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  • 301.
    Selegård, Robert
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Rouhbalchsh, Zeinab
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Shirani, Hamid
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Johansson, Leif
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten.
    Norman, Patrick
    KTH Royal Institute Technology, Sweden.
    Linares, Mathieu
    KTH Royal Institute Technology, Sweden.
    Aili, Daniel
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Distinct Electrostatic Interactions Govern the Chiro-Optical Properties and Architectural Arrangement of Peptide-Oligothiophene Hybrid Materials2017Inngår i: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 50, nr 18, s. 7102-7110Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of chiral optoelectronic materials is of great interest due to their potential of being utilized in electronic devices, biosensors, and artificial enzymes. Herein, we report the chiral optical properties and architectural arrangement of optoelectronic materials generated from noncovalent self-assembly of a cationic synthetic peptide and five chemically defined anionic pentameric oligothiophenes. The peptide-oligothiophene hybrid materials exhibit a three-dimensional ordered helical structure and optical activity in the pi-pi* transition region that are observed due to a single chain induced chirality of the conjugated thiophene backbone upon interaction with the peptide. The latter property is highly dependent on electrostatic interactions between the peptide and the oligothiophene, verifying that a distinct spacing of the carboxyl groups along the thiophene backbone is a major chemical determinant for having a hybrid material with distinct optoelectronic properties. The necessity of the electrostatic interaction between specific carboxyl functionalities along the thiophene backbone and the lysine residues of the peptide, as well as the induced circular dichroism of the thiophene backbone, was also confirmed by theoretical calculations. We foresee that our findings will aid in designing optoelectronic materials with dynamic architectonical precisions as well as offer the possibility to create the next generation of materials for organic electronics and organic bioelectronics.

  • 302.
    Selvaraj, Karthik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Mofers, Arjan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Pellegrini, Paola
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Salomonsson, Johannes
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Ahlner, Alexandra
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Morad, Vivian
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Hillert, Ellin-Kristina
    Karolinska Inst, Sweden.
    Espinosa, Belen
    Karolinska Inst, Sweden.
    Arner, Elias S. J.
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Malmstrom, Jonas
    Recipharm AB, Sweden.
    Turkina, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Walters, Michael A.
    Univ Minnesota, MN 55455 USA.
    Sunnerhagen, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system2019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 9841Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds. We used a chemical library screening approach to demonstrate that a substantial fraction (similar to 20%) of cytotoxic synthetic compounds containing Michael acceptor groups inhibit proteasome substrate processing and induce a cellular response characteristic of proteasome inhibition. Biochemical and structural analyses showed binding to and inhibition of proteasome-associated cysteine deubiquitinases, in particular ubiquitin specific peptidase 14 (USP14). The results suggested that compounds bind to a crevice close to the USP14 active site with modest affinity, followed by covalent binding. A subset of compounds was identified where cell death induction was closely associated with proteasome inhibition and that showed significant antineoplastic activity in a zebrafish embryo model. These findings suggest that proteasome inhibition is a relatively common mode of action by cytotoxic compounds containing Michael acceptor groups and help to explain previous reports on the antineoplastic effects of natural products containing such functional groups.

  • 303.
    Shirani, Hamid
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Appelqvist, Hanna
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Bäck, Marcus
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Klingstedt, Therése
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Cairns, Nigel J.
    Washington University, MO USA.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Synthesis of Thiophene-Based Optical Ligands That Selectively Detect Tau Pathology in Alzheimers Disease2017Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, nr 67, s. 17127-17135Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the development of molecular ligands able to detect these pathological hallmarks is essential. Here, the synthesis of thiophene based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs) that can be utilized for selective assignment of tau aggregates in brain tissue with Alzheimers disease (AD) pathology is reported. The ability of the ligands to selectively distinguish tau deposits from the other AD associated pathological hallmark, senile plaques consisting of aggregated amyloid- (A) peptide, was reduced when the chemical composition of the ligands was altered, verifying that specific molecular interactions between the ligands and the aggregates are necessary for the selective detection of tau deposits. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species consisting of different proteins. In addition, the bTVBT scaffold might be utilized to create powerful practical research tools for studying the underlying molecular events of tau aggregation and for creating novel agents for clinical imaging of tau pathology in AD.

  • 304.
    Shirani, Hamid
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Linares, Mathieu
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk kemi. Linköpings universitet, Tekniska fakulteten.
    Sigurdson, Christina J.
    University of Calif San Diego, CA 92093 USA.
    Lindgren, Mikael
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Norman, Patrick
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk kemi. Linköpings universitet, Tekniska fakulteten.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    A Palette of Fluorescent Thiophene-Based Ligands for the Identification of Protein Aggregates2015Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, nr 43, s. 15133-15137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    By replacing the central thiophene unit of an anionic pentameric oligothiophene with other heterocyclic moities, a palette of pentameric thiophene-based ligands with distinct fluorescent properties were synthesized. All ligands displayed superior selectivity towards recombinant amyloid fibrils as well as disease-associated protein aggregates in tissue sections.

  • 305.
    Sigurdson, Christina J
    et al.
    University of California San Diego.
    Joshi-Barr, Shivanjali
    University of California San Diego.
    Bett, Cyrus
    University of California San Diego.
    Winson, Olivia
    University of California San Diego.
    Manco, Giuseppe
    University of Vet Medical Vienna.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Margalith, Ilan
    Prionics AG.
    Peretz, David
    University of California San Diego.
    Hornemann, Simone
    Swiss Federal Institute of Technology.
    Wuethrich, Kurt
    Scripps Research Institute.
    Aguzzi, Adriano
    University of Spital Zurich.
    Spongiform Encephalopathy in Transgenic Mice Expressing a Point Mutation in the beta 2-alpha 2 Loop of the Prion Protein2011Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, nr 39, s. 13840-13847Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrP(C), into a beta-sheet-rich, aggregated isoform, PrP(Sc). We previously found that expression of mouse PrP with the two amino acid substitutions S170N and N174T, which result in high structural order of the beta 2-alpha 2 loop in the NMR structure at pH 4.5 and 20 C, caused transmissible de novo prion disease in transgenic mice. Here we report that expression of mouse PrP with the single-residue substitution D167S, which also results in a structurally well ordered beta 2-alpha 2 loop at 20 degrees C, elicits spontaneous PrP aggregation in vivo. Transgenic mice expressing PrP(D167S) developed a progressive encephalopathy characterized by abundant PrP plaque formation, spongiform change, and gliosis. These results add to the evidence that the beta 2-alpha 2 loop has an important role in intermolecular interactions, including that it may be a key determinant of prion protein aggregation.

  • 306.
    Silverå Ejneby, Malin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Wu, Xiongyu
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Ottosson, Nina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Münger, E Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk Fysik. Linköpings universitet, Tekniska fakulteten.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten.
    Konradsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Elinder, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid2018Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, nr 5, s. 731-750Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV) channels. The hydrophobic part of DHAA anchors the compound near the channel’s positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel’s voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human KV7.2/7.3 (M type) potassium channel at a concentration of 1 µM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug.

  • 307.
    Simon, Rozalyn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Anionic oligothiophenes: Optical tools for multimodal fluorescent assignment of protein aggregates2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Luminescent conjugated oligothiophenes (LCOs) represent a useful and interesting class of materials well known for their abilities as transducers for colorimetric and fluorometric reporting. Specifically, they have the ability to produce a conformation-dependent spectral signature reflective of changes in their local environment.  This physical property makes conjugated polymers an indispensible tool in the toolbox of fluorescent reporters used for distinguishing protein aggregates. Because fluorescence measurements provide a number of parameters for observing changes within a system (e.g., changes in intensity, wavelength, energy transfer, and emission lifetime), the coupling of such measurements with the unique fluorescence reporting capabilities of LCOs has been successful in a number of biological systems. The Nilsson group has demonstrated the use of both polydisperse and monodisperse conjugated polythiophenes for the purpose of amyloid protein aggregate detection both in vitro and ex vivo. My doctoral studies have included synthesis and the photophysical evaluation of pentameric substituted oligothiophenes for utilization as molecular probes for investigating the structure and conformation of amyloid protein aggregates. Through the synthesis of a library of pentameric probes with variations in side-chain substituents, we have studied the effects of pH, solvent, and viscosity on probe behavior and spectral shifts to elucidate the role of chemical structure on probe performance. Through a clearer understanding of the nature of LCOs and their individual chromic responses, we hope to provide researchers and clinicians additional tools for investigating and “bringing to light” the multifaceted nature of amyloids.

    Delarbeid
    1. A Fluorescent Pentameric Thiophene Derivative Detects in Vitro-Formed Prefibrillar Protein Aggregates
    Åpne denne publikasjonen i ny fane eller vindu >>A Fluorescent Pentameric Thiophene Derivative Detects in Vitro-Formed Prefibrillar Protein Aggregates
    Vise andre…
    2010 (engelsk)Inngår i: BIOCHEMISTRY, ISSN 0006-2960, Vol. 49, nr 32, s. 6838-6845Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Protein aggregation is associated with a wide range of diseases, and molecular probes that are able to detect a diversity of misfolded protein assemblies are of great importance. The identification of prefibrillar states preceding the formation of well-defined amyloid fibrils is of particular interest both because of their likely role in the mechanism of fibril formation and because of the growing awareness that these species are likely to play a critical role in the pathogenesis of protein deposition diseases. Herein, we explore the use of an anionic oligothiophene derivative, p-FTAA, for detection of prefibrillar protein aggregates during in vitro fibrillation of three different amyloidogenic proteins (insulin, lysozyme, and prion protein). p-FTAA generally detected prefibrillar protein aggregates that could not be detected by thioflavine T fluorescence and in addition showed high fluorescence when bound to mature fibrils. Second, the kinetics of protein aggregation or the formation of amyloid fibrils of insulin was not extensively influenced by the presence of various concentrations of p-FTAA. These results establish the use of p-FTAA as an additional tool for studying the process of protein aggregation.

    sted, utgiver, år, opplag, sider
    ACS American Chemical Society, 2010
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-58657 (URN)10.1021/bi100922r (DOI)000280668000003 ()
    Tilgjengelig fra: 2010-08-22 Laget: 2010-08-20 Sist oppdatert: 2019-11-08
    2. Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
    Åpne denne publikasjonen i ny fane eller vindu >>Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates
    Vise andre…
    2011 (engelsk)Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, nr 24, s. 8356-8370Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying protein aggregation diseases. Here we report the chemical design of a library of anionic luminescent conjugated oligothiophenes (LCOs), which can be utilized as ligands for detection of protein aggregates. Certain molecular requirements were shown to be necessary for detecting (i) early non-thioflavinophilic protein assemblies of A beta 1-42 and insulin preceding the formation of amyloid fibrils and (ii) for obtaining distinct spectral signatures of the two main pathological hallmarks observed in human Alzheimers diease brain tissue (A beta plaques and neurofibrillary tangles). Our findings suggest that a superior anionic LCO-based ligand should have a backbone consisting of five to seven thiophene units and carboxyl groups extending the conjugated thiophene backbone. Such LCOs will be highly useful for studying the underlying molecular events of protein aggregation diseases and could also be utilized for the development of novel diagnostic tools for these diseases.

    sted, utgiver, år, opplag, sider
    Royal Society of Chemistry, 2011
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-73487 (URN)10.1039/c1ob05637a (DOI)000297354100019 ()
    Tilgjengelig fra: 2012-01-04 Laget: 2012-01-04 Sist oppdatert: 2019-11-08
    3. Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts
    Åpne denne publikasjonen i ny fane eller vindu >>Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts
    Vise andre…
    2014 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, nr 39, s. 12537-12543Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer’s disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate Aβ and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.

    sted, utgiver, år, opplag, sider
    Wiley-VCH Verlagsgesellschaft, 2014
    Emneord
    fluorescence; imaging agents; luminescent conjugated oligothiophenes; protein aggregates; solvatochromism
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-111655 (URN)10.1002/chem.201402890 (DOI)000342626200026 ()25111601 (PubMedID)
    Tilgjengelig fra: 2014-10-28 Laget: 2014-10-28 Sist oppdatert: 2017-12-05bibliografisk kontrollert
    4. pH-dependent optical transitions in anionic pentameric oligothiophenes
    Åpne denne publikasjonen i ny fane eller vindu >>pH-dependent optical transitions in anionic pentameric oligothiophenes
    Vise andre…
    2014 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Understanding the photo-physical processes in fluorescent probes are essential as such dyes are widely utilized in molecular biology. Here we report the pH-dependent optical transitions of a library of anionic pentameric luminescent conjugated oligothiophenes (LCOs) that have been used for fluorescent identification of protein aggregates, the pathological hallmark of many devastating diseases. Absorption-, excitation- and emission spectra were recorded for all LCOs in different buffers with a pH range from 3.5 to 7. p-FTAA, a LCO having a central core consisting of a trimeric thiophene  building block with head-to-head acetic acid functionalization as well as terminal carboxyl groups extending the pentameric thiophene backbone, displayed pH/dependent optical characteristics correlating to a non-planar to planar transition of the conjugated backbone as well as aggregation between adjacent thiophene chain upon protonation of the  acetic acid side chains. In contrast, chemically related analogues to p-FTAA lacking the  terminal carboxyl groups extending the pentameric thiophene backbone or the conformational ability to undergo a non/planar to planar transition of the  conjugated backbone, displayed different optical characteristics compared to p-FTAA. Overall these studies highlighted that minor chemical alteration of LCOs can result in major difference in the optical characteristics obtained from the dyes and the results might aid in designing novel LCOs that have  superior optical performance as amyloid ligands.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-111656 (URN)
    Tilgjengelig fra: 2014-10-28 Laget: 2014-10-28 Sist oppdatert: 2014-10-28bibliografisk kontrollert
    5. Multimodal fluorescene microscopy of prion strain specific PrP deposits stained by thiophene-bassed amyloid ligands
    Åpne denne publikasjonen i ny fane eller vindu >>Multimodal fluorescene microscopy of prion strain specific PrP deposits stained by thiophene-bassed amyloid ligands
    Vise andre…
    2014 (engelsk)Inngår i: Prion, ISSN 1933-6896, E-ISSN 1933-690X, Vol. 8, nr 4, s. 319-329Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The disease-associated prion protein (PrP) forms aggregates which vary in structural conformation yet share identical primary sequence. These variations in PrP conformation are believed to manifest in prion strains exhibiting distinctly different periods of disease incubation as well as regionally specific aggregate deposition within the brain. The anionic luminescent conjugated polythiophene (LCP), polythiophene acetic acid (PTAA) has previously been used to distinguish PrP deposits associated with distinct mouse adapted strains via distinct fluorescence emission profiles from the dye. Here we employed PTAA and 3 structurally related chemically defined luminescent conjugated oligothiophenes (LCOs) to stain brain tissue sections from mice inoculated with 2 distinct prion strains. Our results showed that in addition to emission spectra, excitation, and fluorescence lifetime imaging microscopy (FLIM) can fruitfully be assessed for optical distinction of PrP deposits associated with distinct prion strains. Our findings support the theory that alterations in LCP/LCO fluorescence are due to distinct conformational restriction of the thiophene backbone upon interaction with PrP aggregates associated with distinct prion strains. We foresee that LCP and LCO staining in combination with multimodal fluorescence microscopy might aid in detecting structural differences among discrete protein aggregates and in linking protein conformational features with disease phenotypes for a variety of neurodegenerative proteinopathies.

    sted, utgiver, år, opplag, sider
    Taylor & Francis, 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-106792 (URN)10.4161/pri.29239 (DOI)000348376000006 ()
    Tilgjengelig fra: 2014-05-23 Laget: 2014-05-23 Sist oppdatert: 2018-04-25bibliografisk kontrollert
  • 308.
    Simon, Rozalyn
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Bäck, Marcus
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Shirani, Hamid
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Lindgren, Mikael
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Nilsson, Peter R
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    pH-dependent optical transitions in anionic pentameric oligothiophenes2014Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Understanding the photo-physical processes in fluorescent probes are essential as such dyes are widely utilized in molecular biology. Here we report the pH-dependent optical transitions of a library of anionic pentameric luminescent conjugated oligothiophenes (LCOs) that have been used for fluorescent identification of protein aggregates, the pathological hallmark of many devastating diseases. Absorption-, excitation- and emission spectra were recorded for all LCOs in different buffers with a pH range from 3.5 to 7. p-FTAA, a LCO having a central core consisting of a trimeric thiophene  building block with head-to-head acetic acid functionalization as well as terminal carboxyl groups extending the pentameric thiophene backbone, displayed pH/dependent optical characteristics correlating to a non-planar to planar transition of the conjugated backbone as well as aggregation between adjacent thiophene chain upon protonation of the  acetic acid side chains. In contrast, chemically related analogues to p-FTAA lacking the  terminal carboxyl groups extending the pentameric thiophene backbone or the conformational ability to undergo a non/planar to planar transition of the  conjugated backbone, displayed different optical characteristics compared to p-FTAA. Overall these studies highlighted that minor chemical alteration of LCOs can result in major difference in the optical characteristics obtained from the dyes and the results might aid in designing novel LCOs that have  superior optical performance as amyloid ligands.

  • 309.
    Simon, Rozalyn
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Shirani, Hamid
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Åslund, K. O. Andreas
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Bäck, Marcus
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Haroutunian, Vahram
    Department of Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, USA.
    Gandy, Sam
    Department of Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, USA.
    Nilsson, Peter R
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts2014Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, nr 39, s. 12537-12543Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer’s disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate Aβ and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.

  • 310.
    Singer, S J
    et al.
    Ohio State Univ, Dept Chem, Columbus, OH 43210 USA.
    McDonald, S
    Ohio State Univ, Dept Chem, Columbus, OH 43210 USA.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Topology versus temperature: Thermal behavior of H+(H2O)(8) and H+(H2O)(16)2000Inngår i: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 112, nr 2, s. 710-716Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Monte Carlo simulations based on the OSS2 potential indicate the structure of the small protonated water clusters, H + (H 2 O) 8 and H + (H 2 O) 16 , is far from what could be expected for the proton solvated in bulk water. Near room temperature we find H + (H 2 O) n , n=8,16 clusters have a treelike topology with chains of waters emanating from a central H 3 O + moiety. Only at lower temperatures do cycles and cages of water appear. These findings bear upon experiments in a variety of disciplines.

  • 311.
    Sjölander, Daniel
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Luminescent molecular recognition of pathognomonic and aging associated protein aggregates2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Various protein inclusions have been recognized to be associated with aging and pathogenic conditions, such as in Alzheimer’s disease, Parkinson’s disease, Type 2 diabetes, and the prionoses Creutzfeldt-Jakob disease, Chronic wasting disease (CWD), and Mad cow disease. The causative transition of protein aggregation is the alteration in the conformation of the protein that renders the protein susceptible towards self-assembly. Variations in the physico-chemical ultrastructure of the protein deposit, i.e. the conformation and the chemical nature of the fibril constituent protein monomers, translate into specific structure-property phenotype, hence clinicopathology. Upon transmission and/or propagation this phenomenon gives rise to specific protein aggregate strains. Today most potential treatments of the protein conformational diseases have been a huge failure, effectively due to late diagnosis and subsequent therapeutic intervention. An imperative for efficient treatment is early detection and accurate identification for proper clinical diagnosis.

    The purpose of the studies in this thesis was to develop highly sensitive methods for detection and discrimination of age- and disease associated protein deposits both for in vitro and ex vivo utilization.

    Herein we have shown that, for in vitro usage, Nile red will bind to amyloid-like protein aggregates derived from a plethora of precursor proteins. It was also found that the fluorescence was insensitive to acidic assay conditions in contrast to the standard in vitro dye Thioflavin T (ThT). Further, Nile red was shown to discriminate between conformational isoforms thus enabling conformational typing of amyloid structures.

    For the development of ex vivo detection methods we employed luminescent conjugated oligothiophenes (LCOs) and utilized the structure-conformation induced optical properties of this class of protein aggregate ligands. The heptameric oligothiophene h-FTAA was successfully used to detect, with high sensitivity, protein deposits from various systemic amyloidoses (ATTR, AA, AL-λ/κ, and the local amyloidosis AIAPP) derived from biopsy specimens. Also aging-associated protein deposits were detected which was found promising for early detection of potentially pathogenic protein inclusions. Further, LCO staining of tissue sections was found compatible with immunolabeling enabling subtyping of involved proteins. Early detection of amyloidosis also requires relatively non-invasive methods, why h-FTAA staining was directed towards fine-needle-aspirated (FNA) abdominal fat tissue smears. Staining of protein deposits and detection with high sensitivity was also found in the fat tissue smears.

    In addition to the relatively rare prionoses it has lately been shown that Alzheimer’s, Parkinson’s diseases share similar properties as the prion pathologies. Hence the urgent need for ligands that will recognize specific disease specific strain aggregates. Using an established murine model for prion strain propagation we were able to discriminate two different prion strains, murine adapted Sheep Scrapie (mSS) and murine adapted Chronic wasting disease (mCWD) from each other by using multimodal fluorescence microscopy entailing emission/excitation spectral imaging and fluorescent lifetime imaging (FLIM).

    In conclusion we have shown that the LCOs will recognize protein aggregates with high sensitivity and selectivity. In addition we have shown that the LCOs detect protein aggregates that Congo red failed to recognize thus allowing potentially early diagnosis. Last, we show that the LCOs will recognize and discriminate between different protein aggregate strains which potentially will allow disease specific therapeutic targeting.

    Delarbeid
    1. Spectroscopic characterization of diverse amyloid fibrils in vitro by the fluorescent dye Nile red
    Åpne denne publikasjonen i ny fane eller vindu >>Spectroscopic characterization of diverse amyloid fibrils in vitro by the fluorescent dye Nile red
    2011 (engelsk)Inngår i: MOLECULAR BIOSYSTEMS, ISSN 1742-206X, Vol. 7, nr 4, s. 1232-1240Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The fluorescence of Nile red (9-diethylamino-5H-benzophenoxazine-5-one) is quenched in aqueous solutions but shows augmented fluorescence in hydrophobic environments. Nile red fluorescence was blue shifted and strongly augmented in the presence of various amyloid fibrils assayed under acidic as well as neutral pH conditions. Fibrils grown from lysozyme and insulin (at pH 1.6 and 65 degrees C), transthyretin (TTR) fibrils grown from the acid unfolded monomer (pH 2.0, 21 degrees C) or from the dissociated tetramer starting from native protein under less acidic conditions (pH 4.4, 37 degrees C) were detected. Nile red was also successfully employed in detecting A beta 1-42 and human prion protein (PrP90-231) amyloid fibrils grown at neutral pH. Nile red was amyloid fibril specific and did not fluoresce appreciably in the presence of the monomeric precursor proteins. Stokes shifts of the wavelength maximum of Nile red bound to various fibrils were different (ranging from 615 nm to 638 nm) indicating sensitivity to the tertiary structure in its respective binding sites of different amyloid proteins. A polarity assay using ethanol-water mixtures and pure octanol ranging from dielectric constants between 10 and 70 showed a linear correlation of Nile red Stokes shift and allowed assignment of amyloid fibril binding site polarity. Fluorescence resonance energy transfer between Thioflavin T (ThT) and Nile red was proven to be efficient and co-staining was employed to discriminate between conformational isoforms of A beta 1-42 amyloid fibrils grown under agitated and quiescent conditions. This paper demonstrates the complementary use of this fluorometric method for conformational typing of amyloid structures.

    sted, utgiver, år, opplag, sider
    Royal Society of Chemistry, 2011
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-67157 (URN)10.1039/c0mb00236d (DOI)000288329300031 ()
    Tilgjengelig fra: 2011-04-01 Laget: 2011-04-01 Sist oppdatert: 2018-04-25
    2. Luminescent conjugated oligothiophenes: A novel dye for amyloid diagnostics
    Åpne denne publikasjonen i ny fane eller vindu >>Luminescent conjugated oligothiophenes: A novel dye for amyloid diagnostics
    Vise andre…
    2013 (engelsk)Inngår i: XIIIth International Symposium on Amyloidosis: From Misfolded Proteins to Well-Designed Treatment: The Proceedings of the XIIIth International Symposium on Amyloidosis,May 6-10, 2012, Groningen, The Netherlands / [ed] Bouke P.C. Hazenberg and Johan Bijzet, GUARD (Groningen Unit for Amyloidosis Research & Development) , 2013, s. 179-182Konferansepaper, Publicerat paper (Fagfellevurdert)
    Abstract [en]

    The alkaline Congo red staining method has, for almost half a century, been the gold standard of amyloid diagnosis. Unfortunately, the method is both laborious and requires great skill to achieve proper diagnosis. In this study we are presenting an alternative method that is compatible with immunofluorescence typing. We used a novel dye, h-FTAA, designed and synthesized by us. The dye belongs to the novel class of conformation sensitive dyes known as Luminescent conjugated oligothiophenes (LCOs). We examined 37 different cases of systemic amyloidoses from various tissues. It was found that h-FTAA binds to amyloid with higher sensitivity and greater selectivity than Congo red, as was determined by both fluorescence- and light polarization microscopy. Due to the methods ease of use and performance compared to Congo red, it is concluded that h-FTAA is a better first choice for screening of systemic amyloidoses.

    sted, utgiver, år, opplag, sider
    GUARD (Groningen Unit for Amyloidosis Research & Development), 2013
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-106789 (URN)978-90-821593-0-1 (ISBN)978-90-821593-1-8 (ISBN)
    Konferanse
    The XIIIth International Symposium on Amyloidosis, May 6-10, 2012, Groningen, The Netherlands
    Tilgjengelig fra: 2014-05-23 Laget: 2014-05-23 Sist oppdatert: 2018-04-25bibliografisk kontrollert
    3. Evaluation of the fluorescent amyloid ligand h-FTAA in human tissues with systemic and localized amyloid
    Åpne denne publikasjonen i ny fane eller vindu >>Evaluation of the fluorescent amyloid ligand h-FTAA in human tissues with systemic and localized amyloid
    Vise andre…
    2014 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Most systemic amyloidosis are progressive and lethal. Disease specific therapy depends on the identification of the offending proteins. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL, and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. Screening of 114 amyloid containing tissues derived from §07 verified (Congo red birefringence and immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. H-FTAA staining can be utilized as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. It was also revealed that within 5 of 15 age matched Congo red negative control samples h-FTAA detects microdeposits of amyloid-like protein aggregates in liver and kidney. The results emphasize the potential of the dye for detection of prodromal amyloidosis as well as for discovery of novel amyloid-like protein aggregates in humans.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-106790 (URN)
    Tilgjengelig fra: 2014-05-23 Laget: 2014-05-23 Sist oppdatert: 2018-04-25bibliografisk kontrollert
    4. Sensitive and rapid assessment of amyloid by oligothiophene fluorescence in subcutaneous fat tissue
    Åpne denne publikasjonen i ny fane eller vindu >>Sensitive and rapid assessment of amyloid by oligothiophene fluorescence in subcutaneous fat tissue
    Vise andre…
    2015 (engelsk)Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, nr 1, s. 19-25Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Systemic amyloidosis (SA) is often diagnosed late. Combining clinical and biochemical biomarkers is necessary for raising suspicion of disease. Fine needle aspiration (FNA) of subcutaneous fat enables SA detection by Congo red staining. The luminescent conjugated probe heptameric formic thiophene acetic acid (h-FTAA) is a sensitive alternative to Congo red-staining of tissue samples. Our objective was to compare h-FTAA fluorescence with the Congo red stain for amyloid detection in FNA-obtained fat tissue. Herein, we studied samples from 57 patients with established SA (19 with AA, 20 with AL, and 18 with ATTR) and 17 age-matched controls (34–75 years). Positivity for h-FTAA was graded according to a Congo red-based grading scale ranging from 0 to 4+. Amyloid grading by both methods correlated strongly (r = 0.87). Here h-FTAA was positive in 53 of 54 Congo red-positive cases (sensitivity 98%) and h-FTAA was negative in 7 of 17 Congo red-negative controls (specificity 41%), but was also positive for 3 Congo red-negative SA cases. We conclude that h-FTAA fluorescence is more sensitive than Congo red staining in this small exploratory study of fat tissue samples, implicating potential sensitivity for prodromal amyloidosis, but is less specific for clinical amyloidosis defined by Congo red positivity. Given its simplicity h-FTAA staining may therefore be the most appropriate method for rapid screening of fat tissue samples but should presently treat grade 1+ as only suggestive, whereas 2+ or higher as positive for amyloidosis. Parallel assessment of h-FTAA and Congo red staining appears highly promising for clinical applications.

    sted, utgiver, år, opplag, sider
    Informa Healthcare, 2015
    Emneord
    AA amyloidosis, amyloid light chain, hyper spectral imaging, systemic amyloidosis, transthyretin
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-117806 (URN)10.3109/13506129.2014.984063 (DOI)000352637800003 ()25847117 (PubMedID)
    Merknad

    At the time for thesis presentation publication was in status: Manuscript

    Funding Agencies|European Commission; Swedish Foundation for Strategic Research; Swedish Research Council; Linkoping University Center for Neuroscience; European Research Council

    Tilgjengelig fra: 2015-05-11 Laget: 2015-05-08 Sist oppdatert: 2018-04-25bibliografisk kontrollert
    5. Multimodal fluorescene microscopy of prion strain specific PrP deposits stained by thiophene-bassed amyloid ligands
    Åpne denne publikasjonen i ny fane eller vindu >>Multimodal fluorescene microscopy of prion strain specific PrP deposits stained by thiophene-bassed amyloid ligands
    Vise andre…
    2014 (engelsk)Inngår i: Prion, ISSN 1933-6896, E-ISSN 1933-690X, Vol. 8, nr 4, s. 319-329Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The disease-associated prion protein (PrP) forms aggregates which vary in structural conformation yet share identical primary sequence. These variations in PrP conformation are believed to manifest in prion strains exhibiting distinctly different periods of disease incubation as well as regionally specific aggregate deposition within the brain. The anionic luminescent conjugated polythiophene (LCP), polythiophene acetic acid (PTAA) has previously been used to distinguish PrP deposits associated with distinct mouse adapted strains via distinct fluorescence emission profiles from the dye. Here we employed PTAA and 3 structurally related chemically defined luminescent conjugated oligothiophenes (LCOs) to stain brain tissue sections from mice inoculated with 2 distinct prion strains. Our results showed that in addition to emission spectra, excitation, and fluorescence lifetime imaging microscopy (FLIM) can fruitfully be assessed for optical distinction of PrP deposits associated with distinct prion strains. Our findings support the theory that alterations in LCP/LCO fluorescence are due to distinct conformational restriction of the thiophene backbone upon interaction with PrP aggregates associated with distinct prion strains. We foresee that LCP and LCO staining in combination with multimodal fluorescence microscopy might aid in detecting structural differences among discrete protein aggregates and in linking protein conformational features with disease phenotypes for a variety of neurodegenerative proteinopathies.

    sted, utgiver, år, opplag, sider
    Taylor & Francis, 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-106792 (URN)10.4161/pri.29239 (DOI)000348376000006 ()
    Tilgjengelig fra: 2014-05-23 Laget: 2014-05-23 Sist oppdatert: 2018-04-25bibliografisk kontrollert
    6. Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
    Åpne denne publikasjonen i ny fane eller vindu >>Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
    Vise andre…
    2013 (engelsk)Inngår i: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 34, nr 9, s. 723-730Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant A 1-42 amyloid fibrils and A deposits in brain tissue sections from a transgenic mouse model with Alzheimers disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiopheneporphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.

    sted, utgiver, år, opplag, sider
    Wiley-VCH Verlag, 2013
    Emneord
    oligothiophene, porphyrin, protein deposits, imaging, fluorescence
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-93385 (URN)10.1002/marc.201200817 (DOI)000318354500004 ()
    Merknad

    Funding Agencies|Swedish Research Council||Knut and Alice Wallenberg Foundation||Swedish Foundation for Strategic Research||European Union FP7 HEALTH (Project LUPAS)||LiU Neuroscience Center||ERC Starting Independent Researcher grant (Project: MUMID)||

    Tilgjengelig fra: 2013-05-31 Laget: 2013-05-31 Sist oppdatert: 2018-08-24
  • 312.
    Sjölander, Daniel
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Bijzet, Johan
    Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Hazenberg, Bouke P.
    Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Sensitive and rapid assessment of amyloid by oligothiophene fluorescence in subcutaneous fat tissue2015Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, nr 1, s. 19-25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Systemic amyloidosis (SA) is often diagnosed late. Combining clinical and biochemical biomarkers is necessary for raising suspicion of disease. Fine needle aspiration (FNA) of subcutaneous fat enables SA detection by Congo red staining. The luminescent conjugated probe heptameric formic thiophene acetic acid (h-FTAA) is a sensitive alternative to Congo red-staining of tissue samples. Our objective was to compare h-FTAA fluorescence with the Congo red stain for amyloid detection in FNA-obtained fat tissue. Herein, we studied samples from 57 patients with established SA (19 with AA, 20 with AL, and 18 with ATTR) and 17 age-matched controls (34–75 years). Positivity for h-FTAA was graded according to a Congo red-based grading scale ranging from 0 to 4+. Amyloid grading by both methods correlated strongly (r = 0.87). Here h-FTAA was positive in 53 of 54 Congo red-positive cases (sensitivity 98%) and h-FTAA was negative in 7 of 17 Congo red-negative controls (specificity 41%), but was also positive for 3 Congo red-negative SA cases. We conclude that h-FTAA fluorescence is more sensitive than Congo red staining in this small exploratory study of fat tissue samples, implicating potential sensitivity for prodromal amyloidosis, but is less specific for clinical amyloidosis defined by Congo red positivity. Given its simplicity h-FTAA staining may therefore be the most appropriate method for rapid screening of fat tissue samples but should presently treat grade 1+ as only suggestive, whereas 2+ or higher as positive for amyloidosis. Parallel assessment of h-FTAA and Congo red staining appears highly promising for clinical applications.

  • 313.
    Sjölander, Daniel
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Mason, Jeffrey
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Westermark, G. T.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Westermark, P.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Luminescent conjugated oligothiophenes: A novel dye for amyloid diagnostics2013Inngår i: XIIIth International Symposium on Amyloidosis: From Misfolded Proteins to Well-Designed Treatment: The Proceedings of the XIIIth International Symposium on Amyloidosis,May 6-10, 2012, Groningen, The Netherlands / [ed] Bouke P.C. Hazenberg and Johan Bijzet, GUARD (Groningen Unit for Amyloidosis Research & Development) , 2013, s. 179-182Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The alkaline Congo red staining method has, for almost half a century, been the gold standard of amyloid diagnosis. Unfortunately, the method is both laborious and requires great skill to achieve proper diagnosis. In this study we are presenting an alternative method that is compatible with immunofluorescence typing. We used a novel dye, h-FTAA, designed and synthesized by us. The dye belongs to the novel class of conformation sensitive dyes known as Luminescent conjugated oligothiophenes (LCOs). We examined 37 different cases of systemic amyloidoses from various tissues. It was found that h-FTAA binds to amyloid with higher sensitivity and greater selectivity than Congo red, as was determined by both fluorescence- and light polarization microscopy. Due to the methods ease of use and performance compared to Congo red, it is concluded that h-FTAA is a better first choice for screening of systemic amyloidoses.

  • 314.
    Sjölander, Daniel
    et al.
    Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi.
    Roecken, Christoph
    University of Kiel, Germany.
    Westermark, Per
    Uppsala University, Sweden.
    Westermark, Gunilla T.
    Uppsala University, Sweden.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid2016Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 23, nr 2, s. 98-108Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. The only functional structure stained with h-FTAA showing the amyloidotypic fluorescence spectrum was Paneth cell granules in intestine. Screening of 114 amyloid containing tissues derived from 107 verified (Congo red birefringence and/or immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence (107/107, 100% sensitivity). The majority of Congo red negative control cases (27 of 32, 85% specificity) were negative with h-FTAA. Small Congo red negative aggregates in kidney, liver, pancreas and duodenum were found by h-FTAA fluorescence in five control patients aged 72-83 years suffering from diverse diseases. The clinical significance of these false-positive lesions is currently not known. Because h-FTAA fluorescence is one magnitude brighter than Congo red and as the staining is performed four magnitudes lower than the concentration of dye, we believe that these inclusions are beyond detection by Congo red. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. Use of h-FTAA can be exploited as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. Our results also implicate the potential of the technique for detection of prodromal amyloidosis as well as for discovery of new amyloid-like protein aggregates in humans.

  • 315.
    Sjölander, Daniel
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Röcken, Christoph
    Institute of Pathology, Christian-Albrechts-Univeristy, Kiel, Germany.
    Westermark, Per
    Department of Immunology, Uppsala University, Uppsala, Sweden.
    Westermark, Gunilla T.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Evaluation of the fluorescent amyloid ligand h-FTAA in human tissues with systemic and localized amyloid2014Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Most systemic amyloidosis are progressive and lethal. Disease specific therapy depends on the identification of the offending proteins. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL, and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. Screening of 114 amyloid containing tissues derived from §07 verified (Congo red birefringence and immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. H-FTAA staining can be utilized as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. It was also revealed that within 5 of 15 age matched Congo red negative control samples h-FTAA detects microdeposits of amyloid-like protein aggregates in liver and kidney. The results emphasize the potential of the dye for detection of prodromal amyloidosis as well as for discovery of novel amyloid-like protein aggregates in humans.

  • 316.
    Sjöqvist, Jonas
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Beräkningsfysik. Linköpings universitet, Tekniska högskolan.
    Maria, Jerôme
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Simon, Rozalyn
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Linares, Mathieu
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Beräkningsfysik. Linköpings universitet, Tekniska högskolan.
    Norman, Patrick
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Beräkningsfysik. Linköpings universitet, Tekniska högskolan.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Lindgren, Mikael
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan. Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Toward a molecular understanding of the detection of amyloid proteins with flexible conjugated oligothiophenes2014Inngår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 118, nr 42, s. 9820-9827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular and electronic structures and optical absorption properties of oligothiophenes used for spectral assignment of amyloid deposits have been investigated for a family of probes known as luminescent conjugated oligothiophenes (LCOs). Theoretical absorption spectra have been determined using conformational averaging, combining classical molecular dynamics (MD) simulations with quantum mechanical/molecular mechanics (QM/MM) time-dependent density functional theory (TD-DFT) spectrum calculations. Theoretical absorption spectra are in excellent agreement with experiments, showing average errors below 5 nm for absorption maxima. To couple observed properties to molecular structures, a measure of planarity is defined, revealing a strong correlation between the transition wavelength of the first and dominating electronically excited state and dihedral rotations. It is shown that from this correlation, predictions can be made of the absorption properties of probes based only on information from MD trajectories. We show experimentally that red shifts observed in the excitation maxima of LCOs when bound to amyloid protein aggregates are also evident in absorption spectra. We predict that these red shifts are due to conformational restriction of the LCO in a protein binding pocket, causing a planarization of the conjugated backbone. On the basis of our studies of planarity, it is shown that such shifts are both possible and realistic.

  • 317.
    Sjöstrand, Linda
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi.
    Method Development for Thermal Stability Analysis by Circular Dichroism: Application to the Abp1p SH3 domain from yeast2018Independent thesis Basic level (degree of Bachelor), 10,5 poäng / 16 hpOppgave
    Abstract [en]

    Thermal stability is an important and interesting physical property of proteins. A common method to study it by is circular dichroism (CD) spectroscopy. The aim of this study was to test methods to improve thermal stability analysis by CD spectroscopy. Experiments were performed using the Abp1p SH3 domain from yeast as a model protein. Thermal denaturation was monitored at multiple wavelengths. It was concluded that for data sets of reasonable quality the choice of wavelength does not affect the results. An approach to estimate stability of thermophilic proteins was tested where thermal stability was measured at different concentrations of the denaturant GuHCl. The thermochemical data was used to estimate the stability in absence of GuHCl by extrapolation. The results were compared to those obtained from CD spectroscopy and differential scanning calorimetry. It was found that a stabilizing effect from low concentrations of GuHCl complicated the extrapolation. It is likely that this method is more successful if there is no stabilizing effect. The effect of ΔCp in stability parameter calculations was investigated with an experimentally and theoretically determined ΔCp. This was further investigated with synthetic data sets. The ΔCp used in calculations had no notable effect, as long as there was no cold denaturation. Although ΔCp is not necessary in calculations, it is an interesting parameter itself. ΔCp can be calculated from the thermochemical data used for extrapolation. The results in this study demonstrate robustness in thermal stability analysis by CD spectroscopy and a potential for development. 

  • 318.
    Skarp-de Haan, Caroline P. A.
    et al.
    University of Helsinki, Finland .
    Culebro, Alejandra
    University of Helsinki, Finland .
    Schott, Thomas
    University of Helsinki, Finland .
    Revez, Joana
    University of Helsinki, Finland .
    Schweda, Elke
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Hanninen, Marja-Liisa
    University of Helsinki, Finland .
    Rossi, Mirko
    University of Helsinki, Finland .
    Comparative genomics of unintrogressed Campylobacter coli clades 2 and 32014Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, nr 129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Campylobacter jejuni and C. coli share a multitude of risk factors associated with human gastrointestinal disease, yet their phylogeny differs significantly. C. jejuni is scattered into several lineages, with no apparent linkage, whereas C. coli clusters into three distinct phylogenetic groups (clades) of which clade 1 has shown extensive genome-wide introgression with C. jejuni, yet the other two clades (2 and 3) have less than 2% of C. jejuni ancestry. We characterized a C. coli strain (76339) with four novel multilocus sequence type alleles (ST-5088) and having the capability to express gamma-glutamyltranspeptidase (GGT); an accessory feature in C. jejuni. Our aim was to further characterize unintrogressed C. coli clades 2 and 3, using comparative genomics and with additional genome sequences available, to investigate the impact of horizontal gene transfer in shaping the accessory and core gene pools in unintrogressed C. coli. Results: Here, we present the first fully closed C. coli clade 3 genome (76339). The phylogenomic analysis of strain 76339, revealed that it belonged to clade 3 of unintrogressed C. coli. A more extensive respiratory metabolism among unintrogressed C. coli strains was found compared to introgressed C. coli (clade 1). We also identified other genes, such as serine proteases and an active sialyltransferase in the lipooligosaccharide locus, not present in C. coli clade 1 and we further propose a unique scenario for the evolution of Campylobacter ggt. Conclusions: We propose new insights into the evolution of the accessory genome of C. coli clade 3 and C. jejuni. Also, in silico analysis of the gene content revealed that C. coli clades 2 and 3 have genes associated with infection, suggesting they are a potent human pathogen, and may currently be underreported in human infections due to niche separation.

  • 319.
    Snipstad, Sofie
    et al.
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Hak, Sjoerd
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
    Baghirov, Habib
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Sulheim, Einar
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway; SINTEF Materials and Chemistry, Trondheim, Norway.
    Mørch, Ýrr
    SINTEF Materials and Chemistry, Trondheim, Norway.
    Lélu, Sylvie
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    von Haartman, Eva
    Pharmaceutical Sciences Laboratory, Åbo Akademi University, Turku, Finland; Laboratory of Physical Chemistry, Åbo Akademi University, Turku, Finland.
    Bäck, Marcus
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Nilsson, K. Peter R.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Klymchenko, Andrey S
    Laboratoire de Biophotonique et Pharmacologie, UMR CNRS 7213, Université de Strasbourg, Strasbourg, France.
    de Lange Davies, Catharina
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Åslund, Andreas K. O.
    Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway.
    Labeling nanoparticles: Dye leakage and altered cellular uptake2017Inngår i: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 91, nr 8, s. 760-766Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vitro and in vivo behavior of nanoparticles (NPs) is often studied by tracing the NPs with fluorescent dyes. This requires stable incorporation of dyes within the NPs, as dye leakage may give a wrong interpretation of NP biodistribution, cellular uptake, and intracellular distribution. Furthermore, NP labeling with trace amounts of dye should not alter NP properties such as interactions with cells or tissues. To allow for versatile NP studies with a variety of fluorescence-based assays, labeling of NPs with different dyes is desirable. Hence, when new dyes are introduced, simple and fast screening methods to assess labeling stability and NP-cell interactions are needed. For this purpose, we have used a previously described generic flow cytometry assay; incubation of cells with NPs at 4 and 37C. Cell-NP interaction is confirmed by cellular fluorescence after 37C incubation, and NP-dye retention is confirmed when no cellular fluorescence is detected at 4C. Three different NP-platforms labeled with six different dyes were screened, and a great variability in dye retention was observed. Surprisingly, incorporation of trace amounts of certain dyes was found to reduce or even inhibit NP uptake. This work highlights the importance of thoroughly evaluating every dye-NP combination before pursuing NP-based applications. © 2016 International Society for Advancement of Cytometry.

  • 320.
    Sole-Domenech, Santiago
    et al.
    Karolinska Institute, Sweden .
    Sjovall, Peter
    SP Technical Research Institute Sweden, Sweden .
    Vukojevic, Vladana
    Karolinska Institute, Sweden .
    Fernando, Ruani
    Hop St Eloi, France .
    Codita, Alina
    Karolinska Institute, Sweden .
    Salve, Sachin
    Karolinska Institute, Sweden .
    Bogdanovic, Nenad
    Karolinska Institute, Sweden .
    H Mohammed, Abdul
    Karolinska Institute, Sweden .
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    M LaFerla, Frank
    University of Calif Irvine, CA USA .
    Jacob, Stefan
    Karolinska Institute, Sweden .
    Berggren, Per-Olof
    Karolinska Institute, Sweden .
    Gimenez-Llort, Lydia
    University of Autonoma Barcelona, Spain .
    Schalling, Martin
    Karolinska Institute, Sweden .
    Terenius, Lars
    Karolinska Institute, Sweden .
    Johansson, Bjorn
    Karolinska Institute, Sweden .
    Localization of cholesterol, amyloid and glia in Alzheimers disease transgenic mouse brain tissue using time-of-flight secondary ion mass spectrometry (ToF-SIMS) and immunofluorescence imaging2013Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 125, nr 1, s. 145-157Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The spatial distributions of lipids, amyloid-beta deposits, markers of neurons and glial cells were imaged, at submicrometer lateral resolution, in brain structures of a mouse model of Alzheimers disease using a new methodology that combines time-of-flight secondary ion mass spectrometry (ToF-SIMS) and confocal fluorescence microscopy. The technology, which enabled us to simultaneously image the lipid and glial cell distributions in Tg2576 mouse brain structures, revealed micrometer-sized cholesterol accumulations in hippocampal regions undergoing amyloid-beta deposition. Such cholesterol granules were either associated with individual amyloid deposits or spread over entire regions undergoing amyloidogenesis. Subsequent immunohistochemical analysis of the same brain regions showed increased microglial and astrocytic immunoreactivity associated with the amyloid deposits, as expected from previous studies, but did not reveal any particular astrocytic or microglial feature correlated with cholesterol granulation. However, dystrophic neurites as well as presynaptic vesicles presented a distribution similar to that of cholesterol granules in regions undergoing amyloid-beta accumulation, thus indicating that these neuronal endpoints may retain cholesterol in areas with lesions. In conclusion, the present study provides evidence for an altered cholesterol distribution near amyloid deposits that would have been missed by several other lipid analysis methods, and opens for the possibility to study in detail the putative liaison between lipid environment and protein structure and function in Alzheimers disease.

  • 321.
    Souqui, Laurent
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tunnfilmsfysik. Linköpings universitet, Tekniska fakulteten.
    Högberg, Hans
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tunnfilmsfysik. Linköpings universitet, Tekniska fakulteten.
    Pedersen, Henrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Surface-Inhibiting Effect in Chemical Vapor Deposition of Boron-Carbon Thin Films from Trimethylboron2019Inngår i: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 31, nr 15, s. 5408-5412Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We use the ability to control surface chemistry in chemical vapor deposition (CVD) to deposit boron-carbon films into pores with an aspect ratio of 60:1 without clogging the opening, and into lateral trenches with ratios of up to 2000:1. In contrast to many other surface-controlled CVD processes, operating at low temperatures (100-250 degrees C) and pressures (10-1000 Pa), we use trimethylboron at a higher temperature (700 degrees C) and pressure (5000 Pa), affording a surface-inhibited. CVD process in hydrogen ambient. We show that the deposition rate is highly dependent on the partial pressure of hydrogen; decreasing proportionally to the logarithm of the partial pressure. The surface-controlled effect is not encountered in argon ambient. We propose that this is explained by a competitive adsorption of growth species and inhibiting dihydrogen or atomic hydrogen species following a Temkin isotherm.

  • 322.
    Souqui, Laurent
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tunnfilmsfysik. Linköpings universitet, Tekniska fakulteten.
    Pedersen, Henrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Högberg, Hans
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tunnfilmsfysik. Linköpings universitet, Tekniska fakulteten.
    Thermal chemical vapor deposition of epitaxial rhombohedral boron nitride from trimethylboron and ammonia2019Inngår i: Journal of Vacuum Science & Technology. A. Vacuum, Surfaces, and Films, ISSN 0734-2101, E-ISSN 1520-8559, Vol. 37, nr 2, artikkel-id 020603Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epitaxial rhombohedral boron nitride (r-BN) films were deposited on alpha-Al2O3(001) substrates by chemical vapor deposition, using trimethylboron, ammonia, and a low concentration of silane in the growth flux. The depositions were performed at temperatures from 1200 to 1485 degrees C, pressures from 30 to 90 mbar, and N/B ratios from 321 to 1286. The most favorable conditions for epitaxy were a temperature of 1400 degrees C, N/B around 964, and pressures below 40 mbar. Analysis by thin film x-ray diffraction showed that most deposited films were polytype-pure epitaxial r-BN with an out-of-plane epitaxial relationship of r-BN[001] parallel to w-AlN[001] parallel to alpha-Al2O3[001] and with two in-plane relationships of r-BN[110] parallel to w-AlN[110] parallel to alpha-Al2O3[100] and r-BN[110] parallel to w-AlN[110] parallel to alpha-Al2O3[(1) over bar 00] due to twinning. Published by the AVS.

  • 323.
    Speda, Jutta
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Methods development for metaproteomics-guided bioprospecting of novel enzymes2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Industrial biotechnology has been announced by several organizations and governments as a key enabling technology for the enhanced economic growth in a low-carbon and knowledge-based bioeconomy. An important goal to promote an environment friendly and sustainable industrial biotechnology is the discovery of new enzymes.

    To date, almost all enzymes used in industry have been discovered by pure culturing of microorganisms, however, it is known that less than 1% of all microorganisms can be obtained in pure cultures. The remaining majority of microorganisms is only viable by close biological interactions provided in microbial communities and is not available for enzyme discovery using the classical pure culture approaches. The investigation of microbial communities, which can be viewed as metaorganisms, has been enabled during the last two decades by refining established methods for the analysis of genes, mRNA or proteins and are called metagenomics, metatranscriptomics and metaproteomics, respectively. To date, these techniques have mostly been used in the field of microbial ecology for the understanding of the composition, function and metabolism of microbial communities but not for the purpose of bioprospecting for novel enzymes. Identification of genes that code for possible enzyme candidates is hindered, due to the fact that 30-40% of the sequenced metagenomes contain genes coding for unidentified proteins. Additionally, the -omics techniques generate large amounts of data that need to be analyzed and the outcome of the analysis does not necessarily lead to the discovery of novel applicable enzymes.

    The work presented in this thesis describes the establishment of the necessary conditions for a metaproteomics-based method that allows for a straightforward and targeted identification of novel enzymes with desired activity from microbial communities. The approach provides a valuable alternative to the incomplete and inefficient analysis of non-targeting data and laborious workflow, which is typically generated by the established meta-omics techniques. In developing the methods presented in this thesis, microbial communities in constructed environments were established, which allowed for the controlled expression of extracellular hydrolytic enzymes under defined conditions. By combination and modulation of advanced metaproteomics and metagenomics techniques, we were able to directly identify the enzymes and the corresponding gene sequences of several cellulolytic enzymes as a first example for the feasibility of this approach.

    Delarbeid
    1. Applying theories of microbial metabolism for induction of targeted enzyme activity in a methanogenic microbial community at a metabolic steady state
    Åpne denne publikasjonen i ny fane eller vindu >>Applying theories of microbial metabolism for induction of targeted enzyme activity in a methanogenic microbial community at a metabolic steady state
    2016 (engelsk)Inngår i: Applied Microbiology and Biotechnology, ISSN 0175-7598, E-ISSN 1432-0614, Vol. 100, nr 18, s. 7989-8002Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Novel enzymes that are stable in diverse conditions are intensively sought because they offer major potential advantages in industrial biotechnology, and microorganisms in extreme environments are key sources of such enzymes. However, most potentially valuable enzymes are currently inaccessible due to the pure culturing problem of microorganisms. Novel metagenomic and metaproteomic techniques that circumvent the need for pure cultures have theoretically provided possibilities to identify all genes and all proteins in microbial communities, but these techniques have not been widely used to directly identify specific enzymes because they generate vast amounts of extraneous data. In a first step towards developing a metaproteomic approach to pinpoint targeted extracellular hydrolytic enzymes of choice in microbial communities, we have generated and analyzed the necessary conditions for such an approach by the use of a methanogenic microbial community maintained on a chemically defined medium. The results show that a metabolic steady state of the microbial community could be reached, at which the expression of the targeted hydrolytic enzymes were suppressed, and that upon enzyme induction a distinct increase in the targeted enzyme expression was obtained. Furthermore, no cross talk in expression was detected between the two focal types of enzyme activities under their respective inductive conditions. Thus, the described approach should be useful to generate ideal samples, collected before and after selective induction, in controlled microbial communities to clearly discriminate between constituently expressed proteins and extracellular hydrolytic enzymes that are specifically induced, thereby reducing the analysis to only those proteins that are distinctively up-regulated.

    sted, utgiver, år, opplag, sider
    Springer, 2016
    Emneord
    Microbial community; Enzyme discovery; Metaproteomics; Biogas; Cellulase; Protease
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-131888 (URN)10.1007/s00253-016-7547-z (DOI)000382008000017 ()27115757 (PubMedID)
    Merknad

    Funding Agencies|Swedish Research Council [621-2009-4150]; InZymes Biotech AB

    Tilgjengelig fra: 2016-10-13 Laget: 2016-10-11 Sist oppdatert: 2018-05-15
    2. Assessment of sample preparation methods for metaproteomics of extracellular proteins
    Åpne denne publikasjonen i ny fane eller vindu >>Assessment of sample preparation methods for metaproteomics of extracellular proteins
    2017 (engelsk)Inngår i: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 516, s. 23-36Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Enzyme discovery in individual strains of microorganisms is compromised by the limitations of pure culturing. In principle, metaproteomics allows for fractionation and study of different parts of the protein complement but has hitherto mainly been used to identify intracellular proteins. However, the extracellular environment is also expected to comprise a wealth of information regarding important proteins. An absolute requirement for metaproteomic studies of protein expression, and irrespective of downstream methods for analysis, is that sample preparation methods provide clean, concentrated and representative samples of the protein complement. A battery of methods for concentration, extraction, precipitation and resolubilization of proteins in the extracellular environment of a constructed microbial community was assessed by means of 2D gel electrophoresis and image analysis to elucidate whether it is possible to make the extracellular protein complement available for metaproteomic analysis. Most methods failed to provide pure samples and therefore negatively influenced protein gel migration and gel background clarity. However, one direct precipitation method (TCA-DOC/acetone) and one extraction/precipitation method (phenol/methanol) provided complementary high quality 2D gels that allowed for high spot detection ability and thereby also spot detection of less abundant extracellular proteins.

    sted, utgiver, år, opplag, sider
    Elsevier, 2017
    Emneord
    Enzyme discovery, Microbial community, Metaproteome, Extracellular, Sample preparation, 2D gel electrophoresis
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-132902 (URN)10.1016/j.ab.2016.10.008 (DOI)000388056800005 ()27742212 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 621-2009-4150
    Merknad

    Funding agencies: Swedish Research Council [621-2009-4150]; Tekniska Verken i Linkoping AB; InZymes Biotech AB

    Tilgjengelig fra: 2016-12-01 Laget: 2016-12-01 Sist oppdatert: 2018-05-15bibliografisk kontrollert
  • 324.
    Speda, Jutta
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Johansson, Mikaela A.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Carlsson, Uno
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. InZymes Biotech AB, Linköping, Sweden.
    Assessment of sample preparation methods for metaproteomics of extracellular proteins2017Inngår i: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 516, s. 23-36Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Enzyme discovery in individual strains of microorganisms is compromised by the limitations of pure culturing. In principle, metaproteomics allows for fractionation and study of different parts of the protein complement but has hitherto mainly been used to identify intracellular proteins. However, the extracellular environment is also expected to comprise a wealth of information regarding important proteins. An absolute requirement for metaproteomic studies of protein expression, and irrespective of downstream methods for analysis, is that sample preparation methods provide clean, concentrated and representative samples of the protein complement. A battery of methods for concentration, extraction, precipitation and resolubilization of proteins in the extracellular environment of a constructed microbial community was assessed by means of 2D gel electrophoresis and image analysis to elucidate whether it is possible to make the extracellular protein complement available for metaproteomic analysis. Most methods failed to provide pure samples and therefore negatively influenced protein gel migration and gel background clarity. However, one direct precipitation method (TCA-DOC/acetone) and one extraction/precipitation method (phenol/methanol) provided complementary high quality 2D gels that allowed for high spot detection ability and thereby also spot detection of less abundant extracellular proteins.

  • 325.
    Speda, Jutta
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Johansson, Mikaela
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Jonsson, Bengt-Harald
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. InZymes Biotech AB, Gjuterigatan 1B, S-58273 Linkoping, Sweden.
    Applying theories of microbial metabolism for induction of targeted enzyme activity in a methanogenic microbial community at a metabolic steady state2016Inngår i: Applied Microbiology and Biotechnology, ISSN 0175-7598, E-ISSN 1432-0614, Vol. 100, nr 18, s. 7989-8002Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Novel enzymes that are stable in diverse conditions are intensively sought because they offer major potential advantages in industrial biotechnology, and microorganisms in extreme environments are key sources of such enzymes. However, most potentially valuable enzymes are currently inaccessible due to the pure culturing problem of microorganisms. Novel metagenomic and metaproteomic techniques that circumvent the need for pure cultures have theoretically provided possibilities to identify all genes and all proteins in microbial communities, but these techniques have not been widely used to directly identify specific enzymes because they generate vast amounts of extraneous data. In a first step towards developing a metaproteomic approach to pinpoint targeted extracellular hydrolytic enzymes of choice in microbial communities, we have generated and analyzed the necessary conditions for such an approach by the use of a methanogenic microbial community maintained on a chemically defined medium. The results show that a metabolic steady state of the microbial community could be reached, at which the expression of the targeted hydrolytic enzymes were suppressed, and that upon enzyme induction a distinct increase in the targeted enzyme expression was obtained. Furthermore, no cross talk in expression was detected between the two focal types of enzyme activities under their respective inductive conditions. Thus, the described approach should be useful to generate ideal samples, collected before and after selective induction, in controlled microbial communities to clearly discriminate between constituently expressed proteins and extracellular hydrolytic enzymes that are specifically induced, thereby reducing the analysis to only those proteins that are distinctively up-regulated.

  • 326.
    Speda, Jutta
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Johansson, Mikaela
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Odnell, Anna
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Karshult Municipal Waste Water Treatment Plant, Sweden.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. InZymes Biotech AB, Gjuterigatan 1B, S-58273 Linkoping, Sweden.
    Enhanced biomethane production rate and yield from lignocellulosic ensiled forage ley by in situ anaerobic digestion treatment with endogenous cellulolytic enzymes2017Inngår i: Biotechnology for Biofuels, ISSN 1754-6834, E-ISSN 1754-6834, Vol. 10, artikkel-id 129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Enzymatic treatment of lignocellulosic material for increased biogas production has so far focused on pretreatment methods. However, often combinations of enzymes and different physicochemical treatments are necessary to achieve a desired effect. This need for additional energy and chemicals compromises the rationale of using enzymes for low energy treatment to promote biogas production. Therefore, simpler and less energy intensive in situ anaerobic digester treatment with enzymes is desirable. However, investigations in which exogenous enzymes are added to treat the material in situ have shown mixed success, possibly because the enzymes used originated from organisms not evolutionarily adapted to the environment of anaerobic digesters. In this study, to examine the effect of enzymes endogenous to methanogenic microbial communities, cellulolytic enzymes were instead overproduced and collected from a dedicated methanogenic microbial community. By this approach, a solution with very high endogenous microbial cellulolytic activity was produced and tested for the effect on biogas production from lignocellulose by in situ anaerobic digester treatment. Results: Addition of enzymes, endogenous to the environment of a mixed methanogenic microbial community, to the anaerobic digestion of ensiled forage ley resulted in significantly increased rate and yield of biomethane production. The enzyme solution had an instant effect on more readily available cellulosic material. More importantly, the induced enzyme solution also affected the biogas production rate from less accessible cellulosic material in a second slower phase of lignocellulose digestion. Notably, this effect was maintained throughout the experiment to completely digested lignocellulosic substrate. Conclusions: The induced enzyme solution collected from a microbial methanogenic community contained enzymes that were apparently active and stable in the environment of anaerobic digestion. The enzymatic activity had a profound effect on the biogas production rate and yield, comparable with the results of many pretreatment methods. Thus, application of such enzymes could enable efficient low energy in situ anaerobic digester treatment for increased biomethane production from lignocellulosic material.

  • 327.
    Speda, Jutta
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Jonsson, Bengt-Harald
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Carlsson, Uno
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. InZymes Biotech AB, Gjuterigatan 1B, S-58273 Linkoping, Sweden.
    Metaproteomics-guided selection of targeted enzymes for bioprospecting of mixed microbial communities2017Inngår i: Biotechnology for Biofuels, ISSN 1754-6834, E-ISSN 1754-6834, Vol. 10, artikkel-id 128Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Hitherto, the main goal of metaproteomic analyses has been to characterize the functional role of particular microorganisms in the microbial ecology of various microbial communities. Recently, it has been suggested that metaproteomics could be used for bioprospecting microbial communities to query for the most active enzymes to improve the selection process of industrially relevant enzymes. In the present study, to reduce the complexity of metaproteomic samples for targeted bioprospecting of novel enzymes, a microbial community capable of producing cellulases was maintained on a chemically defined medium in an enzyme suppressed metabolic steady state. From this state, it was possible to specifically and distinctively induce the desired cellulolytic activity. The extracellular fraction of the protein complement of the induced sample could thereby be purified and compared to a non-induced sample of the same community by differential gel electrophoresis to discriminate between constitutively expressed proteins and proteins upregulated in response to the inducing substance. Results: Using the applied approach, downstream analysis by mass spectrometry could be limited to only proteins recognized as upregulated in the cellulase-induced sample. Of 39 selected proteins, the majority were found to be linked to the need to degrade, take up, and metabolize cellulose. In addition, 28 (72%) of the proteins were non-cytosolic and 17 (44%) were annotated as carbohydrate-active enzymes. The results demonstrated both the applicability of the proposed approach for identifying extracellular proteins and guiding the selection of proteins toward those specifically upregulated and targeted by the enzyme inducing substance. Further, because identification of interesting proteins was based on the regulation of enzyme expression in response to a need to hydrolyze and utilize a specific substance, other unexpected enzyme activities were able to be identified. Conclusions: The described approach created the conditions necessary to be able to select relevant extracellular enzymes that were extracted from the enzyme-induced microbial community. However, for the purpose of bioprospecting for enzymes to clone, produce, and characterize for practical applications, it was concluded that identification against public databases was not sufficient to identify the correct gene or protein sequence for cloning of the identified novel enzymes.

  • 328.
    Speda, Jutta
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Jonsson, Bengt-Harald
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Induced differential metaproteomics: identification of cellulases in a methanogenic microbial community at mesophilic conditions2014Konferansepaper (Annet vitenskapelig)
  • 329.
    Speda, Jutta
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Jonsson, Bengt-Harald
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Induced differential metaproteomics: identification of thermostable cellulases in a methanogenic microbial community2014Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    The identification of novel enzymes for use in industrial biotechnology is an important goal in enzyme discovery. Most industrially relevant enzymes to date have been isolated from pure cultured microorganisms. For future discovery of novel enzymes this is however a major bottleneck since it is well established that only a small fraction of all microorganisms can be obtained in pure cultures. The possibility to identify enzymes directly from complete microbial communities would therefore give access to a huge number of novel enzyme candidates.

    Metaproteomics has hitherto mainly been used to understand ecosystem functions. We have instead used the dynamics of proteomics to develop a method based on “induced differential metaproteomics”, by which a desired enzyme activity is induced in a full microbial population and compared to a non-induced reference of the very same population. In a first example the goal was to induce, select and identify cellulases from a thermophilic methanogenic community.

    Out of several hundred detectable proteins in a 2D-DIGE experiment, 24 proteins could be identified as at least two-fold up-regulated upon induction. For some proteins spots, the cellulolytic activity was further validated by activity staining using 2D-zymography. Mass spectrometry analysis revealed that 21 out of the 24 up-regulated proteins are cellulases or associated to cellulolytic activity giving a remarkable hit-rate of 88%. This demonstrates the high efficiency and precision of the method, by which a much wider span of the microbial world can be scanned for novel and targeted enzymes.

  • 330.
    Stavrinidou, Eleni
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Gabrielsson, Roger
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Nilsson, K. Peter R.
    Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi.
    Singh, Sandeep Kumar
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Franco- Gonzalez, Juan Felipe
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Volkov, Anton V.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Jonsson, Magnus P.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Grimoldi, Andrea
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Elgland, Mathias
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Zozoulenko, Igor V.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Simon, Daniel
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Berggren, Magnus
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    In vivo polymerization and manufacturing of wires and supercapacitors in plants2017Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 11, s. 2807-2812Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Electronic plants, e-Plants, are an organic bioelectronic platform that allows electronic interfacing with plants. Recently we have demonstrated plants with augmented electronic functionality. Using the vascular system and organs of a plant, we manufactured organic electronic devices and circuits in vivo, leveraging the internal structure and physiology of the plant as the template, and an integral part of the devices. However, this electronic functionality was only achieved in localized regions, whereas new electronic materials that could be distributed to every part of the plant would provide versatility in device and circuit fabrication and create possibilities for new device concepts. Here we report the synthesis of such a conjugated oligomer that can be distributed and form longer oligomers and polymer in every part of the xylem vascular tissue of a Rosa floribunda cutting, forming long-range conducting wires. The plant’s structure acts as a physical template, whereas the plant’s biochemical response mechanism acts as the catalyst for polymerization. In addition, the oligomer can cross through the veins and enter the apoplastic space in the leaves. Finally, using the plant’s natural architecture we manufacture supercapacitors along the stem. Our results are preludes to autonomous energy systems integrated within plants and distribute interconnected sensor-actuator systems for plant control and optimization

  • 331.
    Steiner, Emilie
    et al.
    Karolinska Institute, Sweden.
    Schlagnitweit, Judith
    Karolinska Institute, Sweden.
    Lundström, Patrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Petzold, Katja
    Karolinska Institute, Sweden.
    Capturing Excited States in the Fast-Intermediate Exchange Limit in Biological Systems Using (HNMR)-H-1 Spectroscopy2016Inngår i: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, ISSN 1433-7851, Vol. 55, nr 51, s. 15869-15872Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Changes in molecular structure are essential for the function of biomolecules. Characterization of these structural fluctuations can illuminate alternative states and help in correlating structure to function. NMR relaxation dispersion (RD) is currently the only method for detecting these alternative, high-energy states. In this study, we present a versatile H-1 R-1 RD experiment that not only extends the exchange timescales at least three times beyond the rate limits of C-13/N-15 R-1 and ten times for CPMG experiments, but also makes use of easily accessible probes, thus allowing a general description of biologically important excited states. This technique can be used to extract chemical shifts for the structural characterization of excited states and to elucidate complex excited states.

  • 332.
    Stenberg, Pontus
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Booker, Ian Don
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Karhu, Robin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Pedersen, Henrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Janzén, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Ivanov, Ivan Gueorguiev
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Defects in silicon carbide grown by fluorinated chemical vapor deposition chemistry2018Inngår i: Physica. B, Condensed matter, ISSN 0921-4526, E-ISSN 1873-2135, Vol. 535, s. 44-49Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Point defects in n- and p-type 4H-SiC grown by fluorinated chemical vapor deposition (CVD) have been characterized optically by photoluminescence (PL) and electrically by deep-level transient spectroscopy (DLTS) and minority carrier transient spectroscopy (MCTS). The results are considered in comparison with defects observed in non-fluorinated CVD growth (e.g., using SiH4 instead of SiF4 as silicon precursor), in order to investigate whether specific fluorine-related defects form during the fluorinated CVD growth, which might prohibit the use of fluorinated chemistry for device-manufacturing purposes. Several new peaks identifying new defects appear in the PL of fluorinated-grown samples, which are not commonly observed neither in other halogenated chemistries, nor in the standard CVD chemistry using silane (SiH4). However, further investigation is needed in order to determine their origin and whether they are related to incorporation of F in the SiC lattice, or not. The electric characterization does not find any new electrically-active defects that can be related to F incorporation. Thus, we find no point defects prohibiting the use of fluorinated chemistry for device-making purposes.

  • 333.
    Stenberg, Pontus
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Danielsson, Örjan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Erdtman, Edvin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Sukkaew, Pitsiri
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Janzén, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Pedersen, Henrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Matching precursor kinetics to afford a more robust CVD chemistry: a case study of the C chemistry for silicon carbide using SiF4 as Si precursor2017Inngår i: Journal of Materials Chemistry C, ISSN 2050-7526, E-ISSN 2050-7534, Vol. 5, s. 5818-5823Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chemical Vapor Deposition (CVD) is one of the technology platforms forming the backbone of the semiconductor industry and is vital in the production of electronic devices. To upscale a CVD process from the lab to the fab, large area uniformity and high run-to-run reproducibility are needed. We show by a combination of experiments and gas phase kinetics modeling that the combinations of Si and C precursors with the most well-matched gas phase chemistry kinetics gives the largest area of of homoepitaxial growth of SiC. Comparing CH4, C2H4 and C3H8 as carbon precursors to the SiF4 silicon precursor, CH4 with the slowest kinetics renders the most robust CVD chemistry with large area epitaxial growth and low temperature sensitivity. We further show by quantum chemical modeling how the surface chemistry is impeded by the presence of F in the system which limits the amount of available surface sites for the C to adsorb.

  • 334.
    Stenberg, Pontus
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Janzén, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Pedersen, Henrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Incorporation of dopants in epitaxial SiC layers grown with fluorinated CVD chemistry2017Inngår i: Journal of Vacuum Science & Technology B, ISSN 1071-1023, E-ISSN 1520-8567, Vol. 35, nr 3, artikkel-id 031201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Fluorinated chemistry in chemical vapor deposition (CVD) of silicon carbide (SiC) with SiF4 as Si precursor has been shown to fully eliminate the formation of silicon clusters in the gas phase, making SiF4 an interesting Si precursor. However, before a fluorinated CVD chemistry can be adopted, the effect of fluorine on the dopant incorporation must be understood since dopant incorporation is of paramount importance in semiconductor manufacturing. Here, the authors present dopant incorporation studies for n-type doping with N using N-2 and p-type doping with Al using TMAl in fluorinated CVD of homoepitaxial SiC. The precursors used were SiF4 as Si precursor and the source of F together with CH4 as C precursor. The authors find that it is possible to control the doping in SiC epitaxial layers when using a fluorinated CVD chemistry for both n- and p-type materials using the C/Si ratio as in standard SiC CVD. However, large area doping uniformity seems to be a challenge for a fluorinated CVD chemistry, most likely due to the very strong Si-F and Al-F bonds. (C) 2017 American Vacuum Society.

  • 335.
    Stenberg, Pontus
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Sukkaew, Pitsiri
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Farkas, Ildiko
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Kordina, Olof
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Janzén, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Danielsson, Örjan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Pedersen, Henrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Silicon Chemistry in Fluorinated Chemical Vapor Deposition of Silicon Carbide2017Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 121, nr 5, s. 2711-2720Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The use of chlorinated chemical vapor deposition (CVD) chemistry for growth of homoepitaxial layers of silicon carbide (SiC) has diminished the problem of homogenous gas phase nucleation, mainly the formation of Si droplets, in CVD of SiC by replacing Si-Si bonds with stronger Si-Cl bonds. Employing the even stronger Si-F bond could potentially lead to an even more efficient CVD chemistry, however, fluorinated chemistry is very poorly understood for SiC CVD. Here, we present studies of the poorly understood fluorinated CVD chemistry for homoepitaxial SiC layers using SiF4 as Si precursor. We use a combination of experimental growth studies, thermal equilibrium calculations of gas phase composition and quantum chemical computations (i.e. hybrid density functional theory) of the surface chemistry to probe the silicon chemistry in the CVD process. We show that while growth rates on the order of 35 µm/h can be achieved with a fluorinated chemistry, the deposition chemistry is very sensitive to the mass flows of the precursors and not as robust as the chlorinated CVD chemistry which routinely yields 100 µm/h over wide conditions. By using the position for the onset of epitaxial growth along the gas flow direction as a measurable, together with modeling, we conclude that SiF is the main Si growth species with SiHF as a minor Si species contributing to growth.

  • 336.
    Storr, Tim
    et al.
    Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
    Dyrager, Christine
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
    Pinto Vieira, Rafael
    Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada(1);Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil(3);CAPES Foundation, Ministry of Education of Brazil, 70040-020 Brasília, DF, Brazil.
    Nyström, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Synthesis and evaluation of benzothiazole-triazole and benzothiadiazole-triazole scaffolds as potential molecular probes for amyloid-β aggregation.2017Inngår i: New Journal of Chemistry, ISSN 1144-0546, E-ISSN 1369-9261, Vol. 41, nr 4, s. 8s. 1566-1573Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small-molecule ligands that bind to misfolded protein aggregates are essential tools for the study and detection of pathological hallmarks in neurodegenerative disorders, such as Alzheimer's disease (AD). In the present study, three compounds (one benzothiazole-triazole, L1, and two benzothiadiazole-triazoles, L2 and L3) were synthesized via a modular approach (azide–alkyne cycloaddition) and evaluated as potential ligands for amyloid-β (Aβ) aggregates. The binding to amyloid-like fibrils, generated from recombinant Aβ1–42, were studied and the binding specificity to amyloid deposits was evaluated in brain sections from transgenic mice with AD pathology. All three derivatives showed significant reduced emission in the presence of recombinant Aβ1–42 amyloid fibrils. In addition, the observed binding to Aβ deposits in tissue sections suggests that the benzothiazole-triazole and benzothiadiazole-triazole structures are promising molecular scaffolds that can be modified for binding to specific protein aggregates. [ABSTRACT FROM AUTHOR]

  • 337.
    Strömqvist, Malin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Development of quantitative methods for the determination of vemurafenib and its metabolites in human plasma2014Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Vemurafenib is a potent serine/threonine kinase inhibitor and is registered as Zelboraf® for the treatment of metastatic melanomas harboring BRAFV600E mutations. There is a large individual variation in drug response and the side effects observed among patients treated with Zelboraf® has proven to be severe. 

    LC-MS/MS methods were developed to measure vemurafenib and its metabolites in human plasma for prediction of treatment outcome and side effects in order to individualize treatment with Zelboraf®

    A novel, rapid quantification method was developed for vemurafenib using a stable isotope labeled internal standard. The method was validated according to international guidelines with regard to calibration range, accuracy, precision, carry-over, dilution integrity, selectivity, matrix effects, recovery and stability. All parameters met the set acceptance criteria. 

    The first method suitable for quantifying vemurafenib metabolites in human plasma is presented. Lacking commercially available reference substances, human liver microsomes were used to produce the metabolites. In patient samples at steady-state five previously in vitro identified metabolites were quantified for the first time. 

  • 338.
    Sukkaew, Pitsiri
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Danielsson, Örjan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Kordina, Olle
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Janzén, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Ab Initio Study of Growth Mechanism of 4H-SiC: Adsorption and Surface Reaction of C2H2, C2H4, CH4, and CH32017Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 121, nr 2, s. 1249-1256Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Silicon carbide is a semiconductor material with ideal properties for high-temperature and high-power applications. The epitaxial layer fabrication Is usually performed using chemical vapor deposition (CVD) under a hydrogen rich atmosphere and high temperature. At such conditions the surface of the growing layer is expected to be passivatecl,by the abundantly present hydrogen. In this work, we use quantum chemical density functional theory (B3LYP and M06-2X) and transition state theory to study surface reactions related to the deposition of carbon on the (0001) surface of 4H-SiC. We show that it is unlikely for an adsorption to occur on a passivated, site unless the hydrogen termination is removed. We propose that unterminated sites can be effectively created during the CVD by an abstraction process. We provide details of the adsorption process of active carbon species, namely CH3, CH4, C2H2, and C2H4 gases, and their subsequent surface reactions such as desorption, abstraction of neighboring surface, hydrogens and dinner formation. The reaction rates and sticking coefficients are provided for the temperature range of 298-2500 K. Finally, entire reaction paths from adsorptions to stable surface products are presented and discussed.

  • 339.
    Sukkaew, Pitsiri
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Danielsson, Örjan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Growth Mechanism of SiC CVD: Surface Etching by H-2, H Atoms, and HCl2018Inngår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 122, nr 9, s. 2503-2512Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Silicon carbide is a wide bandgap semiconductor with unique characteristics suitable for high temperature and high power applications. Fabrication of SiC epitaxial layers is usually performed using chemical vapor deposition (CVD). In this work, we use quantum chemical density functional theory (B3LYP and M06-2X) and transition state theory to study etching reactions occurring on the surface of SiC during CVD in order to combine etching effects to the surface kinetic model for SiC CVD. H-2, H atoms and HCl gases are chosen in the study as the most likely etchants responsible for surface etching. We consider etchings of four surface sites, namely CH3(ads), SiH3CH2(ads), SiH2(CH2)(2)(ads), and SiH(CH2)(3)(ads), which represent four subsequent snapshots of the surface as the growth proceeds. We find that H atoms are the most effective etchant on CH3(ads) and SiH3CH2(ads), which represent the first and second steps of the growth. HCl and H-2 are shown to be much less effective than H atoms and produce the etching rate constants which are, similar to 10(4) and similar to 10(7) times slower. In comparison to CH3(ads), SiH3CH2(ads) is shown to be less stable and more susceptible to etchings. Unlike the first and second steps of the growth, the third and fourth steps (i.e., SiH2(CH2)(2)(ads) and SiH(CH2)(3)(ads)) are stable and much less susceptible to any of the three etchants considered. This implies that the growth species become more stable via forming Si-C bonds with another surface species. The formation of a larger surface cluster thus helps stabilizing the growth against etchings.

  • 340.
    Sukkaew, Pitsiri
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Kalered, Emil
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Janzén, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Kordina, Olle
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Danielsson, Örjan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Growth Mechanism of SiC Chemical Vapor Deposition: Adsorption and Surface Reactions of Active Si Species2018Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 122, nr 1, s. 648-661Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Silicon carbide is a wide bandgap semiconductor ideally suitable for high temperature and high power applications. An active SiC layer is usually fabricated using halide-assisted chemical vapor deposition (CVD). In this work, we use quantum chemical density functional theory (B3LYP and M06-2X) and transition state theory to study adsorptions of active Si species in the CVD process on both the Si face and the C face of 4H-SiC. We show that adsorptions of SiCl, SiCl2, SiHCl, SiH, and SiH2 on the Si face likely occur on a methylene site, CH2(ads), but the processes are thermodynamically less favorable than their reverse or desorptions. Nevertheless, the adsorbed products become stabilized with the help of subsequent surface reactions to form a larger cluster. These cluster formation reactions happen with rates that are fast enough to compete with the desorption processes. On the C face, the adsorptions likely occur on a surface site terminated by a dangling bond, *(ads), and produce the products which are thermodynamically stable. Lastly, we present the Gibbs free energies of adsorptions of Si atoms, SiX, SiX2, and SiHX, for X being F and Br. Adsorptions of Si atoms are shown to be the most thermodynamically favorable among all the species in the study. Among the halide-containing species, the Gibbs free energies (ARG) from smallest to largest are observed in the adsorptions of SiX, SiHX, and SiX2, for X being the halides. The results in this study suggest that the major Si contributors in the SiC CVD process are Si atoms, SiX (for X being the halide) and SiH.

  • 341.
    Sukkaew, Pitsiri
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska högskolan.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Danielsson, Örjan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska högskolan.
    Kordina, Olle
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska högskolan.
    Janzén, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska högskolan.
    Revisiting the Thermochemical Database of Si-C-H System Related to SiC CVD Modeling2014Inngår i: SILICON CARBIDE AND RELATED MATERIALS 2013, PTS 1 AND 2, Trans Tech Publications , 2014, Vol. 778-780, s. 175-178Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Chemical vapor deposition of silicon carbide (SiC-CVD) is a complex process involving a Si-C-H system wherein a large number of reaction steps occur. To simulate such a system requires knowledge of thermochemical and transport properties of all the species involved in the process. The accuracy of this information consequently becomes a crucial factor toward the correctness of the outcome prediction. In this work, the thermochemical data for several important growth species for SiC CVD using the SiH4/CxHy/H-2 system has been calculated. For the most part an excellent agreement is seen with previously reported data, however for the organosilicons a larger deviation is detected and in particular for the CH3SiH2SiH species which shows a stark deviation from the CHEMKIN database. Impacts of the improved database on SiC CVD modeling are presented in computational fluid dynamics calculations, manifesting the significance of an accurate database.

  • 342.
    Sukkaew, Pitsiri
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Kordina, Olle
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Janzén, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Danielsson, Örjan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Halvledarmaterial. Linköpings universitet, Tekniska fakulteten.
    Thermochemical Properties of Halides and Halohydrides of Silicon and Carbon2016Inngår i: ECS Journal of Solid State Science and Technology, ISSN 2162-8769, E-ISSN 2162-8777, Vol. 5, nr 2, s. P27-P35Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Atomization energies, enthalpies of formation, entropies as well as heat capacities of the SiHnXm and CHnXm systems, with X being F, Cl and Br, have been studied using quantum chemical calculations. The Gaussian-4 theory (G4) and Weizman-1 theory as modified by Barnes et al. 2009 (W1RO) have been applied in the calculations of the electronic, zero point and thermal energies. The effects of low-lying electronically excited states due to spin orbit coupling were included for all atoms and diatomic species by mean of the electronic partition functions derived from the experimental or computational energy splittings. The atomization energies, enthalpies of formation, entropies and heat capacities derived from both methods were observed to be reliable. The thermochemical properties in the temperature range of 298-2500 K are provided in the form of 7-coefficient NASA polynomials. (C) The Author(s) 2015. Published by ECS. All rights reserved.

  • 343.
    Svedhem, Sofia
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Enander, Karin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Karlsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Sjöbom, Hans
    Biacore AB, Uppsala, Sweden.
    Liedberg, Bo
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Löfås, Stefan
    Biacore AB, Uppsala, Sweden.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Sjöstrand, Sven-Erik
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Stefan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Carlsson, Uno
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Subtle differences in dissociation rates of interactions between destabilized human carbonic anhydrase II mutants and immobilized benzenesulfonamide inhibitors probed by a surface plasmon resonance biosensor2001Inngår i: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 296, nr 2, s. 188-196Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of commercial biosensors based on surface plasmon resonance has made possible careful characterization of biomolecular interactions. Here, a set of destabilized human carbonic anhydrase II (HCA II) mutants was investigated with respect to their interaction kinetics with two different immobilized benzenesulfonamide inhibitors. Point mutations were located distantly from the active site, and the destabilization energies were up to 23 kJ/mol. The dissociation rate of wild-type HCA II, as determined from the binding to the inhibitor with higher affinity, was 0.019 s−1. For the mutants, dissociation rates were faster (0.022–0.025 s−1), and a correlation between faster dissociation and a high degree of destabilization was observed. We interpreted these results in terms of increased dynamics of the tertiary structures of the mutants. This interpretation was supported by entropy determinations, showing that the entropy of the native structure significantly increased upon destabilization of the protein molecule. Our findings demonstrate the applicability of modern biosensor technology in the study of subtle details in molecular interaction mechanisms, such as the long-range effect of point mutations on interaction kinetics.

  • 344.
    Tegenfeldt, J
    et al.
    University of Uppsala.
    Ojamäe, Lars
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan. University of Uppsala.
    Svensson, C
    University of Lund.
    Disorder dynamics in solid 9‐hydroxyphenalenone1991Inngår i: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 95, s. 2696-2701Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    1 H nuclear magnetic resonance(NMR)spectra and spin‐lattice relaxation data as well as 1 H decoupled 13C spectra have been utilized to study the dynamics of the molecular disorder in solid 9‐hydroxyphenalenone. In the room‐temperature phase—stable between 255 and 380 K—the protonspectrum is narrowed compared to the spectrum of a static structure. This is consistent with a dynamically disordered structure where one of the two nonequivalent molecules reorients rapidly between its two possible equilibrium orientations. The proton spin‐lattice relaxation has a maximum of 7.2 s−1 in the same phase at about 355 K, in close agreement with a value of 7.6 s−1 calculated from the dynamical disorder model. The 1 H decoupled 13C powderspectrum in the room‐temperature phase is also consistent with this picture. Above the 385 K phase transition, the 13C powderspectrum is approaching axial symmetry, proving that all molecules reorient rapidly in that phase.

  • 345.
    Tengdelius, Mattias
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Fucoidan-Mimetic Glycopolymers: Synthesis and Biomedical Applications2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The marine polysaccharide fucoidan has demonstrated several interesting biological properties, for instance being antiviral, anticoagulant, anti-inflammatory, anticancer, and platelet activating. Many of these properties are desirable for various biomedical applications. Yet, there are few reports on fucoidan being used in such applications. The reasons for this are primarily the heterogeneity and low structural reproducibility of fucoidan.

    This thesis describes the synthesis of polymers with pendant saccharides bearing the key structural features of fucoidan. These glycopolymers were synthesized via different radical polymerization techniques yielding polymers of different chain lengths and dispersity. These glycopolymers showed antiviral and platelet activating properties similar to those of natural fucoidan, thus making them fucoidan-mimetic glycopolymers. However, compared to fucoidan from natural sources, the fucoidan-mimetic glycopolymers had homogeneous and reproducible structures making them suitable for biomedical applications.

    Further studies demonstrated that platelet activation, caused by these glycopolymers, showed dose-response curves almost identical to fucoidan. The platelet activation was induced via intracellular signaling and caused platelet surface changes similar to those of fucoidan. Fucoidan-mimetic glycopolymers can therefore be used as unique biomolecular tools for studying the molecular and cellular responses of human platelets.

    Fucoidan-mimetic glycopolymers generally assert their antiviral activity by blocking viral entry to host cells, thus inhibiting spreading of the viral infection but not acting virucidal, i.e. not killing the viruses. Introduction of hydrophobic groups to the polymer’s chain ends improved the antiviral properties significantly and is an important step towards yielding glycopolymers with virucidal properties.

    The fucoidan-mimetic glycopolymers were also applied as capping agents when synthesizing gold nanoparticles. These fucoidan-mimetic glycopolymer coated gold nanoparticles showed improved colloidal stability compared to uncapped gold nanoparticles. Furthermore, the nanoparticles also demonstrated selective cytotoxicity against a human colon cancer cell line over fibroblast cells.

    Delarbeid
    1. Synthesis and biological evaluation of fucoidan-mimetic glycopolymers through cyanoxyl-mediated free-radical polymerization
    Åpne denne publikasjonen i ny fane eller vindu >>Synthesis and biological evaluation of fucoidan-mimetic glycopolymers through cyanoxyl-mediated free-radical polymerization
    Vise andre…
    2014 (engelsk)Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, nr 7, s. 2359-2368Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The sulfated marine polysaccharide fucoidan has been reported to have health benefits ranging from antivirus and anticancer properties to modulation of high blood pressure. Hence, they could enhance the biological function of materials for biomedical applications. However, the incorporation of fucoidan into biomaterials has been difficult, possibly due to its complex structure and lack of suitable functional groups for covalent anchoring to biomaterials. We have developed an approach for a rapid synthesis of fucoidanmimetic glycopolymer chains through cyanoxyl-mediated free-radical polymerization, a method suitable for chain-end functionalizing and subsequent linkage to biomaterials. The resulting sulfated and nonsulfated methacrylamido alpha-L-fucoside glycopolymers fucoidan-mimetic properties were studied in HSV-1 infection and platelet activation assays. The sulfated glycopolymer showed similar properties to natural fucoidan in inducing platelet activation and inhibiting HSV-1 binding and entry to cells, thus indicating successful syntheses of fucoidan-mimetic glycopolymers.

    sted, utgiver, år, opplag, sider
    American Chemical Society (ACS), 2014
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-109382 (URN)10.1021/bm5002312 (DOI)000339090500003 ()24813544 (PubMedID)
    Tilgjengelig fra: 2014-08-15 Laget: 2014-08-15 Sist oppdatert: 2017-12-05bibliografisk kontrollert
    2. Synthesis and anticancer properties of fucoidan-mimetic glycopolymer coated gold nanoparticles
    Åpne denne publikasjonen i ny fane eller vindu >>Synthesis and anticancer properties of fucoidan-mimetic glycopolymer coated gold nanoparticles