    2018 (English)In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 168, p. 68-75Article in journal (Refereed) In press
    Abstract [en]

    Experimental studies have been made to test the idea that seed proteins from Moringa oleifera which are novel, natural flocculating agents for many particles could be used to promote adhesion at planar interfaces and hence provide routes to useful nanostructures. The proteins bind irreversibly to silica interfaces. Surfaces that had been exposed to protein solutions and rinsed were then exposed to dispersions of sulfonated polystyrene latex. Atomic force microscopy was used to count particle density and identified that the sticking probability was close to 1. Measurements with a quartz crystal microbalance confirmed the adhesion and indicated that repeated exposures to solutions of Moringa seed protein and particles increased the coverage. Neutron reflectivity and scattering experiments indicate that particles bind as a monolayer. The various results show that the 2S albumin seed protein can be used to fix particles at interfaces and suggest routes for future developments in making active filters or improved interfaces for photonic devices.

    National Category
    Physical Chemistry Condensed Matter Physics
    Research subject
    Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-338407 (URN)10.1016/j.colsurfb.2018.01.004 (DOI)000443630200010 ()29373240 (PubMedID)
    Funder
    Swedish Research Council, 348-2011-7241Swedish Research Council, 621-2012-4382
    Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2018-11-01Bibliographically approved
    4. Interactions of perfluoroalkyl substances with a phospholipid bilayer studied by neutron reflectometry
    Open this publication in new window or tab >>Interactions of perfluoroalkyl substances with a phospholipid bilayer studied by neutron reflectometry
    Show others...
    2017 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 511, p. 474-481Article in journal (Refereed) Published
    Abstract [en]

    The interactions between perfluoroalkyl substances (PFASs) and a phospholipid bilayer (1,2-dimyristoyl-sn-glycero-3-phosphocholine) were investigated at the molecular level using neutron reflectometry. Representative PFASs with different chain length and functional groups were selected in this study including: perfluorobutane sulfonate (PFBS), perfluorohexanoate (PFHxA), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA), perfluorooctane sulfonate (PFOS), and perfluorooctane sulfonamide (FOSA). All PFASs were found to interact with the bilayer by incorporation, indicating PFAS ability to accumulate once ingested or taken up by organisms. The interactions were observed to increase with chain length and vary with the functional group as SO2NH2" role="presentation">(FOSA) > SO2O−" role="presentation">(PFOS) > COO(PFNA). The PFAS hydrophobicity, which is strongly correlated with perfluorocarbon chain length, was found to strongly influence the interactions. Longer chain PFASs showed higher tendency to penetrate into the bilayer compared to the short-chain compounds. The incorporated PFASs could for all substances but one (PFNA) be removed from the lipid membrane by gentle rinsing with water (2 mL min−1). Although short-chain PFASs have been suggested to be the potentially less bioaccumulative alternative, we found that in high enough concentrations they can also disturb the bilayer. The roughness and disorder of the bilayer was observed to increase as the concentration of PFASs increased (in particular for the high concentrations of short-chain substances i.e. PFHxA and PFBS), which can be an indication of aggregation of PFASs in the bilayer.

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-330505 (URN)10.1016/j.jcis.2017.09.102 (DOI)000417008200053 ()29073553 (PubMedID)
    Funder
    Swedish Research Council, 621-2012-4382Swedish Research Council, 2015-03938
    Available from: 2017-10-02 Created: 2017-10-02 Last updated: 2018-10-13Bibliographically approved
    5. Distortion of surfactant lamellar phases induced by surface roughness
    Open this publication in new window or tab >>Distortion of surfactant lamellar phases induced by surface roughness
    (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    Self-assembly is a characteristic property of soft matter and understanding the factors which assist or perturb this process is of a great importance in many biological and industrial processes.  Amphiphiles self-assemble and order into a variety of structures including well-ordered lamellar phases.  The present work uses neutron reflectometry to explore the effects of both interface roughness and temperature on the lamellar-phase structure of a non-ionic surfactant at a solid/liquid interface.  The structure of concentrated solutions of tetraethyleneglycol dodecyl ether has been compared against a smooth surface and one with a roughness of the order of the lamellar spacing.  The results showed that the surfactant forms a well-order and aligned structure at smooth surface that extends to a depth of micrometers from the interface.  Increasing the temperature of the sample and subsequent cooling helped the alignment and increased the number of oriented layers at the surface.  The same sample formed a significantly less aligned structure at a rough surface that did not align to same extent after heating.  The perturbation of the structure caused by thermal fluctuations was found to be much less than that imposed by a small surface roughness.

     

    Keywords

    Keywords
    Roughness, thermal fluctuations, disorder, neutron reflectometry, nonionic surfactant
    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-363134 (URN)
    Available from: 2018-10-13 Created: 2018-10-13 Last updated: 2018-10-17Bibliographically approved
  • Public defence: 2018-12-14 09:15 Polhemsalen, 10134, Ångström, Uppsala
    Gustafsson, Simon
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mille-feuille Filter: A Non-woven Nano-cellulose Based Virus Removal Filter for Bioprocessing2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Virus removal filters, produced from synthetic surface-modified polymers or regenerated cellulose by phase inversion, are vital to the production of therapeutic proteins such as monoclonal antibodies and plasma proteins. Use of these filters is also one of the most expensive purification steps in the downstream processing of proteins due to high sales price and being limited to a single use.

    In this thesis, a virus removal filter produced from Cladophora sp. algal nanocellulose has been characterized. The mille-feuille (‘‘a thousand leaves’’) filter paper is the first non-woven, wet-laid filter paper composed of 100% native nanocellulose that is capable of removing the ‘‘worst-case’’ model viruses, the non-enveloped parvoviruses, i.e., minute virus of mice (MVM; 18–20 nm), from water with a log10 reduction value (LRV) ≥5.78 (≥99.9998%). The mille-feuille filter features a unique internal stratified architecture that is the result of nanofiber self-assembly into 2D nanosheets during manufacturing. Such an internal structure has several benefits for achieving highly selective virus removal with high flux.

    The pore size distribution can be tailored to sizes from 10 to 25 nm by altering drying conditions, i.e. temperature and drying rate; therefore, the filter can be customized to target the size cut-off of the smallest virus particles known. The mille-feuille filter has achieved up to 200 L m-2 h-1 (LMH) bar-1 in flux. Furthermore, protein recovery rates of 99% were measured during bovine serum albumin (BSA) filtration. Protein recovery was determined to be dependent on the protein size and charge.

    Filtration of cell culture media was also investigated, and no fouling was observed with fluxes of 400 LMH for an 11 µm filter and 140 LMH for a 33 µm filter at 3 bar. An LRV of >4.8 was measured for the 33 µm filter at 3 bar, but only 2.2 was measured for the 11 µm filter at 3 bar using the small-size ФX174 bacteriophage as a model virus.

    Furthermore, the virus reduction was discovered to be pressure dependent, with the LRV increasing with trans membrane pressure (TMP). The tendency to virus breakthrough was partly mitigated at low TMPs by filter cross-linking.

    In summary, the mille-feuille filter paper has the characteristics to be a promising virus removal filter for both upstream and downstream applications. Further studies shall focus on the area of protein filtration to gain a better understanding of how buffer conditions and the physical characteristics of proteins contribute to filter fouling.

    List of papers
    1. Mille-feuille paper: a novel type of filter architecture for advanced virus separation applications
    Open this publication in new window or tab >>Mille-feuille paper: a novel type of filter architecture for advanced virus separation applications
    Show others...
    2016 (English)In: Materials Horizons, ISSN 2051-6347, E-ISSN 2051-6355, Vol. 3, no 4, p. 320-327Article in journal (Refereed) Published
    Abstract [en]

    Mille-feuille (“a thousand leaves”) paper is the first non-woven, wet-laid filter paper, composed of 100% native cellulose, which is capable of removal of the “worst-case” model virus, the non-enveloped parvoviruses, i.e. minute virus of mice (MVM; 18–20 nm), from water with a log10 reduction value (LRV) >5 (>99.999%). We further illustrate how the flow rate across the mille-feuille paper can be increased exponentially so that flux rates in the order of 350 L m−2 h−1 bar−1 can be potentially achieved.

    Place, publisher, year, edition, pages
    Uppsala: , 2016
    National Category
    Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-294389 (URN)10.1039/C6MH00090H (DOI)000378716500007 ()
    Funder
    Knut and Alice Wallenberg Foundation
    Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2018-10-24Bibliographically approved
    2. Characterization of Regular and Cross-linked Virus Removal Filter Papers: Comparative Analysis of Dry and Wet Porometry Methods and Virus Removal Properties
    Open this publication in new window or tab >>Characterization of Regular and Cross-linked Virus Removal Filter Papers: Comparative Analysis of Dry and Wet Porometry Methods and Virus Removal Properties
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-363986 (URN)
    Available from: 2018-10-22 Created: 2018-10-22 Last updated: 2018-10-24
    3. Strategies for Tailoring the Pore-Size Distribution of Virus Retention Filter Papers
    Open this publication in new window or tab >>Strategies for Tailoring the Pore-Size Distribution of Virus Retention Filter Papers
    2016 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 8, no 22, p. 13759-13767Article in journal (Refereed) Published
    Abstract [en]

    The goal of this work is to demonstrate how the pore-size distribution of the nanocellulose-based virus-retentive filter can be tailored. The filter paper was produced using cellulose nanofibers derived from Cladophora sp. green algae using the hot-press drying at varying drying temperatures. The produced filters were characterized using scanning electron microscopy, atomic force microscopy, and N2 gas sorption analysis. Further, hydraulic permeability and retention efficiency toward surrogate 20 nm model particles (fluorescent carboxylate-modified polystyrene spheres) were assessed. It was shown that by controlling the rate of water evaporation during hot-press drying the pore-size distribution can be precisely tailored in the region between 10 and 25 nm. The mechanism of pore formation and critical parameters are discussed in detail. The results are highly valuable for development of advanced separation media, especially for virus-retentive size-exclusion filtration.

    Place, publisher, year, edition, pages
    Uppsala: , 2016
    Keywords
    virus-retentive filtration; nanocellulose; paper making; size-exclusion filtration; Cladophora cellulose; hydraulic permeability
    National Category
    Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-294387 (URN)10.1021/acsami.6b03093 (DOI)000377642100012 ()27144657 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationStiftelsen Olle Engkvist Byggmästare
    Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2018-10-24Bibliographically approved
    4. Protein-Nanocellulose Interactions in Paper Filters for Advanced Separation Applications
    Open this publication in new window or tab >>Protein-Nanocellulose Interactions in Paper Filters for Advanced Separation Applications
    2017 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 33, no 19, p. 4729-4736Article in journal (Refereed) Published
    Abstract [en]

    Protein-based pharmaceutics are widely explored for healthcare applications, and 6 out of 10 best-selling drugs today are biologicals. The goal of this work was to evaluate the protein nanocellulose interactions in paper filter for advanced separation applications such as virus removal filtration and bioprocessing. The protein recovery was measured for bovine serum albumin (BSA), gamma-globulin, and lysozyme using biuret total protein reagent and polyacrylamide gel electrophoresis (PAGE), and the throughput was characterized in terms of flux values from fixed volume filtrations at various protein concentrations and under worst case experimental conditions. The affinity of cellulose to bind various proteins, such as BSA, lysozyme, gamma-globulin, and human IgG was quantified using a quartz crystal microbalance (QCMB) by developing a new method of fixing the cellulose fibers to the electrode surface without cellulose dissolution-precipitation. It was shown that the. mille-feuille filter exhibits high protein recovery, that is, similar to 99% for both BSA and lysozyme. However, gamma-globulin does not pass through the membrane due to its large size (i.e., >180 kDa). The PAGE data show no substantial change in the amount of dimers and trimers before and after filtration. QCMB analysis suggests a low affinity between the nanocellulose surface and proteins. The nanocellulose-based filter exhibits desirable inertness as a filtering material intended for protein purification.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2017
    National Category
    Nano Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-326244 (URN)10.1021/acs.langmuir.7b00566 (DOI)000401674900015 ()28441870 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationStiftelsen Olle Engkvist Byggmästare
    Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2018-10-24
    5. Significance of Brownian Motion for Nanoparticle and Virus Capture in Nanocellulose-Based Filter Paper
    Open this publication in new window or tab >>Significance of Brownian Motion for Nanoparticle and Virus Capture in Nanocellulose-Based Filter Paper
    2018 (English)In: Membranes, ISSN 2077-0375, E-ISSN 2077-0375, Vol. 8, no 4, article id 90Article in journal (Refereed) Published
    Abstract [en]

    Pressure-dependent breakthrough of nanobioparticles in filtration was observed and it was related to depend on both convective forces due to flow and diffusion as a result of Brownian motion. The aim of this work was to investigate the significance of Brownian motion on nanoparticle and virus capture in a nanocellulose-based virus removal filter paper through theoretical modeling and filtration experiments. Local flow velocities in the pores of the filter paper were modeled through two different approaches (i.e., with the Hagen–Poiseuille equation) and by evaluating the superficial linear flow velocity through the filter. Simulations by solving the Langevin equation for 5 nm gold particles and 28 nm ΦX174 bacteriophages showed that hydrodynamic constraint is favored for larger particles. Filtration of gold nanoparticles showed no difference in retention for the investigated fluxes, as predicted by the modeling of local flow velocities. Filtration of ΦX174 bacteriophages exhibited a higher retention at higher filtration pressure, which was predicted to some extent by the Hagen–Poiseuille equation but not by evaluation of the superficial linear velocity. In all, the hydrodynamic theory was shown able to explain some of the observations during filtration.

    National Category
    Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-362868 (URN)10.3390/membranes8040090 (DOI)
    Available from: 2018-10-11 Created: 2018-10-11 Last updated: 2018-10-24Bibliographically approved
    6. Growth Media Filtration Using Nanocellulose-based Virus Removal Filter for Upstream Biopharmaceutical Processing
    Open this publication in new window or tab >>Growth Media Filtration Using Nanocellulose-based Virus Removal Filter for Upstream Biopharmaceutical Processing
    2018 (English)In: Journal of Membrane Science, ISSN 0376-7388, E-ISSN 1873-3123Article in journal (Other academic) Published
    National Category
    Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-363987 (URN)
    Available from: 2018-10-22 Created: 2018-10-22 Last updated: 2018-11-16
  • Public defence: 2018-12-14 09:15 Rudbecksalen, Uppsala
    Morin, Eric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University.
    Neuropilin-1 regulation of tumor vascularization and growth2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Angiogenesis, the formation of new blood vessels from existing ones, is dysregulated during tumor progression as a result of chronic hypoxia and inflammation. Such alterations lead to a lack of vessel hierarchy, and the formation of poorly perfused, leaky and blunt-ended vessels, contributing to disease progression. This thesis explores the impact of neuropilin-1 (NRP1) presentation of vascular endothelial growth factor-A (VEGF-A) to its cognate receptor, VEGFR2. NRP1 presentation of VEGF-A occurs in cis (when NRP1 and VEGFR2 are present on the same cell) or in trans (when molecules are present on adjacent cells). As shown in this thesis, the different modes of NRP1 presentation influence endothelial cell signaling and tumor angiogenesis. The overall aim with the studies has been to identify new biomarkers for cancer survival and potential therapeutic targets.

    In paper I, we explored if signaling downstream of VEGFR2 was affected by NRP1 presentation in cis compared to trans. Complex formation in trans was readily identified, however, the kinetics were delayed and prolonged, inhibiting VEGFR2 internalization and downstream signaling. Additionally, in vivo tumor studies in mice demonstrated that trans presentation of NRP1 led to early inhibition of angiogenesis and suppressed tumor initiation.

    In paper II, the presence and clinical impact of trans VEGFR2/NRP1 complexes in human cancer was investigated. We first identified gastric and pancreatic adenocarcinomas (PDAC) as candidates for further investigation. VEGFR2/NRP1 complexes were identified in both tumor types but were more prevalent in PDAC. Trans presentation of NRP1 in PDAC correlated with a reduction in several vessel parameters and tumor cell proliferation. Importantly, this study identified the presence of trans complexes as an independent marker of longer overall survival for PDAC patients.

    In paper III, we explored the impact of NRP1 presentation modes on renal cell carcinoma (RCC) patient survival. We performed in situ proximity ligation assay (PLA) and immunofluorescence staining on a RCC cohort. Tumor cell NRP1, either trans-complexed with endothelial cell-expressed VEGFR2 as detected by in situ PLA, or alternatively, detected by immunofluorescent staining, was identified as an independent predictor of increased overall survival. These data reinforce the importance of the cell type-specific expression of cancer biomarkers.

    List of papers
    1. NRP1 Presented in trans to the Endothelium Arrests VEGFR2 Endocytosis, Preventing Angiogenic Signaling and Tumor Initiation
    Open this publication in new window or tab >>NRP1 Presented in trans to the Endothelium Arrests VEGFR2 Endocytosis, Preventing Angiogenic Signaling and Tumor Initiation
    Show others...
    2014 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 28, no 6, p. 633-646Article in journal (Refereed) Published
    Abstract [en]

    Neuropilin 1 (NRP1) modulates angiogenesis by binding vascular endothelial growth factor (VEGF) and its receptor, VEGFR2. We examined the consequences when VEGFR2 and NRP1 were expressed on the same cell (cis) or on different cells (trans). In cis, VEGF induced rapid VEGFR2/NRP1 complex formation and internalization. In trans, complex formation was delayed and phosphorylation of phospholipase C gamma (PLC gamma) and extracellular regulated kinase 2 (ERK2) was prolonged, whereas ERK1 phosphorylation was reduced. Trans complex formation suppressed initiation and vascularization of NRP1-expressing mouse fibrosarcoma and melanoma. Suppression in trans required high-affinity, steady-state binding of VEGF to NRP1, which was dependent on the NRP1 C-terminal domain. Compatible with a trans effect of NRP1, quiescent vasculature in the developing retina showed continuous high NRP1 expression, whereas angiogenic sprouting occurred where NRP1 levels fluctuated between adjacent endothelial cells. Therefore, through communication in trans, NRP1 can modulate VEGFR2 signaling and suppress angiogenesis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-224353 (URN)10.1016/j.devcel.2014.02.010 (DOI)000333765900005 ()
    Available from: 2014-05-13 Created: 2014-05-09 Last updated: 2018-10-26
    2. VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival
    Open this publication in new window or tab >>VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival
    Show others...
    2018 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 3, p. 311-322Article in journal (Refereed) Published
    Abstract [en]

    Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. 

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2018
    Keywords
    VEGF, neuropilin 1, pancreatic adenocarcinoma, trans-complex, branching
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-363966 (URN)10.1002/path.5141 (DOI)30027561 (PubMedID)
    Funder
    Swedish Research Council, 2015-02375Swedish Cancer Society, CAN2016/578Knut and Alice Wallenberg Foundation, KAW 2015.0030Knut and Alice Wallenberg Foundation, KAW 2015.0275
    Available from: 2018-10-22 Created: 2018-10-22 Last updated: 2018-12-05Bibliographically approved
    3. Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma
    Open this publication in new window or tab >>Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma
    Show others...
    (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827Article in journal (Other academic) Submitted
    Abstract [en]

    Background: Considerable progress in renal cell carcinoma (RCC) treatment has been made in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5-year survival of metastatic disease is still only 10-15%. Here, we explored the prognostic significance of compartment-specific expression of Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in RCC tumor vessels, in perivascular tumor cells and generally in the tumor cells. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined.

    Methods: VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay, and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells and general tumor cell expression) was determined by immunofluorescent staining, in a cohort of 64 advanced renal cell carcinoma patients.

    Results: VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 was associated with a reduced tumor vessel density. The presence of VEGFR2/NRP1 trans complexes, perivascular NRP1 and general tumor cell NRP1 expression correlated with improved survival, however, only VEGFR2/NRP1 trans complexes and perivascular NRP1 expression remained significant in multivariable analysis.

    Conclusion: Our work shows that VEGFR2/NRP1 complexes in trans, as well as perivascular NRP1 expression, are independent markers of improved survival in advanced renal cell carcinoma.

    Keywords
    renal cell carcinoma, NRP1, VEGFR2, angiogenesis, trans complex formation
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-363970 (URN)
    Available from: 2018-10-22 Created: 2018-10-22 Last updated: 2018-10-26
  • Public defence: 2018-12-14 09:15 Skoogsalen, Uppsala
    Trbakovic, Amela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Clinical and experimental studies of bone substitutes and dental implants in compromised bone sites2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: With an ageing population, an increase of more challenging implant treatments is expected. In this thesis, we evaluate the outcome of two faster implant protocols, in patients with compromised alveolar bone. We examine the bone integrating abilities of two new synthetic bone substitute materials and in another paper, we discuss the effects of nonsteroidal anti-inflammatory drugs (NSAID) on bone healing.

    Aim: In paper I we investigate implant survival and effect of reduced implant-tooth distance. In paper II we evaluate the long-term implant survival and function of immediately loaded implants. In paper III & IV, we analyse if added NSAID reduce postoperative pain and if it has a reduced effect on new bone formation in a rabbit sinus lift model. We also investigate if a ceramic compound (CPC, granules) and hydrogel (HABP.CaP) result in a similar or larger bone amount, in comparison with bovine bone mineral. In Paper V we assess new bone formation adjacent to a hollow CPC implant.

    Material & Methods: Paper I present a clinical and radiological follow-up, performed on subjects that previously received 3.0-3.3 mm diameter implants in the aesthetic area. In paper II, clinical and radiographic examinations were performed on subjects that had received six implants each with immediate loading in the maxilla 8-11-year ago. For paper III-IV, pain was assessed by clinical examination and scoring of facial expressions from photos. Histomorphometry and histology evaluations were performed. In paper V, a critical radius defect was created and either replaced by particulate autologous bone (AB) or a CPC implant. Qualitative and quantitative radiographic and histology evaluations were performed. 

    Results: In paper I, an implant survival of 97.2% up to 124 months was shown with a tooth-implant distance in many cases of  <1.5 mm. Discoloration and recession of the buccal gingiva was the most frequent patient concern. In paper II a cumulative implant survival rate was 81.9 % at the final follow-up. In paper III and IV it was shown that NSAID had no effect on pain relief or bone formation. No difference was shown between CPC and control, but both showed larger bone amount and BIC than HABP.CaP. In paper V new bone was seen in sites throughout the entire CPC implant.

    Conclusion: Satisfactory long-term dental implant results can be obtained without bone augmentation in most patients with atrophic alveolar bone, but there is still a minority in this group that may benefit of bone enhancement prior to implant treatment. To avoid the negative effects of autologous bone grafting, synthetic materials as the presented CPC, have shown promising results as a solution or alternative to existing bone substitutes in animal models.

    List of papers
    1. A clinical and radiological long-term follow-up study of narrow diameter implants in the aesthetic area
    Open this publication in new window or tab >>A clinical and radiological long-term follow-up study of narrow diameter implants in the aesthetic area
    2018 (English)In: Clinical Implant Dentistry and Related Research, ISSN 1523-0899, E-ISSN 1708-8208, Vol. 20, no 4, p. 598-605Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    To study long-term function of narrow diameter implants (NDI:s) and if reduced implant-tooth distance negatively impacts adjacent teeth.

    Materials and Methods

    A clinical and radiological follow-up of NDI:s replacing maxillary laterals and mandibular incisors was performed. Subjects that received 3.0-3.3 mm-diameter single implants from 3 units in Uppsala and Vasteras, Sweden, between 2002 and 2011 were offered to participate in this retrospective study.

    Results

    Twenty-seven patients (30 implants) underwent clinical and CBCT examination, mean follow-up time was 63.3 months. On average, the implant-tooth distance was 1.6 mm at the cervical region and 17 implants were placed 1 mm or less to the adjacent root. Additionally, 2 patients (3 implants) underwent clinical examination (I). Twenty-seven patients (36 implants) declined the examination but agreed to an interview (II). At the time of the follow-up, all implants had good function, and implant survival of group I and II together was 97.2%. In both groups, the 2 main patient concerns were discoloration and regression of the buccal gingiva.

    Conclusion

    Survival of implants is in accordance to standard diameter studies and although most implants were placed very close to the adjacent teeth, no pathologies could be linked to this except aesthetic concerns.

    Place, publisher, year, edition, pages
    WILEY, 2018
    Keywords
    cbct imaging, implant survival, long-term survival, narrow implants
    National Category
    Dentistry
    Identifiers
    urn:nbn:se:uu:diva-363062 (URN)10.1111/cid.12627 (DOI)000440988300022 ()29920935 (PubMedID)
    Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2018-10-28Bibliographically approved
    2. 8-11-year follow-up of immediately loaded implants placed in edentulous maxillae with compromised bone volume and poor bone quality: A prospective cohort study
    Open this publication in new window or tab >>8-11-year follow-up of immediately loaded implants placed in edentulous maxillae with compromised bone volume and poor bone quality: A prospective cohort study
    2018 (English)In: Article in journal (Refereed) Submitted
    National Category
    Dentistry
    Identifiers
    urn:nbn:se:uu:diva-364439 (URN)
    Available from: 2018-10-28 Created: 2018-10-28 Last updated: 2018-10-28
    3. Carprofen neither reduces postoperative facial expression scores in rabbits treated with buprenorphine nor alters long term bone formation after maxillary sinus grafting
    Open this publication in new window or tab >>Carprofen neither reduces postoperative facial expression scores in rabbits treated with buprenorphine nor alters long term bone formation after maxillary sinus grafting
    Show others...
    2016 (English)In: Research in Veterinary Science, ISSN 0034-5288, E-ISSN 1532-2661, Vol. 107, p. 123-131Article in journal (Refereed) Published
    Abstract [en]

    In connection with bilateral maxillary sinus augmentation, the acute effects of the nonsteroidal anti-inflammatory drug carprofen on facial expressions and long-term effects on bone formation were evaluated in 18 male New Zealand White rabbits. A 10 x 10 mm bone window was drilled in the maxilla, the sinus membrane elevated and a titanium mini-implant inserted. One of two test materials was randomly inserted unilaterally and bovine bone chips (control) on the contralateral side in the created space. Rabbits were randomly allocated to receive buprenorphine plus carprofen (n = 9) or buprenorphine plus saline (n = 9) postoperatively. Buprenorphine was administered subcutaneously every 6 h for 3 days in a tapered dose (0.05-0.01 mg/kg) and carprofen (5 mg/kg) or saline administered subcutaneously 1 h before, and daily for 4 days postoperatively. To assess pain, clinical examination, body weight recording and scoring of facial expressions from photos taken before, and 6-13 h after surgery were performed. Twelve weeks after surgery the rabbits were euthanized and sections of maxillary bones and sinuses were analysed with histomorphometry and by qualitative histology. Carprofen had no effect on mean facial expression scores, which increased from 0.0 to 3.6 (carprofen) and 43 (saline), of a maximum of 8.0. Neither did carprofen have an effect on bone formation or implant incorporation, whereas the test materials had. In conclusion, treatment with 5 mg/kg carprofen once daily for 5 days did not reduce facial expression scores after maxillary sinus augmentation in buprenorphine treated rabbits and did not affect long term bone formation.

    Keywords
    Bone formation, Pain, NSAID, Implant, Sinus-lift, Experimental animal
    National Category
    Veterinary Science
    Identifiers
    urn:nbn:se:uu:diva-304437 (URN)10.1016/j.rvsc.2016.05.010 (DOI)000381541600019 ()27473985 (PubMedID)
    Funder
    Swedish Research Council, VR2013_6373 MR
    Available from: 2016-10-05 Created: 2016-10-05 Last updated: 2018-10-28Bibliographically approved
    4. A new synthetic granular calcium phosphate compound induces new bone in a sinus lift rabbit model
    Open this publication in new window or tab >>A new synthetic granular calcium phosphate compound induces new bone in a sinus lift rabbit model
    Show others...
    2018 (English)In: Journal of Dentistry, ISSN 0300-5712, E-ISSN 1879-176X, Vol. 70, p. 31-39Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: The aim of this study was to investigate if a synthetic granular calcium phosphate compound (CPC) and a composite bisphosphonate-linked hyaluronic acid-calcium phosphate hydrogel (HABP·CaP) induced similar or more amount of bone as bovine mineral in a modified sinus lift rabbit model.

    MATERIAL AND METHODS: Eighteen adult male New Zeeland White rabbits, received randomly one of the two test materials on a random side of the face, and bovine mineral as control on the contralateral side. In a sinus lift, the sinus mucosa was elevated and a titanium mini-implant was placed in the alveolar bone. Augmentation material (CPC, HABP·CaP or bovine bone) was applied in the space around the implant. The rabbits were euthanized three months after surgery and qualitative and histomorphometric evaluation were conducted. Histomorphometric evaluation included three different regions of interest (ROIs) and the bone to implant contact on each installed implant.

    RESULTS: Qualitative assessment (p = <.05), histomorphometric evaluations (p = < .01), and implant incorporation (p = <.05) showed that CPC and bovine mineral induced similar amount of bone and more than the HABP·CaP hydrogel.

    CONCLUSION: CPC induced similar amount of bone as bovine mineral and both materials induced more bone than HABP·CaP hydrogel.

    CLINICAL SIGNIFICANCE: The CPC is suggested as a synthetic alternative for augmentations in the maxillofacial area.

    Keywords
    Animal experiments, Bone implant interactions, Bone regeneration, Bone substitutes, Ceramic granules
    National Category
    Dentistry
    Identifiers
    urn:nbn:se:uu:diva-341457 (URN)10.1016/j.jdent.2017.12.009 (DOI)000425888900004 ()29258851 (PubMedID)
    Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-10-28Bibliographically approved
    5. Guided bone tissue regeneration using a hollow calcium phosphate based implant in a critical size rabbit radius defect
    Open this publication in new window or tab >>Guided bone tissue regeneration using a hollow calcium phosphate based implant in a critical size rabbit radius defect
    Show others...
    (English)In: Article, review/survey (Refereed) Submitted
    National Category
    Surgery Medical Biotechnology
    Identifiers
    urn:nbn:se:uu:diva-364438 (URN)
    Available from: 2018-10-28 Created: 2018-10-28 Last updated: 2018-10-28
  • Public defence: 2018-12-14 10:15 the Humanities Theatre, Uppsala
    Nilsson Jobs, Elisabeth
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Recognizing Disability and Ability in Young Autistic Children2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Autism Spectrum Disorder (ASD) is characterized by impairments, or disabilities, in social communication and interaction (SCI), and restricted and repetitive behaviors (RRBs), but is also associated with enhanced abilities. Early identification of disability in ASD has been a primary focus in clinical practice, while abilities associated with ASD have neither been recognized nor assessed. The overarching purpose of this thesis was to improve early recognition of both disability and ability in young autistic children. Three studies were conducted in a largely overlapping sample of 3-year-old high-risk-for-ASD siblings, either with or without ASD, and low-risk-for-ASD siblings. Study I and II focused on the value of preschool staff as informants in early identification of autistic symptoms, while Study III investigated potential strengths in visual ability in autistic children. Study I investigated how accurately parents and preschool staff rated autistic symptoms in relation to diagnoses and clinical assessment of autistic symptoms. Results showed that ratings by preschool staff were more accurate than parent ratings at differentiating the ASD group from the two other groups, and more closely associated with clinical autistic symptoms. Study II focused on preschool staff’s ratings of social communication and interaction (SCI) and restricted and repetitive behaviors (RRBs). Results showed that ratings of SCI were more accurate than RRBs in differentiating the ASD group from the two other groups, and only the SCI ratings correlated with clinical assessment of social impairment. Study III investigated specific aspects of visual ability with five visual tasks. Similar performance on visual ability was found among groups, except for the Hidden Pictures (HP) task. The children with ASD had superior performance on HP compared with the other two groups. Results of Study I and II suggest that preschool staff report on autistic symptoms may complement parent report in diagnostic assessment of ASD, although their report on RRBs should be interpreted with caution. The results of Study III indicate that enhanced visual ability can be identified in autistic children already at age three. Overall, this thesis suggests that information from preschool staff and assessment of visual ability can contribute to the early recognition of disability and ability in young children with ASD.

    List of papers
    1. Local and Global Visual Processing in 3-year olds With and Without Autism
    Open this publication in new window or tab >>Local and Global Visual Processing in 3-year olds With and Without Autism
    2018 (English)In: Journal of autism and developmental disorders, ISSN 0162-3257, E-ISSN 1573-3432, Vol. 48, no 6, p. 2249-2257Article in journal (Refereed) Published
    Abstract [en]

    Research on visual local and global perception in autism spectrum disorder (ASD) is incomplete in young children. We investigated 35 three-year-old siblings of children with ASD, either diagnosed (n =12) or not diagnosed (n = 23) with ASD as well as 14 controls with typical development and with no family history of ASD. Data from the local tasks Children´s Embedded Figures Test, Hidden Pictures, Figure-Ground and the global tasks Closure and Fragmented Picture Test were collected. Enhanced performance on the local task Hidden Pictures differentiated children with ASD from the other groups. Implications of these results are discussed.  

    Keywords
    Autism, Neurodevelopmental disorder, Cognition, Visual perception, Local processing, Child development
    National Category
    Psychology Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-338729 (URN)10.1007/s10803-018-3470-8 (DOI)000431955400035 ()29411217 (PubMedID)
    Funder
    EU, FP7, Seventh Framework ProgrammeSwedish Research CouncilSwedish Research Council FormasVINNOVA
    Available from: 2018-01-12 Created: 2018-01-12 Last updated: 2018-10-24Bibliographically approved
    2. Spotting Signs of Autism in 3-Year-Olds: Comparing Information from Parents and Preschool Staff
    Open this publication in new window or tab >>Spotting Signs of Autism in 3-Year-Olds: Comparing Information from Parents and Preschool Staff
    2018 (English)In: Journal of autism and developmental disorders, ISSN 0162-3257, E-ISSN 1573-3432Article in journal (Other academic) Published
    Keywords
    Autism Spectrum Disorder; Early Development; Rating Scales
    National Category
    Social Sciences
    Research subject
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-364104 (URN)
    Note

    Preschool informants may provide valuable information about symptoms of autism spectrum disorder (ASD) in young children. We compared the diagnostic accuracy of ratings by preschool staff with those by parents of 3-year-old children using the Achenbach System of Empirically Based Assessment (ASEBA) Preschool Forms. The sample consisted of 32 children at familial risk for ASD without diagnosis, 10 children at risk for ASD with diagnosis, and 14 low-risk typically developing controls. Preschool staff ratings were more accurate than parent ratings at differentiating children with and without ASD, and more closely associated with clinician-rated symptoms. These results point to the value of information from preschool informants in early detection and diagnostic assessments.

    Available from: 2018-10-23 Created: 2018-10-23 Last updated: 2018-11-28
    3. Preschool Staff Spot Social Communication Difficulties, but Not Restricted and Repetitive Behaviors in Young Autistic Children
    Open this publication in new window or tab >>Preschool Staff Spot Social Communication Difficulties, but Not Restricted and Repetitive Behaviors in Young Autistic Children
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    To fulfill the criteria for autism spectrum disorder (ASD), symptoms must be present across domains and contexts. We assessed preschool staff’s ratings of social communication and interaction (SCI) and restricted and repetitive behaviors (RRBs) in 3-year-old siblings of children with ASD, either diagnosed (n = 12) or not diagnosed (n = 36) with ASD, and typically developing siblings with no family history of ASD (n = 16). Ratings of SCI were more accurate than RRBs in differentiating the ASD group from the two other groups, and only the SCI ratings correlated with SCI symptoms rated by clinical experts. We conclude that while preschool staff ratings of SCI behaviors are adequate, ratings of RRBs should be treated with more caution.

    Keywords
    Autism Spectrum Disorder; Early Development; Rating Scales
    National Category
    Social Sciences
    Research subject
    Psychology; Psychology
    Identifiers
    urn:nbn:se:uu:diva-364105 (URN)
    Available from: 2018-10-23 Created: 2018-10-23 Last updated: 2018-10-24
  • Public defence: 2018-12-14 13:00 Auditorium minus, Uppsala
    Axfors, Cathrine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Anxious personality traits in pregnant women: Associations with postpartum depression, delivery complications and health care use2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Anxious personality traits, including those encompassed by negative emotionality (neuroticism) and the tendency to worry about close relationships (attachment anxiety) during pregnancy were the focus of this thesis. The overall aim was to examine perinatal correlates of these characteris-tics in terms of psychiatric and obstetric health as well as antenatal care (ANC).

    Papers I-II were part of a large population-based project on pregnant women in Uppsala in 2009-2012 (n=2160). Papers III-IV adjoined participants from several projects in 2005-2011, on oral contraceptive use, infertility, induced abortion, premenstrual mood disorder, and perina-tal depression (n=2819). The participants reported on the Swedish universities Scales of Per-sonality for neuroticism (papers II-IV) and the Attachment Style Questionnaire (ASQ) for attachment anxiety (papers I-II). The participants also answered the Edinburgh Postnatal De-pression Scale on depressive symptoms (paper II). In paper III, information on obstetric com-plications for primiparous women with singleton pregnancies (n=1969) was extracted from Swedish national health registers. In paper IV, ANC use was derived from medical records of obstetric low-risk women residing in Uppsala (n=1052).

    The ASQ had similar psychometric properties in pregnant women (n=1631) as in previous reports (paper I). In non-depressed pregnant women (n=1431), the combination of neuroticism and attachment anxiety was the best risk indicator of postpartum depressive symptoms (paper II). Whereas high neuroticism was not related to obstetric complications (paper III), it was associated with higher use of ANC (paper IV).

    Summarized, this thesis illustrates how anxious personality traits may predispose for post-partum depression and higher use of ANC in the absence of obstetric complications. Future development of these findings should be to evaluate individual and societal benefits of a greater emphasis on psychological support in ANC.

    List of papers
    1. Psychometric properties of the attachment style questionnaire in Swedish pregnant women: short and full versions
    Open this publication in new window or tab >>Psychometric properties of the attachment style questionnaire in Swedish pregnant women: short and full versions
    2017 (English)In: Journal of Reproductive and Infant Psychology, ISSN 0264-6838, E-ISSN 1469-672X, Vol. 35, no 5, p. 450-461Article in journal (Refereed) Published
    Abstract [en]

    Objectives: (i) To evaluate the reliability and factor structure of the Attachment Style Questionnaire – Short Form (ASQ-SF) for use in pregnant women and (ii) to compare the reliability and factor structure of the short- and full version-ASQ among pregnant women. Background: Adult attachment insecurity is currently included as a major risk factor in studies of perinatal health. None of the self-report measures with a Swedish translation have been psychometrically evaluated in a pregnant cohort.

    Methods: A population-based cohort of 1631 pregnant women answered the ASQ in late pregnancy. Internal consistency (item- subscale correlations, Cronbach’s α, and α if item deleted) was evaluated for the seven available subscales. Con rmatory factor analysis (CFA) was run to examine the factor structure of the short form compared with the full-version. Test–retest correlations were assessed in a subgroup (n = 48).

    Results: All mean item-subscale correlations for the ASQ-SF were > 0.30. Cronbach’s α’s for ASQ-SF dimensions were as follows: Avoidance (0.87); Anxiety (0.89); Discomfort with Closeness (0.85); Relationships as Secondary (0.54); Con dence (0.83); Need for Approval (0.76); and Preoccupation with Relationships (0.77). No item removal substantively increased subscale α’s. The CFA demonstrated better model t for the ASQ-SF than for the full-version ASQ, while other reliability measures were similar. Test–retest correlations ranged from 0.65 to 0.84.

    Conclusion: The ASQ-SF showed similar psychometric properties in pregnant women as in the general population and had good reliability, but the optimal factor structure needs to be studied further. Results support the usage of the ASQ-SF in pregnant cohorts. 

    Place, publisher, year, edition, pages
    Routledge, 2017
    Keywords
    adult attachment, attachment style questionnaire, reliability, pregnancy
    National Category
    Clinical Medicine
    Research subject
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-342268 (URN)10.1080/02646838.2017.1342786 (DOI)000416753300003 ()
    Funder
    Swedish Research Council, 521-2013-2339
    Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-10-24Bibliographically approved
    2. Adult attachment's unique contribution in the prediction of postpartum depressive symptoms, beyond personality traits
    Open this publication in new window or tab >>Adult attachment's unique contribution in the prediction of postpartum depressive symptoms, beyond personality traits
    2017 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 222, p. 177-184Article in journal (Refereed) Published
    Abstract [en]

    Background:

    Personality traits such as neuroticism can help identify pregnant women at risk of postpartum depressive symptoms (PPDS). However, it is unclear whether attachment style could have an additional contribution to this risk elevation. This study aimed to examine the overlap of adult attachment insecurity and neuroticism/trait anxiety as PPDS predictors, taking into account baseline depressive symptoms.

    Methods:

    A Swedish population-based sample of pregnant women reported on adult attachment and either neuroticism (n = 1063) or trait anxiety (n = 555). Depressive symptoms were assessed at baseline, and at six weeks and six months postpartum. Correlations between attachment and neuroticism/trait anxiety were calculated. Generalized linear models of PPDS tested the effect of attachment anxiety and avoidance, adjusting for neuroticism/trait anxiety and baseline depression. Logistic regression models with combined high attachment anxiety and-neuroticism/trait anxiety visualized their value as risk factors beyond antenatal depression.

    Results:

    Attachment and neuroticism/trait anxiety were highly correlated (r = .55.77). Attachment anxiety exerted a partially independent effect on PPDS at six weeks (p < .05) and at six months (p < .05) adjusting for neuroticism. Among antenatally non-depressed, combined high attachment anxiety and high neuroticism or trait anxiety was predictive of PPDS at both assessment points. Limitations: Low acceptance rate, exclusive use of self-reports.

    Conclusions:

    Beyond personality, attachment anxiety had a small independent effect on the risk of PPDS. Combining items of adult attachment and neuroticism/trait anxiety could prove useful in antenatal screening for high risk of PPDS.

    Keywords
    Adult attachment, Neuroticism, Trait anxiety, Personality, Pregnancy, Postpartum depression
    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-333735 (URN)10.1016/j.jad.2017.07.005 (DOI)000407657100027 ()28709025 (PubMedID)
    Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2018-10-24Bibliographically approved
    3. Neuroticism is not independently associated with adverse obstetric or neonatal outcomes: An observational study
    Open this publication in new window or tab >>Neuroticism is not independently associated with adverse obstetric or neonatal outcomes: An observational study
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Psychiatry Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Psychiatry; Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-361592 (URN)
    Available from: 2018-09-25 Created: 2018-09-25 Last updated: 2018-10-24
    4. Neuroticism is associated with higher antenatal care utilization in obstetric low-risk women
    Open this publication in new window or tab >>Neuroticism is associated with higher antenatal care utilization in obstetric low-risk women
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    Place, publisher, year, edition, pages
    Uppsala:
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-364260 (URN)
    Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-24
  • Public defence: 2018-12-14 13:15 Sal IV, Universitetshuset, Uppsala
    Alm Fjellborg, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Social and Economic Geography. Uppsala University.
    Housing tenure and residential mobility in Stockholm 1990-20142018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis the links between housing tenure, income and selective, segregation generating, residential mobility are explored. The development of these links is analysed against the background of housing regime changes in Stockholm between 1990 and 2014. Housing policy changes in Sweden, and Stockholm, promote ownership through, for instance, housing tenure conversions and the tax-system. What this development means for residential mobility trends and may mean for ethnic and economic segregation is explored in three articles. Paper 1 contrasts two time periods and provides an analysis of residential mobility and economic sorting. It is shown that the socioeconomic composition of movers is relatively stable over time while the increasingly owner dominated housing market in Stockholm contributes to stronger socio-spatial residential patterns through the strengthened economic sorting of movers across the whole income scale. Paper 2 has a focus on ethnic and socioeconomic differences in out-mobility from poor neighbourhoods. The findings indicate that foreign background residents are dependent upon housing wealth and income to be able to leave poor neighbourhoods when they move, while the Swedish background group has a variety of resources at their disposal when they move. Paper 3 analyses how housing tenure affects moving, and movers' destinations, in neighbourhoods with high concentrations of non-western foreign-born residents in Stockholm. By comparing two cohorts (1993-2000 and 2001-2008) it is analysed how this relationship develops over time. Housing tenure and income do not seem to be pivotal for who moves, but increasingly important for where movers end up. Results display ethnic differences and how the changing housing market in Stockholm reproduces ethnic segregation. Two main conclusions from the thesis are that (i) the changing housing regime in Stockholm produces stronger economic sorting of movers – this has been affected by the geographically, socioeconomically and ethnically uneven gains from the housing market transformations experienced over the last three decades. (ii) The residential mobility patterns and the economic stratification of residential mobility opportunities that the reconfiguration of Stockholm’s housing market gives rise to increases the economic, political and social marginalization of neighbourhoods characterized by low income levels and high shares of foreign-born residents. Combating ethnic segregation is today even more closely related to the socioeconomic differences between the foreign-born and native-born parts of the population.

    List of papers
    1. Residential mobility and spatial sorting in Stockholm 1990-2014: The changing importance of housing tenure and income
    Open this publication in new window or tab >>Residential mobility and spatial sorting in Stockholm 1990-2014: The changing importance of housing tenure and income
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In this paper an analysis of residential mobility and sorting by income in Stockholm is carried out. The study contrasts two periods: one (1990-2001) characterised by recovery after the economic crisis in 1991-1992 and one (2002-2014) characterised by large changes to the housing stock composition. With the use of a longitudinal full population data set, it is shown that the socioeconomic composition of movers is relatively stable over time, while the economic sorting of movers increases. People with low income are increasingly likely to move into low-income neighbourhoods, whether they move into the rental or owner segments of the housing market. Those who own their housing unit and mid- to high-income earners increasingly avoid moving to low-income neighbourhoods. The paper concludes that the increasingly owner-dominated housing market in Stockholm contributes to stronger socio-spatial residential patterns through the economic sorting of movers across the whole income scale. 

    Keywords
    Residential mobility, housing tenure, spatial sorting, Stockholm
    National Category
    Human Geography
    Research subject
    Social and Economic Geography
    Identifiers
    urn:nbn:se:uu:diva-363443 (URN)
    Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-26
    2. Leaving poor neighbourhoods: the role of income and housing tenure
    Open this publication in new window or tab >>Leaving poor neighbourhoods: the role of income and housing tenure
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    To date, few studies have adopted a particular focus on the role of housing tenure when analysing ethnic and socioeconomic differences in out-mobility from poor neighbourhoods. This study contributes to filling this gap. The paper uses a full population data set covering every individual residing in the capital region of Sweden during the period 2006-2008. The findings indicate that those with foreign background are dependent on housing wealth and higher income to be able to leave poor neighbourhoods when moving, while native Swedes seem to be less constrained by income. The results warrant efforts to broaden mix policy beyond the discussion on housing tenure if policy-makers want to counteract the ethnic and socioeconomic imbalances of residential mobility upholding segregation.

    Keywords
    selective mobility, poor neighbourhoods, segregation, housing tenure, Stockholm
    National Category
    Human Geography
    Identifiers
    urn:nbn:se:uu:diva-364228 (URN)
    Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-26
    3. Out-mobility from Stockholm’s foreign-born concentration neighbourhoods – a study of two cohorts
    Open this publication in new window or tab >>Out-mobility from Stockholm’s foreign-born concentration neighbourhoods – a study of two cohorts
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In this study the central theme is how housing tenure affects moving from neighbourhoods with high concentrations of non-western foreign-born residents in Stockholm and, by comparing two cohorts (1993-2000 and 2001-2008), how this relationship between housing tenure, ethnic background and residential mobility develops over time. Attention is also given to the sorting of movers. The findings disclose that housing tenure’s effect on moving marginally varies between neighbourhood types, and earlier existing differences between housing tenures are reduced over time. Out-mobility destination data suggest that owning is important, and increasingly important, for moving towards areas with fewer non-western foreign-born residents. The findings show that housing tenure mix as a policy tool to counteract high mobility frequencies in distressed neighbourhoods is losing strength. Results indicate how the increasingly owner-dominated housing market in Stockholm reproduces ethnic segregation through stronger residential sorting by income and housing tenure. 

    National Category
    Human Geography
    Identifiers
    urn:nbn:se:uu:diva-364255 (URN)
    Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-26
  • Public defence: 2018-12-14 13:15 Häggsalen, Ångströmlaboratoriet, Uppsala
    Phuyal, Dibya
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    An X-ray Spectroscopic Study of Perovskites Oxides and Halides for Emerging Devices2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis investigates the electronic structures on several perovskite oxide and halide materials with a focus on light harvesting applications. The systematic study of the electronic properties of the transition metal oxides and post-transition metal halides is a key point if one is to understand their properties. The element and site selective nature of several x-ray based spectroscopic techniques are given special emphasis in order to obtain a complete picture of the electronic properties of the compounds in question. Much of the experimental studies are accompanied by ab initio calculations that corroborate with our experimental results.

    In the oxide portion of this work, a new class of metallic oxides based on doping of an antiferromagnetic LaFeO3 was synthesized and systematically studied with x-ray absorption, x-ray emission, and photoemission spectroscopies. The compound’s electronic structure is complex, having itinerant as well as localized components that give rise to a unique physical state where antiferromagnetism, metallicity and charge-disproportionation coexist. Our resonant photoemission results establish that the Fe states in both magnetically ordered oxides show insulting properties, while the Mo states provide an itinerant band crossing the Fermi level. An excitation energy-dependent RIXS investigation on LaFe1-xMoxO3 and the double perovskite Sr2FeMoO6 revealed a double peak structure located in proximity to the elastic peak that is identified to purely d-d excitations, attributed to the strongly correlated nature of these transition metal compounds.

    The growth of high-quality thin film ferroelectric based on BaTiO3 grown epitaxially by means of pulsed laser deposition were investigated. We systematically reduce the band gap of the ferroelectric thin film while retaining its polarization at ambient conditions in spite of the aliovalent doping. The electronic structure is studied by several x-ray techniques that show how the ferroelectricity persists as well as the effective reduction of the band gap through hybridized states.

    In the post-transition metal halides, the valence and conduction bands were mapped using x-ray absorption, emission, and photoemission spectroscopies. The spectroscopic results identify the constituent states that form the valence band as well as the band energy positions, which is an imperative parameter in optoelectronic devices. In addition, x-ray based spectroscopy was used to demonstrate the stereochemical activity of lone-pair states (5s2 and 6s2) for several different halide compounds and their influence on the chemical, structural, and electronic properties of the material. Nanostructured halide perovskites are also explored. The position of iodine p states and valence band states in reduced dimensional lead-based compounds were examined, as their states are found to be confined in one crystallographic direction in contrast to their three-dimensional counterpart. This information highlights the interesting material properties and their use in current third generation solar cell research.

    List of papers
    1. Electronic structure of the charge disproportionate and metallicity in LaFe1-xMoxO3 studied by resonant x-ray spectroscopies
    Open this publication in new window or tab >>Electronic structure of the charge disproportionate and metallicity in LaFe1-xMoxO3 studied by resonant x-ray spectroscopies
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    A metal-insulator transition and its intriguing properties were recently reported based on doping of the antiferromagnetic insulator LaFeO3. Through doping at the B site by Mo to the insulating perovskite LaFeO3 exhibits a coexistence of an antiferromagnetic ordering with room-temperature metallicity at higher doping levels, an unusual ground state for an oxide perovskite. Replacing Fe by Mo in the Fe-O6 octahedra enhances the separation of the two 2 Fe-O bonds relative to the orthorhombic LaFeO3, largely retaining the centrosymmetric character of the Fe sites, as confirmed through extended x-ray absorption fine structure. Mo ions appear to be homogeneously doped, with average valency of both metal sites monotonically decreasing with increasing Mo concentration. Resonant photoemission was recorded for both Fe and Mo to obtain element specific spectral information on the projected 3d and 4d partial density of states. The data shows gradual increase of spectral weight at the Fermi level that is attributed to Mo d states, while the Fe d states primarily reside at higher binding energy in the valence band, with significant hybridization with O 2p states. The RIXS spectra show strong electron correlation effects from d-d inelastic features and broad charge-transfer excitations for x = 0.2 where the compound becomes metallic. This is in contrast to the insulating parent LaFeO3 compound and insulating samples with lower Mo content. The coexistence of both bound and continuum excitations observed in the RIXS spectra provides strong evidence for charge disproportionation with features that are linked to the disproportionate Fe sites.

    National Category
    Condensed Matter Physics
    Research subject
    Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-364367 (URN)
    Funder
    Knut and Alice Wallenberg Foundation, 2012.0031Swedish Energy Agency, P45349-1Swedish Research Council, 2014-6019Carl Tryggers foundation , CTS-17:376
    Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-26
    2. Valence electronic structure of the double perovskite Sr2FeMoO6 through resonant x-ray spectroscopies
    Open this publication in new window or tab >>Valence electronic structure of the double perovskite Sr2FeMoO6 through resonant x-ray spectroscopies
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Resonant x-ray spectroscopies were used to investigate the double perovskite Sr2FeMoO6 (SFMO) in order to identify the compounds valence electronic structure known for its half-metallicity and ferrimagnetism above room temperature. A comprehensive resonant photoelectron spectroscopy (RPES) and resonant inelastic x-ray scattering (RIXS) study was carried out to acquire a more detailed understanding and interpretation of the valence band electronic structure and hybridization between Fe and Mo d bands. The RPES spectrum clearly show enhancement of Mo d states at the Fermi level that are partly responsible for the metallic behavior. The RPES data at the Fe L3 edge shows strong hybridization with O 2p states as well hybridization with Mo d states. At the same time, characteristic d-d excitations are observed in the RIXS spectra at the Fe L edge indicative of Fe d states of more localized character. Although there are many valid definitions to the valency of the Fe and Mo ions and magnetic moments, the total electronic structure represented through element-resolved x-ray spectroscopies studies distinctly identifies the electronic states that results in its established correlated behavior and half-metallicity.

    National Category
    Condensed Matter Physics
    Research subject
    Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-364368 (URN)
    Funder
    Carl Tryggers foundation , CTS-17:376Swedish Energy Agency, P43549-1Swedish Research Council, 2016-4524Knut and Alice Wallenberg Foundation, 2012.0031Swedish Foundation for Strategic Research , 15-0130
    Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-26
    3. The origin of low bandgap and ferroelectricity of a co-doped BaTiO3
    Open this publication in new window or tab >>The origin of low bandgap and ferroelectricity of a co-doped BaTiO3
    Show others...
    2018 (English)In: Europhysics letters, ISSN 0295-5075, E-ISSN 1286-4854Article in journal (Refereed) Accepted
    Abstract [en]

    We recently demonstrated the lowest bandgap bulk ferroelectric material, BaTi1-x(Mn1/2Nb1/2)xO3, a promising candidate material for visible light absorption in opto- electronic devices. Using a combination of x-ray spectroscopies and density functional theory (DFT) calculations, we here elucidate this compound’s electronic structure and the modifications induced by Mn doping. In particular, we are able to rationalize how this compound retains its ferroelectricity even through a significant reduction of the optical gap upon Mn doping. The local electronic structure and atomic coordination are investigated using x-ray absorption at the Ti K, Mn K, and O K edges, which suggests only small distortions to the parent tetragonal ferroelectric system, BaTiO3, thereby providing a clue to the substantial retention of ferroelectricity in spite of doping. Features at the Ti K edge, which are sensitive to local symmetry and an indication of Ti off-centering within the Ti-O6 octahedra, show modest changes with doping and strongly corroborates with our measured polarization values. Resonant photoelectron spectroscopy results suggest the origin of the reduction of the bandgap in terms of newly created Mn d bands that hybridize with O 2p states. X-ray absorption spectra at the O K-edge provide evidence for new states below the conduction band of the parent compound, illustrating additional contributions facilitating bandgap reduction.

    National Category
    Condensed Matter Physics
    Research subject
    Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-364369 (URN)
    Funder
    Swedish Foundation for Strategic Research , 15-0130Knut and Alice Wallenberg Foundation, 2012.0031Swedish Energy Agency, P43549-1Swedish Energy Agency, P43294-1Swedish Research Council, 2014-7019Swedish Research Council, 2016-4524
    Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-26
    4. Ferroelectric properties of doped BaTiO3 thin film by pulsed laser deposition
    Open this publication in new window or tab >>Ferroelectric properties of doped BaTiO3 thin film by pulsed laser deposition
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    BaTiO3 thin films co-doped at the Ti site with Mn and Nb were grown on 0.5% Nb-doped (001) oriented SrTiO3 substrates by pulsed laser deposition. The films show single-phase tetragonal structure, growing epitaxially with a smooth interface to the substrate. Using piezoforce microscopy, we find that both doped and undoped films exhibit good ferroelectric response. The piezoelectric domain switching in the films was confirmed by measuring local hysteresis of the polarization at several different areas across the thin films, demonstrating a switchable ferroelectric state for these films. The doping of the BaTiO3 also reduces the bandgap of the material from 3.18 eV for BaTiO3 to nearly 2.7 eV for the 7.5% doped sample, potentially making the films effective light-harvesters in the visible spectrum. The results demonstrate co-doping as an effective strategy for bandgap engineering and a guide for the realization of visible-light applications of related thin film systems.

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-364370 (URN)
    Funder
    Swedish Research Council, 2014-6019Swedish Research Council, 2016-4524Swedish Energy Agency, P43549-1Knut and Alice Wallenberg Foundation, 2012.0031Swedish Foundation for Strategic Research , 15-0130
    Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-26
    5. Impact of synthetic routes on the structural and physical properties of butyl-1,4-diammonium lead iodide semiconductors
    Open this publication in new window or tab >>Impact of synthetic routes on the structural and physical properties of butyl-1,4-diammonium lead iodide semiconductors
    Show others...
    2017 (English)In: Journal of Materials Chemistry A, ISSN 2050-7488, Vol. 5, no 23, p. 11730-11738Article in journal (Refereed) Published
    Abstract [en]

    We report the significant role of synthetic routes and the importance of solvents in the synthesis of organic-inorganic lead iodide materials. Through one route, the intercalation of dimethylformamide in the crystal structure was observed leading to a one-dimensional (1D) [NH3(CH2)(4)NH3]Pb2I6 structure of the product. This product was compared with the two-dimensional (2D) [NH3(CH2)(4)NH3]PbI4 recovered from aqueous solvent based synthesis with the same precursors. UV-visible absorption spectroscopy showed a red-shift of 0.1 eV for the band gap of the 1D network in relation to the 2D system. This shift primarily originates from a shift in the valence band edge as determined from photoelectron-and X-ray spectroscopy results. These findings also suggest the iodide 5p orbital as the principal component in the density of states in the valence band edge. Single crystal data show a change in the local coordination around iodide, while in both materials, lead atoms are surrounded by iodide atoms in octahedral units. The conductivity of the one-dimensional material ([NH3(CH2)(4)NH3]Pb2I6) was 50% of the two-d(i)mensional material ([NH3(CH2)(4)NH3]PbI4). The fabricated solar cells reflect these changes in the chemical and electronic structure of both materials, although the total light conversion efficiencies of solar cells based on both products were similar.

    Place, publisher, year, edition, pages
    ROYAL SOC CHEMISTRY, 2017
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-329653 (URN)10.1039/c6ta10123b (DOI)000403228200030 ()
    Funder
    StandUpSwedish Energy AgencySwedish Research CouncilKnut and Alice Wallenberg Foundation
    Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2018-10-26Bibliographically approved
    6. Electronic Structure of Two-Dimensional Lead(II) Iodide Perovskites: An Experimental and Theoretical Study
    Open this publication in new window or tab >>Electronic Structure of Two-Dimensional Lead(II) Iodide Perovskites: An Experimental and Theoretical Study
    Show others...
    2018 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 30, no 15, p. 4959-4967Article in journal (Refereed) Published
    Abstract [en]

    Layered two-dimensional (2D) hybrid organic-inorganic perovskites (HOP) are promising materials for light-harvesting applications because of their chemical stability, wide flexibility in composition and dimensionality, and increases in photovoltaic power conversion efficiencies. Three 2D lead iodide perovskites were studied through various X-ray spectroscopic techniques to derive detailed electronic structures and band energetics profiles at a titania interface. Core-level and valence band photoelectron spectra of HOP were analyzed to resolve the electronic structure changes due to the reduced dimensionality of inorganic layers. The results show orbital narrowing when comparing the HOP, the layered precursor PbI2, and the conventional 3D (CH3NH3)PbI3 such that different localizations of band edge states and narrow band states are unambiguously due to the decrease in dimensionality of the layered HOPs. Support from density functional theory calculations provide further details on the interaction and band gap variations of the electronic structure. We observed an interlayer distance dependent dispersion in the near band edge electronic states. The results show how tuning the interlayer distance between the inorganic layers affects the electronic properties and provides important design principles for control of the interlayer charge transport properties, such as the change in effective charge masses as a function of the organic cation length. The results of these findings can be used to tune layered materials for optimal functionality and new applications.

    National Category
    Condensed Matter Physics Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-361922 (URN)10.1021/acs.chemmater.8b00909 (DOI)000442186500014 ()
    Funder
    StandUpSwedish Energy AgencySwedish Research CouncilKnut and Alice Wallenberg Foundation
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2018-09-27 Created: 2018-09-27 Last updated: 2018-11-02Bibliographically approved
    7. The electronic structure and band interface of cesium bismuth iodide on a titania heterostructure using hard X-ray spectroscopy
    Open this publication in new window or tab >>The electronic structure and band interface of cesium bismuth iodide on a titania heterostructure using hard X-ray spectroscopy
    Show others...
    2018 (English)In: Journal of Materials Chemistry A, ISSN 2050-7488, Vol. 6, no 20, p. 9498-9505Article in journal (Refereed) Published
    Abstract [en]

    Bismuth halide compounds as a non-toxic alternative are increasingly investigated because of their potential in optoelectronic devices and their rich structural chemistry. Hard X-ray spectroscopy was applied to the ternary bismuth halide Cs3Bi2I9 and its related precursors BiI3 and CsI to understand its electronic structure at an atomic level. We specifically investigated the core levels and valence band using X-ray photoemission spectroscopy (PES), high-resolution X-ray absorption (HERFD-XAS), and resonant inelastic X-ray scattering (RIXS) to get insight into the chemistry and the band edge properties of the two bismuth compounds. Using these element specific X-ray techniques, our experimental electronic structures show that the primary differences between the two bismuth samples are the position of the iodine states in the valence and conduction bands and the degree of hybridization with bismuth lone pair (6s(2)) states. The crystal structure of the two layered quasi-perovskite compounds plays a minor role in modifying the overall electronic structure, with variations in bismuth lone pair states and iodine band edge states. Density Functional Theory (DFT) calculations are used to compare with experimental data. The results demonstrate the effectiveness of hard X-ray spectroscopies to identify element specific bulk electronic structures and their use in optoelectronic devices.

    National Category
    Materials Chemistry Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-357561 (URN)10.1039/c8ta00947c (DOI)000433427300020 ()
    Funder
    Swedish Research Council, 2014-6019Swedish Research Council, 2016-4524Swedish Energy Agency, P43549-1Swedish Foundation for Strategic Research , 15-0130Wallenberg Foundations, 2012.0031StandUp
    Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-10-26Bibliographically approved
    8. An effective approach of vapour assisted morphological tailoring for reducing metal defect sites in lead-free, (CH3NH3)(3)Bi2I9 bismuth-based perovskite solar cells for improved performance and long-term stability
    Open this publication in new window or tab >>An effective approach of vapour assisted morphological tailoring for reducing metal defect sites in lead-free, (CH3NH3)(3)Bi2I9 bismuth-based perovskite solar cells for improved performance and long-term stability
    Show others...
    2018 (English)In: Nano Energy, ISSN 2211-2855, E-ISSN 2211-3282, Vol. 49, p. 614-624Article in journal (Refereed) Published
    Abstract [en]

    We present a controlled, stepwise formation of methylammonium bismuth iodide (CH3NH3)(3)Bi2I9 perovskite films prepared via the vapour assisted solution process (VASP) by exposing BiI3 films to CH3NH3I (MAI) vapours for different reaction times, (CH3NH3)(3)Bi2I9 semiconductor films with tunable optoelectronic properties are obtained. Solar cells prepared on mesoporous TiO2 substrates yielded hysteresis-free efficiencies upto 3.17% with good reproducibility. The good performance is attributed mainly to the homogeneous surface coverage, improved stoichiometry, reduced metallic content in the bulk, and desired optoelectronic properties of the absorbing material. In addition, solar cells prepared using pure BiI3 films without MAI exposure achieved a power conversion efficiency of 0.34%. The non-encapsulated (CH3NH3)(3)Bi2I9 devices were found to be stable for as long as 60 days with only 0.1% drop in efficiency. This controlled formation of (CH3NH3)(3)Bi2I9 perovskite films highlights the benefit of the VASP technique to optimize material stoichiometry, morphology, solar cell performance, and long-term durability.

    Place, publisher, year, edition, pages
    ELSEVIER SCIENCE BV, 2018
    Keywords
    Vapour assisted solution process (VASP), Lead free perovskite, (CH3NH3)(3)Bi2I9, Morphological tailoring, High resolution X-ray photoelectron (HAXPES) spectroscopy
    National Category
    Materials Chemistry Condensed Matter Physics Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-358277 (URN)10.1016/j.nanoen.2018.05.003 (DOI)000434829500071 ()
    Funder
    Swedish Research CouncilEU, Horizon 2020, 663830
    Available from: 2018-08-27 Created: 2018-08-27 Last updated: 2018-10-26Bibliographically approved
    9. Inorganic CsPbI3 Perovskite Coating on PbS Quantum Dot for Highly Efficient and Stable Infrared Light Converting Solar Cells
    Open this publication in new window or tab >>Inorganic CsPbI3 Perovskite Coating on PbS Quantum Dot for Highly Efficient and Stable Infrared Light Converting Solar Cells
    Show others...
    2018 (English)In: Advanced Energy Materials, ISSN 1614-6832, Vol. 8, no 6, article id 1702049Article in journal (Refereed) Published
    Abstract [en]

    Solution-processed colloidal quantum dot (CQD) solar cells harvesting the infrared part of the solar spectrum are especially interesting for future use in semitransparent windows or multilayer solar cells. To improve the device power conversion efficiency (PCE) and stability of the solar cells, surface passivation of the quantum dots is vital in the research of CQD solar cells. Herein, inorganic CsPbI3 perovskite (CsPbI3-P) coating on PbS CQDs with a low-temperature, solution-processed approach is reported. The PbS CQD solar cell with CsPbI3-P coating gives a high PCE of 10.5% and exhibits remarkable stability both under long-term constant illumination and storage under ambient conditions. Detailed characterization and analysis reveal improved passivation of the PbS CQDs with the CsPbI3-P coating, and the results suggest that the lattice coherence between CsPbI3-P and PbS results in epitaxial induced growth of the CsPbI3-P coating. The improved passivation significantly diminishes the sub-bandgap trap-state assisted recombination, leading to improved charge collection and therefore higher photovoltaic performance. This work therefore provides important insight to improve the CQD passivation by coating with an inorganic perovskite ligand for photovoltaics or other optoelectronic applications.

    Place, publisher, year, edition, pages
    WILEY-V C H VERLAG GMBH, 2018
    Keywords
    charge recombination, inorganic perovskite, quantum dots, solar cells, surface passivation
    National Category
    Physical Chemistry Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-348982 (URN)10.1002/aenm.201702049 (DOI)000426152400017 ()
    Funder
    Swedish Energy AgencySwedish Research CouncilSwedish Research Council Formas
    Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2018-10-26Bibliographically approved
    10. Doping induced site-selective Mott insulating phase in LaFeO3
    Open this publication in new window or tab >>Doping induced site-selective Mott insulating phase in LaFeO3
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Tailoring transport properties of strongly correlated electron systems in a controlled fashion counts among the dreams of materials scientists. In copper oxides, vary- ing the carrier concentration is a tool to obtain high- temperature superconducting phases. In manganites, dop- ing results in exotic physics such as insulator-metal tran- sitions (IMT), colossal magnetoresistance (CMR), orbital- or charge-ordered (CO) or charge-disproportionate (CD) states. In most oxides, antiferromagnetic order and CD phase is asssociated with insulating behavior. Here we re- port the realization of a unique physical state that can be induced by Mo doping in LaFeO3: the resulting metallic state is a site-selective Mott insulator where itinerant elec- trons evolving on low-energy Mo states coexist with local- ized carriers on the Fe sites. In addition, a local breathing- type lattice distortion induces charge disproportionation on the latter, without destroying the antiferromagnetic order. A state, combining antiferromangetism, metallic- ity and CD phenomena is rather rare in oxides and have utmost significance for future antiferromagnetic memory devices.

    National Category
    Condensed Matter Physics
    Research subject
    Physics with spec. in Atomic, Molecular and Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-364365 (URN)
    Funder
    Swedish Research Council, 2014-6019Swedish Energy Agency, P43549-1Knut and Alice Wallenberg Foundation, 2012.0031
    Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-11-01
  • Public defence: 2018-12-15 11:00 Ihresalen, Uppsala
    Odyniec, Pawel
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Linguistics and Philology.
    Engaging Advaita: Conceptualising liberating knowledge in the face of Western modernity2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This dissertation is a study of modern Indian philosophy. It examines three engaging articulations of the Advaitic notion of liberating knowledge or brahmajñāna provided by three prominent Indian philosophers of the twentieth century, namely, Badrīnāth Śukla (1898-1988), Krishnachandra Bhattacharyya (1875-1949), and Sarvepalli Radhakrishnan (1888-1975). Particular attention is paid to the existing relation between their distinctive conceptualisations of liberating knowledge and the doxastic attitudes that these authors professed towards the Sanskrit intellectual past of South Asia and the presence of the Western Other.

    In the main, it argues that the profound differences to be found, on the one hand, in Śukla’s elucidation of this key Advaitic notion and, on the other, in Bhattacharyya’s and Radhakrishnan’s take on the same, betray their commitment to two radically different doxastic attitudes. Classifying these into (a) non-dialogical and (b) dialogical in relation to the Western Other as well as into (c) exegetic and (d) hermeneutic in relation to the Sanskrit intellectual past of South Asia, it contends that, in comparison to the conceptual scheme and the parameters of intelligibility that shaped and underpinned the precolonial Advaitic discourse on brahmajñāna in Sanskrit, there is a certain kind of epistemic discontinuity in the dialogical cum hermeneutic stance taken by Bhattacharyya and Radhakrishnan that is not to be found in the non-dialogical cum exegetic engagement enacted by Śukla. It suggests that this particular sort of discontinuity, absent as it is from Śukla’s elucidation of the process of knowing Brahman, reflects the far-reaching commitment of Krishnachandra Bhattacharyya and Sarvepalli Radhakrishnan to appropriate the precolonial Advaitic notion of liberating knowledge hermeneutically and to conceptualise it in the face of Western modernity, that is, rendering it meaningful in terms and within the parameters of intelligibility of the Western Other in order to contest what they took to be a troublesome predicament of Western modernity.

    By examining their ways of engaging with the Advaitic notion of liberating knowledge, this dissertation contributes to the on-going debate about the nature and the driving forces of modern Indian philosophy.

  • Public defence: 2018-12-15 13:00 Auditorium minus, Uppsala
    Grip, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery. Välj ....
    Acute limb ischaemia: Treatment, outcome and time trends2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute limb ischaemia (ALI) is a frequent emergency associated with high rates of amputation and death. Traditionally, patients with ALI were treated with open surgical removal of the occlusion or bypass surgery. During the past few decades, new endovascular techniques developed.  

    No larger studies have investigated the optimal contemporary treatment for patients with ALI. Today, there are no international consensus for recommendations for the treatment of ALI, leaving it open to every surgeon or department to decide the best treatment option. 

    This thesis aimed to study patients with ALI as a means to extend the understanding of this group of patients, as well as to investigate treatment options. Data sources included hospital charts or information was gathered from the Swedish nationwide Vascular Registry (Swedvasc), the Swedish Population Registry for deaths and the Swedish Patient Registry for amputations.

    Paper I compared the results from thrombolysis with and without continuous heparin infusion in 749 thrombolytic procedures, concluding that both treatment strategies were equally successful in achieving revascularisation, with acceptable complication rates for both strategies. Continuous heparin infusion during intra-arterial thrombolysis offered no advantage. Although the regime with continuous heparin infusion was associated with a higher frequency of bleeding complications (p<0.001), this difference disappeared after adjustment for confounders.

    Paper II studied long-term outcome after thrombolysis and showed that thrombolytic therapy achieves good medium- and long-term clinical outcome, which reduces the need for open surgical treatment in most patients. More than half of the patients in paper II did not require any surgical reintervention or amputation in their remaining lifetime or during a mean of 6.2 years of follow-up. Long-term outcome differed between the aetiological groups. This information is valuable when deciding on the optimal treatment strategy for patients with ALI.

    Paper III compared outcomes after open and endovascular revascularisation for the treatment of ALI in 16,229 patients treated in 1994-2014. The large propensity score-matched nationwide cohort study revealed that endovascular treatment of ALI was associated with significantly better short-term survival and amputation-free survival compared with open revascularisation.

    Paper IV investigated acute aortic occlusion (AAO) and subsequent ALI. This study showed that mortality after AAO is high but has improved in the past 20 years. The proportion of AAO secondary to occluded graft/stent/stentgrafts increases over time as a result of the endovascular shift in treating aortic diseases and the proportion of AAO secondary to native artery thrombosis decreases.

    Taken together, the main findings of this thesis demonstrate a gradual improvement in survival and that endovascular techniques are becoming more frequently used as a first- line treatment of patients with ALI.

    List of papers
    1. Outcome and complications after intra-arterial thrombolysis for lower limb ischaemia with or without continuous heparin infusion
    Open this publication in new window or tab >>Outcome and complications after intra-arterial thrombolysis for lower limb ischaemia with or without continuous heparin infusion
    Show others...
    2014 (English)In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 101, no 9Article in journal (Refereed) Published
    Abstract [en]

    Background

    Thrombolysis is a common treatment for acute leg ischaemia. The purpose of this study was to evaluate different thrombolytic treatment strategies, and risk factors for complications

    This was a retrospective analysis of prospective databases from two vascular centres. One centre used a higher dose of heparin and recombinant tissue plasminogen activator (rtPA).

    Results

    Some 749 procedures in 644 patients of median age 73 years were studied; 353 (47·1 per cent) of the procedures were done in women. The aetiology of ischaemia was graft occlusion in 38·8 per cent, acute arterial thrombosis in 32·2 per cent, embolus in 22·3 per cent and popliteal aneurysm in 6·7 per cent. Concomitant heparin infusion was used in 63·2 per cent. The mean dose of rtPA administered was 21·0 mg, with a mean duration of 25·2 h. Technical success was achieved in 80·2 per cent. Major amputation and death within 30 days occurred in 13·1 and 4·4 per cent respectively. Bleeding complications occurred in 227 treatments (30·3 per cent). Blood transfusion was needed in 104 (13·9 per cent). Three patients (0·4 per cent of procedures) had intracranial bleeding; all were fatal. Amputation‐free survival was 83·6 per cent at 30 days at both centres. In multivariable analysis, preoperative severe ischaemia with motor deficit was the only independent risk factor for major bleeding (odds ratio (OR) 2·98; P <0·001). Independent risk factors for fasciotomy were severe ischaemia (OR 2·94) and centre (OR 6·50). Embolic occlusion was protective for major amputation at less than 30 days (OR 0·30; P = 0·003). Independent risk factors for death within 30 days were cerebrovascular disease (OR 3·82) and renal insufficiency (OR 3·86).

    Conclusion

    Both treatment strategies were successful in achieving revascularization with acceptable complication rates. Continuous heparin infusion during intra‐arterial thrombolysis appeared to offer no advantage.

    Place, publisher, year, edition, pages
    Uppsala: , 2014
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-360872 (URN)10.1002/bjs.9579 (DOI)
    Available from: 2018-09-19 Created: 2018-09-19 Last updated: 2018-12-12Bibliographically approved
    2. Long-term Outcome after Thrombolysis for Acute Lower Limb Ischaemia
    Open this publication in new window or tab >>Long-term Outcome after Thrombolysis for Acute Lower Limb Ischaemia
    2017 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 53, no 6, p. 853-861Article in journal (Refereed) Published
    Abstract [en]

    Objectives: The purpose was to study long-term outcome after thrombolysis for acute arterial lower limb ischaemia, and to evaluate the results depending on the underlying aetiology of arterial occlusion.

    Methods: This was a retrospective study of patients entered into a prospective database. Patients were identified in prospective databases from two vascular centres, including a large number of variables. Case records were analysed retrospectively. Through cross linkage with the Population Registry 100% accurate survival data were obtained. Between January 2001 and December 2013, 689 procedures were included. The aetiology of ischaemia was graft/stent/stent graft occlusion in 39.8%, arterial thrombosis in 27.7%, embolus in 25.1% and popliteal aneurysm in 7.4%.

    Results: The mean follow-up was 59.4 months (95% CI, 56.1-62.7), during which 32.9% needed further re interventions, 16.4% underwent amputation without re-intervention, and 50.7% had no re-intervention. The need for re-intervention during follow-up was 48.0% in the graft/stent occlusions group, 34.0% of the popliteal aneurysm group, 25.4% in the thrombosis group, and 16.3% in the embolus group (p < .001). The overall primary patency rates were 69.1% and 55.9% at 1 and 5 years, respectively. Primary patency at 5 years was higher for the embolus group (83.3%, p = .002) and lower for the occluded graft/stent group (43.3%, p < .001). Secondary patency rates were 80.1% and 75.2% at 1 and 5 years, respectively, without difference between the subgroups. The amputation rate was lower in the embolic group at 1 and 5 years (8.1% and 11.1%, respectively, p = .001). Survival was higher in the group with occluded.popliteal aneurysms at 5 years (83.3%, p = 0.004). Amputation free survival was 72.1% and 45.2% at 1 and 5 years; lower in the occluded graft/stent group at five years (37.9%, p = .007).

    Conclusion: Intra-arterial thrombolytic therapy achieves good medium and long-term clinical outcome, reducing the need of open surgical treatment in most patients.

    Keywords
    Thrombolysis, Acute limb ischaemia, Long-term outcome, Long-term follow-up, Amputation free survival, Aetiological subgroups
    National Category
    Cardiac and Cardiovascular Systems Surgery
    Identifiers
    urn:nbn:se:uu:diva-329713 (URN)10.1016/j.ejvs.2017.02.003 (DOI)000403518800018 ()28291676 (PubMedID)
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2018-10-24Bibliographically approved
    3. Open versus endovascular revascularization in the treatment of acute lower limb ischaemia
    Open this publication in new window or tab >>Open versus endovascular revascularization in the treatment of acute lower limb ischaemia
    Show others...
    2018 (English)In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 105, no 12, p. 1598-1606Article in journal (Refereed) Published
    Abstract [en]

    Background: Consensus is lacking regarding intervention for patients with acute lower limb ischaemia (ALI). The aim was to study amputation-free survival in patients treated for ALI by either primary open or endovascular revascularization.

    Methods: The Swedish Vascular Registry (Swedvasc) was combined with the Population Registry and National Patient Registry to determine follow-up on mortality and amputation rates. Revascularization techniques were compared by propensity score matching 1:1.

    Results: Of 9736 patients who underwent open surgery and 6493 who had endovascular treatment between 1994 and 2014, 3365 remained in each group after propensity score matching. Results are from the matched cohort only. Mean age of the patients was 74⋅7 years; 47⋅5 per cent were women and mean follow-up was 4⋅3 years. At 30-day follow-up, the endovascular group had better patency (83⋅0 versus 78⋅6 per cent; P < 0⋅001). Amputation rates were similar at 30 days (7⋅0 per cent in the endovascular group versus 8⋅2 per cent in the open group; P = 0⋅113) and at 1 year (13⋅8 versus 14⋅8 per cent; P = 0⋅320). The mortality rate was lower after endovascular treatment, at 30 days (6⋅7 versus 11⋅1 per cent; P < 0⋅001) and after 1 year (20⋅2 versus 28⋅6 per cent; P < 0⋅001). Accordingly, endovascular treatment had better amputation-free survival at 30 days (87⋅5 versus 82⋅1 per cent; P < 0⋅001) and 1 year (69⋅9 versus 61⋅1 per cent; P < 0⋅001). The number needed to treat to prevent one death within the rst year was 12 with an endovascular compared with an open approach. Five years after surgery, endovascular treatment still had improved survival (HR 0⋅78, 99 per cent c.i. 0⋅70 to 0⋅86) but the difference between the treatment groups occurred mainly in the rst year.

    Conclusion: Primary endovascular treatment for ALI appeared to reduce mortality compared with open surgery, without any difference in the risk of amputation.

    National Category
    Medical and Health Sciences Surgery
    Research subject
    Medical Science; Surgery
    Identifiers
    urn:nbn:se:uu:diva-363353 (URN)10.1002/bjs.10954 (DOI)000447124200007 ()
    Available from: 2018-10-17 Created: 2018-10-17 Last updated: 2018-12-12Bibliographically approved
    4. Time-trends and management of acute aortic occlusion: a 21-years´ experience
    Open this publication in new window or tab >>Time-trends and management of acute aortic occlusion: a 21-years´ experience
    (English)In: Article in journal (Other academic) Submitted
    Abstract [en]

    Background: Acute aortic occlusion (AAO) is a rare and potentially catastrophic event. The aim was to study epidemiology and outcome of surgical treatment of AAO in a population-based cohort.

    Method: The Swedish nationwide vascular database (Swedvasc) was used to identify cases, and the Population Registry to study long-term survival.

    Results: During the 21-year study-period (1994-2014), 715 cases of AAO were included with a yearly incidence of 3.8 per million inhabitants. Mean age was 69.7 years, 50.5% were women and mean follow-up was 5.2 years. Most patients presented with bilateral acute limb ischemia. The aetiology for AAO was in-situ thrombosis in 64.1%, saddle embolus in 21.3% and occluded graft/stent/stentgrafts in 14.7%. The proportion of occluded grafts/stent/stentgrafts increased during the study period with a simultaneous reduction in the proportion of in-situ thrombosis.

    The most commonly used methods for revascularization were thromboembolectomy (32.0%), thrombolysis (22.4%), axillary-bifemoral bypass (18.9%) and aorto-biiliacal/bifemoral bypass (18.2%). The choice of revascularization technique depended on the aetiology of the occlusion.

    Amputation was preformed in 8.6%, and 19.9% of the patients died within 30-days after surgery. The 30-days mortality rate was lower after occluded grafts/stents/stentgrafts (9.5%) and higher after saddle embolus (30.9%, p<0.001). There was a reduction in overall 30-days mortality over time (25.0% 1994-2000 versus 15.3% 2008-2014, p=0.008). Long-term survival revealed significant differences between the subgroups, although the difference occurred early after the event (log-rank, p<0.001).

    Conclusion: Mortality after AAO is improving over time, but remains high. The proportion of AAO secondary to occluded grafts/stents/stentgrafts increased over time.

    National Category
    Medical and Health Sciences
    Research subject
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-363356 (URN)
    Available from: 2018-10-17 Created: 2018-10-17 Last updated: 2018-10-24Bibliographically approved
  • Public defence: 2018-12-17 13:00 Häggsalen, Uppsala
    Edin, Elle
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Composite Regenerative Scaffolds2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Regenerative medicine and tissue engineering solutions of heavily innervated tissues are at this point lacklustre. This thesis expands our knowledge of appropriate acellular scaffolds for tissue repair in general and nerve regeneration in particular. The optimal surgical procedure for the implantation of artificial extracellular matrix (ECM) was evaluated for recombinant human collagen (RHCIII) implants. Suturing techniques, as well as the usage of human amniotic membrane “bandages” were evaluated. While complete regeneration of corneal tissues occurred, only slight differences in effects of surgical technique could be found.

    The safety and efficacy of clinical trials using mesenchymal stromal cells (MSCs) was evaluated by conducting a systematic review and meta-analysis. MSC therapy was shown to be safe, with no increases mortality, rehospitalization or adverse events. There was also an indication of efficacy, as the overall mortality in the studies included was significantly smaller in the MSC treated group.

    Multicomponent hydrogel capsules encapsulating single cells were developed. Capsules manufactured from gelatin, agarose and fibrinogen were compared to pure gelatin capsules. The composite capsules successfully delayed cell release and prolonged cell survival.

    Surface patterning of collagen based biomimetic corneas was performed by microcontact printing. The ability of different sizes of fibronectin stripes to stimulate cell adhesion and proliferation was compared. The patterned surfaces improved cell adhesion, as well as proliferation markers.

    Conductive polymer composites were manufactured for use as nerve guides. The guides were created from electrospun polycaprolactone fibers coated with a series of different poly(3,4-ethylenedioxythiophene) films. A comparison of nerve progenitor growth and differentiation on the composite fibers was performed. Both the effects of fiber composition and MSC co-culture was investigated, with or without electrostimulation. MSC treatments and polymer coating was both important for nerve cell differentiation and growth.

    List of papers
    1. Effect of Surgical Technique on Corneal Implant Performance.
    Open this publication in new window or tab >>Effect of Surgical Technique on Corneal Implant Performance.
    Show others...
    2014 (English)In: Translational vision science & technology, ISSN 2164-2591, Vol. 3, no 2, article id 6Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Our aim was to determine the effect of a surgical technique on biomaterial implant performance, specifically graft retention.

    METHODS: Twelve mini pigs were implanted with cell-free, 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) cross-linked recombinant human collagen type III (RHCIII) hydrogels as substitutes for donor corneal allografts using overlying sutures with or without human amniotic membrane (HAM) versus interrupted sutures with HAM. The effects of the retention method were compared as well as the effects of collagen concentration (13.7% to 15% RHCIII).

    RESULTS: All implanted corneas showed initial haze that cleared with time, resulting in corneas with optical clarity matching those of untreated controls. Biochemical analysis showed that by 12 months post operation, the initial RHCIII implants had been completely remodeled, as type I collagen, was the major collagenous protein detected, whereas no RHCIII could be detected. Histological analysis showed all implanted corneas exhibited regeneration of epithelial and stromal layers as well as nerves, along with touch sensitivity and tear production. Most neovascularization was seen in corneas stabilized by interrupted sutures.

    CONCLUSIONS: This showed that the surgical technique used does have a significant effect on the overall performance of corneal implants, overlying sutures caused less vascularization than interrupted sutures.

    TRANSLATIONAL RELEVANCE: Understanding the significance of the suturing technique can aid the selection of the most appropriate procedure when implanting artificial corneal substitutes. The same degree of regeneration, despite a higher collagen content indicates that future material development can progress toward stronger, more resistant implants.

    Keywords
    biomaterials, biosynthetic cornea, corneal regeneration, corneal transplantation, recombinant human collagen
    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-364450 (URN)10.1167/tvst.3.2.6 (DOI)24749003 (PubMedID)
    Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
    2. Conductive PEDOT based coatings on microfibrous scaffolds: a nerve guide component
    Open this publication in new window or tab >>Conductive PEDOT based coatings on microfibrous scaffolds: a nerve guide component
    Show others...
    2018 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Biomaterials Science
    Identifiers
    urn:nbn:se:uu:diva-364452 (URN)
    Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
    3. Mesenchymal Stromal Cells for the Treatment of Ischemic Injury and Vascular Trauma: A Systematic Review and Meta-Analysis
    Open this publication in new window or tab >>Mesenchymal Stromal Cells for the Treatment of Ischemic Injury and Vascular Trauma: A Systematic Review and Meta-Analysis
    Show others...
    2018 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Other Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-364451 (URN)
    Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
    4. Functional fabrication of recombinant human collagen-phosphorylcholine hydrogels for regenerative medicine applications.
    Open this publication in new window or tab >>Functional fabrication of recombinant human collagen-phosphorylcholine hydrogels for regenerative medicine applications.
    Show others...
    2015 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 12, p. 70-80, article id S1742-7061(14)00486-3Article in journal (Refereed) Published
    Abstract [en]

    The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) as substitutes for the corneal extracellular matrix that promote endogenous regeneration of corneal tissue. To render them functional for clinical application, we have now optimized their composition and thereby enhanced their mechanical properties. We have demonstrated that such optimized RHCIII-MPC hydrogels are suitable for precision femtosecond laser cutting to produce complementing implants and host surgical beds for subsequent tissue welding. This avoids the tissue damage and inflammation associated with manual surgical techniques, thereby leading to more efficient healing. Although we previously demonstrated in clinical testing that RHCIII-based implants stimulated cornea regeneration in patients, the rate of epithelial cell coverage of the implants needs improvement, e.g. modification of the implant surface. We now show that our 500μm thick RHCIII-MPC constructs comprising over 85% water are suitable for microcontact printing with fibronectin. The resulting fibronectin micropatterns promote cell adhesion, unlike the bare RHCIII-MPC hydrogel. Interestingly, a pattern of 30μm wide fibronectin stripes enhanced cell attachment and showed the highest mitotic rates, an effect that potentially can be utilized for faster integration of the implant. We have therefore shown that laboratory-produced mimics of naturally occurring collagen and phospholipids can be fabricated into robust hydrogels that can be laser profiled and patterned to enhance their potential function as artificial substitutes of donor human corneas.

    Keywords
    Collagen, Cornea, Hydrogel, Laser profiling, Surface modification
    National Category
    Biomaterials Science
    Identifiers
    urn:nbn:se:uu:diva-364449 (URN)10.1016/j.actbio.2014.10.035 (DOI)25448347 (PubMedID)
    Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
    5. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules.
    Open this publication in new window or tab >>Controlled Delivery of Human Cells by Temperature Responsive Microcapsules.
    Show others...
    2015 (English)In: Journal of Functional Biomaterials, ISSN 2079-4983, E-ISSN 2079-4983, Vol. 6, no 2, p. 439-53Article in journal (Refereed) Published
    Abstract [en]

    Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line-human umbilical vein endothelial cells (HUVECs). While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation.

    Keywords
    cell delivery, cell encapsulation, human fibroblast, human umbilical vein endothelial cells, hydrogel, microcapsules, temperature responsive
    National Category
    Biomaterials Science
    Identifiers
    urn:nbn:se:uu:diva-364448 (URN)10.3390/jfb6020439 (DOI)26096147 (PubMedID)
    Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29
  • Public defence: 2018-12-17 13:00 B42, Uppsala
    Papoutsoglou, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Regulation of TGFβ signaling by long non-coding RNAs and ADP-ribosylation2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Transforming growth factor β (TGFβ) signaling pathways participate in embryonic development and tissue homeostasis and have a dual role in cancer. TGFβ acts as a tumor suppressor that promotes cell cycle arrest and apoptosis at initial stages of tumorigenesis. In contrast, TGFβ, induces epithelial to mesenchymal transition (EMT), a normal embryonic process which is employed by advanced cancers, in order to acquire mesenchymal traits and metastasize.

    Bone morphogenetic protein (BMP) family members belong to the TGFβ superfamily and are involved in cell differentiation, development and bone formation.

    Non-coding RNAs (ncRNAs) are not translated into proteins, are important regulators of gene expression and physiological processes and are often de-regulated in cancer. They control gene expression through physical association with chromatin, DNA, RNA molecules or proteins.

    Poly(ADP-ribose) polymerases (PARPs) catalyze the poly (ADP)-ribosylation of proteins, whereas the enzyme poly(ADP-ribose) glycohydrolase (PARG) removes ADP-ribose units. Members of the PARP family function in the DNA damage response, regulation of transcription and cell death.

    In this thesis, we investigated the importance of the TGFβ signaling pathway in regulating the expression of long non-coding RNAs (lncRNAs). We identified TGFβ-regulated lncRNAs and observed that a substantial number of them act in a feedback loop to modulate the magnitude of TGFβ signaling. Interestingly, the nuclear lncRNA TGFB2-antisense RNA 1 (TGFB2-AS1) is induced by TGFβ and negatively regulates expression of members of the TGFβ and BMP pathways, through interaction with EED, a protein of the polycomb repressor complex 2 (PRC2). Also, TGFβ signaling promoted the expression of mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG), which enhanced TGFβ signaling and affected TGFβ-mediated cell cycle arrest. The MIR100HG-derived miRNAs let-7a-2-3p, miR125b-5p and miR-125b-1-3p, were also induced by TGFβ. In contrast, the long intergenic non-protein coding RNA 707 (LINC00707), was reduced in response to TGFβ and affected the expression of a group of genes related to inflammatory responses and interferon-γ (IFN-γ) signaling.

    We also report that TGFβ and BMP pathways are regulated by ADP-ribosylation of Smad proteins, the signaling mediators of these pathways. We observed that PARP1 and PARP2 attenuated, while PARG favored TGFβ signaling. Furthermore, PARP1 negatively regulated BMP signaling, by ADP-ribosylating Smad1 and Smad5, whereas PARG enhanced BMP signaling by de-ADP-ribosylating Smads.

    Collectively, we provide evidence that lncRNAs and ADP-ribosylating enzymes modulate TGFβ and BMP signaling pathways and propose models for their molecular mechanisms and functional roles.

    List of papers
    1. The TGFB2-AS1 lncRNA regulates TGFβ signaling by modulating corepressor activity
    Open this publication in new window or tab >>The TGFB2-AS1 lncRNA regulates TGFβ signaling by modulating corepressor activity
    Show others...
    2018 (English)Article in journal (Refereed) Submitted
    Abstract [en]

    LncRNAs regulate cell function through many physiological processes. We have identified lncRNAs whose expression is regulated by transforming growth factor β (TGFβ), by a transcriptomic screen. We focused on TGFB2-antisense RNA1 (TGFB2-AS1), which was induced by TGFβ through Smad and protein kinase pathways, and exhibited predominantly nuclear localization. Depleting TGFB2-AS1 enhanced TGFβ/Smad-mediated transcription and expression of the TGFβ-target genes FN1 and SERPINE1. Overexpression of TGFB2-AS1 reduced expression of these genes, attenuated TGFβ-induced cell growth arrest, and altered BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1 mainly via its 3’ terminal region, bound to EED, an adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me3 modifications at TGFβ-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity, partially rescued TGFB2-AS1 mediated gene repression. Our observations support the notion that TGFB2-AS1 is a TGFβ-induced lncRNA with inhibitory functions on TGFβ and BMP pathways output, constituting an auto-regulatory negative feedback mechanism that balances TGFβ- and BMP-mediated responses.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-363700 (URN)
    Available from: 2018-10-20 Created: 2018-10-20 Last updated: 2018-12-03
    2. TGFβ signaling down-regulates LINC00707 to inhibit inflammatory responses
    Open this publication in new window or tab >>TGFβ signaling down-regulates LINC00707 to inhibit inflammatory responses
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The class of long non-coding RNAs (lncRNAs) consists of RNA molecules, which lack protein coding potential and regulate a wide variety of cellular processes. At the molecular level, lncRNAs act as regulators of gene expression by interacting with chromatin, other types of RNA or proteins. Transforming growth factor β (TGFβ) plays pivotal roles in diverse biological processes, such as cell growth arrest, embryonic development and regulation of the immune system. In this study, we describe the long intergenic non-protein coding RNA 707 (LINC00707) as a TGFβ responsive gene. By combining transcriptomic data from human keratinocytes and glioblastoma cancer stem cells, we observed that TGFβ signaling down-regulates the expression of LINC00707. RNA sequencing revealed that in keratinocytes knockdown of LINC00707 or stimulation by TGFβ, affected expression of genes involved in inflammatory responses and interferon-γ-mediated signaling. In summary, we suggest that the immune suppressive actions of TGFβ involve suppression of the pro-inflammatory LINC00707.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-363898 (URN)
    Available from: 2018-10-19 Created: 2018-10-19 Last updated: 2018-12-03
    3. The non-coding MIR100HG RNA mediates cytostatic responses of epithelial cells to transforming growth factor β
    Open this publication in new window or tab >>The non-coding MIR100HG RNA mediates cytostatic responses of epithelial cells to transforming growth factor β
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Transforming growth factor β (TGFβ) stimulation modulates the expression of many epithelial genes involved in cell growth arrest, epithelial-to-mesenchymal transition and development. Many recent reports provide evidence that TGFβ signaling regulates the expression of long non-coding RNAs (lncRNAs), i.e. RNAs lacking protein coding potential. After screening for lncRNAs whose expression is regulated by TGFβ signaling, we observed that TGFβ induced the expression of the mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG), a genetic locus which gives rise to multiple lncRNAs (MIR100HG splice variants), as well as the micro-RNA clusters miR-100, let-7a-2 and miR-125b-1. In addition, TGFβ stimulation led to increased levels of mature let-7a-2-3p, miR-125b-5p and miR-125b-1-3p miRNAs. MIR100HG depletion attenuated the TGFβ/Smad-mediated transcriptional responses, the expression of the TGFβ-target genes SERPINE1 (PAI-1) and fibronectin 1 (FN1), and TGFβ-mediated cell growth arrest. Moreover, overexpressing let-7a-2-3p, but not miR-125b-5p or miR-125b-1-3p miRNAs, mimicked enhanced TGFβ/Smad-mediated transcription and inhibited cell proliferation, while inhibition of let-7a-2-3p slightly reduced PAI-1 and fibronectin expression. Thus, we identified MIR100HG and the miRNA clusters generated by its locus as TGFβ-target non-coding RNAs, and ascribed to them a potential role in mediating cytostatic responses by modulating the magnitude of TGFβ signaling.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-363899 (URN)
    Available from: 2018-10-19 Created: 2018-10-19 Last updated: 2018-10-23
    4. Fine-Tuning of Smad Protein Function by Poly(ADP-Ribose) Polymerases and Poly(ADP-Ribose) Glycohydrolase during Transforming Growth Factor β Signaling
    Open this publication in new window or tab >>Fine-Tuning of Smad Protein Function by Poly(ADP-Ribose) Polymerases and Poly(ADP-Ribose) Glycohydrolase during Transforming Growth Factor β Signaling
    Show others...
    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e103651-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Initiation, amplitude, duration and termination of transforming growth factor β (TGFβ) signaling via Smad proteins is regulated by post-translational modifications, including phosphorylation, ubiquitination and acetylation. We previously reported that ADP-ribosylation of Smads by poly(ADP-ribose) polymerase 1 (PARP-1) negatively influences Smad-mediated transcription. PARP-1 is known to functionally interact with PARP-2 in the nucleus and the enzyme poly(ADP-ribose) glycohydrolase (PARG) can remove poly(ADP-ribose) chains from target proteins. Here we aimed at analyzing possible cooperation between PARP-1, PARP-2 and PARG in regulation of TGFβ signaling.

    METHODS:

    A robust cell model of TGFβ signaling, i.e. human HaCaT keratinocytes, was used. Endogenous Smad3 ADP-ribosylation and protein complexes between Smads and PARPs were studied using proximity ligation assays and co-immunoprecipitation assays, which were complemented by in vitro ADP-ribosylation assays using recombinant proteins. Real-time RT-PCR analysis of mRNA levels and promoter-reporter assays provided quantitative analysis of gene expression in response to TGFβ stimulation and after genetic perturbations of PARP-1/-2 and PARG based on RNA interference.

    RESULTS:

    TGFβ signaling rapidly induces nuclear ADP-ribosylation of Smad3 that coincides with a relative enhancement of nuclear complexes of Smads with PARP-1 and PARP-2. Inversely, PARG interacts with Smads and can de-ADP-ribosylate Smad3 in vitro. PARP-1 and PARP-2 also form complexes with each other, and Smads interact and activate auto-ADP-ribosylation of both PARP-1 and PARP-2. PARP-2, similar to PARP-1, negatively regulates specific TGFβ target genes (fibronectin, Smad7) and Smad transcriptional responses, and PARG positively regulates these genes. Accordingly, inhibition of TGFβ-mediated transcription caused by silencing endogenous PARG expression could be relieved after simultaneous depletion of PARP-1.

    CONCLUSION:

    Nuclear Smad function is negatively regulated by PARP-1 that is assisted by PARP-2 and positively regulated by PARG during the course of TGFβ signaling.

    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-231920 (URN)10.1371/journal.pone.0103651 (DOI)000341302700014 ()25133494 (PubMedID)
    Available from: 2014-09-11 Created: 2014-09-11 Last updated: 2018-10-23Bibliographically approved
    5. Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
    Open this publication in new window or tab >>Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
    Show others...
    2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 24, p. 12706-12723Article in journal (Refereed) Published
    Abstract [en]

    We previously established a mechanism of negative regulation of transforming growth factor beta signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling proteins of the pathway. Here we demonstrate that the bone morphogenetic protein (BMP) pathway can also be regulated by the opposing actions of PARP1 and PARG. PARG positively contributes to BMP signaling and forms physical complexes with Smad5 and Smad4. The positive role PARG plays during BMP signaling can be neutralized by PARP1, as demonstrated by experiments where PARG and PARP1 are simultaneously silenced. In contrast to PARG, ectopic expression of PARP1 suppresses BMP signaling, whereas silencing of endogenous PARP1 enhances signaling and BMP-induced differentiation. The two major Smad proteins of the BMP pathway, Smad1 and Smad5, interact with PARP1 and can be ADP-ribosylated in vitro, whereas PARG causes deribosylation. The overall outcome of this mode of regulation of BMP signal transduction provides a fine-tuning mechanism based on the two major enzymes that control cellular ADP-ribosylation.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-299724 (URN)10.1074/jbc.M116.729699 (DOI)000378119900024 ()27129221 (PubMedID)
    Funder
    Swedish Research Council, K2010-67X-14936-07-3 K2013-66X-14936-10-5
    Available from: 2016-07-26 Created: 2016-07-26 Last updated: 2018-10-23Bibliographically approved
  • Public defence: 2018-12-17 13:15 Hörsal 2, 753 13 Uppsala
    Brandén, Gunnar
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Understanding Intergenerational Mobility: Inequality, Student Aid and Nature-Nurture Interactions2018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Essay I: A body of evidence has emerged in the literature on intergenerational mobility documenting that unequal countries experience less social mobility: a relationship known as the Great Gatsby Curve. In this paper I estimate the Great Gatsby Curve within Sweden across 125 commuting zones and 20 cohorts, exploiting both cross-sectional and longitudinal variation. I find that children who were exposed to higher levels of inequality during childhood experienced less social mobility as adults, thereby confirming the existence of a Great Gatsby Curve in Sweden. I also present new evidence on the underlying mechanisms of the Great Gatsby Curve. By decomposing intergenerational mobility into separate transmission channels, I find that the Great Gatsby Curve is exclusively driven by the mediating effect that children's educational attainment and development of cognitive and non-cognitive skills has on the persistence of income across generations. Hence, the results suggest that adverse effects of inequality on mobility can be alleviated by policies that target children's educational attainment and development of cognitive and non-cognitive skills.

  • Public defence: 2018-12-19 09:00 Polhemsalen, Uppsala
    Carstensen, Hauke
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Physics.
    Self-assembly of magnetic particles2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Self-assembly is the spontaneous formation of larger structures from small building blocks. This process is driven and determined by the interactions between the constituents. Examples of self assembly are found almost everywhere and, in particular, biological systems in general rely on a hierarchical formation of structures over a range of length scales. Technologically, self-assembly can be used to form mesoscopic structures and artificial crystals. In the case of particles with micrometer size suspended in a liquid phase, it is possible to use optical microscopy for the the investigation of self-assembly.

    In this thesis, the self-assembly of microbeads with tunable magnetic interactions is studied, based on the statistic analysis of microscope images and computer simulations. Magnetic and non-magnetic microbeads are suspended in a ferrofluid, which is a dispersion of magnetic nanoparticles in water. As a result, the magnetic properties of the microbeads in the ferrofluid are altered and can be described by effective magnetic susceptibilities and magnetic dipole moments, which can be tuned continuously. The liquid is confined between glass slides and effectively the microbeads are studied in a 2D geometry under a magnetic field, applied either in- or out-of-plane. The resulting structures are detected by image analysis algorithms, analyzed and correlated to the dipolar interaction between the beads, as well as to macroscopic quantities, like the particle density and ratio. For the in-plane field a phase transition from square to hexagonal lattice is observed. This phase transition is explained by the change in dipole interaction between the microbeads as the moments change from anti-parallel to parallel alignment.  For the out-of-plane field the situation becomes diverse and more phases appear. It turns out that the phase formation in this case is strongly dependent on the bead ratio, density and interactions.

    We identify regions in the phase diagram, where isolated beads, percolated structures, and crystals dominate. To cover a wide parameter range the experiments are complemented by computer simulations. The tools developed in this thesis enable us to construct phase diagrams extracted from direct imaging and dependence on the extracted relevant parameters.

    List of papers
    1. Phase formation in colloidal systems with tunable interaction
    Open this publication in new window or tab >>Phase formation in colloidal systems with tunable interaction
    2015 (English)In: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics, ISSN 1539-3755, E-ISSN 1550-2376, Vol. 92, no 1, article id 012303Article in journal (Refereed) Published
    Abstract [en]

    Self-assembly is one of the most fascinating phenomena in nature and is one key component in the formation of hierarchical structures. The formation of structures depends critically on the interaction between the different constituents, and therefore the link between these interactions and the resulting structure is fundamental for the understanding of materials. We have realized a two-dimensional system of colloidal particles with tunable magnetic dipole forces. The phase formation is studied by transmission optical microscopy and a phase diagram is constructed. We report a phase transition from hexagonal to random and square arrangements when the magnetic interaction between the individual particles is tuned from antiferromagnetic to ferrimagnetic.

    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-259093 (URN)10.1103/PhysRevE.92.012303 (DOI)000357262700007 ()
    Funder
    Swedish Research Council, A0505501Carl Tryggers foundation , CT 13:513
    Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2018-11-12Bibliographically approved
    2. Statistical analysis of phase formation in 2D colloidal systems
    Open this publication in new window or tab >>Statistical analysis of phase formation in 2D colloidal systems
    2018 (English)In: The European Physical Journal E Soft matter, ISSN 1292-8941, E-ISSN 1292-895X, Vol. 41, no 1, article id 9Article in journal (Refereed) Published
    Abstract [en]

    Colloidal systems offer unique opportunities for the study of phase formation and structure since their characteristic length scales are accessible to visible light. As a model system the two-dimensional assembly of colloidal magnetic and non-magnetic particles dispersed in a ferrofluid (FF) matrix is studied by transmission optical microscopy. We present a method to statistically evaluate images with thousands of particles and map phases by extraction of local variables. Different lattice structures and long-range connected branching chains are observed, when tuning the effective magnetic interaction and varying particle ratios.

    Place, publisher, year, edition, pages
    SPRINGER, 2018
    National Category
    Physical Sciences
    Identifiers
    urn:nbn:se:uu:diva-346233 (URN)10.1140/epje/i2018-11615-x (DOI)000423452000001 ()29353322 (PubMedID)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2011-2067Swedish Research Council, A0505501Carl Tryggers foundation , CT 13:513
    Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-11-12Bibliographically approved
    3. Tunable self assembly of crystals and branching chain networks
    Open this publication in new window or tab >>Tunable self assembly of crystals and branching chain networks
    (English)Manuscript (preprint) (Other academic)
    National Category
    Condensed Matter Physics
    Research subject
    Physics
    Identifiers
    urn:nbn:se:uu:diva-365206 (URN)
    Available from: 2018-11-11 Created: 2018-11-11 Last updated: 2018-11-12
  • Public defence: 2018-12-20 09:15 A1:111a, BMC, Uppsala
    Ahnfelt, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In vitro evaluation of formulations used in the treatment of hepatocellular carcinoma2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hepatocellular carcinoma (HCC) causes ~ 600,000 deaths annually, making it the second most deadly cancer form. HCC is classified into five stages and for the intermediate HCC treatment, the two most commonly used drug delivery systems (DDSs) are lipiodol-based emulsions and drug-eluting beads. The aims of this thesis were to develop in vitro methods suitable for studying these DDSs. It is important to investigate the release mechanisms and release rates with relevant in vitro methods, as this can improve the understanding of the in vivo performance. Miniaturized in vitro methods with sample reservoirs separated from the release medium by a diffusion barrier were developed and shown to be suitable for studying drug release from particle DDSs (Paper I). In Paper II these methods were further developed and used to study the release of doxorubicin (DOX) from the clinically used drug-eluting beads. DOX release rates were affected by the method set-up and the characteristics of the release medium. The choice of method and volume of release medium could improve the in vivo-likeness of the in vitro release profiles. Applied theoretical models suggested a film-controlled type of DOX release mechanism from the beads when self-aggregation, DOX-bead interaction, and DOX deprotonation were taken into account.

    A micropipette-assisted microscopy method was used to further improve the understanding of the release mechanism of amphiphilic molecules from the beads (Paper III). A detailed analysis suggested an internal depletion-layer model dependent on molecular self-aggregation for the release. It was further suggested that a simple ion-exchange mechanism is unrealistic in physiological conditions.

    The important pharmaceutical factors for the emulsion-based formulations were investigated in Paper IV. DOX solubility, lipid phase distribution, and emulsion stability increased when the contrast agent iohexol was added. Also, an increase in release half-life (h) was observed from emulsions with iohexol.

    The in vitro methods and theoretical models presented in this thesis can be used during development and optimization of future DDSs.

    List of papers
    1. A miniaturized in vitro release method for investigating drug-release mechanisms
    Open this publication in new window or tab >>A miniaturized in vitro release method for investigating drug-release mechanisms
    2015 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, no 1-2, p. 339-349Article in journal (Refereed) Published
    Abstract [en]

    We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

    Keywords
    In vitro release methods, Release mechanisms, Weibull function, GI-Sim, In vivo prediction
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-255064 (URN)10.1016/j.ijpharm.2015.03.076 (DOI)000353999100037 ()25843760 (PubMedID)
    Available from: 2015-06-22 Created: 2015-06-12 Last updated: 2018-10-30Bibliographically approved
    2. In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System
    Open this publication in new window or tab >>In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System
    2016 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, p. 3387-3398Article in journal (Refereed) Published
    Abstract [en]

    The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

    Keywords
    controlled release, diffusion, dissolution, dissolution rate, drug-delivery systems, in vitro models, mathematical model, microspheres
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-311211 (URN)10.1016/j.xphs.2016.08.011 (DOI)000388268200018 ()27663384 (PubMedID)
    Funder
    Swedish Research Council, 521-2011-373
    Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-10-30Bibliographically approved
    3. Single bead investigation of a clinical drug delivery system – a novel release mechanism
    Open this publication in new window or tab >>Single bead investigation of a clinical drug delivery system – a novel release mechanism
    Show others...
    2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, p. 235-247Article in journal (Other academic) Published
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-360988 (URN)10.1016/j.jconrel.2018.11.011 (DOI)
    Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-11-19
    4. In vitro evaluation of lipiodol-based emulsions in clinical use
    Open this publication in new window or tab >>In vitro evaluation of lipiodol-based emulsions in clinical use
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-360987 (URN)
    Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-10-30
  • Public defence: 2018-12-20 13:15 Rosénsalen, Uppsala
    Georgantzi, Kleopatra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    On the Diagnostics of Neuroblastoma: Clinical and Experimental Studies2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neuroblastoma (NB) is one of the most common childhood cancers. Patients with low stage tumor have high survival rate, while those with advanced stage and/or unfavorable molecular biology have poor prognosis. A correct histopathological diagnosis, clinical stage, and identified genetic aberrations are crucial for treatment stratification according to current protocol. The tumor sample is obtained either by fine needle aspiration, cutting needle biopsy or open biopsy. NB exhibits neuroendocrine differentiation by showing immunoreactivity for chromogranin A (CgA), synaptophysin (syn), and neuron specific enolase (NSE) and 90% of the patients have increased levels of urine catecholamine metabolites.

    Experimental and clinical NB tumor samples were immunostained for somatostatin receptors (SSTRs) 1-5, somatostatin and CgA. Clinical tumor samples were also immunostained for syn, synaptic vesicle protein 2 (SV2), and vesicle monoamine transporter 1 (VMAT1) and 2 (VMAT 2). Blood samples from 92 patients were analyzed for level of CgA, NSE, and chromogranin B and compared with control groups. The urinary excretion of catecholamine metabolites was analyzed in samples collected at diagnosis. Clinical and laboratory data were extracted from patient records, including information on the diagnostic accuracy of ultrasound guided cutting needle biopsies (UCNB) and potential complications.

    We found that NB expressed the different SSTRs and that receptor 2 was the most frequently expressed before chemotherapy. Furthermore, NB tumors showed immunoreactivity for SV2, VMAT 1 and VMAT2 alongside CgA and syn. The immunoreactivity of SV2 was comparable to CgA and superior to syn. Patients with NB had higher blood concentrations of CgA and NSE compared with controls. Patients with advanced stage disease, MYCN amplification and 1 p deletion had higher concentrations of both CgA and NSE while only NSE was correlated to outcome with higher concentrations in the deceased patients.

    A high urinary excretion of homovanillic acid and dopamine were correlated to inferior outcome. UCNB were found to be safe and may provide all necessary diagnostic requirements for adequate therapy stratification according to current treatment protocols.

    List of papers
    1. Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma
    Open this publication in new window or tab >>Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma
    Show others...
    2011 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 56, no 4, p. 584-589Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Neuroblastoma (NB) is a solid tumor of childhood originating from the adrenal medulla or sympathetic nervous system. Somatostatin (SS) is an important regulator of neural and neuroendocrine function, its actions being mediated through five specific membrane receptors. The aim of this study was to investigate the expression of the different somatostatin receptors (SSTRs) in NB tumor cells that may form targets for future therapeutic development.

    PROCEDURE:

    Tumor specimens from 11 children with stage II-IV disease were collected before and/or after chemotherapy. Experimental tumors derived from five human NB cell lines were grown subcutaneously in nude mice. Expression of SSRTs, the neuroendocrine marker chromogranin A (CgA) and SS was detected by immunohistochemistry using specific antibodies.

    RESULTS:

    SSTR2 was detected in 90%, SSTR5 in 79%, SSTR1 in 74%, SSTR3 in 68% whereas SSTR4 was expressed in 21% of the clinical tumors. The experimental tumors expressed SSTRs in a high but variable frequency. All clinical tumors showed immunoreactivity for CgA but not for SS.

    CONCLUSION:

    The frequent expression of SSTRs indicates that treatment with unlabeled or radiolabeled SS analogs should be further explored in NB.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-140509 (URN)10.1002/pbc.22913 (DOI)000287986700013 ()21120894 (PubMedID)
    Available from: 2011-01-05 Created: 2011-01-05 Last updated: 2018-10-31
    2. Chromogranin A and neuron-specific enolase in neuroblastoma: Correlation to stage and prognostic factors.
    Open this publication in new window or tab >>Chromogranin A and neuron-specific enolase in neuroblastoma: Correlation to stage and prognostic factors.
    Show others...
    2018 (English)In: Pediatric Hematology & Oncology, ISSN 0888-0018, E-ISSN 1521-0669, Vol. 35, no 2, p. 156-165Article in journal (Refereed) Published
    Abstract [en]

    Chromogranin A (CgA) and neuron specific enolase (NSE) are important markers in adult neuroendocrine tumors (NET). Neuroblastoma (NB) has certain neuroendocrine properties. The aim of this study was to correlate blood concentrations of CgA, chromogranin B (CgB), and NSE to prognostic factors and outcome in children with NB. Blood samples from 92 patients with NB, 12 patients with benign ganglioneuroma (GN), 21 patients with non-NB solid tumors, 10 patients with acute leukemias, and 69 healthy children, were analyzed. CgA concentrations were higher in neonates vs. children older than one month in the control group (p < 0.0001), and in neonates with NB vs. the control group (p < 0.01). CgA and NSE concentrations were higher in patients with stages 3 and 4 disease (p < 0.05 and p < 0.05), in patients having tumors with amplification of MYCN (p < 0.05 and p < 0.001), or chromosome 1 p deletion (p < 0.05 and p < 0.05). NSE correlated to the tumor size at diagnosis (p < 0.001) and to tumor related death (p < 0.01) in NB. CgA and NSE concentrations were elevated in patients with NB and especially in those with advanced disease. Both CgA and NSE correlated to genetic markers, while only NSE correlated to primary tumor size and outcome in NB. We found that CgA and NSE are clinically valuable tumor markers in NB and they merit prospective clinical evaluations as such.

    Keywords
    Chromogranin A, neuroblastoma, neuron-specific enolase, prognosis, tumor markers
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-360970 (URN)10.1080/08880018.2018.1464087 (DOI)000446356300007 ()29737901 (PubMedID)
    Funder
    Swedish Childhood Cancer Foundation
    Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-12-07Bibliographically approved
    3. Synaptic Vesicle Protein 2 and Vesicular Monoamine Transporter 1 and 2 are expressed in Neuroblastoma
    Open this publication in new window or tab >>Synaptic Vesicle Protein 2 and Vesicular Monoamine Transporter 1 and 2 are expressed in Neuroblastoma