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  • 251.
    Doak, Bradley C.
    et al.
    Monash Univ, Dept Med Chem, MIPS, 381 Royal Parade, Parkville, Vic 3052, Australia.
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Cyclophilin Succumbs to a Macrocyclic Chameleon2018Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, nr 21, s. 9469-9472Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Targets that have large and groove-shaped binding sites, such as cyclophilin, are difficult to drug with small molecules. Macrocycles of natural product origin can be ideal starting points for such targets as illustrated by the transformation of sanglifehrin A into an orally bioavailable potential candidate drug. Optimization benefits from development of convergent, modular synthetic routes in combination with structure and property based methods for lead optimization.

  • 252.
    Doak, Bradley C.
    et al.
    Monash Univ, MIPS, Dept Med Chem, Parkville, Vic, Australia..
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Drug discovery beyond the rule of 5-Opportunities and challenges2017Inngår i: Expert Opinion on Drug Discovery, ISSN 1746-0441, E-ISSN 1746-045X, Vol. 12, nr 2, s. 115-119Artikkel i tidsskrift (Fagfellevurdert)
  • 253.
    Doak, Bradley C
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Zheng, Jie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Dobritzsch, Doreen
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets.2016Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, nr 6, s. 2312-2327Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To improve discovery of drugs for difficult targets, the opportunities of chemical space beyond the rule of 5 (bRo5) were examined by retrospective analysis of a comprehensive set of structures for complexes between drugs and clinical candidates and their targets. The analysis illustrates the potential of compounds far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.

  • 254.
    Doak, Bradley Croy
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Over, Bjorn
    Giordanetto, Fabrizio
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates2014Inngår i: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 21, nr 9, s. 1115-1142Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compounds with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clinical candidates with molecular weight (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramolecular hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets.

  • 255.
    Doak, Bradley
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Over, Bjorn
    Giordanetto, Fabrizio
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Macrocyclic drugs and clinical candidates - what are the limits of oral bioavailability?2014Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Artikkel i tidsskrift (Annet vitenskapelig)
  • 256.
    Dobritzsch, Doreen
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Wang, Huaming
    Schneider, Gunter
    Yu, Shukun
    Structural and functional characterization of ochratoxinase, a novel mycotoxin-degrading enzyme2014Inngår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 462, nr 3, s. 441-452Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ochratoxin, with ochratoxin A as the dominant form, is one of the five major mycotoxins most harmful to humans and animals. It is produced by Aspergillus and Penicillium species and occurs in a wide range of agricultural products. Detoxification of contaminated food is a challenging health issue. In the present paper we report the identification, characterization and crystal structure (at 2.2 angstrom) of a novel microbial ochratoxinase from Aspergillus niger. A putative amidase gene encoding a 480 amino acid polypeptide was cloned and homologously expressed in A. niger. The recombinant protein is N-terminally truncated, thermostable, has optimal activity at pH similar to 6 and 66 degrees C, and is more efficient in ochratoxin A hydrolysis than carboxypeptidase A and Y, the two previously known enzymes capable of degrading this mycotoxin. The subunit of the homo-octameric enzyme folds into a two-domain structure characteristic of a metal dependent amidohydrolase, with a twisted TIM (triosephosphateisomerase)-barrel and a smaller beta-sandwich domain. The active site contains an aspartate residue for acid base catalysis, and a carboxylated lysine and four histidine residues for binding of a binuclear metal centre.

  • 257.
    Dollevoet, Kim
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    C-H activation of indoles catalyzed by a ruthenium-complex: Synthesis of 2-3-hexene-1-(pyrimidin-2-yl)1H-indole2013Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 258. Dominguez, Jose L.
    et al.
    Gossas, Thomas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Carmen Villaverde, M.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Sussman, Fredy
    Experimental and 'in silico' analysis of the effect of pH on HIV-1 protease inhibitor affinity: Implications for the charge state of the protein ionogenic groups2012Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 20, nr 15, s. 4838-4847Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pH dependence of the HIV-1 protease inhibitor affinity was studied by determining the interaction kinetics of a series of inhibitors at three pH values by surface plasmon resonance (SPR) biosensor analysis. The results were rationalized by molecular mechanics based protocols that have as a starting point the structures of the HIV-1 protease inhibitor complexes differing in the protonation states as predicted by our calculations. The SPR experiments indicate a variety of binding affinity pH dependencies which are rather well reproduced by our simulations. Moreover, our calculations are able to pinpoint the possible changes in the charged state of the protein binding site and of the inhibitor that underlie the observed effects of the pH on binding affinity. The combination of SPR and molecular mechanics calculations has afforded novel insights into the pH dependence of inhibitor interactions with their target. This work raises the possibility of designing inhibitors with different pH binding affinity profiles to the ones described here.

  • 259. Dourado, Daniel F. A. R.
    et al.
    Fernandes, Pedro Alexandrino
    Mannervik, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Ramos, Maria Joao
    Isomerization of Delta(5)-Androstene-3,17-dione into Delta(4)-Androstene-3, 17-dione Catalyzed by Human Glutathione Transferase A3-3: A Computational Study Identifies a Dual Role for Glutathione2014Inngår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 118, nr 31, s. 5790-5800Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glutathione transferases (GSTs) are important enzymes in the metabolism of electrophilic xenobiotic and endobiotic toxic compounds. In addition, human GST A3-3 also catalyzes the double bond isomerization of Delta 5-androstene-3,17-dione (Delta(5)-AD) and Delta(5)-pregnene-3,20-dione (Delta(5)-PD), which are the immediate precursors of testosterone and progesterone. In fact, GST A3-3 is the most efficient human enzyme known to exist in the catalysis of these reactions. In this work, we have used density functional theory (DFT) calculations to propose a refined mechanism for the isomerization of Delta(5)-AD catalyzed by GST A3-3. In this mechanism the glutathione (GSH) thiol and Tyr9 catalyze the proton transfer from the Delta(5)-AD C4 atom to the Delta(5)-AD C6 atom, with a rate limiting activation energy of 15.8 kcal.mol(-1). GSH has a dual function, because it is also responsible for stabilizing the negative charge that is formed in the 03 atom of the enolate intermediate. The catalytic role of Tyr9 depends on significant conformational rearrangements of its side chain. Neither of these contributions to catalysis has been observed before. Residues Phe10, Leul11, Ala 208, and Ala 216 complete the list of the important catalytic residues. The mechanism detailed here is based on the GST A3-3:GSH:Delta(4)-AD crystal structure and is consistent with all available experimental data.

  • 260.
    Dourado, Daniel F. A. R.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Fernandes, Pedro Alexandrino
    Ramos, Maria Joao
    Mannervik, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Mechanism of Glutathione Transferase P1-1-Catalyzed Activation of the Prodrug Canfosfamide (TLK286, TELCYTA)2013Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 52, nr 45, s. 8069-8078Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Canfosfamide (TLK286, TELCYTA) is a prodrug that upon activation by glutathione transferase P1-1 (GST P1-1) yields an anticancer alkylating agent and a glutathione derivative. The rationale underlying the use of TLK286 in chemotherapy is that tumor cells overexpressing GST P1-1 will be locally exposed to the released alkylating agent with limited collateral toxicity to the surrounding normal tissues. TLK286 has demonstrated clinical effects in phase II and III clinical trials for the treatment of malignancies, such as ovarian cancer, nonsmall cell lung cancer, and breast cancer, as a single agent and in combination with other chemotherapeutic agents. In spite of these promising results, the detailed mechanism of GST P1-1 activation of the prodrug has not been elucidated. Here, we propose a mechanism for the TLK286 activation by GST P1-1 on the basis of density functional theory (DFT) and on potential of mean force (PMF) calculations. A catalytic water molecule is instrumental to the activation by forming a network of intermolecular interactions between the active-site Tyr7 hydroxyl and the sulfone and COO- groups of TLK286. The results obtained are consistent with the available experimental kinetic data and provide an atomistic understanding of the TLK286 activation mechanism.

  • 261.
    Drevinskas, Tomas
    et al.
    Vytautas Magnus Univ, Fac Nat Sci, Instrumental Anal Open Access Ctr, Vileikos Str 8, LT-44404 Kaunas, Lithuania;Vytautas Magnus Univ, Fac Informat, Dept Syst Anal, Vileikos Str 8, LT-44404 Kaunas, Lithuania.
    Maruska, Audrius
    Vytautas Magnus Univ, Fac Nat Sci, Instrumental Anal Open Access Ctr, Vileikos Str 8, LT-44404 Kaunas, Lithuania.
    Telksnys, Laimutis
    Vytautas Magnus Univ, Fac Informat, Dept Syst Anal, Vileikos Str 8, LT-44404 Kaunas, Lithuania;Vilnius Univ, Inst Data Sci & Digital Technol, Gostauto 12, LT-01108 Vilnius, Lithuania.
    Hjertén, Stellan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Stankevicius, Mantas
    Vytautas Magnus Univ, Fac Nat Sci, Instrumental Anal Open Access Ctr, Vileikos Str 8, LT-44404 Kaunas, Lithuania.
    Lelesius, Raimundas
    Lithuanian Univ Hlth Sci, Vet Acad, Dept Vet Pathobiol, Tilzes Str 18, LT-47181 Kaunas, Lithuania;Lithuanian Univ Hlth Sci, Vet Acad, Inst Microbiol & Virol, Tilzes Str 18, LT-47181 Kaunas, Lithuania.
    Mickiene, Ruta
    Vytautas Magnus Univ, Fac Nat Sci, Instrumental Anal Open Access Ctr, Vileikos Str 8, LT-44404 Kaunas, Lithuania.
    Karpovaite, Agneta
    Lithuanian Univ Hlth Sci, Vet Acad, Dept Vet Pathobiol, Tilzes Str 18, LT-47181 Kaunas, Lithuania.
    Salomskas, Algirdas
    Lithuanian Univ Hlth Sci, Vet Acad, Dept Vet Pathobiol, Tilzes Str 18, LT-47181 Kaunas, Lithuania.
    Tiso, Nicola
    Vytautas Magnus Univ, Fac Nat Sci, Instrumental Anal Open Access Ctr, Vileikos Str 8, LT-44404 Kaunas, Lithuania.
    Ragazinskiene, Ona
    Vytautas Magnus Univ, Kaunas Bot Garden, Sect Med Plants, ZE Zilibero Str 6, LT-46324 Kaunas, Lithuania.
    Chromatographic Data Segmentation Method: A Hybrid Analytical Approach for the Investigation of Antiviral Substances in Medicinal Plant Extracts2019Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 91, nr 1, s. 1080-1088Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The methodology described in this article will significantly reduce the time required for understanding the relations between chromatographic data and bioactivity assays. The methodology is a hybrid of hypothesis-based and data driven scientific approaches. In this work, a novel chromatographic data segmentation method is proposed, which demonstrates the capability of finding what volatile substances are responsible for antiviral and cytotoxic effects in the medicinal plant extracts. Up until now, the full potential of the separation methods has not been exploited in the life sciences. This was due to the lack of data ordering methods capable of adequately preparing the chromatographic information. Furthermore, the data analysis methods suffer from multidimensionality, requiring a large number of investigated data points. A new method is described for processing any chromatographic information into a vector. The obtained vectors of highly complex and different origin samples can be compared mathematically. The proposed method, efficient with relatively small sized data sets, does not suffer from multidimensionality. In this novel analytical approach, the samples did not need fractionation and purification, which is typically used in hypothesis-based scientific research. All investigations were performed using crude extracts possessing hundreds of phyto-substances. The antiviral properties of medicinal plant extracts were investigated using gas chromatography-mass spectrometry, antiviral tests, and proposed data analysis methods. The findings suggested that (i) beta-cis-caryophyllene, linalool, and eucalyptol possess antiviral activity, while (ii) thujones do not, and (iii) alpha-thujone, beta-thujone, cis-p-menthan-3-one, and estragole show cytotoxic effects.

  • 262.
    Dubois, Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ronquist, K Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ek, Bo
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Ronquist, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Proteomic profiling of detergent resistant membranes (lipid rafts) of prostasomes2015Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 14, nr 11, s. 3015-3022Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prostasomes are exosomes derived from prostate epithelial cells through exocytosis by multivesicular bodies. Prostasomes have a bilayered membrane and readily interact with sperm. The membrane lipid composition is unusual with a high contribution of sphingomyelin at the expense of phosphatidylcholine and saturated and monounsaturated fatty acids are dominant. Lipid rafts are liquid-ordered domains that are more tightly packed than the surrounding non-raft phase of the bilayer. Lipid rafts are proposed to be highly dynamic, submicroscopic assemblies that float freely within the liquid disordered membrane bilayer and some proteins preferentially partition into the ordered raft domains. We asked the question whether lipid rafts do exist in prostasomes and, if so, which proteins might be associated with them. Prostasomes of density range 1.13-1.19g/mL were subjected to density gradient ultracentrifugation in sucrose fabricated by phosphate buffered saline (PBS) containing 1% Triton X-100 with capacity for banding at 1.10g/mL, i.e. the classical density of lipid rafts. Prepared prostasomal lipid rafts (by gradient ultracentrifugation) were analyzed by mass spectrometry and electron microscopy. The clearly visible band on top of 1.10g/mL sucrose in the Triton X-100 containing gradient was subjected to LC-MS/MS and more than 370 lipid raft associated proteins were identified. Several of them were involved in intraluminal vesicle formation, e.g. tetraspanins, ESCRTs and Ras-related proteins. This is the first comprehensive LC-MS/MS profiling of proteins in lipid rafts derived from exosomes. Data are available via ProteomeXchange with identifier PXD002163.

  • 263.
    Duehrkop, Claudia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Leneweit, Gero
    Heyder, Christoph
    Fromell, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Ekdahl, Kristina N
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Nilsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Development and characterization of an innovtive heparin coating to stabilize and protect liposomes against adverse immune reactions2016Inngår i: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 141, s. 576-583Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Liposomes have been recognized as excellent drug delivery systems, but when they come in direct contact with different blood components they may trigger an immediate activation of the innate immune system. The aim of the present study was to produce long-circulating, blood-compatible liposomes by developing a construct of liposomes covered by a novel unique heparin complex (CHC; 70 heparin molecules per complex) to avoid recognition by the innate immune system. Unilamellar, cationic liposomes were produced by hand extrusion through a 100-nm polycarbonate membrane. Coating of liposomes with the macromolecular CHC was accomplished by electrostatic interactions. Dynamic light scattering as well as QCM-D measurements were used to verify the electrostatic deposition of the negatively charged CHC to cationic liposomes. The CHC-coated liposomes did not aggregate when in contact with lepirudin anti coagulated plasma. Unlike previous attempts to coat liposomes with heparin, this technique produced freely moveable heparin strands sticking out from the liposome surface, which exposed AT binding sites reflecting the anticoagulant potentials of the liposomes. In experiments using lepirudin-anticoagulated plasma, CHC-coated liposomes, in contrast to non-coated control liposomes, did not activate the complement system, as evidenced by low C3a and sC5b-9 generation and reduced leakage from the liposomes. In conclusion, we show that liposomes can be successfully coated with the biopolymer CHC, resulting in biocompatible and stable liposomes that have significant application potential.

  • 264.
    Duncan, Kyle D.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Andersson, Ingela
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Oversampling To Improve Spatial Resolution for Liquid Extraction Mass Spectrometry Imaging2018Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, nr 4, s. 2451-2455Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Liquid extraction mass spectrometry imaging (MSI) experiments provide users with direct analysis of biological surfaces with minimal sample preparation. Until now, much of the effort to increase spatial resolution for MSI with liquid extraction techniques has focused on reducing the size of the sampling area. However, this can be experimentally challenging. Here, we present oversampling as a simple alternative to increase the spatial resolution using nanospray desorption electrospray ionization (nano-DESI) MSI. By imaging partial rat spinal cord tissue sections, two major concerns with oversampling are addressed: whether endogenous molecules are significantly depleted from repeated sampling events and whether analytes are redistributed as a result of oversampling. In depth examination of ion images for representative analytes show that depletion and redistribution do not affect analyte localization in the tissue sample. Nano-DESI MSI experiments using three times oversampling provided higher spatial resolution, allowing the observation of features not visible with undersampling. Although proper care must be taken to ensure that oversampling will work in specific applications, we envision oversampling as a simple approach to increase image quality for liquid extraction MSI techniques.

  • 265.
    Duncan, Kyle D.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergman, Hilde-Marlene
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Andersson, Ingela
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    A pneumatically assisted nanospray desorption electrospray ionization source for increased solvent versatility and enhanced metabolite detection from tissue2017Inngår i: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 142, nr 18, s. 3424-3431Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nanospray desorption electrospray ionization (nano-DESI) has been established as a powerful technique for mass spectrometry imaging (MSI) of biomolecules from tissue samples. The direct liquid extraction of analytes from a surface at ambient pressure negates the need for significant sample preparation or matrix application. Although many recent studies have applied nano-DESI to new and exciting applications, there has not been much work in the development and improvement of the nano-DESI source. Here, we incorporate a nebulizer to replace the self-aspirating secondary capillary in the conventional nano-DESI setup, and characterize the device by use of rat kidney tissue sections. We find that the pneumatically assisted nano-DESI device offers improved sensitivity for metabolite species by 1-3 orders of magnitude through more complete desolvation and reduced ionization suppression. Further, the pneumatically assisted nano-DESI device reduces the dependence on probe-to-surface distance and enables sampling and imaging using pure water as the nano-DESI solvent. This provides exclusive detection and imaging of many highly polar endogenous species. Overall, the developed pneumatically assisted nano-DESI device provides more versatile solvent selection and an increased sensitivity for metabolites, which generates ion images of higher contrast - allowing for more intricate studies of metabolite distribution.

  • 266.
    Duncan, Kyle D.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Fang, Ru
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Yuan, Jia
    Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA.
    Chu, Rosalie K.
    Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA.
    Dey, Sudhansu K.
    Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA.
    Burnum-Johnson, Kristin E.
    Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA.
    Lanekoff, Ingela
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Quantitative Mass Spectrometry Imaging of Prostaglandins as Silver Ion Adducts with Nanospray Desorption Electrospray Ionization2018Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, nr 12, s. 7246-7252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prostaglandins (PG) are an important class of lipid biomolecules that are essential in many biological processes, including inflammation and successful pregnancy. Despite a high bioactivity, physiological concentrations are typically low, which makes direct mass spectrometric analysis of endogenous PG species challenging. Consequently, there have not been any studies investigating PG localization to specific morphological regions in tissue sections using mass spectrometry imaging (MSI) techniques. Herein, we show that silver ions, added to the solvent used for nanospray desorption electrospray ionization (nano-DESI) MSI, enhances the ionization of PGs and enables nano-DESI MSI of several species in uterine tissue from day 4 pregnant mice. It was found that detection of [PG + Ag](+) ions increased the sensitivity by similar to 30 times, when compared to [PG - H](-) ions. Further, the addition of isotopically labeled internal standards enabled generation of quantitative ion images for the detected PG species. Increased sensitivity and quantitative MSI enabled the first proof-of-principle results detailing PG localization in mouse uterus tissue sections. These results show that PG species primarily localized to cellular regions of the luminal epithelium and glandular epithelium in uterine tissue. Further, this study provides a unique scaffold for future studies investigating the PG distribution within biological tissue samples.

  • 267.
    Duncan, Kyle D.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Fyrestam, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lanekoff, Ingela
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Advances in mass spectrometry based single-cell metabolomics2019Inngår i: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 144, nr 3, s. 782-793Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Metabolomics has grown into a prominent field contributing to the molecular understanding of complex biological processes in both health and disease. Furthermore, single-cells are known to display metabolic differences between seemingly homogeneous populations of cells. Single-cell metabolomics attempts to analyze many cellular metabolites from single cells to understand phenotypic heterogeneity, which is a significant challenge due to the low analyte abundances and limited sample volumes. Label-free metabolite detection can be achieved with mass spectrometry, which is capable of simultaneously analyzing hundreds of metabolites. Herein, we review the recent advances in mass spectrometry based single-cell metabolomics, highlighting the current state-of-the-art within the last three years, and identify the challenges to move the field forward.

  • 268.
    Duncan, Kyle D.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lanekoff, Ingela
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Spatially Defined Surface Sampling Capillary Electrophoresis Mass Spectrometry2019Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 91, nr 12, s. 7819-7827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Capillary electrophoresis mass spectrometry (CE-MS) is an established technique for targeted and untargeted analysis of metabolites from complex biological samples. However, current CE-MS devices rely on liquid sample extracts, which restricts acquisition of spatially defined chemical information from tissue samples. The ability to chemically profile distinct cellular regions in tissue can contribute better understanding to molecular foundations in health and disease. Therefore, we describe the first CE-MS device capable of untargeted metabolite profiling directly from defined morphological regions of solid tissue sections. With surface sampling capillary electrophoresis mass spectrometry (SS-CE-MS), endogenous molecules are sampled and detected from a single defined tissue location. Characterization of SS-CE MS from different locations of the outer epidermal layer of A. Cepa demonstrated reproducible relative migration times and a peak area RSD of 20% (n = 5). Further, relative migration times were conserved for endogenous metabolites in tissues with varying complexities, including brain, spinal cord, and kidney. Results from proof-of-principle experiments from distinct morphological tissue regions reveal simultaneous analysis of small and large biomolecules, confident metabolite annotation, identification of in-source fragmentation interferences, and discrete isomeric abundances related to biological function. We envision that this new tool will provide in-depth chemical profiling and annotation of molecules in distinct cellular regions of tissue for improved biological understanding.

  • 269.
    Duong-Thi, Minh-Dao
    et al.
    Linnaeus University, Department of Chemistry and Biomedical Sciences, SE-39182 Kalmar, Sweden.
    Bergström, Maria
    Linnaeus University, Department of Chemistry and Biomedical Sciences, SE-39182 Kalmar, Sweden.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Eriksson, Jonny
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Ohlson, Sten
    Nanyang Technological University, School of Biological Sciences, Singapore 637551, Republic of Singapore.
    To Yiu Ying, Janet
    Nanyang Technological University, School of Biological Sciences, Singapore 637551, Republic of Singapore.
    Torres, Jaume
    Nanyang Technological University, School of Biological Sciences, Singapore 637551, Republic of Singapore.
    Agmo Hernández, Víctor
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lipodisks integrated with weak affinity chromatography enable fragment screening of integral membrane proteins2016Inngår i: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 141, nr 3, s. 981-988Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Membrane proteins constitute the largest class of drug targets but they present many challenges in drug discovery. Importantly, the discovery of potential drug candidates is hampered by the limited availability of efficient methods for screening drug-protein interactions. In this work we present a novel strategy for rapid identification of molecules capable of binding to a selected membrane protein. An integral membrane protein (human aquaporin-1) was incorporated into planar lipid bilayer disks (lipodisks), which were subsequently covalently coupled to porous derivatized silica and packed into HPLC columns. The obtained affinity columns were used in a typical protocol for fragment screening by weak affinity chromatography (WAC), in which one hit was identified out of a 200 compound collection. The lipodisk-based strategy, which ensures a stable and native-like lipid environment for the protein, is expected to work also with other membrane proteins and screening procedures.

  • 270.
    Díaz-Álvarez, Alba E.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Mesas Sanchez, Laura
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Dinér, Peter
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Non-Enzymatic Dynamic Kinetic Resolution of Secondary Aryl Alcohols: Planar Chiral Ferrocene and Ruthenium Catalysts in Cooperation2013Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 52, nr 2, s. 502-504Artikkel i tidsskrift (Fagfellevurdert)
  • 271.
    Díaz-Álvarez, Alba E.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Mesas-Sánchez, Laura
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Dinér, Peter
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC. KTH-Royal Institute of Technology.
    Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst2014Inngår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, nr 9, s. 14273-14291Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of new approaches to obtain optically pure β-hydroxy esters is an important area in synthetic organic chemistry since they are precursors of other high value compounds. Herein, the kinetic resolution of racemic β-hydroxy esters using a planar-chiral DMAP derivative catalyst is presented. Following this procedure, a range of aromatic β-hydroxy esters was obtained in excellent selectivities (up to = 107) and high enantiomeric excess (up to 99% ee). Furthermore, the utility of the present method was demonstrated in the synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide, a key intermediate for bioactive molecules such as fluoxetine, tomoxetine or nisoxetine, in its enantiomerically pure form.

  • 272.
    Díaz-Álvarez, Alba E.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Mesas-Sánchez, Laura
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Dinér, Peter
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Nichtenzymatische dynamische kinetische Racematspaltung sekundärer Arylalkohole: planar-chirale Ferrocen- und Rutheniumkatalysatoren im Zusammenspiel2013Inngår i: Angewandte Chemie, ISSN 1521-3757, Vol. 125, nr 2, s. 522-524Artikkel i tidsskrift (Fagfellevurdert)
  • 273.
    Edström, Lena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Adsorption Studies with Liquid Chromatography: Experimental Preparations for Thorough Determination of Adsorption Data2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Analytical chemistry is a field with a vast variety of applications. A robust companion in the field is liquid chromatography, the method used in this thesis, which is an established workhorse and a versatile tool in many different disciplines. It can be used for identification and quantification of interesting compounds generally present in low concentrations, called analytical scale chromatography. It can also be used for isolation and purification of high value compounds, called preparative chromatography. The latter is usually conducted in large scale with high concentrations. With high concentrations it is also possible to determine something called adsorption isotherms.

    Determination of adsorption isotherms is a useful tool for quite a wide variety of reasons. It can be used for characterisation of chromatographic separation systems, and then gives information on the retention mechanism as well as provides the possibility to study column-column and batch-batch reproducibility. If a protein is immobilised on a solid support, adsorption isotherms can be used for pharmacological characterisation of drug-protein interactions. Moreover, they can be used for the study of unexpected chromatographic phenomena.

    If the adsorption isotherm is known it is also possible to simulate chromatograms, and subsequently optimise the separation process numerically. The gain of a numerically optimised separation process is higher purity or yield of valuable compounds such as pharmaceuticals or antioxidants, as well as reducing the solvent usage. Taken all together, it saves time, money and the environment.

    However, the process of the adsorption isotherm determination requires a number of careful experimental considerations and preparations, and these are the main focus of the thesis. Important steps along the way include the choice of separation system and of suitable analytes, preparation of mobile phases and sample solutions, calibration, determination of injection profiles and column void, and of course the adsorption isotherm determination method itself. It is also important to keep track of parameters such as temperature and pH. These issues are discussed in this thesis.

    At the end, a description of useful methods for processing of the raw adsorption isotherm data is presented, as well as a brief passage on methods for numerical optimisation.

    Delarbeid
    1. Injection profiles in liquid chromatography: I. A fundamental investigation
    Åpne denne publikasjonen i ny fane eller vindu >>Injection profiles in liquid chromatography: I. A fundamental investigation
    2010 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1217, s. 4306-4312Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    This is a fundamental experimental and theoretical investigation on how the injection profile depends on important experimental parameters. The experiments revealed that the injection profile becomes more eroded with increased (i) flow rate, (ii) viscosity of the eluent, (iii) size of the solute, (iv) injection volume and (v) inner diameter of the injection loop capillary. These observations cannot be explained by a 1D-convection-diffusion equation, since it does not account for the effect of the parabolic flow and the radial diffusion on the elution profile. Therefore, the 1D model was expanded into a 2D-convection-diffusion equation with cylindrical coordinates, a model that showed a good agreement with the experimental injection profiles dependence on the experimental parameters. For a deeper understanding of the appearance of the injection profile the 2D model is excellent, but to account for injection profiles of various injection volumes and flow rates in preparative and process-chromatography using computer-optimizations, a more pragmatic approach must be developed. The result will give guidelines about how to reduce the extra-column variance caused by the injection profile. This is important both for preparative and analytical chromatography; in particular for modern analytical systems using short and narrow columns.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-151696 (URN)10.1016/j.chroma.2010.04.045 (DOI)000278920900009 ()
    Tilgjengelig fra: 2011-04-15 Laget: 2011-04-15 Sist oppdatert: 2018-01-23bibliografisk kontrollert
    2. Injection profiles in liquid chromatography II: predicting accurate injection-profiles for computer-assisted preparative optimizations.
    Åpne denne publikasjonen i ny fane eller vindu >>Injection profiles in liquid chromatography II: predicting accurate injection-profiles for computer-assisted preparative optimizations.
    2011 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, nr 34, s. 5794-5800Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In computer assisted optimization of liquid chromatography it has been known for some years that it is important to use experimental injection profiles, instead of rectangular ones, in order to calculate accurate elution bands. However, the incorrectly assumed rectangular profiles are still mostly used especially in numerical optimizations. The reason is that the acquisition of injection profiles, for each injection volume and each flow rate considered in a computer-assisted optimization requires a too large number of experiments. In this article a new function is proposed, which enables highly accurate predictions of the injection profiles and thus more accurate computer optimizations, with a minimum experimental effort. To model the injection profiles for any injection volume at a constant flow rate, as few as two experimental injection profiles are required. If it is desirable to also take the effect of flow rate on the injection profiles into account, then just two additional experiments are required. The overlap between fitted and experimental injection profiles at different flow rates and different injection volumes were excellent, more than 90%, using experimental injection profiles from just four different injection volumes at two different flow rates. Moreover, it was demonstrated that the flow rate has a minor influence on the injection profiles and that the injection volume is the main parameter that needs to be accounted for.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-159084 (URN)10.1016/j.chroma.2011.06.063 (DOI)21782187 (PubMedID)
    Tilgjengelig fra: 2011-09-26 Laget: 2011-09-21 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    3. Deformations of overloaded bands under pH-stable conditions in reversed phase chromatography
    Åpne denne publikasjonen i ny fane eller vindu >>Deformations of overloaded bands under pH-stable conditions in reversed phase chromatography
    2011 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, nr 15, s. 1966-1973Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    It has recently been demonstrated, using mathematical models, how peculiar overloaded band profiles of basic compounds are due to the local pH in the column when using low capacity buffers. In this study, overloaded peak shapes resulting after injection of carefully pH matched samples close to the pK(a) of the chosen solute are investigated primarily on two columns; one hybrid silica C18 column (Kromasil Eternity) and one purely polymeric column (PLRP-S), the latter lacking C18 ligands. It was found that distorted peaks of the basic test compound appear even though there is no difference in pH between the injected sample solution and the eluent; the previous explanation to why these effects occur is based on a pH mismatch. Thus, the unusual band shapes are not due to an initial pH difference. Furthermore, it was observed that the effect does not appear on polymeric columns without C18 ligands, but only on columns with C18 ligands, independently of the base matrix (silica, hybrid silica, polymeric).

    HSV kategori
    Forskningsprogram
    Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-151463 (URN)10.1016/j.chroma.2010.09.002 (DOI)000289331200006 ()20888565 (PubMedID)
    Tilgjengelig fra: 2011-04-15 Laget: 2011-04-12 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    4. Why ultra high performance liquid chromatography produces more tailing peaks than high performance liquid chromatography, why it does not matter and how it can be addressed.
    Åpne denne publikasjonen i ny fane eller vindu >>Why ultra high performance liquid chromatography produces more tailing peaks than high performance liquid chromatography, why it does not matter and how it can be addressed.
    Vise andre…
    2011 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, nr 39, s. 6914-21Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The purpose of this study is to demonstrate, with experiments and with computer simulations based on a firm chromatographic theory, that the wide spread perception of that the United States Pharmacopeia tailing factor must be lower than 2 (T(f)<2) is questionable when using the latest generation of LC equipment. It is shown that highly efficient LC separations like those obtained with sub-2μm porous and 2.7μm superficially porous particles (UHPLC) produce significantly higher T(f)-values than the corresponding separation based on 3μm porous particles (HPLC) when the same amount of sample is injected. Still UHPLC separations provide a better resolution to adjacent peaks. Expressions have been derived that describe how the T(f)-value changes with particle size or number of theoretical plates. Expressions have also been derived that can be used to scale the injection volume based on particle size or number of theoretical plates to maintain the T(f)-value when translating a HPLC separation to the corresponding UHPLC separation. An aspect that has been ignored in previous publications. Finally, data obtained from columns with different age/condition indicate that T(f)-values should be complemented by a peak width measure to provide a more objective quality measure.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-159085 (URN)10.1016/j.chroma.2011.08.018 (DOI)21872875 (PubMedID)
    Tilgjengelig fra: 2011-09-26 Laget: 2011-09-21 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    5. Optimization strategies accounting for the additive in preparative chiral liquid chromatography
    Åpne denne publikasjonen i ny fane eller vindu >>Optimization strategies accounting for the additive in preparative chiral liquid chromatography
    Vise andre…
    2012 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1269, nr SI, s. 279-286Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    This study is an in-depth investigation on how numerical optimization strategies that also account for the additive type and concentration, in preparative batch chromatography, should be performed. As a model system, the separation of Z-(R,S)-2-aminobutyric acid enantiomers on a quinidine carbamate-based chiral stationary phase in polar organic mode was used, with different additive strengths of acetic acid or hexanoic acid in methanol. The inverse method was used to determine the competitive adsorption isotherm parameters for the enantiomers and the additives. Three different optimization strategies were examined: (1) injection volume optimization, (2) optimization of injection volume and additive concentration, and (3) full optimization including injection volume, additive concentration, sample concentration and flow rate. It was concluded that (i) it is important to incorporate the additive concentration in the optimization procedure to achieve the highest production rates, (ii) the full optimization strategy had the overall best results, and (iii) the selection of additive is very important (here acetic acid additive was superior to the hexanoic acid additive). By including the additive in the adsorption model and in the numerical optimization it is not only possible to achieve higher production rates but also to properly select the additive that is most advantageous for the specific separation problem.

    Emneord
    Additive, Chiral preparative Chromatography, Enantiomers, Inverse method, Optimization, Acid additives, Additive concentrations, Adsorption model, Aminobutyric acids, Batch chromatography, Chiral liquid chromatography, Chiral stationary phase, Competitive adsorption isotherms, Full optimization, Hexanoic acids, In-depth investigation, Injection volume, Inverse methods, Model system, Numerical optimizations, Optimization procedures, Optimization strategy, Production rates, Sample concentration, Separation problems, Acetic acid, Adsorption, Amino acids, Chirality, Inverse problems, Liquid chromatography, Methanol, pH, Saturated fatty acids, Separation, Additives, 2 aminobutyric acid, carbamic acid, hexanoic acid, quinidine, adsorption kinetics, article, chemical composition, chiral chromatography, concentration (parameters), elution, enantiomer, flow rate, ion exchange, priority journal, process optimization, reaction time, separation technique
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-192063 (URN)10.1016/j.chroma.2012.05.052 (DOI)000312475300023 ()
    Tilgjengelig fra: 2013-01-17 Laget: 2013-01-15 Sist oppdatert: 2018-01-23bibliografisk kontrollert
  • 274.
    Edvardsson Rasmussen, Jesper
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Laurell, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Rask-Andersen, Helge
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Eriksson, Per Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    The proteome of perilymph in patients with vestibular schwannoma: A possibility to identify biomarkers for tumor associated hearing loss?2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 6, artikkel-id e0198442Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Due to the surrounding bone, the human inner ear is relatively inaccessible and difficult to reach for cellular and molecular analyses. However, these types of investigations are needed to better understand the etiology, pathophysiology and progression of several inner ear disorders. Moreover, the fluid from the inner ear cannot be sampled for micro-chemical analyses from healthy individuals in vivo. Therefore, in the present paper, we studied patients with vestibular schwannoma (VS) undergoing trans-labyrinthine surgery (TLS). Our primary aim was to identify perilymph proteins in patients with VS on an individual level. Our second aim was to investigate the proteins identified at a functional level and our final aim was to search for biological markers for tumor-associated hearing loss and tumor diameter. Methods and findings Sixteen patients underwent TLS for sporadic VS. Perilymph was aspirated through the round window before opening the labyrinth. One sample was contaminated and excluded resulting in 15 usable samples. Perilymph samples were analyzed with an online tandem LTQ-Orbitrap mass spectrometer. Data were analyzed with MaxQuant software to identify the total number of proteins and to quantify proteins in individual samples. Protein function was analyzed using the PANTHER Overrepresentation tool. Associations between perilymph protein content, clinical parameters, tumor-associated hearing loss and tumor diameter were assessed using Random Forest and Boruta. In total, 314 proteins were identified; 60 in all 15 patients and 130 proteins only once in 15 patients. Ninety-one proteins were detected in at least 12 out of 15 patients. Random Forest followed by Boruta analysis confirmed that alpha-2-HS-glycoprotein (P02765) was an independent variable for tumor-associated hearing loss. In addition, functional analysis showed that numerous processes were significantly increased in the perilymph. The top three enriched biological processes were: 1) secondary metabolic processes; 2) complement activation and 3) cell recognition. Conclusions The proteome of perilymph in patients with vestibular schwannoma has an inter-individual stable section. However, even in a cohort with homogenous disease, the variation between individuals represented the majority of the detected proteins. Alpha-2-HS-glycoprotein, P02765, was shown to be an independent variable for tumor-associated hearing loss, a finding that needs to be verified in other studies. In pathway analysis perilymph had highly enriched functions, particularly in terms of increased immune and metabolic processes.

  • 275.
    Edvinsson, Åsa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Bränn, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Obstetrisk och reproduktiv hälsoforskning.
    Hellgren, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Freyhult, Eva
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    White, Richard
    Norwegian Inst Publ Hlth, Oslo, Norway..
    Kamali-Moghaddam, Masood
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Olivier, Jocelien
    Univ Groningen, Groningen Inst Evolutionary Life Sci, Unit Behav Neurosci, Dept Neurobiol, Groningen, Netherlands..
    Bergquist, Jonas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Boström, Adrian E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Skalkidou, Alkistis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Cunningham, Janet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Lower inflammatory markers in women with antenatal depression brings the M1/M2 balance into focus from a new direction2017Inngår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 80, s. 15-25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Antenatal depression and use of serotonin reuptake inhibitors (SSRI) in pregnancy have both been associated with an increased risk of poor pregnancy outcomes, such as preterm birth and impaired fetal growth. While the underlying biological pathways for these complications are poorly understood, it has been hypothesized that inflammation may be a common physiological pathway. The aim of the present study was to assess peripheral inflammatory markers in healthy women, women with antenatal depression, and in women using SSRI during pregnancy.

    Methods: 160 healthy pregnant controls, 59 women with antenatal depression and 39 women on treatment with SSRIs were included. The relative levels of 92 inflammatory proteins were analyzed by proximity extension assay technology.

    Results: Overall, 23 of the inflammatory markers were significantly lower in women with antenatal depression and in women on treatment with SSRIs in comparison with the healthy controls. No difference in any of the inflammatory markers was observed between women with antenatal depression and those who were using SSRI. Top three inflammatory markers that were down-regulated in women with antenatal depression were TNF-related apoptosis-inducing ligand (TRAIL), p = 0.000001, macrophage colony-stimulating factor 1 (CSF-1), p = 0.000004, and fractalkine (CX3CL1), p =0.000005. Corresponding inflammatory markers in SSRI users were CSF-1, p = 0.000011, vascular endothelial growth factor A (VEGF-A), p =0.000016, and IL-15 receptor subunit alpha (IL-15RA), p = 0.000027. The inflammatory markers were negatively correlated with cortisone serum concentrations in controls, but not in the cases. Differential DNA methylation of was found for seven of these inflammatory markers in an independent epigenetics cohort.

    Conclusion: Women with antenatal depression or on SSRI treatment have lower levels of a number of peripheral inflammatory markers than healthy pregnant controls. Hypothetically, this could be due to dysregulated switch to the pro-M2 milieu that characterizes normal third trimester pregnancy. However, longitudinal blood sampling is needed to elucidate whether the presumably dysregulated M2 shift is driving the development of antenatal depression or is a result of the depression.

  • 276.
    Egea-Jimenez, Antonio Luis
    et al.
    Aix Marseille Univ, Inst Paoli Calmettes, INSERM, CRCM,U1068,CNRS UMR7258, F-13009 Marseille, France; Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Gallardo, Rodrigo
    Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium;Katholieke Univ Leuven, Dept Mol Cellular & Mol Med, VIB, VIB Switch Lab, B-3000 Leuven, Belgium.
    Garcia-Pino, Abel
    Vrije Univ Brussel, Struct Biol Brussels, Dept Biotechnol DBIT, Pl Laan 2, B-1050 Brussels, Belgium; VIB, Mol Recognit Unit, Struct Biol Res Ctr, Pl Laan 2, B-1050 Brussels, Belgium; Univ Libre Bruxelles, Biol Struct & Biophys, CP300,Rue Prof Jeener & Brachet 12, B-6041 Gosselies, Belgium.
    Ivarsson, Ylva
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi. Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Wawrzyniak, Anna Maria
    Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Kashyap, Rudra
    Aix Marseille Univ, Inst Paoli Calmettes, INSERM, CRCM,U1068,CNRS UMR7258, F-13009 Marseille, France; Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Loris, Remy
    Vrije Univ Brussel, Struct Biol Brussels, Dept Biotechnol DBIT, Pl Laan 2, B-1050 Brussels, Belgium; VIB, Mol Recognit Unit, Struct Biol Res Ctr, Pl Laan 2, B-1050 Brussels, Belgium.
    Schymkowitz, Joost
    Katholieke Univ Leuven, Dept Mol Cellular & Mol Med, VIB, VIB Switch Lab, B-3000 Leuven, Belgium.
    Rousseau, Frederic
    Katholieke Univ Leuven, Dept Mol Cellular & Mol Med, VIB, VIB Switch Lab, B-3000 Leuven, Belgium.
    Zimmermann, Pascale
    Aix Marseille Univ, Inst Paoli Calmettes, INSERM, CRCM,U1068,CNRS UMR7258, F-13009 Marseille, France; Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling2016Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikkel-id 12101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PDZ domain-containing proteins work as intracellular scaffolds to control spatio-temporal aspects of cell signalling. This function is supported by the ability of their PDZ domains to bind other proteins such as receptors, but also phosphoinositide lipids important for membrane trafficking. Here we report a crystal structure of the syntenin PDZ tandem in complex with the carboxy-terminal fragment of Frizzled 7 and phosphatidylinositol 4,5-bisphosphate (PIP2). The crystal structure reveals a tripartite interaction formed via the second PDZ domain of syntenin. Biophysical and biochemical experiments establish co-operative binding of the tripartite complex and identify residues crucial for membrane PIP2-specific recognition. Experiments with cells support the importance of the syntenin-PIP2 interaction for plasma membrane targeting of Frizzled 7 and c-jun phosphorylation. This study contributes to our understanding of the biology of PDZ proteins as key players in membrane compartmentalization and dynamics.

  • 277.
    Ehrenberg, Angelica
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Novel Procedures for Identification and Characterization of Viral Proteases Inhibitors2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Viral proteases are often considered to be attractive drug targets because of their crucial function in the viral replication machinery. In order to increase our knowledge of these important targets and to contribute to the discovery and development of new antiviral drugs, the proteases from hepatitis C virus (HCV) and human cytomegalovirus (HCMV) have been produced and their interactions with inhibitors and fragments have been characterized, using enzyme inhibition and SPR biosensor based interaction assay.

    The structure activity relationships and the resistance profiles of a series of HCV NS3 protease inhibitors based on either P2 proline or phenylglycine residues were analyzed using wild type genotype 1a and the major resistant variants A156T and D168V. The observed susceptibility to substitutions associated with these resistance variants was concluded to depend on the P2 and the P1 residue, and not only on the P2 residue as previously had been suggested. In order to be able to evaluate how the potency of inhibitors is affected by genetic variation, their effect was evaluated on wild type NS3 from genotype 1a, 1b and 3a as well as on the resistant variant R155K from genotype 1a. To enable a comparison of the inhibitory effect on the enzyme variants, the compounds were analyzed under conditions optimized for each variant. VX-950 was found to be the least susceptible compound to resistance and genetic variation. A more detailed analysis showed that the kinetic and mechanistic features of the inhibitors were significantly different for the different genotypes. The reversible non covalent macrocyclic inhibitor ITMN 191 was revealed to have favorable kinetics for all three genotypes. This is an advantage for the design of broad spectrum drugs.

    A fragment based procedure for identifying and validating novel scaffolds for inhibitors of HCMV protease was established. It identified fragments that may serve as starting points for the discovery of effective inhibitors against this challenging target.  

    The procedures developed for the evaluation and identification of novel HCV NS3 and HCMV protease inhibitors have contributed to a deeper understanding of protease-inhibitor interactions that is expected to have an impact on the design of novel antiviral drugs. 

    Delarbeid
    1. Structure-activity relationships of HCV NS3 protease inhibitors evaluated on the drug-resistant variants A156T and D168V
    Åpne denne publikasjonen i ny fane eller vindu >>Structure-activity relationships of HCV NS3 protease inhibitors evaluated on the drug-resistant variants A156T and D168V
    Vise andre…
    2010 (engelsk)Inngår i: Antiviral Therapy, ISSN 1359-6535, E-ISSN 2040-2058, Vol. 15, nr 6, s. 841-852Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: HCV infections are a serious threat to public health. An important drug target is the NS3 protease, for which several inhibitors are in clinical trials. Because of the high mutation rate of the virus, resistance against any HCV-specific drug is likely to become a substantial problem. Structure-activity data for the major resistant variants are therefore needed to guide future designs of protease inhibitors. METHODS: The inhibitory potency of tripeptide NS3 protease inhibitors, with either a P2 proline or phenylglycine, in combination with different P3 and P1-P1' groups, was assessed in enzyme activity assays using the full-length NS3 protein with known resistance-conferring substitutions A156T or D168V. The results obtained from these variants were compared with the inhibition of the wild-type enzyme. Molecular modelling was used to rationalize the biochemical results. RESULTS: Inhibitors combining the P2 proline and P1 (1R,2S)-1-amino-2-vinylcyclopropyl-carboxylic acid (vinylACCA) lost much of their potency on the resistant variants. Exchange of the P2 proline for phenylglycine yielded inhibitors that were equipotent on the wild-type and on the A156T and D168V variants. The same result was obtained from the combination of either the P2 residue with a norvaline or an aromatic scaffold in the P1 position. CONCLUSIONS: The combination of a substituted P2 proline and P1 vinylACCA appears to be the main problem behind the observed resistance. Molecular modelling suggests an enforced change in binding conformation for the P2 proline-based inhibitors, whereas the phenylglycine-based inhibitors retained their wild-type binding conformation in the substituted forms of the enzyme.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-131962 (URN)10.3851/IMP1655 (DOI)000282390300004 ()20834096 (PubMedID)
    Tilgjengelig fra: 2010-10-12 Laget: 2010-10-12 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    2. Accounting for strain variations and resistance mutations in the characterization of hepatitis C NS3 protease inhibitors
    Åpne denne publikasjonen i ny fane eller vindu >>Accounting for strain variations and resistance mutations in the characterization of hepatitis C NS3 protease inhibitors
    Vise andre…
    2014 (engelsk)Inngår i: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 29, nr 6, s. 868-876Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Context: Natural strain variation and rapid resistance development makes development of broad spectrum hepatitis C virus (HCV) drugs very challenging and evaluation of inhibitor selectivity and resistance must account for differences in the catalytic properties of enzyme variants.

    Objective: To understand how to study selectivity and relationships between efficacy and genotype or resistant mutants for NS3 protease inhibitors.

    Materials and methods: The catalytic properties of NS3 protease from genotypes 1a, 1b and 3a, and their sensitivities to four structurally and mechanistically different NS3 protease inhibitors have been analysed under different experimental conditions.

    Results: The optimisation of buffer conditions for each protease variant enabled the comparison of their catalytic properties and sensitivities to the inhibitors. All inhibitors were most effective against genotype 1a protease, with VX-950 having the broadest selectivity.

    Discussion and conclusion: A new strategy for evaluation of inhibitors relevant for the discovery of broad spectrum HCV drugs was established.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-193252 (URN)10.3109/14756366.2013.864651 (DOI)000345518000013 ()24517372 (PubMedID)
    Tilgjengelig fra: 2013-01-29 Laget: 2013-01-29 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    3. Identification of Weak Points of Hepatitis C Virus NS3 Protease Inhibitors Using Surface Plasmon Resonance Biosensor-Based Interaction Kinetic Analysis and Genetic Variants
    Åpne denne publikasjonen i ny fane eller vindu >>Identification of Weak Points of Hepatitis C Virus NS3 Protease Inhibitors Using Surface Plasmon Resonance Biosensor-Based Interaction Kinetic Analysis and Genetic Variants
    Vise andre…
    2014 (engelsk)Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, nr 5, s. 1802-1811Artikkel i tidsskrift (Annet vitenskapelig) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-193251 (URN)10.1021/jm401690f (DOI)000333005800012 ()
    Tilgjengelig fra: 2013-01-29 Laget: 2013-01-29 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    4. Challenges in the discovery of fragment targeting human cytomegalovirus protease
    Åpne denne publikasjonen i ny fane eller vindu >>Challenges in the discovery of fragment targeting human cytomegalovirus protease
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    CMV, cytomagalovirus, protease, SPR, biosensor, fragments-based drug discovery, screening, inhibitor
    HSV kategori
    Forskningsprogram
    Biokemi
    Identifikatorer
    urn:nbn:se:uu:diva-215703 (URN)
    Tilgjengelig fra: 2014-01-15 Laget: 2014-01-15 Sist oppdatert: 2014-02-10
  • 278.
    Ehrenberg, Angelica
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Schmuck, Benjamin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Anwar, Muhammad Ikram
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Svahn Gustafsson, Sofia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Stenberg, Gun
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Danielson, Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Accounting for strain variations and resistance mutations in the characterization of hepatitis C NS3 protease inhibitors2014Inngår i: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 29, nr 6, s. 868-876Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Natural strain variation and rapid resistance development makes development of broad spectrum hepatitis C virus (HCV) drugs very challenging and evaluation of inhibitor selectivity and resistance must account for differences in the catalytic properties of enzyme variants.

    Objective: To understand how to study selectivity and relationships between efficacy and genotype or resistant mutants for NS3 protease inhibitors.

    Materials and methods: The catalytic properties of NS3 protease from genotypes 1a, 1b and 3a, and their sensitivities to four structurally and mechanistically different NS3 protease inhibitors have been analysed under different experimental conditions.

    Results: The optimisation of buffer conditions for each protease variant enabled the comparison of their catalytic properties and sensitivities to the inhibitors. All inhibitors were most effective against genotype 1a protease, with VX-950 having the broadest selectivity.

    Discussion and conclusion: A new strategy for evaluation of inhibitors relevant for the discovery of broad spectrum HCV drugs was established.

  • 279.
    Ek, Pia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ek, Bo
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Zetterqvist, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Phosphohistidine phosphatase 1 (PHPT1) also dephosphorylates phospholysine of chemically phosphorylated histone H1 and polylysine2015Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 1, s. 20-27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Phosphohistidine phosphatase 1 (PHPT1), also named protein histidine phosphatase (PHP), is a eukaryotic enzyme dephosphorylating proteins and peptides that are phosphorylated on a histidine residue. A preliminary finding that histone H1, which lacks histidine, was phosphorylated by phosphoramidate and dephosphorylated by PHPT1 prompted the present investigation. Methods. Histone H1 and polylysine were phosphorylated at a low concentration (3.9 mM) of phosphoramidate. Their dephosphorylation by recombinant human PHPT1 was investigated by using a DEAE-Sepharose spin column technique earlier developed by us for studies on basic phosphoproteins and phosphopeptides. Determination of protein-bound, acid-labile phosphate was performed by a malachite green method. Mass spectrometry (MS) was used to investigate the occurrence of N-epsilon-phospholysine residues in a phosphorylated histone H 1.2 preparation, and to measure the activity of PHPT1 against free N-omega-phosphoarginine. Results. Histone H1.2, which lacks histidine, was phosphorylated by phosphoramidate on several lysine residues, as shown by MS. PHPT1 was shown to dephosphorylate phosphohistone H1 at a rate similar to that previously described for the dephosphorylation of phosphohistidine-containing peptides. In addition, phosphopolylysine was an equally good substrate for PHPT1. However, no dephosphorylation of free phosphoarginine by PHPT1 could be detected. Conclusion. The finding that PHPT1 can dephosphorylate phospholysine in chemically phosphorylated histone H1 and polylysine demonstrates a broader specificity for this enzyme than known so far.

  • 280.
    Eklund, Sandra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Lindås, Ann-Christin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Hamnevik, Emil
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Widersten, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Tomkinson, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Exploring the active site of tripeptidyl-peptidase II through studies of pH dependence of reaction kinetics2012Inngår i: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1824, nr 4, s. 561-570Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is a subtilisin-like serine protease which forms a large enzyme complex (> 4 MDa). It is considered a potential drug target due to its involvement in specific physiological processes. However, information is scarce concerning the kinetic characteristics of TPP II and its active site features, which are important for design of efficient inhibitors. To amend this, we probed the active site by determining the pH dependence of TPP II catalysis. Access to pure enzyme is a prerequisite for kinetic investigations and herein we introduce the first efficient purification system for heterologously expressed mammalian TPP II. The pH dependence of kinetic parameters for hydrolysis of two different chromogenic substrates, Ala-Ala-Phe-pNA and Ala-Ala-Ala-pNA, was determined for murine, human and Drosophila melanogaster TPP II as well as mutant variants thereof. The investigation demonstrated that TPP II, in contrast to subtilisin, has a bell-shaped pH dependence of kcatapp/KM probably due to deprotonation of the N-terminal amino group of the substrate at higher pH. Since both the KM and kcatapp are lower for cleavage of AAA-pNA than for AAF-pNA we propose that the former can bind non-productively to the active site of the enzyme, a phenomenon previously observed with some substrates for subtilisin. Two mutant variants, H267A and D387G, showed bell-shaped pH-dependence of kcatapp, possibly due to an impaired protonation of the leaving group. This work reveals previously unknown differences between TPP II orthologues and subtilisin as well as features that might be conserved within the entire family of subtilisin-like serine peptidases.

  • 281.
    Ekman, Pia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Eller, Marika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Biokemi.
    Ragnarsson, Ulf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Two methods to avoid the effect of endogenous inhibitors during the assay of protein kinase C activity in tissue extracts.1992Inngår i: Preparative Biochemistry, ISSN 0032-7484, Vol. 22, nr 2, s. 165-175Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Using H1 as substrate the protein kinase C activity of rat liver cell sap was increased about fourfold by treatment with DEAE-cellulose at pH 7.5 at an intermediate ionic strength due to removal of protein inhibitors. The activity of cell sap from rat spleen, brain or muscle was about doubled by the same treatment. In contrast, when a specific synthetic peptide substrate was used the corresponding increase of enzyme activity was not obtained when the inhibitors were removed. This shows that this type of substrates should be preferred for reliable assays of protein kinase C in crude extracts. The possible role of the protein inhibitors for the substrate specificity of protein kinase C is briefly discussed.

  • 282.
    Elf, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Shevchenko, Ganna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Nygren, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Askmark, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Artemenko, Konstantin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Alterations in muscle proteome of patients diagnosed with amyotrophic lateral sclerosis2014Inngår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 108, s. 55-64Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle paralysis. Currently clinical tools for ALS diagnostics do not perform well enough and their improvement is needed. The objective of this study was to identify specific protein alterations related to the development of ALS using tiny muscle biopsies. We applied a shotgun proteomics and quantitative dimethyl labeling in order to analyze the global changes in human skeletal muscle proteome of ALS versus healthy subjects for the first time. 235 proteins were quantified and 11 proteins were found significantly regulated in ALS muscles. These proteins are involved in muscle development and contraction, metabolic processes, enzyme activity, regulation of apoptosis and transport activity. In order to eliminate a risk to confuse ALS with other denervations, muscle biopsies of patients with postpolio syndrome and Charcot Marie Tooth disease (negative controls) were compared to those of ALS and controls. Only few proteins significantly regulated in ALS patients compared to controls were affected differently in negative controls. These proteins (BTB and kelch domain-containing protein 10, myosin light chain 3, glycogen debranching enzyme, transitional endoplasmic reticulum ATPase), individually or as a panel, could be selected for estimation of ALS diagnosis and development. Biological significance ALS is a devastating neurodegenerative disease, and luckily, very rare: only one to two people out of 100,000 develop ALS yearly. This fact, however, makes studies of ALS very challenging since it is very difficult to collect the representative set of clinical samples and this may take up to several years. In this study we collected the muscle biopsies from 12 ALS patients and compared the ALS muscle proteome against the one from control subjects. We suggested the efficient method for such comprehensive quantitative analysis by LC-MS and performed it for the first time using human ALS material. This gel- and antibody-free method can be widely applied for muscle proteome studies and has been used by us for revealing of the specific protein alterations associated with ALS.

  • 283.
    Elfineh, Lioudmila
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Classon, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Asplund, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Sara Bergström
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tyrosine phosphorylation profiling via in situ proximity ligation assay2014Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, s. 435-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Tyrosine phosphorylation (pTyr) is an important cancer relevant posttranslational modification since it regulates protein activity and cellular localization. By controlling cell growth and differentiation it plays an important role in tumor development. This paper describes a novel approach for detection and visualization of a panel of pTyr proteins in tumors using in situ proximity ligation assay. Methods: K562 leukemia cells were treated with tyrosine kinase and/or phosphatase inhibitors to induce differences in pTyr levels and mimic cells with different malignant properties. Cells were then probed with one antibody against the pTyr modification and another probe against the detected protein, resulting in a detectable fluorescent signal once the probes were in proximity. Results: Total and protein specific pTyr levels on ABL, SHC, ERK2 and PI3K proteins were detected and samples of control and treated cells were distinguished at the pTyr level using this novel approach. Promising results were also detected for formalin fixed and paraffin embedded cells in the micro array format. Conclusions: This application of in situ proximity ligation assay is valuable in order to study the pTyr modification of a panel of proteins in large data sets to validate mass spectrometric data and to be combined with tissue microarrays. The approach offers new opportunities to reveal the pTyr signatures in cells of different malignant properties that can be used as biomarker of disease in the future.

  • 284.
    Elhamili, Anisa
    et al.
    Department of Medicinal & Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tripoli, Libya.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    El-Attug, M
    Department of Medicinal & Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tripoli, Libya.
    Saad, S
    Department of Pharmacology, Faculty of Pharmacy, University of Tripoli, Tripoli, Libya.
    Hemiss, G
    Department of Medicinal & Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tripoli, Libya.
    Almog, T.
    Department of Medicinal & Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tripoli, Libya.
    Pharmaceutical Evaluation of Type II Oral Antidiabetic Agent2014Inngår i: International Journal of Pharma Research & Review, ISSN 2278-6074, Vol. 3, nr 6, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
  • 285. Elinder, Malin
    et al.
    Danielson, U Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Unge, Torsten
    van Ham, Guido
    Öberg, Bo
    MIV-170, a novel NNRTI exhibiting tight binding to HIV-1 reverse transcriptase (RT)2008Inngår i: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 78, s. A37-A37Artikkel i tidsskrift (Fagfellevurdert)
  • 286.
    Eller, Marika
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Järv, Jaak
    Tartu universitet.
    Toomik, Reet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ragnarsson, Ulf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Ekman, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Peptide fragments of myelin basic protein as substrates of protein kinase C.1992Inngår i: Biochemistry International, ISSN 0158-5231, Vol. 27, nr 4, s. 625-631Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A set of peptides derived from myelin basic protein was synthesized and the kinetics of their phosphorylation by protein kinase C was studied. The replacement or the removal of the N-terminal Gln had no effect on the activity of the parent peptide. The removal of the following Lys or Arg led to a systematic decrease in substrate activity. The modifications in the C-terminal part of the peptide had a weaker influence on the parameters Vmax and KM than those in the N-terminal. The rather regular dependence of the activity of substrates upon their structure does not allow the strict definition of a minimum substrate for protein kinase C.

  • 287.
    Eller, Marika
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Järv, Jaak
    Tartu universitet.
    Toomik, Reet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Ragnarsson, Ulf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Ekman, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Substrate specificity of protein kinase C studied with peptides containing D-amino acid residues.1993Inngår i: Journal of Biochemistry, ISSN 0021-924X, Vol. 114, nr 2, s. 177-180Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A set of stereoisomeric nonapeptides KRPSQRAKY with one, two, or all L-amino acid residues replaced by the corresponding D-amino acids, and two analogs with L- and D-threonine instead of serine, were synthesized and tested as substrates for protein kinase C. All of the peptides were phosphorylated by the enzyme. The maximal rate of the reaction with the all-D peptide was more than one order of magnitude lower than that for all-L peptide with serine. The same applied to the peptides with D-Ser or with D-Arg in position +2 with respect to Ser. The Km values for the peptides containing one D-amino acid were close to that for the prototype peptide (53 microM). On the other hand, when two or more D-amino acids were present, the Km value increased considerably. Replacement of serine by threonine also reduced the phosphorylation rate and increased the Km values. One can conclude that the stereospecificity of protein kinase C is much less pronounced than that of protein kinase A, which is in agreement with the less clearly pronounced substrate specificity of the former enzyme.

  • 288.
    Eller, Marika
    et al.
    Tartu universitet.
    Sepp, A
    Tartu universitet.
    Toomik, Reet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ekman, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Järv, Jaak
    Tartu universitet.
    Ragnarsson, Ulf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Studies on the substrate specificity of cAMP-dependent protein kinase using diastereomeric peptides1991Inngår i: Biochemistry International, ISSN 0158-5231, Vol. 25, nr 3, s. 453-460Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A set of six different diastereomeric hexapeptides RRASVA, each with a D-amino acid residue successively in the six positions, was synthesized and tested as substrates of protein kinase A. It was found that the peptide with D-Ser was neither a substrate, nor an inhibitor of the enzyme. The other five peptides were active as substrates with slightly lower kcat values than that of the all-L amino acid peptide. However, the apparent Km values increased by one to two orders of magnitude, especially when the second arginine or the alanine residue preceding the serine was substituted. The results are discussed.

  • 289.
    Ellis, Hanna
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Fysikalisk kemi.
    Leandri, Valentina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Hagfeldt, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Fysikalisk kemi.
    Boschloo, Gerrit
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Fysikalisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Shevchenko, Denys  
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Laser desorption/ionization mass spectrometry of dye-sensitized solar cells: identification of the dye-electrolyte interaction2015Inngår i: Journal of Mass Spectrometry, ISSN 1076-5174, E-ISSN 1096-9888, Vol. 50, nr 5, s. 734-739Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dye-sensitized solar cells (DSCs) have great potential to provide sustainable electricity from sunlight. The photoanode in DSCs consists of a dye-sensitized metal oxide film deposited on a conductive substrate. This configuration makes the photoanode a perfect sample for laser desorption/ionization mass spectrometry (LDI-MS). We applied LDI-MS for the study of molecular interactions between a dye and electrolyte on the surface of a TiO2 photoanode. We found that a dye containing polyoxyethylene groups forms complexes with alkali metal cations from the electrolyte, while a dye substituted with alkoxy groups does not. Guanidinium ion forms adducts with neither of the two dyes.

  • 290. Elmlund, Louise
    et al.
    Kack, Camilla
    Aastrup, Teodor
    Nicholls, Ian A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Study of the Interaction of Trastuzumab and SKOV3 Epithelial Cancer Cells Using a Quartz Crystal Microbalance Sensor2015Inngår i: Sensors, ISSN 1424-8220, E-ISSN 1424-8220, Vol. 15, nr 3, s. 5884-5894Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Analytical methods founded upon whole cell-based assays are of importance in early stage drug development and in fundamental studies of biomolecular recognition. Here we have studied the binding of the monoclonal antibody trastuzumab to human epidermal growth factor receptor 2 (HER2) on human ovary adenocarcinoma epithelial cancer cells (SKOV3) using quartz crystal microbalance (QCM) technology. An optimized procedure for immobilizing the cells on the chip surface was established with respect to fixation procedure and seeding density. Trastuzumab binding to the cell decorated sensor surface was studied, revealing a mean dissociation constant, K-D, value of 7 +/- 1 nM (standard error of the mean). This study provides a new perspective on the affinity of the antibody-receptor complex presented a more natural context compared to purified receptors. These results demonstrate the potential for using whole cell-based QCM assay in drug development, the screening of HER2 selective antibody-based drug candidates, and for the study of biomolecular recognition. This real time, label free approach for studying interactions with target receptors present in their natural environment afforded sensitive and detailed kinetic information about the binding of the analyte to the target.

  • 291. Elmlund, Louise
    et al.
    Suriyanarayanan, Subramanian
    Wiklander, Jesper G.
    Aastrup, Teodor
    Nicholls, Ian A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Biotin selective polymer nano-films2014Inngår i: Journal of Nanobiotechnology, ISSN 1477-3155, E-ISSN 1477-3155, Vol. 12, s. 8-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The interaction between biotin and avidin is utilized in a wide range of assay and diagnostic systems. A robust material capable of binding biotin should offer scope in the development of reusable assay materials and biosensor recognition elements. Results: Biotin-selective thin (3-5 nm) films have been fabricated on hexadecanethiol self assembled monolayer (SAM) coated Au/quartz resonators. The films were prepared based upon a molecular imprinting strategy where N, N'-methylenebisacrylamide and 2-acrylamido-2-methylpropanesulfonic acid were copolymerized and grafted to the SAM-coated surface in the presence of biotin methyl ester using photoinitiation with physisorbed benzophenone. The biotinyl moiety selectivity of the resonators efficiently differentiated biotinylated peptidic or carbohydrate structures from their native counterparts. Conclusions: Molecularly imprinted ultra thin films can be used for the selective recognition of biotinylated structures in a quartz crystal microbalance sensing platform. These films are stable for periods of at least a month. This strategy should prove of interest for use in other sensing and assay systems.

  • 292.
    Emami Khoonsari, Payam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Haggmark, Anna
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Lönnberg, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Mikus, Maria
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Shevchenko, Ganna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala Univ, Dept Chem BMC, Analyt Chem, Uppsala, Sweden..
    Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 3, artikkel-id e0150672Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alzheimer's disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer's disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer's disease patients and non-demented controls to identify potential biomarkers for Alzheimer's disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer's disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer's disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system.

  • 293.
    Emami Khoonsari, Payam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Musunri, Sravani
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Herman, Stephanie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Svensson, Camilla I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden..
    Tanum, Lars
    Department of R&D in Mental Health, Akershus University Hospital, Lørenskog, Norway..
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Systematic Analysis of the Cerebrospinal Fluid Proteome of Fibromyalgia patients2019Inngår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, s. 35-43Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome. Based on our multivariate and univariate analyses, we found that the relative differences in the CSF proteome between FM patients and controls were moderate. Four proteins, important to discriminate FM patients from non-pain controls, were found: Apolipoprotein C-III, Galectin-3-binding protein, Malate dehydrogenase cytoplasmic and the neuropeptide precursor protein ProSAAS. These proteins are involved in lipoprotein lipase (LPL) activity, inflammatory signaling, energy metabolism and neuropeptide signaling.

  • 294.
    Emami Khoonsari, Payam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Shevchenko, Ganna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Herman, Stephanie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Remnestal, Julia
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, SciLifeLab, Stockholm, Sweden.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Brundin, RoseMarie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Degerman Gunnarsson, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Zetterberge, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Mölndal, Sweden; Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden; UK Dementia Res Inst UCL, London, England; UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England.
    Nilsson, Peter
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, SciLifeLab, Stockholm, Sweden.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers2019Inngår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, nr 2, s. 639-651Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

    Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

    Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable.

    Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.

    Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

  • 295.
    Emanuelsson, Rikard
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Conjugation in Organic Group 14 Element Compounds: Design, Synthesis and Experimental Evaluation2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis focuses on the chemical concept of conjugation, i.e., electron delocalization, and the effect it has on electronic and optical properties of molecules. The emphasis is on electron delocalization across a saturated σ-bonded segment, and in our studies these segments are either inserted between π-conjugated moieties or joined together to form longer chains. The electronic and optical properties of these compounds are probed and compared to those of traditionally π-conjugated compounds. The investigations utilize a combination of qualitative chemical bonding theories, quantum chemical calculations, chemical syntheses and different spectroscopic methods.

    Herein, it is revealed that a saturated σ-bonded segment inserted between two π-systems can have optical and electronic properties similar to a cross-conjugated compound when substituents with heavy Group 14 elements (Si, Ge or Sn) are attached to the central atom. We coined the terminology cross-hyperconjugation for this interaction, and have shown it by both computational and spectroscopic means. This similarity is also found in cyclic compounds, for example in the 1,4-disilacyclohexa-2,5-dienes, as we reveal that there is a cyclic aspect of cross-hyperconjugation. Cross-hyperconjugation can further also be found in smaller rings such as siloles and cyclopentadienes, and we show on the similarities between these and their cross-π-conjugated analogues, the fulvenes. Here, this concept is combined with that of excited state aromaticity and the electronic properties of these systems are rationalized in terms of “aromatic chameleon” effects. We show that the optical properties of these systems can be rationally tuned and predicted through the choice of substituents and knowledge about the aromaticity rules in both ground and excited states.

    We computationally examine the relation between conjugation and conductance and reveal that oligomers of 1,4-disilacyclohexa-2,5-dienes and related analogues can display molecular cord properties. The conductance through several σ-conjugated silicon compounds were also examined and show that mixed silicon and carbon bicyclo[2.2.2]octane compounds do not provide significant benefits over the open-chain oligosilanes. However, cyclohexasilanes, a synthetic precursor to the bicyclic compounds, displayed conformer-dependent electronic structure variations that were not seen for cyclohexanes. This allowed for computational design of a mechanically activated conductance switch.

    Delarbeid
    1. Cross-hyperconjugation: An unexplored orbital interaction between pi-conjugated and saturated molecular segments
    Åpne denne publikasjonen i ny fane eller vindu >>Cross-hyperconjugation: An unexplored orbital interaction between pi-conjugated and saturated molecular segments
    Vise andre…
    2013 (engelsk)Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 52, nr 3, s. 983-987Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Crossing a barrier: Molecules with saturated ER2 units (E=C or Si, R=electron-releasing group) inserted between two π-conjugated segments have electronic and optical properties that resemble those of cross-conjugated molecules (see figure). This cross-hyperconjugation provides a deeper understanding of the conjugation phenomenon, and is an alternative to cross-conjugation in the design of molecules for nano and materials applications.

    Emneord
    conjugation, cross-conjugation, Group 14 elements, hyperconjugation, optical tuning
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-194990 (URN)10.1002/anie.201206030 (DOI)000313688100036 ()
    Tilgjengelig fra: 2013-02-21 Laget: 2013-02-20 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    2. Charge transfer through cross-hyperconjugated versus cross-pi-conjugated bridges: an intervalence charge transfer study
    Åpne denne publikasjonen i ny fane eller vindu >>Charge transfer through cross-hyperconjugated versus cross-pi-conjugated bridges: an intervalence charge transfer study
    Vise andre…
    2013 (engelsk)Inngår i: Chemical Science, ISSN 2041-6520, Vol. 4, nr 9, s. 3522-3532Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Recently there has been much interest in electron transfer and transport through cross-conjugated molecules as interesting test cases for the interplay between molecular and electronic structure as well as potential motifs in the design of new compounds for molecular electronics. Herein we expand on this concept and present the synthesis and characterization of a series of four organic mixed-valence dyads to probe the effect of the bridge structure on the electronic coupling. The electronic coupling between two triarylamine units could be mediated either by cross-hyperconjugation through a saturated ER2 bridge (E = C or Si, R = alkyl or silyl group), or via a cross-conjugated pi-system. The aim of the study is to compare the electron transfer through the various saturated bridges to that of a cross-pi-conjugated bridge. The electronic coupling in these mixed-valence compounds was determined by analysis of intervalence charge transfer bands, and was found to be in the range of 100-400 cm(-1). A complementary DFT and TD-DFT study indicated that the electronic coupling in the dyads with saturated ER2 segments is highly conformer dependant. Furthermore, the calculations showed that two types of interactions contribute to the electronic coupling; a through-bond cross-(hyper)conjugation mechanism and a through-space mechanism. Taken together, these findings suggest the possibility for new architectures for molecular electronics applications utilizing cross-hyperconjugation through properly selected saturated segments which have comparable electron transfer characteristics as regular cross-pi-conjugated molecules.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-208680 (URN)10.1039/c3sc50844g (DOI)000322391800021 ()
    Tilgjengelig fra: 2013-10-07 Laget: 2013-10-07 Sist oppdatert: 2014-06-30bibliografisk kontrollert
    3. 1,4-Disilacyclohexa-2,5-diene: a molecular building block that allows for remarkably strong neutral cyclic cross-hyperconjugation
    Åpne denne publikasjonen i ny fane eller vindu >>1,4-Disilacyclohexa-2,5-diene: a molecular building block that allows for remarkably strong neutral cyclic cross-hyperconjugation
    Vise andre…
    2014 (engelsk)Inngår i: Chemical Science, ISSN 2041-6520, Vol. 5, nr 1, s. 360-371Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    2,3,5,6-Tetraethyl-1,4-disilacyclohexa-2,5-dienes with either four chloro (1a), methyl (1b), or trimethylsilyl (TMS) (1c) substituents at the two silicon atoms were examined in an effort to design rigid compounds with strong neutral cross-hyperconjugation between pi- and sigma-bonded molecular segments arranged into a cycle. Remarkable variations in the lowest electronic excitation energies, lowest ionization energies, and the first oxidation potentials were observed upon change of substituents, as determined by gas phase ultraviolet (UV) absorption spectroscopy, ultraviolet photoelectron spectroscopy (UPS), and cyclic voltammetry. A particularly strong neutral cyclic cross-hyperconjugation was observed in 1c. Its lowest electron binding energy (7.1 eV) is distinctly different from that of 1b (8.5 eV). Molecular orbital analysis reveals a stronger interaction between filled pi(C=C) and pi(SiR2) group orbitals in 1c than in 1a and 1b. The energy shift in the highest occupied molecular orbital is also reflected in the first oxidation potentials as observed in the cyclic voltammograms of the respective compounds (1.47, 0.88, and 0.46 V for 1a, 1b and 1c, respectively). Furthermore, 1,4-disilacyclohexadiene 1c absorbs strongly at 273 nm (4.55 eV), whereas 1a and 1b have no symmetry allowed excitations above 215 nm (below 5.77 eV). Thus, suitably substituted 1,4-disilacyclohexa-2,5-dienes could represent novel building blocks for the design of larger cross-hyperconjugated molecules as alternatives to traditional purely cross-p-conjugated analogues, and could allow for design of molecules with properties that are not accessible to those that are exclusively pi-conjugated.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-213891 (URN)10.1039/c3sc52389f (DOI)000327601600045 ()
    Tilgjengelig fra: 2014-01-06 Laget: 2014-01-05 Sist oppdatert: 2016-03-08bibliografisk kontrollert
    4. Optimization of the Cyclic Cross-Hyperconjugation in 1,4-Ditetrelcyclohexa-2,5-dienes
    Åpne denne publikasjonen i ny fane eller vindu >>Optimization of the Cyclic Cross-Hyperconjugation in 1,4-Ditetrelcyclohexa-2,5-dienes
    2014 (engelsk)Inngår i: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 33, nr 12, s. 2997-3004Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Cyclic cross-hyperconjugation can exist to variable extents in 1,4-ditetrelcyclohexa-2,5-dienes, i.e., all-carbon cyclohexa-1,4-dienes and 1,4-disila/digerma/distanna/diplumbacyclohexa-2,5-dienes. In this study we first use density functional theory (DFT) computations to optimize the conjugation strength by seeking the optimal atom E and substituent group E'Me-3 in the two saturated E(E'Me-3)(2) moieties (E and E' as the same or different tetrel (group 14) elements). We reveal that the all-carbon cyclohexadienes with gradually heavier E'Me-3 substituents at the two saturated carbon atoms display significant cross-hyperconjugation. The first electronic excitations in these compounds, which formally have two isolated C=C bonds, are calculated to reach wavelengths as long as 400 nm (excitation energies of 3.1 eV). These transitions are mostly forbidden, and the lowest allowed transitions are found at 387 nm (3.2 eV). The silicon analogues are also cross-hyperconjugated, while a decline is observed in the 1,4-digerma/distanna/diplumbacyclohexa-2,5-diene. Experiments on two substituted 1,4-disilacyclohexa-2,5-dienes confirm the effect of the E'Me3 substituents, with regard to both electronic excitations and geometries as determined by UV absorption spectroscopy and X-ray crystallography, respectively. At the end, we reveal through computations how electron-donating and electron-withdrawing substituents at the C=C double bonds influence the electronic properties of the all-carbon ring. We find that the first calculated excitation, which is forbidden, can be shifted to 440 nm (2.83 eV). This shows to what extent cyclic cross-hyperconjugation can affect the electronic and optical properties of a compound with two formally isolated C=C double bonds.

    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-221022 (URN)10.1021/om5001875 (DOI)000337936800008 ()
    Tilgjengelig fra: 2014-03-24 Laget: 2014-03-24 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    5. Using Ground and Excited State Aromaticity to Understand Cyclopentadiene and Silole Excitation Energies and Excited State Polarities
    Åpne denne publikasjonen i ny fane eller vindu >>Using Ground and Excited State Aromaticity to Understand Cyclopentadiene and Silole Excitation Energies and Excited State Polarities
    Vise andre…
    (engelsk)Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-221027 (URN)
    Tilgjengelig fra: 2014-03-24 Laget: 2014-03-24 Sist oppdatert: 2014-06-30bibliografisk kontrollert
    6. In Search of Flexible Molecular Wires with Near Conformer-Independent Conjugation and Conductance: A Computational Study
    Åpne denne publikasjonen i ny fane eller vindu >>In Search of Flexible Molecular Wires with Near Conformer-Independent Conjugation and Conductance: A Computational Study
    Vise andre…
    2014 (engelsk)Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 118, nr 11, s. 5637-5649Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Oligomers of 1,4-disila/germa/stannacyclohexa-2,5-dienes as well as all-carbon 1,4-cyclohexadienes connected via E—E single bonds (E = C, Si, Ge, or Sn) were studied through quantum chemical calculations in an effort to identify conformationally flexible molecular wires that act as molecular “electrical cords” having conformer-independent conjugative and conductive properties. Our oligomers display neutral hyperconjugative interactions (σ/π-conjugation) between adjacent σ(E—E) and π(C═C) bond orbitals, and these interactions do not change with conformation. The energies and spatial distributions of the highest occupied molecular orbitals of methyl-, silyl-, and trimethylsilyl (TMS)-substituted 1,4-disilacyclohexa-2,5-diene dimers, and stable conformers of trimers and tetramers, remain rather constant upon Si–Si bond rotation. Yet, steric congestion may be a concern in some of the oligomer types. The calculated conductances for the Si-containing tetramers are similar to that of a σ-conjugated linear all-anti oligosilane (a hexadecasilane) with equally many bonds in the conjugated paths. Moreover, the Me-substituted 1,4-disilacyclohexadiene tetramer has modest conductance fluctuations with Si–Si bond rotations when the electrode–electrode distance is locked (variation by factor 30), while the fluctuations under similar conditions are larger for the analogous TMS-substituted tetramer. When the electrode–electrode distance is changed several oligomers display small conductance variations within certain distance intervals, e.g., the mean conductance of TMS-substituted 1,4-disilacyclohexa-2,5-diene tetramer is almost unchanged over 9 Å of electrode–electrode distances.

    sted, utgiver, år, opplag, sider
    American Chemical Society (ACS), 2014
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-209260 (URN)10.1021/jp409767r (DOI)000333381300003 ()
    Tilgjengelig fra: 2013-10-16 Laget: 2013-10-16 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    7. Coupling of Disilane and Trisilane Segments Through Zero, One, Two, and Three Disilanyl Bridges in Cyclic and Bicyclic Saturated Carbosilanes
    Åpne denne publikasjonen i ny fane eller vindu >>Coupling of Disilane and Trisilane Segments Through Zero, One, Two, and Three Disilanyl Bridges in Cyclic and Bicyclic Saturated Carbosilanes
    Vise andre…
    2013 (engelsk)Inngår i: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, nr 2, s. 396-405Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Several six-membered cyclic and [2.2.2]bicyclic organo-silanes with varying proportions of silicon atoms in the bridges have been prepared following a stepwise approach that exploits dianionic polysilanes. Focus in our analysis was placed on the bicyclic compounds which all have silicon atoms at the bridgehead positions. Quantum chemical calculations of these compounds revealed the possibility to enhance the coupling through a single cisoid tetrasilane cage segment by replacing one or two of the other -SiMe2SiMe2- bridges with -CH2CH2- bridges. UV absorption spectroscopy revealed a red shift in the lowest visible transitions when going from a bicyclo[2.2.2]octane with three -SiMe2SiMe2- bridges to those with two or one such bridge. However, these red shifts are deceptive, as the lowest vertically excited singlet states, which are dark according to TD-DFT calculations, do not display the same trend. Still, since these compounds have (i) excellent structural rigidity, (ii) provide potentials for functionalization through their exocyclic trimethylsilyl groups, and (iii) display electronic structure variations with the number of -SiMe2SiMe2- bridges, they could be interesting for further studies: e.g., in single-molecule electronics.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-196040 (URN)10.1021/om3006678 (DOI)000314332100007 ()
    Tilgjengelig fra: 2013-03-04 Laget: 2013-03-04 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    8. Conductance through Carbosilane Cage Compounds: A Computational Investigation
    Åpne denne publikasjonen i ny fane eller vindu >>Conductance through Carbosilane Cage Compounds: A Computational Investigation
    Vise andre…
    2013 (engelsk)Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 117, nr 42, s. 21692-21699Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Silicon is still the dominating material in microelectronics, yet primarily π-conjugated hydrocarbons are investigated in the field of single-molecule electronics even though linear oligosilanes are σ-conjugated. A drawback with the latter is their high conformational flexibility which strongly affects conductance. Here we report on a first principles density functional theory investigation of a series of rigid [2.2.2]bicyclic carbosilanes with 3, 2, 1, or 0 disilanylene bridges, providing all-silicon paths for charge transport. It is explored if these paths can be seen as independent and equivalent current paths acting as parallel resistors. For high conductance through the carbosilanes they need to be anchored to the gold electrodes via groups that are matched with the σ-conjugated paths of the oligosilane cage segment, and we find that silyl (SiH3) groups are better matched than thiophenol groups. Even for the carbosilane with three disilanylene bridges we find that the most transmitting conductance channel is not equally distributed on the three parallel bridges. In addition, there is significant communication between the various pathways, which results in destructive interference lowering the conductance. Taken together, the different disilanylene bridges in the cage compounds do not act as parallel resistors.

    Emneord
    Molecular electronics, organosilicon chemistry, electronic structure, density functional theory, sigma conjugation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-209236 (URN)10.1021/jp407485n (DOI)000326260000008 ()
    Tilgjengelig fra: 2013-10-16 Laget: 2013-10-15 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    9. Configuration- and Conformation-Dependent Electronic Structure Variations in 1,4-Disubstituted Cyclohexanes Enabled by a Carbon-to-Silicon Exchange
    Åpne denne publikasjonen i ny fane eller vindu >>Configuration- and Conformation-Dependent Electronic Structure Variations in 1,4-Disubstituted Cyclohexanes Enabled by a Carbon-to-Silicon Exchange
    Vise andre…
    2014 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, nr 30, s. 9304-9311Artikkel i tidsskrift (Annet vitenskapelig) Published
    Abstract [en]

    Cyclohexane, with its well-defined conformers, could be an ideal force-controlled molecular switch if it were to display substantial differences in electronic and optical properties between its conformers. We utilize sigma conjugation in heavier analogues of cyclohexanes (i.e. cyclohexasilanes) and show that 1,4-disubstituted cyclohexasilanes display configuration-and conformation-dependent variations in these properties. Cis- and trans-1,4-bis(trimethylsilylethynyl)-cyclohexasilanes display a 0.11 V difference in their oxidation potentials (computed 0.11 V) and a 0.34 eV difference in their lowest UV absorption (computed difference between first excitations 0.07 eV). This is in stark contrast to differences in the corresponding properties of analogous all-carbon cyclohexanes (computed 0.02 V and 0.03 eV, respectively). Moreover, the two chair conformers of the cyclohexasilane trans isomer display large differences in electronic-structure-related properties. This enables computational design of a mechanically force-controlled conductance switch with a calculated single-molecule ON/OFF ratio of 213 at zero-bias voltage.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-209259 (URN)10.1002/chem.201402610 (DOI)000339568800023 ()
    Merknad

    De 2 sista författarna delar sistaförfattarskapet.

    Tilgjengelig fra: 2013-10-16 Laget: 2013-10-16 Sist oppdatert: 2017-12-06bibliografisk kontrollert
  • 296.
    Emanuelsson, Rikard
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Denisova, Aleksandra
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Baumgartner, Judith
    Institut für Chemie, Universität Graz.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Optimization of the Cyclic Cross-Hyperconjugation in 1,4-Ditetrelcyclohexa-2,5-dienes2014Inngår i: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 33, nr 12, s. 2997-3004Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cyclic cross-hyperconjugation can exist to variable extents in 1,4-ditetrelcyclohexa-2,5-dienes, i.e., all-carbon cyclohexa-1,4-dienes and 1,4-disila/digerma/distanna/diplumbacyclohexa-2,5-dienes. In this study we first use density functional theory (DFT) computations to optimize the conjugation strength by seeking the optimal atom E and substituent group E'Me-3 in the two saturated E(E'Me-3)(2) moieties (E and E' as the same or different tetrel (group 14) elements). We reveal that the all-carbon cyclohexadienes with gradually heavier E'Me-3 substituents at the two saturated carbon atoms display significant cross-hyperconjugation. The first electronic excitations in these compounds, which formally have two isolated C=C bonds, are calculated to reach wavelengths as long as 400 nm (excitation energies of 3.1 eV). These transitions are mostly forbidden, and the lowest allowed transitions are found at 387 nm (3.2 eV). The silicon analogues are also cross-hyperconjugated, while a decline is observed in the 1,4-digerma/distanna/diplumbacyclohexa-2,5-diene. Experiments on two substituted 1,4-disilacyclohexa-2,5-dienes confirm the effect of the E'Me3 substituents, with regard to both electronic excitations and geometries as determined by UV absorption spectroscopy and X-ray crystallography, respectively. At the end, we reveal through computations how electron-donating and electron-withdrawing substituents at the C=C double bonds influence the electronic properties of the all-carbon ring. We find that the first calculated excitation, which is forbidden, can be shifted to 440 nm (2.83 eV). This shows to what extent cyclic cross-hyperconjugation can affect the electronic and optical properties of a compound with two formally isolated C=C double bonds.

  • 297.
    Emanuelsson, Rikard
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Huang, Hao
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Gogoll, Adolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Sjödin, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Enthalpic versus Entropic Contribution to the Quinone Formal Potential in a Polypyrrole-Based Conducting Redox Polymer2016Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 120, nr 38, s. 21178-21183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A conducting redox polymer (CPR) based on pyrrole with a hydroquinone pendant group was synthesized through electropolymerization of the corresponding monomer. The formal potential (E-0') in aqueous solution at different pH as well as in MeCN containing equal amounts of pyridiniumtriflates and the corresponding free pyridine with different pK(a) was investigated. E-0' could be completely recovered in MeCN, and by utilizing pyridine bases with different donor acceptor strengths, a decrease of 61 meV/pK(a) was found that corresponded exactly to the pH dependence of E-0' in aqueous electrolyte. To separate the entropic and enthalpic contributions to E-0', temperature-dependent electrochemistry was performed. Two different modes of operation with changing pH/pK(a) between the two media were revealed. In MeCN, E-0' varies only because of the enthalpic contribution as the entropic contribution is unaffected by change in pKa. In water, there is primarily an entropic contribution to E-0' with changing pH due to solvation of the proton. The presented results are expected to open up for new design possibilities of CRPs based on ion coordinating redox groups for electrical energy storage.

  • 298.
    Emanuelsson, Rikard
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Löfås, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Wallner, Andreas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi. Institut für Anorganische Chemie, Technische Universität Graz.
    Nauroozi, Djawed
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström.
    Baumgartner, Judith
    Institut für Anorganische Chemie, Technische Universität Graz.
    Marschner, Christoph
    Institut für Anorganische Chemie, Technische Universität Graz.
    Ahuja, Rajeev
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Ott, Sascha
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Grigoriev, Anton
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Configuration- and Conformation-Dependent Electronic Structure Variations in 1,4-Disubstituted Cyclohexanes Enabled by a Carbon-to-Silicon Exchange2014Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, nr 30, s. 9304-9311Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Cyclohexane, with its well-defined conformers, could be an ideal force-controlled molecular switch if it were to display substantial differences in electronic and optical properties between its conformers. We utilize sigma conjugation in heavier analogues of cyclohexanes (i.e. cyclohexasilanes) and show that 1,4-disubstituted cyclohexasilanes display configuration-and conformation-dependent variations in these properties. Cis- and trans-1,4-bis(trimethylsilylethynyl)-cyclohexasilanes display a 0.11 V difference in their oxidation potentials (computed 0.11 V) and a 0.34 eV difference in their lowest UV absorption (computed difference between first excitations 0.07 eV). This is in stark contrast to differences in the corresponding properties of analogous all-carbon cyclohexanes (computed 0.02 V and 0.03 eV, respectively). Moreover, the two chair conformers of the cyclohexasilane trans isomer display large differences in electronic-structure-related properties. This enables computational design of a mechanically force-controlled conductance switch with a calculated single-molecule ON/OFF ratio of 213 at zero-bias voltage.

  • 299.
    Emanuelsson, Rikard
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Löfås, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Zhu, Jun
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi. State Key Laboratory of Physical Chemistry of Solid Surfaces, Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University.
    Ahuja, Rajeev
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Grigoriev, Anton
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    In Search of Flexible Molecular Wires with Near Conformer-Independent Conjugation and Conductance: A Computational Study2014Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 118, nr 11, s. 5637-5649Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oligomers of 1,4-disila/germa/stannacyclohexa-2,5-dienes as well as all-carbon 1,4-cyclohexadienes connected via E—E single bonds (E = C, Si, Ge, or Sn) were studied through quantum chemical calculations in an effort to identify conformationally flexible molecular wires that act as molecular “electrical cords” having conformer-independent conjugative and conductive properties. Our oligomers display neutral hyperconjugative interactions (σ/π-conjugation) between adjacent σ(E—E) and π(C═C) bond orbitals, and these interactions do not change with conformation. The energies and spatial distributions of the highest occupied molecular orbitals of methyl-, silyl-, and trimethylsilyl (TMS)-substituted 1,4-disilacyclohexa-2,5-diene dimers, and stable conformers of trimers and tetramers, remain rather constant upon Si–Si bond rotation. Yet, steric congestion may be a concern in some of the oligomer types. The calculated conductances for the Si-containing tetramers are similar to that of a σ-conjugated linear all-anti oligosilane (a hexadecasilane) with equally many bonds in the conjugated paths. Moreover, the Me-substituted 1,4-disilacyclohexadiene tetramer has modest conductance fluctuations with Si–Si bond rotations when the electrode–electrode distance is locked (variation by factor 30), while the fluctuations under similar conditions are larger for the analogous TMS-substituted tetramer. When the electrode–electrode distance is changed several oligomers display small conductance variations within certain distance intervals, e.g., the mean conductance of TMS-substituted 1,4-disilacyclohexa-2,5-diene tetramer is almost unchanged over 9 Å of electrode–electrode distances.

  • 300.
    Emanuelsson, Rikard
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Tibbelin, Julius
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Wallner, Andreas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Smith, Joshua R.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Strong neutral cross-hyperconjugation and linear hyperconjugation enabled by saturated Group 14 element E(E ' R-3)(2), (E ' R-3)E-E(E ' R-3), and E(E ' R-2)(2)E segments2013Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 245, s. 1246-INOR-Artikkel i tidsskrift (Annet vitenskapelig)
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