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  • 201.
    Chu, Jiangtao
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Undin, Torgny
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergström Lind, Sara
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Hjort, Klas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Dahlin, Andreas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Influence of surface modification and static pressure on microdialysis protein extraction efficiency2015Inngår i: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781, Vol. 17, nr 5, artikkel-id UNSP 96Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is growing interest in using microdialysis (MD) for monitoring larger and more complexmolecules such as neuropeptides and proteins. This promotes the use of MD membranes withmolecular weight cut off (MWCO) of 100 kDa or above. The hydrodynamic property of themembrane goes to ultrafiltration or beyond, making the MD catheters more sensitive to pressure.In the meantime, despite the large pore size, studies have shown that membrane biofouling stilllead to unstable catheter performance. The objective is to study in vitro how 500 kDa dextranand Poloxamer 407 surface modification affect the fluid recovery (FR) and extraction efficiency(EE) of 100 kDa MWCO MD catheters. A pressure chamber was designed to facilitate the tests,using as MD sample a protein standard with similar concentrations as in human cerebral spinalfluid, comparing native and Poloxamer 407 modified MD catheters. The collected dialysatefractions were examined for FR and protein EE, employing Dot-it Spot-it Protein Assay for totalprotein EE and targeted mass spectrometry (MS) for EE of individual proteins and peptides. TheFR results suggested that the surface modified catheters were less sensitive to the pressure andprovide higher precision, and provided a FR closer to 100%. The surface modification did notshow a significant effect on the protein EE. The average total protein EE of surface modifiedcatheters was slightly higher than that of the native ones. The MS EE data of individual proteinsshowed a clear trend of complex response in EE with pressure.

  • 202.
    Chu, Jiangtao
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Undin, Torgny
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Dahlin, Andreas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Wang, Cong
    Park, Jungyul
    Hjort, Klas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Protein Desalination Chip for Mass Spectrometry Sample Preparation2015Konferansepaper (Fagfellevurdert)
    Abstract [en]

    This work focuses on desalination of a protein sample in a lab-on-chip device using the ion concentration polarization (ICP) technique. It was demonstrated with a salt containing buffer with four proteins and two peptides of concentrations typical to cerebrospinal fluid (CSF). Not only was the output desalinated but its protein concentration with large molecular weight (MW) was as much as 3 times higher for the largest protein compared to the original. We conclude that ICP based microfluidic chips have great potential for desalination and protein concentration in microdialysis sampling coupled to mass spectroscopy (MS).

  • 203.
    Chu, Jiangtao
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Undin, Torgny
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Lind, Sara
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Dahlin, Andreas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Hjort, Klas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Influence of different pluronic surface modifications and pressure on microdialysis protein extraction efficiency2015Inngår i: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is growing interest in using microdialysis (MD) for monitoring larger and more complexmolecules such as neuropeptides and proteins. This promotes the use of MD membranes withmolecular weight cut off (MWCO) of 100 kDa. Hence, the hydrodynamic property of themembrane goes to ultrafiltration, making the sampling more sensitive to pressure changes. Also,despite the large membrane pore size, studies have shown that membrane biofouling still leads tounstable catheter performance. Our objective is to study in vitro how four kinds of surfacemodifications (Pluronic L31, L44, F87 and F127+L31) affect the fluid recovery (FR) andextraction efficiency (EE) of 100 kDa MWCO MD catheters, under controlled pressure. Apressure chamber was employed to facilitate the tests, using as MD sample a protein standardwith proteins of similar concentrations as in human cerebral spinal fluid. The collected dialysatefractions were examined for FR and EE. Targeted mass spectrometry analysed the EE ofindividual proteins and peptides. The thicker the pluronic adsorption layer, the less thehydrodynamic diameter of the membrane pores, leading to lower and more stable FR. The foursurface modifications had three different behaviours: Pluronic F127 + L31 showed similarbehavior to the Pluronic F127 and the native original membrane; Pluronic F87 showed acontinuous EE increase with pressure; Pluronic L31 and L44 showed similar EE values, whichwere stable with pressure. Different surface modifications are clearly selective to differentproteins and peptides. We conclude that a pluronic surface modification could provide MDsampling with more stable FR, and more stable or enhanced EE with high FR, depending on theobjective of the sampling.

  • 204. Cleland, Dougal
    et al.
    Olsson, Gustaf D.
    Karlsson, Bjorn C. G.
    Nicholls, Ian A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    McCluskey, Adam
    Molecular dynamics approaches to the design and synthesis of PCB targeting molecularly imprinted polymers: interference to monomer-template interactions in imprinting of 1,2,3-trichlorobenzene2014Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, nr 5, s. 844-853Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The interactions between each component of the pre-polymerisation mixtures used in the synthesis of molecularly imprinted polymers (MIP) specific for 1,2,3,4,5-pentachlorobenzene (1) and 1,2,3-trichlorobenzene (2) were examined in four molecular dynamics simulations. These simulations revealed that the relative frequency of functional monomer template (FM T) interactions was consistent with results obtained by the synthesis and evaluation of the actual MIPs. The higher frequency of 1 interaction with tri-methylstyrene (TMS; 54.7%) than 1 interaction with pentafluorostyrene (PFS; 44.7%) correlated with a higher imprinting factor (IF) of 2.1 vs. 1.7 for each functional monomer respectively. The higher frequency of PFS interactions with 2 (29.6%) than TMS interactions with 2 (1.9%) also correlated well with the observed differences in IF (3.7) of 2 MIPs imprinted using PFS as the FM than the IF (2,8) of 2 MIPs imprinted using TMS as the FM. The TMS-1 interaction dominated the molecular simulation due to high interaction energies, but the weaker TMS-2 resulted in low interaction maintenance, and thus lower IF values. Examination of the other pre-polymerisation mixture components revealed that the low levels of TMS-2 interaction was, in part, due to interference caused by the cross linker (CL) ethyleneglycol dimethylacrylate (EGDMA) interactions with TMS. The main reason was, however, attributed to MeOH interactions with TMS in both a hydrogen bond and perpendicular configuration. This positioned a MeOH directly above the it-orbital of all TMS for an average of 63.8% of MD2 creating significant interference to pi-pi stacking interactions between 2 and TMS. These findings are consistent with the deviation from the 'normal' molecularly imprinted polymer synthesis ratio of 1 : 4 : 20 (T : FM : CL) of 20 : 1 : 29 and 15 : 6 : 29 observed with 2 and TMS and PFS respectively. Our molecular dynamics simulations correctly predicted the high level of interference from other MIP synthesis components. The effect on PFS-1 interaction by MeOH was significantly lower and thus this system was not adversely affected.

  • 205.
    Co, Michelle
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Fagerlund, Amelie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Sunnerheim, Kerstin
    Department of Natural Sciences, Engineering and Mathematics, Mid Sweden University.
    Sjöberg, Per J. R
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Turner, Charlotta
    Dept of Organic Chemistry, Lund University.
    Extraction of Antioxidants from Spruce (Picea abies) Bark using Eco-Friendly Solvents2012Inngår i: Phytochemical Analysis, ISSN 0958-0344, E-ISSN 1099-1565, Vol. 23, nr 1, s. 1-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction-Antioxidants are known to avert oxidation processes and they are found in trees and other plant materials. Tree bark is a major waste product from paper pulp industries; hence it is worthwhile to develop an extraction technique to extract the antioxidants.

    Objective- To develop a fast and environmentally sustainable extraction technique for the extraction of antioxidants from bark of spruce (Picea abies) and also to identify the extracted antioxidants that are abundant in spruce bark.

    Methodology- A screening experiment that involved three different techniques, was conducted to determine the best technique to extract antioxidants.The antioxidant capacity of the extracts was determined with DPPH (2,2-diphenyl-2’-picrylhydrazyl) assay. Pressurised fluid extraction (PFE) turned out to be the best technique and a response surface design was therefore utilised to optimise PFE. Furthermore, NMR and HPLC-DAD-MS/MS were applied to identify the extracted antioxidants.

    Results- PFE using water and ethanol as solvent at 160 and 180°C, respectively, gave extracts of the highest antioxidant capacity. Stilbene glucosides such as isorhapontin, piceid and astringin were identified in the extracts.

    Conclusion-The study has shown that PFE is a fast and environmentally sustainable technique, using water and ethanol as solvent for the extraction of antioxidants from spruce bark.

  • 206.
    Co, Michelle
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Zettersten, Camilia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Nyholm, Leif
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Oorganisk kemi.
    Sjöberg, Per J.R
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Turner, Charlotta
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Degradation effects in the extraction of antioxidants from birch bark using water at elevated temperature and pressure2012Inngår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 716, s. 40-48Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Experiments with birch bark samples have been carried to enable a distinction between extraction and degradation effects during pressurised hot water extraction. Two samples, E80 and El 80, contained birch bark extracts obtained after extraction at 80 and 180 degrees C for up to 45 min, respectively. Two other samples, P80 and P180, were only extracted for 5 min at the two temperatures and were thereafter filtered and hydrothermally treated at 80 and 180 degrees C, respectively. During the latter treatment, samples were collected at different times to assess the stability of the extracted compounds. An offline DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, as well as a high performance liquid chromatographic separation coupled to an electrochemical detector, were used to determine the antioxidant capacity of the processed samples. The results obtained with the different techniques were compared to assess the yield of the extraction and degradation processes. In addition, an online hyphenated system comprising high performance liquid chromatography coupled to diode-array; electrochemical; and tandem mass spectrometric detection (HPLC-DAD-ECD-MS/MS) was used to study the compositions of the extracts in more detail. The results for the samples processed at 80 degrees C showed that the extraction reached a steady-state already after 5 min, and that the extracted compounds were stable throughout the entire extraction process. Processing at 180 degrees C, on the other hand, gave rise to partly degraded extracts with a multitude of peaks in both the diode array and electrochemical detectors, and a higher antioxidant capacity compared to for the extracts obtained at 80 degrees C. It is concluded that HPLC-DAD-ECD is a more appropriate technique for the determination of antioxidants than the DPPH assay. The mass spectrometric results indicate that one of the extracted antioxidants, catechin, was isomerised to its diastereoisomers; (+)-catechin, (-)-catechin, (+)-epicatechin, and (-)-epicatechin.

     

  • 207.
    Colbin, Simon
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    SCC-DFTB for Transition Metals: Tight Binding Parametrisation2018Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Fulltekst tilgjengelig fra 2020-07-01 22:00
  • 208.
    Corbella, Marina
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi. Univ Barcelona, Fac Pharm & Food Sci, Dept Pharm & Pharmaceut Technol & Phys Chem, Av Joan XXIII S-N, E-08028 Barcelona, Spain;Univ Barcelona, Fac Pharm & Food Sci, Inst Theoret & Computat Chem IQTC UB, Av Joan XXIII S-N, E-08028 Barcelona, Spain.
    Cupellini, Lorenzo
    Univ Pisa, Dipartimento Chim & Chim Ind, Via Risorgimento 35, I-56126 Pisa, Italy;Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10, Barcelona 08028, Spain.
    Lipparini, Filippo
    Univ Pisa, Dipartimento Chim & Chim Ind, Via Risorgimento 35, I-56126 Pisa, Italy.
    Scholes, Gregory D.
    Princeton Univ, Dept Chem, Washington Rd, Princeton, NJ 08544 USA.
    Curutchet, Cartes
    Univ Barcelona, Fac Pharm & Food Sci, Dept Pharm & Pharmaceut Technol & Phys Chem, Av Joan XXIII S-N, E-08028 Barcelona, Spain;Univ Barcelona, Fac Pharm & Food Sci, Inst Theoret & Computat Chem IQTC UB, Av Joan XXIII S-N, E-08028 Barcelona, Spain.
    Spectral Variability in Phycocyanin Cryptophyte Antenna Complexes is Controlled by Changes in the alpha-Polypeptide Chains2019Inngår i: CHEMPHOTOCHEM, ISSN 2367-0932, Vol. 3, nr 9, s. 945-956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Quantitative models of light harvesting in photosynthetic antenna complexes depend sensitively on the challenging determination of the relative site energies of the pigments. Herein we analyze the basis of the light harvesting properties of four antennae from cryptophyte algae, phycocyanines PC577, PC612, PC630 and PC645, by comparing two alternative theoretical strategies to derive the excitonic Hamiltonian. The first is based on molecular dynamics simulations and subsequent polarizable quantum/molecular mechanics (QM/MMPol) calculations, whereas the second is based on three-layer QM/MMPol/ddCOSMO calculations performed on optimized geometries of the pigments, where the water solvent is described using the ddCOSMO continuum model. We find the latter approach to be remarkably accurate, suggesting that these four phycobiliproteins share a common energetic ordering PCB82 < PCB158 < DBV51/61 for pigments located in the highly-conserved beta chains, whereas bilins in the more divergent alpha chains cause their spectral differences. In addition, we predict a strong screening of the coupling among central dihydrobiliverdins (DBVs) in "open" form complexes PC577 and PC612 compared to "closed" form ones, which together with the increased interpigment separation explains the attenuation of coherence beatings observed for these complexes.

  • 209.
    Corpeno, Rebeca
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Dworkin, Barry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Cacciani, Nicola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Salah, Heba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Bergman, Hilde-Marlene
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ravara, B
    Vitadello, M
    Gorza, Luisa
    Gustafson, Ann-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Hedström, Yvette
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Petersson, J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Feng, H-Z
    Jin, Jian-Ping
    Iwamoto, Hiroyuki
    Yagi, Naoto
    Artemenko, Konstantin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Time-course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat2014Inngår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 592, nr 17, s. 3859-3880Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Controlled mechanical ventilation (CMV) plays a key role in triggering the impaired diaphragm muscle function and the concomitant delayed weaning from the respirator in critically ill intensive care unit (ICU) patients. To date, experimental and clinical studies have primarily focused on early effects on the diaphragm by CMV, or at specific time points. To improve our understanding of the mechanisms underlying the impaired diaphragm muscle function in response to mechanical ventilation, we have performed time‐resolved analyses between 6 h and 14 days using an experimental rat ICU model allowing detailed studies of the diaphragm in response to long‐term CMV. A rapid and early decline in maximum muscle fibre force and preceding muscle fibre atrophy was observed in the diaphragm in response to CMV, resulting in an 85% reduction in residual diaphragm fibre function after 9–14 days of CMV. A modest loss of contractile proteins was observed and linked to an early activation of the ubiquitin proteasome pathway, myosin:actin ratios were not affected and the transcriptional regulation of myosin isoforms did not show any dramatic changes during the observation period. Furthermore, small angle X‐ray diffraction analyses demonstrate that myosin can bind to actin in an ATP‐dependent manner even after 9–14 days of exposure to CMV. Thus, quantitative changes in muscle fibre size and contractile proteins are not the dominating factors underlying the dramatic decline in diaphragm muscle function in response to CMV, in contrast to earlier observations in limb muscles. The observed early loss of subsarcolemmal neuronal nitric oxide synthase activity, onset of oxidative stress, intracellular lipid accumulation and post‐translational protein modifications strongly argue for significant qualitative changes in contractile proteins causing the severely impaired residual function in diaphragm fibres after long‐term mechanical ventilation. For the first time, the present study demonstrates novel changes in the diaphragm structure/function and underlying mechanisms at the gene, protein and cellular levels in response to CMV at a high temporal resolution ranging from 6 h to 14 days.

  • 210.
    Costeira-Paulo, Joana
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Gault, Joseph
    University of Oxford.
    Popova, Gergana
    Ladds, Marcus J G W
    van Leeuwen, Ingeborg M M
    Sarr, Médoune
    Olsson, Anders
    Lane, David P
    Laín, Sonia
    Marklund, Erik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Landreh, Michael
    Lipids Shape the Electron Acceptor-Binding Site of the Peripheral Membrane Protein Dihydroorotate Dehydrogenase2018Inngår i: Cell Chemical Biology, ISSN 2451-9456, E-ISSN 2451-9448, Vol. 25, nr 3, s. 309-317Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The interactions between proteins and biological membranes are important for drug development, but remain notoriously refractory to structural investigation. We combine non-denaturing mass spectrometry (MS) with molecular dynamics (MD) simulations to unravel the connections among co-factor, lipid, and inhibitor binding in the peripheral membrane protein dihydroorotate dehydrogenase (DHODH), a key anticancer target. Interrogation of intact DHODH complexes by MS reveals that phospholipids bind via their charged head groups at a limited number of sites, while binding of the inhibitor brequinar involves simultaneous association with detergent molecules. MD simulations show that lipids support flexible segments in the membrane-binding domain and position the inhibitor and electron acceptor-binding site away from the membrane surface, similar to the electron acceptor-binding site in respiratory chain complex I. By complementing MS with MD simulations, we demonstrate how a peripheral membrane protein uses lipids to modulate its structure in a similar manner as integral membrane proteins.

  • 211.
    Cui, Zhong-Kai
    et al.
    Department of Chemistry, Centre for Self-Assembled Chemical Structures (CSACS), Université de Montréal, Canada.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Orellana, Alejandro Nieto
    INSERM U1066, Micro et Nanomédecines Biomimétiques-MINT, France AND LUNAM Université, UMR-S1066, Angers F-49933, France.
    Bastiat, Guillaume
    INSERM U1066, Micro et Nanomédecines Biomimétiques-MINT, France AND LUNAM Université, UMR-S1066, Angers F-49933, France.
    Benoit, Jean-Pierre
    INSERM U1066, Micro et Nanomédecines Biomimétiques-MINT, France AND LUNAM Université, UMR-S1066, Angers F-49933, France.
    Lafleur, Michel
    Department of Chemistry, Centre for Self-Assembled Chemical Structures (CSACS), Université de Montréal, Canada.
    Impact of interfacial cholesterol-anchored polyethylene glycol on sterol-rich non-phospholipid liposomes2014Inngår i: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 428, s. 111-120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hypothesis

    Liposomes made of single-chain amphiphiles and a large amount of sterols display several advantages including a limited permeability. In the present paper, we examine the possibility to prepare such non-phospholipid liposomes with interfacial polyethylene glycol (PEG) in order to improve their circulation in the blood stream. Cholesterol (Chol) was chosen as the PEG anchor.

    Experiments

    The phase behavior of mixtures of palmitic acid (PA) and cholesterol including various proportions of PEGylated cholesterol (PEG-Chol) was characterized. In conditions leading to the formation of fluid bilayers, properties of the resulting liposomes were assessed.

    Findings

    Up to 20 mol% of PEGylated cholesterol could be introduced without significant perturbations in fluid bilayers made of PA and cholesterol. With 10 mol% PEG-Chol, PA/Chol/PEG-Chol liposomes showed a very limited permeability to calcein and doxorubicin. Doxorubicin could be actively loaded in PA/Chol/PEG-Chol liposomes with a high drug loading efficiency and a high drug to lipid ratio. Pharmaco-kinetic experiments in rats indicated that interfacial PEG reduced the clearance of PA/Chol liposomes compared to the naked ones. However the lifetime of these non-phospholipid liposomes in the blood circulation was considerably shorter than that observed for control PEGylated phospholipid liposomes, a phenomenon associated with the negative interfacial charge of the PA/Chol/PEG-Chol liposomes. 

  • 212. Czyzewski, Michal
    et al.
    Sellars, Jonathan D.
    Guliashvili, Tamaz
    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, Fysikalisk-organisk kemi.
    Johnstone, Lisa
    Bower, Justin
    Box, Matthew
    Davies, Robert D. M.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Steel, Patrick G.
    The first intramolecular silene Diels-Alder reactions2014Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 50, nr 22, s. 2919-2921Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The synthesis of silaheterocycles through the first examples of an intramolecular silene Diels-Alder reaction is described.

  • 213.
    da Silva, Marcelo A.
    et al.
    Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
    Weinzaepfel, Evelyne
    Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
    Afifi, Hala
    Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
    Eriksson, Jonny
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Grillo, Isabelle
    Institut Laue-Langevin (ILL), DS/LSS, 6, rue Jules Horowitz, B.P. 156, 38042 Grenoble Cedex, France.
    Valero, Margarita
    Departamento de Química Física, Universidad de Salamanca, 37008 Salamanca, Spain.
    Dreiss, Cécile A.
    Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
    Tuning the Viscoelasticity of Nonionic Wormlike Micelles with beta-Cyclodextrin Derivatives: A Highly Discriminative Process2013Inngår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 29, nr 25, s. 7697-7708Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report the influence of five β-cyclodextrin (β-CD) derivatives, namely: randomly methylated β-cyclodextrin (MBCD), heptakis (2,6-di-O-methyl)-β-cyclodextrin (DIMEB), heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB), 2-hydroxyethyl-β-cyclodextrin (HEBCD) and 2-hydroxypropyl-β-cyclodextrin (HPBCD), on the self-assembly of mixtures of nonionic surfactants: polyoxyethylene cholesteryl ether (ChEO10) and monocaprylin (MCL). Mixtures of ChEO10/MCL in water form highly viscoelastic wormlike micelle solutions (WLM) over a range of concentrations; herein, the composition was fixed at 10 wt % ChEO10/3 wt % MCL. The addition of methylated β-CDs (MBCD, DIMEB, TRIMEB) induced a substantial disruption of the solid-like viscoelastic behavior, as shown from a loss of the Maxwell behavior, a large reduction in G′ and G″ in oscillatory frequency-sweep measurements, and a drop of the viscosity. The disruption increased with the degree of substitution, following: MBCD < DIMEB < TRIMEB. Cryo-TEM images confirmed a loss of the WLM networks, revealing short rods and disc-like aggregates, which were corroborated by small-angle neutron scattering (SANS) measurements. Critical aggregation concentrations (CAC), measured by fluorescence spectroscopy, increased in the presence of DIMEB for both ChEO10 and MCL, suggesting the existence of interactions between methylated β-CDs and both surfactants involved in WLM formation. Instead, hydroxyl-β-CDs had a very different effect on the WLM. HPBCD only slightly reduced the solid-like behavior, without suppressing it. Quite remarkably, the addition of HEBCD reinforced the solid-like characteristics and increased the viscosity 10-fold. Cryo-TEM images confirmed the subsistence of WLM in ChEO10/MCL/HEBCD solutions, while SANS data revealed a slight elongation and thickening of the worms, and an increase of associated water molecules. CAC data showed that HPBCD had little effect on either surfactant, while HEBCD strongly affected the CAC of MCL and only slightly affected the ChEO10. For both DIMEB and HEBCD, time-resolved SANS measurements showed that morphology changes underlying these macroscopic changes occur in less than 100 ms.

  • 214.
    Dahlin, Andreas P
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Hjort, Klas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Sjödin, Marcus O D
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Wetterhall, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Quantification of Proteins Adsorbed to Surface Modified and Non-Modified Microdialysis Membranes using on-Surface Enzymatic Digestion (oSED) iTRAQ-MALDI-TOF/TOF MS2012Inngår i: 60th ASMS Conference on Mass Spectrometry and Allied Topics, May 20 - 24, Vancouver, Canada, 2012Konferansepaper (Fagfellevurdert)
  • 215.
    Dahlin, Andreas P
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Hjort, Klas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Hillered, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Sjödin, Marcus O.D.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Wetterhall, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Multiplexed quantification of proteins adsorbed to surface-modified and non-modified microdialysis membranes2012Inngår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 402, nr 6, s. 2057-2067Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A simple and straightforward method for discovery and quantification of proteins adsorbed onto delicate and sensitive membrane surfaces is presented. The adsorbed proteins were enzymatically cleaved while still adsorbed onto the membranes using an on-surface enzymatic digestion (oSED). This was followed by isobaric tagging, nanoliquid chromatography, and tandem mass spectrometry. Protein adsorption on tri-block copolymer Poloxamer 407 surface-modified microdialysis (MD) membranes were compared with protein adsorption on unmodified MD membranes. Ventricular cerebrospinal fluid (vCSF) kept at 37 °C was used as sample matrix. In total, 19 proteins were quantified in two biological replicates. The surface-modified membranes adsorbed 33% less proteins than control membranes and the most abundant proteins were subunits of hemoglobin and clusterin. The adsorption of clusterin on the modified membranes was on average 36% compared to control membranes. The most common protein in vCSF, Albumin, was not identified adsorbed to the surface at all. It was also experimentally verified that oSED, in conjunction with tandem mass spectrometry can be used to quantify femtomole amounts of proteins adsorbed on limited and delicate surfaces, such as MD membranes. The method has great potential and can be used to study much more complex protein adsorption systems than previously reported.

  • 216.
    Dahlstrand, Christian
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Ground and Excited State Aromaticity: Design Tools for π-Conjugated Functional Molecules and Materials2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The main focus of this thesis is on the aromaticity of the ground state and electronically excited states of π-conjugated molecules and polymers, as well as how aromaticity is connected to their properties.

    The electronic structures of polybenzenoid hydrocarbons (PBHs) were explored through density functional theory (DFT) calculations and the π-component of the electron localization function (ELFπ). The study revealed how the π-electronic structure is influenced by the fusion of double bonds or benzene rings to the PBHs. We also demonstrated that the π-electrons of benzene extend to accommodate as much aromaticity as possible when bond length distorted.  

    The aromatic chameleon property displayed by fulvenes, isobenzofulvenes, fulvalenes, bis(fulvene)s, and polyfulvenes were investigated using DFT calculations. The tria-, penta-, and heptafulvenes were shown to possess ionization energies and electron affinities which can be tuned extensively by substitution, some of which even outperform TTF and TCNQ, the prototypical electron donor and acceptor, respectively. The singlet-triplet energy gap of pentafulvenes can be tuned extensively by substitution to the point that the triplet state is lower than the singlet state and thus becomes the ground state. The ELFπ of isobenzofulvene shows that the benzene ring in an electronically excited state can be more aromatic than the corresponding ring in the ground state. We have shown that the 6-ring of [5.6.7]quinarene is influenced by a Hückel aromatic resonance structure with 4n+2 π-electrons in the excited quintet state. The bis(fulvene)s which are composed of a donor type heptafulvene and an acceptor type pentafulvene, retain the basic donor-acceptor properties of the two fragments and could function as compact donor-acceptor dyads. A few of the designed polyfulvenes were found to have band gaps below 1 eV at the PBC-B3LYP/6-31G(d) level.

    Various 2,7-disubstituted fluorenones and dibenzofulvenes were synthesized and their excited state properties were investigated by absorption spectroscopy and time-dependent DFT calculations. It was found that the 1A1B transition of ππ* character can be tuned by substitution in the 2,7-positions. The 2,7-bis(N,N-dimethyl) derivatives of fluorenone and dibenzofulvene displayed low energy transitions at 2.18 and 1.61 eV, respectively, in toluene.

    Delarbeid
    1. On the Importance of Clar Structures of Polybenzenoid Hydrocarbons as Revealed by the n-Contribution to the Electron Localization Function
    Åpne denne publikasjonen i ny fane eller vindu >>On the Importance of Clar Structures of Polybenzenoid Hydrocarbons as Revealed by the n-Contribution to the Electron Localization Function
    Vise andre…
    2010 (engelsk)Inngår i: Symmetry, ISSN 2073-8994, E-ISSN 2073-8994, Vol. 2, nr 3, s. 1653-1682Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The degree of p-electron (de)localization and aromaticity of a series of polybenzenoid hydrocarbons (PBHs) has been analyzed through the π-contribution to the electron localization function (ELFπ), calculated at the B3LYP/6-311G(d,p) hybrid density functional theory level. The extent of p-electron delocalization in the various hexagons of a PBH was determined through analysis of the bifurcation values of the ELFp basins (BV(ELFp)), the spans in the bifurcation values in each hexagon (ΔBV(ELFπ)), and the ring-closure bifurcation values of the ELFπ (RCBV(ELFπ)). These computed results were compared to the qualitative description of local aromaticities of the different hexagons in terms of Clar structures with p-sextets. Benzene, [18]annulene, and thirty two PBHs were analyzed at their equilibrium geometries, and benzene and triphenylene were also analyzed at bond length distorted structures. In general, the description of PBHs in terms of Clar valence structures is supported by the ELFp properties, although there are exceptions. For PBHs at their equilibrium geometries there is a clear sigmoidal relationship between the CC bond lengths and the amount of p-electron (de)localization at these bonds, however, this relationship is lost for bond distorted geometries. In the latter cases, we specifically examined benzene in D3h symmetric “1,3,5-cyclohexatriene” structures and triphenylene in eight different structures. From the distorted benzenes and triphenylenes it becomes clear that there is a distinct tendency for the p-electron network to retain delocalization (aromaticity). The ELFp analysis thus reveals an antidistortive rather than a distortive behavior of the p-electrons in these investigated compounds.

    sted, utgiver, år, opplag, sider
    Basel: MDPI, 2010
    Emneord
    Clar structures, electron localization function, polybenzenoid hydrocarbons
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot organisk kemi; Kemi med inriktning mot kvantkemi
    Identifikatorer
    urn:nbn:se:uu:diva-140983 (URN)10.3390/sym2031653 (DOI)000208831900018 ()
    Tilgjengelig fra: 2011-01-10 Laget: 2011-01-10 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    2. Substituent Effects on the Electron Affinities and Ionization Energies of Tria-, Penta-, and Heptafulvenes: A Computational Investigation
    Åpne denne publikasjonen i ny fane eller vindu >>Substituent Effects on the Electron Affinities and Ionization Energies of Tria-, Penta-, and Heptafulvenes: A Computational Investigation
    2010 (engelsk)Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, nr 23, s. 8060-8068Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The extent of substituent influence on the vertical electron affinities (EAs) and ionization energies (IEs) of 43 substituted tria-, penta-, and heptafulvenes was examined computationally at the OVGF/6-311G(d)//B3LYP/6-311G(d) level of theory and compared with those of tetracyanoquinodimethane (TCNQ) and tetrathiafulvalene (TTF) as representing strong electron-acceptor and -donor compounds, respectively. The substituents X at the exocyclic positions of the fulvenes were either NH2, H, or CN, while the substituents Y at the ring positions were H, CI, F, CN, or NH2. The variations of the EAs and lEs were rationalized by qualitative arguments based on frontier orbital symmetries for the different fulvene classes with either X or Y being constant. The minimum and maximum values found for the calculated EAs of the tria-, penta-, and heptafulvenes were 0.51-2.05, 0.24-3.63, and 0.53-3.14 eV, respectively, and for the IEs 5.27-9.96, 7.07-10.31, and 6.35-10.59 eV, respectively. Two of the investigated fulvenes outperform TCNQ (calcd EA = 2.63 eV) and one outperforms TTF (calcd IE = 6.25 eV) with regard to acceptor and donor abilities, respectively. We also evaluated the properties of bis(fulvene)s, i.e., compounds composed of a donor-type heptafulvene fused with an acceptor-type pentafulvene, and it was revealed that these bis(fulvene)s can be designed so that the IE and EA of the two separate fulvene segments are retained, potentially allowing for the design of compact donor-acceptor dyads.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-140156 (URN)10.1021/jo101634v (DOI)000284519900008 ()21067236 (PubMedID)
    Tilgjengelig fra: 2011-01-04 Laget: 2011-01-04 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    3. Fulvenes: Compounds for which the Singlet-Triplet Energy Gaps are Closely Linked to Aromaticity and  Aromaticity Differences
    Åpne denne publikasjonen i ny fane eller vindu >>Fulvenes: Compounds for which the Singlet-Triplet Energy Gaps are Closely Linked to Aromaticity and  Aromaticity Differences
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-172869 (URN)
    Tilgjengelig fra: 2012-04-16 Laget: 2012-04-16 Sist oppdatert: 2012-08-01
    4. Exploration of the π-Electronic Structure of Singlet, Triplet, and Quintet States of Fulvenes and Fulvalenes Using the Electron Localization Function
    Åpne denne publikasjonen i ny fane eller vindu >>Exploration of the π-Electronic Structure of Singlet, Triplet, and Quintet States of Fulvenes and Fulvalenes Using the Electron Localization Function
    2012 (engelsk)Inngår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 116, nr 20, s. 5008-5017Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The singlet ground states and lowest triplet states of penta- and heptafulvene, their benzannulated derivatives, as well as the lowest quintet states of pentaheptafulvalenes, either the parent compound or compounds in which the two rings are intercepted by either an alkynyl or a phenyl segment, were investigated at the (U)OLYP/6-311G(d,p) density functional theory level. The influence of (anti)-aromaticity was analyzed by the structure-based aromaticity index HOMA, the harmonic oscillator model of aromaticity. The extent of (anti)aromatic character was also evaluated in terms of the pi-electron (de)localization as measured by the pi component of the electron localization function (ELF pi). The natural atomic orbital (NAO) occupancies were calculated in order to evaluate the degree of pi-electron shift caused by the opposing electron-counting rules for aromaticity in the electronic ground state (S-0; Hiickel's rule) and the first pi pi* excited triplet state (T-1; Baird's rule). Pentaheptafulvalene (5) shows a shift of 0.5 pi electrons from the 5-ring to the 7-ring when going from the S-0 state to the lowest quintet state (Qu(1)). The pentaheptafulvalene 5 and [5.6.7]quinarene 7 were also investigated in their 90 degrees twisted conformations. From our study it is apparent that excitation localization in fulvalenes, but not in fulvenes, to a substantial degree is determined by aromaticity localization to triplet biradical 4n pi-electron cycles. Isolated benzene rings in these compounds tend to remain as closed-shell 6 pi-electron cycles.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-172377 (URN)10.1021/jp3032397 (DOI)000304338600021 ()
    Tilgjengelig fra: 2012-04-09 Laget: 2012-04-09 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    5. Manipulation of Excited State Energies in Fulvenic Molecules
    Åpne denne publikasjonen i ny fane eller vindu >>Manipulation of Excited State Energies in Fulvenic Molecules
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-172871 (URN)
    Tilgjengelig fra: 2012-04-16 Laget: 2012-04-16 Sist oppdatert: 2012-08-01
    6. Tuning the Band Gap of Polyfulvenes by Use of “Handles”: On the Effects of Exocyclic Substitution, Benzannulation, and Ring Methylation.
    Åpne denne publikasjonen i ny fane eller vindu >>Tuning the Band Gap of Polyfulvenes by Use of “Handles”: On the Effects of Exocyclic Substitution, Benzannulation, and Ring Methylation.
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-172872 (URN)
    Tilgjengelig fra: 2012-04-16 Laget: 2012-04-16 Sist oppdatert: 2012-08-01
  • 217.
    Dahlstrand, Christian
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Jahn, Burkhard
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Grigoriev, Anton
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi.
    Villaume, Sebastien
    Ahuja, Rajeev
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Tuning the Band Gap of Polyfulvenes by Use of “Handles”: On the Effects of Exocyclic Substitution, Benzannulation, and Ring Methylation.Manuskript (preprint) (Annet vitenskapelig)
  • 218.
    Dahlstrand, Christian
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Jahn, Burkhard O.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Grigoriev, Anton
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Villaume, Sebastien
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Ahuja, Rajeev
    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 - Ångström, Molekylär biomimetik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Polyfulvenes: Polymers with "Handles" That Enable Extensive Electronic Structure Tuning2015Inngår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 119, nr 46, s. 25726-25737Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The fundamental electronic structure properties of substituted poly(penta)fulvenes and pentafulvene-based polymers are analyzed through qualitative molecular orbital (MO) theory combined with calculations at the B3LYP and HSE06 hybrid density functional theory (DFT) levels. We argue that the pentafulvene monomer unit has a unique character because electron density in the exocyclic C=C double bond can be polarized into and out of the five-membered ring, a feature that is not available to other more commonly used monomers. It is investigated how the energy gaps between the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO, respectively), as approximate band gaps, are influenced by exocyclic substitution, introduction of linker groups, benzannulation, and ring substitution. In particular, the exocyclic positions of the fulvene act as handles by which the electronic structure of the polymer can be tuned between the quinoid and fulvenoid valence bond isomers; electron-withdrawing exocyclic substituents lead to polyfulvenes in the quinoid form while those with electron-donating substituents prefer the fulvenoid. Taken together, the HOMO-LUMO gaps of polyfulvenes can be tuned extensively, varying in ranges 0.77-2.44 eV (B3LYP) and 0.35-2.00 eV (HSE06) suggesting that they are a class of polymers with highly interesting, yet nearly unexplored, properties.

  • 219.
    Dahlstrand, Christian
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Rosenberg, Martin
    Department of Chemistry, University of Copenhagen.
    Kilså, Kristine
    Department of Chemistry, University of Copenhagen.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Exploration of the π-Electronic Structure of Singlet, Triplet, and Quintet States of Fulvenes and Fulvalenes Using the Electron Localization Function2012Inngår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 116, nr 20, s. 5008-5017Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The singlet ground states and lowest triplet states of penta- and heptafulvene, their benzannulated derivatives, as well as the lowest quintet states of pentaheptafulvalenes, either the parent compound or compounds in which the two rings are intercepted by either an alkynyl or a phenyl segment, were investigated at the (U)OLYP/6-311G(d,p) density functional theory level. The influence of (anti)-aromaticity was analyzed by the structure-based aromaticity index HOMA, the harmonic oscillator model of aromaticity. The extent of (anti)aromatic character was also evaluated in terms of the pi-electron (de)localization as measured by the pi component of the electron localization function (ELF pi). The natural atomic orbital (NAO) occupancies were calculated in order to evaluate the degree of pi-electron shift caused by the opposing electron-counting rules for aromaticity in the electronic ground state (S-0; Hiickel's rule) and the first pi pi* excited triplet state (T-1; Baird's rule). Pentaheptafulvalene (5) shows a shift of 0.5 pi electrons from the 5-ring to the 7-ring when going from the S-0 state to the lowest quintet state (Qu(1)). The pentaheptafulvalene 5 and [5.6.7]quinarene 7 were also investigated in their 90 degrees twisted conformations. From our study it is apparent that excitation localization in fulvalenes, but not in fulvenes, to a substantial degree is determined by aromaticity localization to triplet biradical 4n pi-electron cycles. Isolated benzene rings in these compounds tend to remain as closed-shell 6 pi-electron cycles.

  • 220.
    Dahlström, Kathe M.
    et al.
    Abo Akad Univ, Struct Bioinformat Lab, Biochem, Turku, Finland..
    Blikstad, Cecilia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Widersten, Mikael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Salminen, Tiina A.
    Abo Akad Univ, Struct Bioinformat Lab, Biochem, Turku, Finland..
    Directed evolution on FucO - structural explanations for changes in substrate scope2015Inngår i: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 24, s. 199-200Artikkel i tidsskrift (Annet vitenskapelig)
  • 221.
    Dalenius, Emma
    et al.
    CHU St Justine, Res Ctr, Dept Pediat, Montreal, PQ H3T 1C5, Canada; Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA.
    Ohm, Ragnhild G.
    Univ Montreal, Dept Chim, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada.
    Ahsanullah, Ahsanullah
    Univ Montreal, Dept Chim, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada; Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Ong, Huy
    Univ Montreal, Fac Pharm, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada.
    Chemtob, Sylvain
    Univ Montreal, Dept Pediat, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada; CHU St Justine, Res Ctr, Dept Pediat, Montreal, PQ H3T 1C5, Canada.
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC. The Swedish NMR Centre, Gothenburg.
    D. Lubell, William
    Univ Montreal, Dept Chim, Stn Ctr Ville, CP 6128, Montreal, PQ H3C 3J7, Canada.
    Dynamic Chirality in the Mechanism of Action of Allosteric CD36 Modulators of Macrophage-Driven Inflammation2019Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, nr 24, s. 111071-11079Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dynamic chirality influences numerous processes in nature from protein folding to catalysis. Azapeptides are peptidomimetics possessing semicarbazide residues that can interconvert between sp2 and sp3 hybridization, resulting in stereodynamic interconversions of pseudo-R and -S-configurations by means of a planar intermediate. Cyclic azapeptides have shown unprecedented binding affinity to the cluster of differentiation 36 receptor (CD36) and ability to mitigate macrophage-driven inflammation by modulation of the toll-like receptor 2/6 pathway. A novel approach to synthesize cyclic peptides via A3-macrocyclization has been used to make R- and S-configuration controls to study the relevance of semicarbazide hybridization for modulator activity. Nuclear magnetic resonance spectroscopy analysis of potent cyclic azapeptide CD36 modulators (e.g., 1 and 2) and related cyclic peptides demonstrated that binding affinity correlated with conformational rigidity, and a hybridization preference for sp2 > S- > R-sp3 semicarbazide nitrogen configuration was evaluated. Evidence of the active conformation and the relevance for dynamic chirality serve as insights for creating cyclic (aza)peptide CD36 modulators to curb inflammation.

  • 222.
    Damjanovic Vesterlund, Justina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Establishment of immunohistochemical double staining on formalin fixed paraffin embedded tissue samples with Pax 5, PD1, PDL1 and PDL2.2016Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 223.
    Danelius, Emma
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Andersson, Hanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Solution ensemble analysis of macrocycles2018Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Macrocycles are key drug leads for protein targets with large, flat and featureless binding sites, including protein-protein interfaces.  Due to their conformational flexibility macrocycles typically exist as a mixture of interconverting geometries in solution, and hence cannot be represented by a single, averaged conformation.  This flexibility is a result of continuously forming and breaking a number of weak intramolecular interactions.  The yielded conformations in solution vastly impact the bioactivity, solubility and membrane permeability of the macrocycles.  Therefore, describing their conformational ensembles, as well as the impact of conformation stabilizing weak interactions, is of fundamental importance, and the knowledge gained is directly applicable to medicinal chemistry.

    In order to describe macrocycle structure and dynamics, time-averaged solution spectroscopic data has to be deconvoluted into the present conformations along with their respective probability.  We have studied the solution ensembles of a series of macrocycles using the NAMFIS (NMR analysis of molecular flexibility in solution) algorithm.  This combined computational and spectroscopic ensembles analysis deconvolutes time averaged NMR data by identifying the real conformations and assigning them with their molar fractions.  Theoretical ensembles were predicted using Monte Carlo conformational searches with molecular mechanics minimization.  The generated ensembles, typically containing 40-150 conformers, were then used together with experimental NOE-based distances and J-coupling-based dihedral angles to identify the molar fractions of the conformations present in solution.

    We applied this technique to gain understanding of weak chemical interactions in a biologically relevant environment, by analyzing macrocyclic β-hairpin peptides.  The stabilizing effect provided by an interstrand weak interaction, as compared to a reference peptide lacking this interaction, was quantified through ensemble analysis.  We have shown that a single interstrand hydrogen [1,2,3] or halogen bond (Figure 1) [4], can significantly influence the folding, and increase the population of the folded conformation by up to 40%.  The NMR results were corroborated by CD-spectroscopy and MD-calculations.

  • 224.
    Danelius, Emma
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Andersson, Hanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Jarvoll, Patrik
    Lood, Kajsa
    Gräfenstein, Jürgen
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Halogen bond promoted peptide folding2018Konferansepaper (Fagfellevurdert)
    Abstract [en]

    We have developed a β-hairpin peptide model system that permits quantitative evaluation of weak interactions in a biologically relevant environment. The influence of a single weak force was measured by detection of the extent to which it modulates peptide folding. Initially we have optimized a β-hairpin model system, using the simpler to synthesize hydrogen bonding analogues of our target system encompassing halogen bond donor and acceptor sites [1,2,3]. Using a combined computational and NMR spectroscopic ensemble analysis, we have quantified the stabilizing effect of a single secondary interaction on the folded β-hairpin conformation. We have demonstrated that a chlorine centered halogen bond, formed between two amino acid side chains in an interstrand manner (Figure 1), provides a conformational stabilization comparable to the analogous hydrogen bond [4]. The negative control, i.e. the peptide containing a noninteracting aliphatic side chain, was ~30% less folded than the hydrogen and halogen bonding analogues, revealing the high impact of the interstrand interaction on folding. The experimental results are corroborated by computation on the DFT level. This is the first report of quantification of a conformation-stabilizing chlorine centered halogen bond in a peptide system.  

  • 225.
    Danelius, Emma
    et al.
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Andersson, Hanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Jarvoll, Patrik
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Lood, Kajsa
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Gräfenstein, Jürgen
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Erdélyi, Máté
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Halogen Bonding: A Powerful Tool for Modulation of Peptide Conformation2017Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Biochemistry, ISSN 0006-2960, Vol. 56, nr 25, s. 3265-3272Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Halogen bonding is a weak chemical force that has so far mostly found applications in crystal engineering. Despite its potential for use in drug discovery, as a new molecular tool in the direction of molecular recognition events, it has rarely been assessed in biopolymers. Motivated by this fact, we have developed a peptide model system that permits the quantitative evaluation of weak forces in a biologically relevant proteinlike environment and have applied it for the assessment of a halogen bond formed between two amino acid side chains. The influence of a single weak force is measured by detection of the extent to which it modulates the conformation of a cooperatively folding system. We have optimized the amino acid sequence of the model peptide on analogues with a hydrogen bond-forming site as a model for the intramolecular halogen bond to be studied, demonstrating the ability of the technique to provide information about any type of weak secondary interaction. A combined solution nuclear magnetic resonance spectroscopic and computational investigation demonstrates that an interstrand halogen bond is capable of conformational stabilization of a β-hairpin foldamer comparable to an analogous hydrogen bond. This is the first report of incorporation of a conformation-stabilizing halogen bond into a peptide/protein system, and the first quantification of a chlorine-centered halogen bond in a biologically relevant system in solution.

  • 226.
    Danielson, U Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Integrating surface plasmon resonance biosensor-based interaction kinetic analyses into the lead discovery and optimization process2009Inngår i: Future Medicinal Chemistry, ISSN 1756-8919, E-ISSN 1756-8927, Vol. 1, s. 1399-1414Artikkel i tidsskrift (Fagfellevurdert)
  • 227.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Molecular Interaction Analysis for Discovery of Drugs Targeting Enzymes and for Resolving Biological Function2015Inngår i: Multifaceted Roles Of Crystallography In Modern Drug Discovery / [ed] Scapin, G; Patel, D; Arnold, E, 2015, s. 223-240Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Analysis of molecular interactions using surface plasmon resonance (SPR) biosensor technology has become a powerful tool for discovery of drugs targeting enzymes and resolving biological function. A major advantage of this technology over other methods for interaction analysis is that it can provide the kinetic details of interactions. This is a consequence of the time resolution of the analysis, which allows individual kinetic rate constants as well as affinities to be determined. A less commonly recognized feature of this technology is that it can reveal the characteristics of more complex mechanisms, e.g. involving multiple steps or conformations of the target or ligand, as well as the energetics, thermodynamics and forces involved.

  • 228.
    Danielson, U Helena
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Huang, H H
    Seeger, Christian
    Lindblad, Peter
    Analysis of the leakage of gene repression by an artificial TetR-regulated promoter in cyanobacteria2015Inngår i: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 8, s. 459-Artikkel i tidsskrift (Fagfellevurdert)
  • 229. Darreh-Shori, Taher
    et al.
    Vijayaraghavan, Swetha
    Aeinehband, Shahin
    Piehl, Fredrik
    Lindblom, Rickard P F
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Nilsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ekdahl, Kristina Nilsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Almkvist, Ove
    Nordberg, Agneta
    Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease2013Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, nr 11, s. 2465-2481Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1 beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1b and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status.

  • 230.
    Davey, Norman E.
    et al.
    Univ Coll Dublin, Conway Inst Biomol & Biomed Sci, Dublin 4, Ireland..
    Seo, Moon-Hyeong
    Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada..
    Yadav, Vikash Kumar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Jeon, Jouhyun
    Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada..
    Nim, Satra
    Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada..
    Krystkowiak, Izabella
    Univ Coll Dublin, Conway Inst Biomol & Biomed Sci, Dublin 4, Ireland..
    Blikstad, Cecilia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Dong, Debbie
    Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada..
    Markova, Natalia
    Malvern Instruments Nord AB, Solna, Sweden..
    Kim, Philip M.
    Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON M5S 1A1, Canada..
    Ivarsson, Ylva
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Discovery of short linear motif-mediated interactions through phage display of intrinsically disordered regions of the human proteome2017Inngår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 284, nr 3, s. 485-498Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The intrinsically disordered regions of eukaryotic proteomes are enriched in short linear motifs (SLiMs), which are of crucial relevance for cellular signaling and protein regulation; many mediate interactions by providing binding sites for peptide-binding domains. The vast majority of SLiMs remain to be discovered highlighting the need for experimental methods for their large-scale identification. We present a novel proteomic peptide phage display (ProP-PD) library that displays peptides representing the disordered regions of the human proteome, allowing direct large-scale interrogation of most potential binding SLiMs in the proteome. The performance of the ProP-PD library was validated through selections against SLiM-binding bait domains with distinct folds and binding preferences. The vast majority of identified binding peptides contained sequences that matched the known SLiM-binding specificities of the bait proteins. For SHANK1 PDZ, we establish a novel consensus TxF motif for its non-C-terminal ligands. The binding peptides mostly represented novel target proteins, however, several previously validated protein-protein interactions (PPIs) were also discovered. We determined the affinities between the VHS domain of GGA1 and three identified ligands to 40-130 mu M through isothermal titration calorimetry, and confirmed interactions through coimmunoprecipitation using full-length proteins. Taken together, we outline a general pipeline for the design and construction of ProP-PD libraries and the analysis of ProP-PD-derived, SLiM-based PPIs. We demonstrated the methods potential to identify low affinity motif-mediated interactions for modular domains with distinct binding preferences. The approach is a highly useful complement to the current toolbox of methods for PPI discovery.

  • 231.
    Dawange, Monali
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Galkin, Maxim V.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Samec, Joseph S. M.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Selective Aerobic Benzylic Alcohol Oxidation of Lignin Model Compounds: Route to Aryl Ketones2015Inngår i: ChemCatChem, ISSN 1867-3880, E-ISSN 1867-3899, Vol. 7, nr 3, s. 401-404Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A mild and chemoselective oxidation of the -alcohol in -O-4-ethanoaryl and -O-4-glycerolaryl ethers has been developed. The benzylic alcohols were selectively dehydrogenated to the corresponding ketones in 60-93% yield. A one-pot selective route to aryl ethyl ketones was performed. The catalytic system comprises recyclable heterogeneous palladium, mild reaction conditions, green solvents, and oxygen in air as oxidant. Catalytic amounts of a coordinating polyol were found pivotal for an efficient aerobic oxidation.

  • 232.
    De Conto, Charlène
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Effect of Ubiquinone and Solanesole on liposome behaviour under osotic stress2015Student paper second term, 10 poäng / 15 hpOppgave
  • 233.
    de Kock, Neil
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    A novel targeted analysis of peripheral steroids by ultra–performance supercritical fluid chromatography hyphenated to mass spectrometryInngår i: Artikkel i tidsskrift (Annet vitenskapelig)
  • 234.
    de Kock, Neil
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    A novel ultra-performance supercritical fluid chromatography–tandem mass spectrometry method for separation of fourteen cholesterol oxidation productsManuskript (preprint) (Annet vitenskapelig)
  • 235.
    de Kock, Neil
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Mass spectrometry based analysis of endogenous sterols and hormones2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Bioanalytical applications using supercritical fluid chromatography (SFC) as analytical technique are of increasing interest. In essence, bioanalysis involves measurement of bioactive or endogenous compounds in biological matrices. SFC has emerged as an excellent choice for bioanalytical analysis, attributable to its speed, selectivity and efficiency compared with high performance liquid chromatography. Moreover, coupling of SFC with mass spectrometry (MS) provides the additional benefits of specificity and sensitivity.

    The aim of this thesis was to exploit these features by developing methods for the analysis of endogenous steroids, cholesterol oxidation products (COPs) and thyroid hormones (THs) by using ultra-performance supercritical fluid chromatography–tandem mass spectrometry (UPSFC–MS/MS) as analytical technique.

    Endogenous steroids control many physiological processes, including reproduction, maturation, gene expression and neurological functions in humans and animals. In the first study, three steroids were measured in domesticated White Leghorn (WL) chickens and ancestral Red Junglefowl (RJF) birds. Restraining stress caused a significantly larger increase in corticosterone levels in RJF than in WL, indicating a blunted hypothalamic–pituitary–adrenal (HPA) axis activity in domesticated chickens. The second study was a continuation of the first study and corticosterone levels from the F12 generation of an intercross between WL and RJF birds were measured before and after physical restraint stress. The expression levels of the glucocorticoid receptor (GR) in the hypothalamus and several genes in the adrenal glands were correlated with the post-stress levels of corticosterone in plasma. In the third study, the measurement of steroids was extended to assess more endogenous steroids from the four major classes, i.e. estrogens, androgens, progestogens and corticosterone.

    Endogenous COPs are of interest in pathophysiology. COPs are more readily disposed by cells than cholesterol. Therefore, cholesterol is oxidised to the more polar COPs and are generally more bioactive than cholesterol. Moreover, if their production in cells and tissues and/or their introduction with dietary animal fat are excessive, COPs could indeed contribute to the pathogenesis of various disease processes. Fourteen COPs were included in the fourth study and a novel method for their separation was developed.

    The last study in this thesis, involved the analysis of five THs. These hormones are vital for growth, developmental and metabolic processes of vertebrate life and play an important role in energy homeostasis. Measurements of circulating thyroid hormone levels are used in thyroid disorder diagnoses or treatment status monitoring. Two rapid methods for the separation of five THs were developed.

    In summary, the work in this thesis demonstrates the applicability of UPSFC–MS/MS as an analytical technique in bioanalysis of endogenous compounds.

    Delarbeid
    1. Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens
    Åpne denne publikasjonen i ny fane eller vindu >>Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens
    Vise andre…
    2015 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikkel-id 15345Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-265144 (URN)10.1038/srep15345 (DOI)000362885300001 ()
    Forskningsfinansiär
    Swedish Research Council, 621-2011-4731Swedish Research Council Formas, 221-2011-1088EU, European Research Council, 322206
    Tilgjengelig fra: 2015-10-23 Laget: 2015-10-23 Sist oppdatert: 2018-08-06bibliografisk kontrollert
    2. QTL mapping of stress related gene expression in a cross between domesticated chickens and ancestral red junglefowl
    Åpne denne publikasjonen i ny fane eller vindu >>QTL mapping of stress related gene expression in a cross between domesticated chickens and ancestral red junglefowl
    Vise andre…
    2017 (engelsk)Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 446, nr C, s. 52-58Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Domestication of animals is associated with numerous alterations in physiology, morphology, and behavior. Lower reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and reduced fearfulness is seen in most studied domesticates, including chickens. Previously we have shown that the physiological stress response as well as expression levels of hundreds of genes in the hypothalamus and adrenal glands are different between domesticated White Leghorn and the progenitor of modern chickens, the Red Junglefowl. To map genetic loci associated with the transcription levels of genes involved in the physiological stress response, we conducted an eQTL analysis in the F12 generation of an inter-cross between White Leghorn and Red Junglefowl. We selected genes for further studies based on their known function in the regulation of the HPA axis or sympathoadrenal (SA) system, and measured their expression levels in the hypothalamus and the adrenal glands after a brief stress exposure (physical restraint). The expression values were treated as quantitative traits for the eQTL mapping. The plasma levels of corticosterone were also assessed. We analyzed the correlation between gene expression and corticosterone levels and mapped eQTL and their potential effects on corticosterone levels. The effects on gene transcription of a previously found QTL for corticosterone response were also investigated. The expression levels of the glucocorticoid receptor (GR) in the hypothalamus and several genes in the adrenal glands were correlated with the post-stress levels of corticosterone in plasma. We found several cis- and transacting eQTL for stress-related genes in both hypothalamus and adrenal. In the hypothalamus, one eQTL for c-FOS and one QTL for expression of GR were found. In the adrenal tissue, we identified eQTL for the genes NROB1, RGS4, DBH, MAOA, GRIN1, GABRB2, GABRB3, and HSF1. None of the found eQTL were significant predictors of corticosterone levels. The previously found QTL for corticosterone was associated with GR expression in hypothalamus. Our data suggests that domestication related modification in the stress response is driven by changes in the transcription levels of several modulators of the HPA and SA systems in hypothalamus and adrenal glands and not by changes in the expression of the steroidogenic genes. The presence of eQTL for GR in hypothalamus combined with the negative correlation between GR expression and corticosterone response suggests GR as a candidate for further functional studies regarding modification of stress response during chicken domestication.

    Emneord
    Animal domestication, Stress response, HPA axis, QTL, eQTL
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-322082 (URN)10.1016/j.mce.2017.02.010 (DOI)000399509600006 ()
    Forskningsfinansiär
    Swedish Research Council, 621-2011-4731Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, 221-2011-1088EU, European Research Council, Genewell 322206
    Tilgjengelig fra: 2017-05-18 Laget: 2017-05-18 Sist oppdatert: 2018-08-24bibliografisk kontrollert
    3. A novel targeted analysis of peripheral steroids by ultra–performance supercritical fluid chromatography hyphenated to mass spectrometry
    Åpne denne publikasjonen i ny fane eller vindu >>A novel targeted analysis of peripheral steroids by ultra–performance supercritical fluid chromatography hyphenated to mass spectrometry
    (engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-356766 (URN)
    Tilgjengelig fra: 2018-08-06 Laget: 2018-08-06 Sist oppdatert: 2018-08-06
    4. A novel ultra-performance supercritical fluid chromatography–tandem mass spectrometry method for separation of fourteen cholesterol oxidation products
    Åpne denne publikasjonen i ny fane eller vindu >>A novel ultra-performance supercritical fluid chromatography–tandem mass spectrometry method for separation of fourteen cholesterol oxidation products
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    COPs, oxycholesterols, supercritical fluid chromatography–tandem mass spectrometry
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-356763 (URN)
    Tilgjengelig fra: 2018-08-06 Laget: 2018-08-06 Sist oppdatert: 2018-08-24
    5. Rapid mass spectrometric methods for separation of five thyroid hormones by ultra-performance supercritical fluid chromatography and ultra-performance liquid chromatography
    Åpne denne publikasjonen i ny fane eller vindu >>Rapid mass spectrometric methods for separation of five thyroid hormones by ultra-performance supercritical fluid chromatography and ultra-performance liquid chromatography
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    thyroid hormones, UPSFC–MS/MS, UPLC–MS/MS, derivatisation
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-356765 (URN)
    Tilgjengelig fra: 2018-08-06 Laget: 2018-08-06 Sist oppdatert: 2018-08-24
  • 236.
    de Kock, Neil
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Rapid mass spectrometric methods for separation of five thyroid hormones by ultra-performance supercritical fluid chromatography and ultra-performance liquid chromatographyManuskript (preprint) (Annet vitenskapelig)
  • 237.
    de Kock, Neil
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala University.
    Targeted analysis of bioactive steroids and oxycholesterols: Method development and application2016Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Peripheral steroids and oxycholesterols are important lipid compounds controlling various functions in the human body. Steroid analysis of biological samples is routinely employed in the clinical environment as an essential source of information on endocrine and metabolic disorders. It has been reported that stress related neurosteroids have been implicated in the development and prognoses of neurodegenerative disorders such as Alzheimer’s disease (AD). These compounds have been identified as possible biomarkers in the diagnosis of AD and other neurodegenerative disorders. Therefore, methods for the simultaneous analysis of steroids from the four major classes (estrogens, androgens, progestogens and corticosteroids) are vital in providing useful and more comprehensive data.

    Homeostasis of cholesterol in the brain is maintained primarily by metabolism to oxysterols, including oxycholesterols. These oxycholesterols act as a transport form of cholesterol as it readily navigates the blood-brain barrier. Oxycholesterols are generally more bioactive than cholesterol and is of interest in pathophysiology. Moreover, if their production in cells and tissues and/or their introduction with dietary animal fat are excessive, oxycholesterols could indeed contribute to the pathogenesis of various disease processes.

    The first study in this thesis focuses on a novel supercritical fluid chromatography–tandem mass spectrometry method for targeted analysis of eighteen peripheral steroids. The method is simple and fast. It has sufficient sensitivity for quantification of 18 different steroids in small volume human plasma. Therefore, this novel method can be applied for screening many steroids within 5 minutes providing the possibility to use for routine healthcare practice. The second study involves the quantification of three adrenal steroids in plasma from domesticated White Leghorn (WL) chickens and Red Junglefowl (RJF) birds. The domestication effects on stress induced steroid secretion and adrenal gene expression in chickens are evaluated. The third study focuses on determination of more than ten oxycholesterols in biological samples with a gas chromatography–mass spectrometry method and a supercritical fluid–tandem mass spectrometry method.

    Delarbeid
    1. Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens
    Åpne denne publikasjonen i ny fane eller vindu >>Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens
    Vise andre…
    2015 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikkel-id 15345Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-265144 (URN)10.1038/srep15345 (DOI)000362885300001 ()
    Forskningsfinansiär
    Swedish Research Council, 621-2011-4731Swedish Research Council Formas, 221-2011-1088EU, European Research Council, 322206
    Tilgjengelig fra: 2015-10-23 Laget: 2015-10-23 Sist oppdatert: 2018-08-06bibliografisk kontrollert
  • 238.
    de Kock, Neil
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Acharya, Santosh R.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Ubhayasekera, S. J. Kumari A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala Univ, Dept Chem, Biomed Ctr, Analyt Chem, Box 599, S-75124 Uppsala, Sweden.
    A Novel Targeted Analysis of Peripheral Steroids by Ultra-Performance Supercritical Fluid Chromatography Hyphenated to Tandem Mass Spectrometry2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 16993Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS) is an alternative method for steroid analysis. Continuous development of analytical methodologies for steroid profiling is of major importance in the clinical environment to provide useful and more comprehensive data. The aim of this study was to identify and quantify a large number of endogenous steroids from the four major classes (estrogens, androgens, progestogens and corticosteroids) simultaneously within a short analytical time. This novel UPSFC-MS/MS method with electrospray in positive ionisation (ESI+) mode is robust, selective and present sufficiently high sensitivity to profile nineteen steroids in 50 mu L human plasma. Under optimised conditions, nineteen different steroids were separated with high efficiency in the multiple reaction monitoring (MRM) mode. The linearity of the method was good with correlation coefficients (R-2) in the range of 0.9983-0.9999 and with calibration range from 0.05-500 ng/mL in human plasma. The intraday and interday precision of the method, as RSD, was less than 15%. The accuracy of the nineteen analytes varied between 80 to 116%. Finally, the novel method was successfully applied for the determination of nineteen steroids within 5 minutes providing the possibility to use it for research as well as routine healthcare practice.

  • 239.
    de la Fuente Revenga, Mario
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Enzyme Catalysis in Deep Eutectic Solvents2009Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
  • 240. Deligkiozi, Ioanna
    et al.
    Voyiatzis, Evangelos
    Tsolomitis, Athanase
    Papadakis, Raffaello
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Synthesis and characterization of new azobenzene-containing bis pentacyanoferrate(II) stoppered push-pull [2]rotaxanes, with alpha- and beta-cyclodextrin. Towards highly medium responsive dyes2015Inngår i: Dyes and pigments, ISSN 0143-7208, E-ISSN 1873-3743, Vol. 113, s. 709-722Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The solvatochromic behavior of novel synthesized azo-containing viologen-based rotaxanes, combining push-pull linear and alpha or beta-cyclodextrin macrocyclic components is examined. These rotaxanes are stoppered by pentacyanoferrate(II) units. The latter stabilize these systems and furthermore act as strong electron donors. These units are linked to strong electron withdrawing viologen units thus giving rise to an exceptionally intense solvatochromic behavior. Suitable solvent polarity scales and Linear Solvation Energy Relationships (LSERs) were employed in order to rationalize the solvent polarity effects observed, both specific and non-specific ones. The results for the title compounds as well as their Cyclodextrin-Free-Dumbbell (CFD) like analogue, are compared to recent published solvatochromic data regarding similar smaller pentacyanoferrate(II) complexes as well as other highly solvatochromic compounds. Structural effects on the solvatochromic intensity as well as the contribution of different solvent-solute interactions are rationalized and quantified. (C) 2014 Elsevier Ltd. All rights reserved.

  • 241.
    Demory, Emilien
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Devaraj, Karthik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC. Uppsala Univ, Dept Chem BMC, S-75123 Uppsala, Sweden..
    Orthaber, Andreas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Gates, Paul J.
    Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England..
    Pilarski, Lukasz T.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Boryl (Hetero)aryne Precursors as Versatile Arylation Reagents: Synthesis through C-H Activation and Orthogonal Reactivity2015Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 54, nr 40, s. 11765-11769Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    (Pinacolato)boryl ortho-silyl(hetero)aryl triflates are presented as a new class of building blocks for arylation. They demonstrate unique versatility by delivering boronate or (hetero)aryne reactivity chemoselectively in a broad range of transformations. This approach enables the unprecedented postfunctionalization of fluoride-activated (hetero)aryne precursors, for example, as substrates in transition-metal catalysis, and offers valuable new possibilities for aryl boronate postfunctionalization without the use of specialized protecting groups.

  • 242.
    Denisova V, Aleksandra
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    Tibbelin, Julius
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Emanuelsson, Rikard
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Molekylär biomimetik.
    A Computational Investigation of the Substituent Effects on Geometric, Electronic, and Optical Properties of Siloles and 1,4-Disilacyclohexa-2,5-dienes2017Inngår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, nr 3, artikkel-id 370Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thirty two differently substituted siloles 1a–1p and 1,4-disilacyclohexa-2,5-dienes 2a–2p were investigated by quantum chemical calculations using the PBE0 hybrid density functional theory (DFT) method. The substituents included σ-electron donating and withdrawing, as well as π-electron donating and withdrawing groups, and their effects when placed at the Si atom(s) or at the C atoms were examined. Focus was placed on geometries, frontier orbital energies and the energies of the first allowed electronic excitations. We analyzed the variation in energies between the orbitals which correspond to HOMO and LUMO for the two parent species, here represented as ΔεHL, motivated by the fact that the first allowed transitions involve excitation between these orbitals. Even though ΔεHL and the excitation energies are lower for siloles than for 1,4-disilacyclohexa-2,5-dienes the latter display significantly larger variations with substitution. The ΔεHL of the siloles vary within 4.57–5.35 eV (ΔΔεHL = 0.78 eV) while for the 1,4-disilacyclohexa-2,5-dienes the range is 5.49–7.15 eV (ΔΔεHL = 1.66 eV). The excitation energy of the first allowed transitions display a moderate variation for siloles (3.60–4.41 eV) whereas the variation for 1,4-disilacyclohexa-2,5-dienes is nearly doubled (4.69–6.21 eV). Cyclobutadisiloles combine the characteristics of siloles and 1,4-disilacyclohexa-2,5-diene by having even lower excitation energies than siloles yet also extensive variation in excitation energies to substitution of 1,4-disilacyclohexa-2,5-dienes (3.47–4.77 eV, variation of 1.30 eV).

  • 243.
    Devaraj, Karthik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Ruthenium-catalyzed C-H Functionalization of (Hetero)arenes2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis concerned about the Ru-catalyzed C-H functionalizations on the synthesis of 2-arylindole unit, silylation of heteroarenes and preparation of aryne precursor.

    In the first project, we developed the Ru-catalyzed C2-H arylation of N-(2-pyrimidyl) indoles and pyrroles with nucleophilic arylboronic acids under oxidative conditions. Wide variety of arylboronic acids afforded the desired product in excellent yield regardless of the substituents or functional group electronic nature. Electron-rich heteroarenes are well suited for this method than electron-poor heteroarenes. Halides such as bromide and iodide also survived, further derivatisation of the halide is shown by Heck alkenylation. In order to find catalytic on-cycle intermediate extensive mechanistic experiments have been carried out by preparing presumed ruthenacyclic complexes and C-H/D exchange reactions. It suggested that para-cymene ligand is not present in the catalytic on-cycle intermediate and we suspect that metalation occurs with electrophilic ruthenium center via SEAr mechanism.

    In the second project, we developed the Ru-catalyzed silylation of gramine, tryptamine and their congeners using silanes as coupling partner. The transformation worked well with many different silanes. Regarding directing group, nitrogen atom containing directing groups are more favoured than the oxygen containing directing groups. Wide range of gramines and tryptamines also yielded the desired product in poor to excellent yield. At higher temperature, albeit in low yield, undirected silylation occurred. In order to get some insights about the reaction pathway of the silylation C-H/D exchange experiments were performed, and it revealed the possibility of C4-H activation of gramines by an electron rich metal- Si-H/D experiments showed Si-H activation by Ru is easy.

    In the final project, we presented the closely related aryne precursors from arylboronic acids via Ru-catalyzed C-H silylation of arylboronates and their selective oxidation. Worthy of note, the aryne capture products obtained from arylboronic acids in a single purification.

    Delarbeid
    1. Ru-Catalysed C-H Arylation of Indoles and Pyrroles with Boronic Acids: Scope and Mechanistic Studies
    Åpne denne publikasjonen i ny fane eller vindu >>Ru-Catalysed C-H Arylation of Indoles and Pyrroles with Boronic Acids: Scope and Mechanistic Studies
    Vise andre…
    2015 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, nr 14, s. 5380-5386Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The Ru-catalysed C2-H arylation of indoles and pyrroles by using boronic acids under oxidative conditions is reported. This reaction can be applied to tryptophan derivatives and tolerates a wide range of functional groups on both coupling partners, including bromides and iodides, which can be further derivatised selectively. New indole based ruthenacyclic complexes are described and investigated as possible intermediates in the reaction. Mechanistic studies suggest the on-cycle intermediates do not possess a para-cymene ligand and that the on-cycle metalation occurs through an electrophilic attack by the Ru centre.

    Emneord
    catalysis, C-H activation, heterocycles, reaction mechanisms, ruthenium
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-252711 (URN)10.1002/chem.201405931 (DOI)000352504500017 ()25689052 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2015-05-18 Laget: 2015-05-11 Sist oppdatert: 2017-12-04bibliografisk kontrollert
    2. Ru-Catalysed C-H Silylation of Gramines, Tryptamines and their Congeners
    Åpne denne publikasjonen i ny fane eller vindu >>Ru-Catalysed C-H Silylation of Gramines, Tryptamines and their Congeners
    2016 (engelsk)Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, nr 34, s. 5868-5871Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Selective Ru-catalysed C2–H silylation of heteroarenes is presented. The transformation works with or without directing group assistance and requires no protecting groups. Gramines and tryptamines may be converted efficiently whilst avoiding deleterious elimination side-reactions. Mechanistic studies reveal an unusual activation of the indole C4–H bond by an electron-rich metal.

    sted, utgiver, år, opplag, sider
    Royal Society of Chemistry, 2016
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-286545 (URN)10.1039/C6CC00803H (DOI)000374396500022 ()27050747 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2016-04-20 Laget: 2016-04-20 Sist oppdatert: 2017-11-30bibliografisk kontrollert
    3. Synthesis of aryne precursors via transition metal-catalyzed C-H silylation
    Åpne denne publikasjonen i ny fane eller vindu >>Synthesis of aryne precursors via transition metal-catalyzed C-H silylation
    2014 (engelsk)Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-247860 (URN)000349167403600 ()
    Konferanse
    248th National Meeting of the American-Chemical-Society (ACS), AUG 10-14, 2014, San Francisco, CA
    Tilgjengelig fra: 2015-03-26 Laget: 2015-03-24 Sist oppdatert: 2017-12-04bibliografisk kontrollert
  • 244.
    Devaraj, Karthik
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Ingner, Fredric
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Sollert, Carina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Gates, Paul J.
    Univ Bristol, Sch Chem, Cantocks Close, Bristol BS8 1TS, Avon, England.
    Orthaber, Andreas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Syntetisk molekylär kemi.
    Pilarski, Lukasz T.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Arynes and Their Precursors from Arylboronic Acids via Catalytic C-H Silylation2019Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, nr 9, s. 5863-5871Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A new, operationally simple approach is presented to access arynes and their fluoride-activated precursors based on Ru-catalyzed C-H silylation of arylboronates. Chromatographic purification may be deferred until after aryne capture, rendering the arylboronates de facto precursors. Access to various new arynes and their derivatives is demonstrated, including, for the first time, those based on a 2,3-carbazolyne and 2,3-fluorenyne core, which pave the way for novel derivatizations of motifs relevant to materials chemistry.

  • 245.
    Devaraj, Karthik
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Sollert, Carina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Gates, P. J.
    Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England.
    Pilarski, Lukasz
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Ru-Catalysed C-H Silylation of Gramines, Tryptamines and their Congeners2016Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, nr 34, s. 5868-5871Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Selective Ru-catalysed C2–H silylation of heteroarenes is presented. The transformation works with or without directing group assistance and requires no protecting groups. Gramines and tryptamines may be converted efficiently whilst avoiding deleterious elimination side-reactions. Mechanistic studies reveal an unusual activation of the indole C4–H bond by an electron-rich metal.

  • 246.
    Devaraj, Karthik
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Sollert, Carina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Gates, Paul
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Pilarski, Lukasz
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Synthesis of aryne precursors via transition metal-catalyzed C-H silylation2014Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Artikkel i tidsskrift (Annet vitenskapelig)
  • 247.
    Dickman, Rachael
    et al.
    UCL, Dept Chem, 20 Gordon St, London WC1H 0AJ, England.
    Danelius, Emma
    Swedish NMR Ctr, Medicinaregatan 5, S-40530 Gothenburg, Sweden.
    Mitchell, Serena A.
    UCL, Dept Chem, 20 Gordon St, London WC1H 0AJ, England.
    Hansen, D. Flemming
    UCL, Div Biosci, Inst Struct & Mol Biol, Gower St, London WC1E 6BT, England.
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. Swedish NMR Ctr, Medicinaregatan 5, S-40530 Gothenburg, Sweden.
    Tabor, Alethea B.
    UCL, Dept Chem, 20 Gordon St, London WC1H 0AJ, England.
    A Chemical Biology Approach to Understanding Molecular Recognition of Lipid II by Nisin(1-12): Synthesis and NMR Ensemble Analysis of Nisin(1-12) and Analogues2019Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 25, nr 64, s. 14572-14582Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Natural products that target lipid II, such as the lantibiotic nisin, are strategically important in the development of new antibacterial agents to combat the rise of antimicrobial resistance. Understanding the structural factors that govern the highly selective molecular recognition of lipid II by the N-terminal region of nisin, nisin(1-12), is a crucial step in exploiting the potential of such compounds. In order to elucidate the relationships between amino acid sequence and conformation of this bicyclic peptide fragment, we have used solid-phase peptide synthesis to prepare two novel analogues of nisin(1-12) in which the dehydro residues have been replaced. We have carried out an NMR ensemble analysis of one of these analogues and of the wild-type nisin(1-12) peptide in order to compare the conformations of these two bicyclic peptides. Our analysis has shown the effects of residue mutation on ring conformation. We have also demonstrated that the individual rings of nisin(1-12) are pre-organised to an extent for binding to the pyrophosphate group of lipid II, with a high degree of flexibility exhibited in the central amide bond joining the two rings.

  • 248.
    Dinér, Peter
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Superacid-Promoted Ionization of Alkanes Without Carbonium Ion Formation: A Density Functional Theory Study2012Inngår i: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 116, nr 40, s. 9979-9984Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The carbonium ion has been suggested to be the intermediate in superacid-promoted reactions (SbF5-HF) such as hydrogen-deuterium exchange and in the electrophilic C-H cleavage into hydrogen and the carbenium ion. In this study, the superacid-promoted C-H cleavage into hydrogen and the carbenium ion was studied using density functional theory (B3LYP and M062X) and ab initio methods (MP2 and CCSD). The calculations suggest that the superacid-promoted C-H cleavage proceeds via a concerted transition state leading to hydrogen (H-2) and the carbenium ion without the formation of the elusive carbonium ion. The reactivity for the superacid promoted C-H cleavage decreases upon going from isobutane (tertiary) > propane (secondary) > isobutane (primary) > propane (primary) > ethane >> methane.

  • 249.
    Dinér, Peter
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Alao, John P.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Söderlund, Johan
    Sunnerhagen, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Grøtli, Morten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Preparation of 3-Substituted-1-Isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines as RET Kinase Inhibitors2012Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 10, s. 4872-4876Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.

  • 250.
    Diwakarla, Shanti
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nylander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Grönbladh, Alfhild
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Reddy Vanga, Sudarsana
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Shamsudin Khan, Yasmin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Gutierrez-de-Teran, Hugo
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Ng, Leelee
    Pham, Vi
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lundback, Thomas
    Jenmalm-Jensen, Annika
    Andersson, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Engen, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Åqvist, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Yeen Chai, Siew
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density2016Inngår i: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 89, nr 4, s. 413-424Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

2345678 201 - 250 of 1348
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