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  • 1. Adriani, O.
    et al.
    Barbarino, G. C.
    Bazilevskaya, G. A.
    Bellotti, R.
    Boezio, M.
    Bogomolov, E. A.
    Bonechi, L.
    Bongi, M.
    Bonvicini, V.
    Borisov, S.
    Bottai, S.
    Bruno, A.
    Cafagna, F.
    Campana, D.
    Carbone, R.
    Carlson, Per
    KTH, School of Engineering Sciences (SCI), Physics, Particle and Astroparticle Physics.
    Casolino, M.
    Castellini, G.
    Consiglio, L.
    De Pascale, M. P.
    De Santis, C.
    De Simone, N.
    Di Felice, V.
    Galper, A. M.
    Gillard, W.
    Grishantseva, L.
    Hofverberg, Petter
    KTH, School of Engineering Sciences (SCI), Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Jerse, G.
    Koldashov, S. V.
    Krutkov, S. Y.
    Kvashnin, A. N.
    Leonov, A.
    Malvezzi, V.
    Marcelli, L.
    Menn, W.
    Mikhailov, V. V.
    Mocchiutti, E.
    Monaco, A.
    Mori, N.
    Nikonov, N.
    Osteria, G.
    Papini, P.
    Pearce, Mark
    KTH, School of Engineering Sciences (SCI), Physics, Particle and Astroparticle Physics.
    Picozza, P.
    Ricci, M.
    Ricciarini, S. B.
    Rossetto, L.
    Simon, M.
    Sparvoli, R.
    Spillantini, P.
    Stozhkov, Y. I.
    Vacchi, A.
    Vannuccini, E.
    Vasilyev, G.
    Voronov, S. A.
    Wu, Juan
    KTH, School of Engineering Sciences (SCI), Physics, Particle and Astroparticle Physics.
    Yurkin, Y. T.
    Zampa, G.
    Zampa, N.
    Zverev, V. G.
    Marinucci, D.
    A statistical procedure for the identification of positrons in the PAMELA experiment2010In: Astroparticle physics, ISSN 0927-6505, E-ISSN 1873-2852, Vol. 34, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    The PAMELA satellite experiment has measured the cosmic-ray positron fraction between 1.5 GeV and 100 GeV. The need to reliably discriminate between the positron signal and proton background has required the development of an ad hoc analysis procedure. In this paper, a method for positron identification is described and its stability and capability to yield a correct background estimate is shown. The analysis includes new experimental data, the application of three different fitting techniques for the background sample and an estimate of systematic uncertainties due to possible inaccuracies in the background selection. The new experimental results confirm both solar modulation effects on cosmic-rays with low rigidities and an anomalous positron abundance above 10 GeV. (c) 2010 Elsevier B.V. All rights reserved.

  • 2. Agnarsdottir, Margret
    et al.
    Sooman, Linda
    Bolander, Asa
    Stromberg, Sara
    Rexhepaj, Elton
    Bergqvist, Michael
    Ponten, Fredrik
    Gallagher, William
    Lennartsson, Johan
    Ekman, Simon
    Uhlen, Mathias
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hedstrand, Hakan
    SOX10 expression in superficial spreading and nodular malignant melanomas2010In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 20, no 6, p. 468-478Article in journal (Refereed)
    Abstract [en]

    SOX10 is a transcription factor expressed in nerve cells and melanocytes. The aim of this study was to investigate the protein expression pattern of SOX10 in malignant melanoma tumors and to analyze whether the results correlated with clinical parameters and the proliferation marker Ki-67. Furthermore, proliferation and migration were analyzed in three different cell lines employing SOX10 small interfering RNA-mediated silencing. Expression patterns were determined in 106 primary tumors and 39 metastases in addition to 16 normal skin samples and six benign nevi employing immunohistochemistry and tissue microarrays. The immunohistochemical staining was evaluated manually and with an automated algorithm. SOX10 was strongly expressed in the benign tissues, but for the malignant tumors superficial spreading melanomas stained stronger than nodular malignant melanomas (P = 0.008). The staining intensity was also inversely correlated with T-stage (Spearman's rho = -0.261, P = 0.008). Overall survival and time to recurrence were significantly correlated with SOX10 intensity, but not in multivariate analysis including T-stage. With the automated algorithm there was an inverse correlation between the SOX10 staining intensity and the proliferation marker, Ki-67 (rho = -0.173, P = 0.02) and a significant difference in the intensity signal between the benign tissues, the primary tumors and the metastases where the metastases stained the weakest (P <= 0.001). SOX10 downregulation resulted in variable effects on proliferation and migration rates in the melanoma cell lines. In conclusion, the SOX10 intensity level differed depending on the tissue studied and SOX10 might have a role in survival. No conclusion regarding the role of SOX10 for in-vitro proliferation and migration could be drawn. Melanoma Res 20:468-478

  • 3.
    Ahrenstedt, Lage
    et al.
    KTH, School of Biotechnology (BIO). KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Olksanen, Antti
    VTT Technical Research Centre of Finland.
    Salmien, Kristian
    VTT Technical Research Centre of Finland.
    Brumer, Harry
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Paper dry strength improvement by xyloglucan addition: Wet-end application, spray coating and synergism with borate2008In: Holzforschung, ISSN 0018-3830, E-ISSN 1437-434X, Vol. 62, no 1, p. 8-14Article in journal (Refereed)
    Abstract [en]

    The polysaccharide xyloglucan as a wet-end additive improves paper properties. In the present study, paper strength improvement was analysed for dry handsheets made from chemical, mechanical and recycled pulps coated with xyloglucan in a spray application. Results are compared with sheets made from the same pulps treated with xyloglucan in the wet-end. Kraft pulp handsheets of bleached hardwood and softwood showed significant improvements of tensile, tear and Z-strength by xyloglucan spray treatment versus wet-end application, whereas handsheets of de-inked and thermomechanical pulp were improved only slightly. In both wet-end and spray applications, the effect of xyloglucan addition was intimately related to the presence of non-cellulosic components on the fibre surface. Further strength improvements were obtained for chemical pulps by addition of borax to the spray solution, which were likely to be due to the formation of borate-mediated xyloglucan cross-links. Spray coating of xyloglucan, with or without borax, thus represents a potential new application of this polysaccharide to increase paper dry strength.

  • 4.
    Alm, Tove
    et al.
    KTH, School of Biotechnology (BIO), Proteomics.
    Yderland, Louise
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Nilvebrant, Johan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Halldin, Anneli
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Proteomics.
    A small bispecific protein selected for orthogonal affinity purification2010In: BIOTECHNOL J, ISSN 1860-6768, Vol. 5, no 6, p. 605-617Article in journal (Refereed)
    Abstract [en]

    A novel protein domain with dual affinity has been created by randomization and selection. The small alkali-stabilized albumin-binding domain (ABD(star)), used as scaffold to construct the library, has affinity to human serum albumin (HSA) and is constituted of 46 amino acids of which 11 were randomized. To achieve a dual binder, the binding site of the inherent HSA affinity was untouched and the randomization was made on the opposite side of the molecule. Despite its small size and randomization of almost a quarter of its amino acids, a bifunctional molecule, ABDz1, with ability to bind to both HSA and the Z(2) domain/protein A was successfully selected using phage display. Moreover, the newly selected variant showed improved affinity for HSA compared to the parental molecule. This novel protein domain has been characterized regarding secondary structure and affinity to the two different ligands. The possibility for affinity purification on two different matrices has been investigated using the two ligands, the HSA matrix and the protein A-based, MabSelect SuRe matrix, and the new protein domain was purified to homogeneity. Furthermore, gene fusions between the new domain and three different target proteins with different characteristics were made. To take advantage of both affinities, a purification strategy referred to as orthogonal affinity purification using two different matrices was created. Successful purification of all three versions was efficiently carried out using this strategy.

  • 5.
    Altai, Mohamed
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden.;Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
    Leitao, Charles Dahlsson
    KTH, School of Engineering Sciences (SCI). KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden..
    Rinne, Sara S.
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden..
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Atterby, Christina
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Löfblom, John
    KTH, School of Engineering Sciences (SCI). KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden..
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, S-75237 Uppsala, Sweden..
    Influence of Molecular Design on the Targeting Properties of ABD-Fused Mono- and Bi-Valent Anti-HER3 Affibody Therapeutic Constructs2018In: CELLS, ISSN 2073-4409, Vol. 7, no 10, article id 164Article in journal (Refereed)
    Abstract [en]

    Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD 035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified.

  • 6. Altai, Mohamed
    et al.
    Strand, Joanna
    Rosik, Daniel
    Selvaraju, Ram Kumar
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Molecular Biotechnology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Orlova, Anna
    Tolmachev, Vladimir
    Influence of Nuclides and Chelators on Imaging Using Affibody Molecules: Comparative Evaluation of Recombinant Affibody Molecules Site-Specifically Labeled with Ga-68 and In-111 via Maleimido Derivatives of DOTA and NODAGA2013In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 24, no 6, p. 1102-1109Article in journal (Refereed)
    Abstract [en]

    Accurate detection of cancer-associated molecular abnormalities in tumors could make cancer treatment more of personalized. Affibody molecules enable high contrast imaging of tumor-associated protein expression shortly after injection. The use should increase sensitivity of HER2 imaging. The chemical nature of the generator-produced positron-emitting radionuclide Ga-68 of radionuclides and chelators influences the biodistribution of Affibody molecules, providing an opportunity to further increase the imaging contrast. The aim of the study was to compare maleimido derivatives of DOTA and NODAGA for site-specific labeling of a recombinant Z(HER2:2395) HER2-binding Affibody molecule with Ga-68. DOTA and NODAGA were site-specifically conjugated to the Z(HER2:2395) Affibody molecule having a C-terminal cysteine and labeled with Ga-68 and In-111. All labeled conjugates retained specificity to HER2 in vitro. Most of the cell-associated activity was membrane-bound with a minor difference in internalization rate. All variants demonstrated specific targeting of xenografts and a high tumor uptake. The xenografts were dearly visualized using all conjugates. The influence of chelator on the biodistribution and targeting properties was much less pronounced for Ga-68 than for In-111. The tumor uptake of Ga-68-NODAGA-Z(HER2:2395) and Ga-68-NODAGA-Z(HER2:2395) and tumor-to-blood ratios at 2 h p.i. did not differ significantly. However, the tumor-to-liver ratio was significantly higher for Ga-68-NODAGA- Z(HER2:2395) (8 +/- 2 vs 5.0 +/- 0.3) offering the advantage of better liver metastases visualization. In conclusion, influence of chelators on biodistribution of Affibody molecules depends on the radionuclides and reoptimization of labeling chemistry is required when a radionuclide label is changed.

  • 7.
    Ban, Shufang
    et al.
    KTH, Superseded Departments, Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Meng, J
    Wyss, Ramon
    KTH, Superseded Departments, Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Nuclear symmetry energy for A=48 isobars in relativistic mean field theory2004In: Gaoneng wuli yu he wuli, ISSN 0254-3052, Vol. 28, p. 66-68Article in journal (Refereed)
    Abstract [en]

    Recently it was found that the nuclear symmetry energy can be directly associated with the mean level density and an iso-vector potential. In this paper, the nuclear symmetry energy is studied within the relativistic mean field (RMF) theory. The potential of the RMF theory can be separated into an isovector and isoscalar components. The nuclear binding energies in A = 48 isobaric chain calculated from RMF theory with or without the isovector terms for effective interactions PK1, NLSH, NL3, and TM1 have been used to analyze the nuclear symmetry energy in detail, i.e., mean level spacing epsilon and the effective isovector potential strength K.

  • 8.
    Baryshnikov, Gleb V.
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.;Tomsk State Univ, 36 Lenin Ave, Tomsk, Russia..
    Sunchugashev, Dmitry A.
    Tomsk State Univ, 36 Lenin Ave, Tomsk, Russia..
    Valiev, Rashid R.
    Tomsk State Univ, 36 Lenin Ave, Tomsk, Russia..
    Minaev, Boris F.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Vibronic absorption spectra of the angular fused bisindolo- and biscarbazoloanthracene blue fluorophores for OLED applications2018In: Chemical Physics, ISSN 0301-0104, E-ISSN 1873-4421, Vol. 513, p. 105-111Article in journal (Refereed)
    Abstract [en]

    An in-depth analysis of the vibronic absorption spectra for the recently synthesized blue-fluorescent OLED emitters bis[(1,2)(5,6)]indoloanthracene and biscarbazolo[3,4-a:3',4'-h]anthracene has been carried out computationally at the density functional theory level within the Franck-Condon approximation. These molecules are characterized by extended and rich electronic absorption spectra with most absorption bands being of vibronic origin. The first excited singlet state of bis[(1,2)(5,6)]indoloanthracene compound demonstrates a clear observable double-peak vibronic progression for two different active modes in the absorption spectrum, while the S-2 state is vibronically inactive. In contrast, for the larger biscarbazolo[3,4-a:3',4'-h]anthracene compound the S-0 -> S-2 transition demonstrates well-resolved intense vibronic bands which overlap the less intense progressions of few modes in the S-0 -> S-1 transition. We have also found, that even the higher-lying and very intense S-0 -> S-4 and S-0 -> S-5 transitions for bis[(1,2)(5,6)]indoloanthracene and biscarbazolo[3,4-a:3',4'-h]anthracene, respectively, are characterized by clear vibronic progressions in excellent agreement with experimental spectra.

  • 9.
    Belonoshko, A. B.
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Condensed Matter Theory. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Rosengren, Anders
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Condensed Matter Theory. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Ab Initio Study of Water Interaction with a Cu Surface2010In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 21, p. 16267-16270Article in journal (Refereed)
    Abstract [en]

    We have performed a first principles investigation of water interaction with a Cu surface. The calculated surface energy of a Cu(100) slab is in reasonable agreement with experimental data. The energy of water dissociation is in agreement with experiment. The results of the ab initio calculations are compared to experimental data on hydrogen partial pressure. It is concluded that Cu(OH)(ads) is formed due to a reaction between Cu and anoxic water. The energy of the Cu(100) slab with OH and H adsorbed is lower than the energy of the same slab with an adsorbed water molecule.

  • 10.
    Beven, Laure
    et al.
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Charenton, Claire
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Dautant, Alain
    Univ Bordeaux, Bordeaux, France ; IBMC, CNRS, Bordeaux, France.
    Bouyssou, Guillaume
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Labroussaa, Fabien
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Sköllermo, Anna
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Persson, Anja
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Blanchard, Alain
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Sirand-Pugnet, Pascal
    Univ Bordeaux, Villenave Dornon, France ; INRA Villenave Dornon, France .
    Specific Evolution of F-1-Like ATPases in Mycoplasmas2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e38793-Article in journal (Refereed)
    Abstract [en]

    F1F0 ATPases have been identified in most bacteria, including mycoplasmas which have very small genomes associated with a host-dependent lifestyle. In addition to the typical operon of eight genes encoding genuine F1F0 ATPase (Type 1), we identified related clusters of seven genes in many mycoplasma species. Four of the encoded proteins have predicted structures similar to the alpha, beta, gamma and e subunits of F-1 ATPases and could form an F-1-like ATPase. The other three proteins display no similarity to any other known proteins. Two of these proteins are probably located in the membrane, as they have three and twelve predicted transmembrane helices. Phylogenomic studies identified two types of F-1-like ATPase clusters, Type 2 and Type 3, characterized by a rapid evolution of sequences with the conservation of structural features. Clusters encoding Type 2 and Type 3 ATPases were assumed to originate from the Hominis group of mycoplasmas. We suggest that Type 3 ATPase clusters may spread to other phylogenetic groups by horizontal gene transfer between mycoplasmas in the same host, based on phylogeny and genomic context. Functional analyses in the ruminant pathogen Mycoplasma mycoides subsp. mycoides showed that the Type 3 cluster genes were organized into an operon. Proteomic analyses demonstrated that the seven encoded proteins were produced during growth in axenic media. Mutagenesis and complementation studies demonstrated an association of the Type 3 cluster with a major ATPase activity of membrane fractions. Thus, despite their tendency toward genome reduction, mycoplasmas have evolved and exchanged specific F-1-like ATPases with no known equivalent in other bacteria. We propose a model, in which the F-1-like structure is associated with a hypothetical X-0 sector located in the membrane of mycoplasma cells.

  • 11.
    Bhagwat, A.
    et al.
    UM DAE Ctr Excellence Basic Sci, Mumbai 400098, Maharashtra, India.;AlbaNova Univ Ctr, Dept Nucl Phys, KTH Royal Inst Technol, S-10691 Stockholm, Sweden..
    Liotta, Roberto
    KTH, School of Engineering Sciences (SCI), Physics, Nuclear Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Cluster emission from superheavy nuclei2018In: European Physical Journal A, ISSN 1434-6001, E-ISSN 1434-601X, Vol. 54, no 11, article id 200Article in journal (Refereed)
    Abstract [en]

    The process leading to cluster emission from superheavy nuclei in the range 100 122 has been systematically investigated. This topic is of importance because it opens up the possibility of identifying superheavy elements through deposition of clusters in the detection system. In this paper we evaluate the cluster decay half lives by considering the cluster as a particle. The motion of this particle in the field induced by the daughter nucleus is determined by solving the corresponding Schrodinger equation imposing outgoing boundary conditions (Gamow state). The corresponding Wood-Saxon potential is fitted to obtain the energies provided by a mass formula that has been established recently to have a very high degree of precision. The resulting expression for the decay width is exact, i.e. no approximation besides the assumption of a preformed cluster is introduced. It is found that the heavy cluster emission probability in the superheavy region is much smaller than the corresponding a emission probability.

  • 12. Borsics, Tamas
    et al.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Geerts, Dirk
    Koomoa, Dana-Lynn T.
    Koster, Jan
    Wester, Kenneth
    Bachmann, Andres S.
    Subcellular distribution and expression of prenylated Rab acceptor 1 domain family, member 2 (PRAF2) in malignant glioma: Influence on cell survival and migration2010In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 101, no 7, p. 1624-1631Article in journal (Refereed)
    Abstract [en]

    Our previous studies revealed that the expression of the 19-kDa protein prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is elevated in cancer tissues of the breast, colon, lung, and ovary, when compared to noncancerous tissues of paired samples. PRAF2 mRNA expression also correlated with several genetic and clinical features and is a candidate prognostic marker in the pediatric cancer neuroblastoma. The PRAF2-related proteins, PRAF1 and PRAF3, play multiple roles in cellular processes, including endo/exocytic vesicle trafficking and glutamate uptake. PRAF2 shares a high sequence homology with these family members, but its function remains unknown. In this study, we examined PRAF2 mRNA and protein expression in 20 different human cancer types using Affymetrix microarray and human tissue microarray (TMA) analyses, respectively. In addition, we investigated the subcellular distribution of PRAF2 by immunofluorescence microscopy and cell fractionation studies. PRAF2 mRNA and protein expression was elevated in several cancer tissues with highest levels in malignant glioma. At the molecular level, we detected native PRAF2 in small, vesicle-like structures throughout the cytoplasm as well as in and around cell nuclei of U-87 malignant glioma cells. We further found that monomeric and dimeric forms of PRAF2 are associated with different cell compartments, suggesting possible functional differences. Importantly, PRAF2 down-regulation by RNA interference significantly reduced the cell viability, migration, and invasiveness of U-87 cells. This study shows that PRAF2 expression is elevated in various tumors with exceptionally high expression in malignant gliomas, and PRAF2 therefore presents a candidate molecular target for therapeutic intervention. (Cancer Sci 2010).

  • 13. Boström, Johan
    et al.
    Sramkova, Zuzana
    Salasova, Alena
    Johard, Helena
    Mahdessian, Diana
    Fedr, Radek
    Marks, Carolyn
    Medalova, Jirina
    Soucek, Karel
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Linnarsson, Sten
    Bryja, Vitezslav
    Sekyrova, Petra
    Altun, Mikael
    Andang, Michael
    Comparative cell cycle transcriptomics reveals synchronization of developmental transcription factor networks in cancer cells2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0188772Article in journal (Refereed)
    Abstract [en]

    The cell cycle coordinates core functions such as replication and cell division. However, cell-cycle-regulated transcription in the control of non-core functions, such as cell identity maintenance through specific transcription factors (TFs) and signalling pathways remains unclear. Here, we provide a resource consisting of mapped transcriptomes in unsynchro-nized HeLa and U2OS cancer cells sorted for cell cycle phase by Fucci reporter expression. We developed a novel algorithm for data analysis that enables efficient visualization and data comparisons and identified cell cycle synchronization of Notch signalling and TFs associated with development. Furthermore, the cell cycle synchronizes with the circadian clock, providing a possible link between developmental transcriptional networks and the cell cycle. In conclusion we find that cell cycle synchronized transcriptional patterns are temporally compartmentalized and more complex than previously anticipated, involving genes, which control cell identity and development.

  • 14. Bourbeillon, Julie
    et al.
    Orchard, Sandra
    Benhar, Itai
    Borrebaeck, Carl
    de Daruvar, Antoine
    Duebel, Stefan
    Frank, Ronald
    Gibson, Frank
    Gloriam, David
    Haslam, Niall
    Hiltker, Tara
    Humphrey-Smith, Ian
    Hust, Michael
    Juncker, David
    Koegl, Manfred
    Konthur, Zoltan
    Korn, Bernhard
    Krobitsch, Sylvia
    Muyldermans, Serge
    Nygren, Per-Åke
    KTH, School of Biotechnology (BIO), Molecular Biotechnology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Palcy, Sandrine
    Polic, Bojan
    Rodriguez, Henry
    Sawyer, Alan
    Schlapshy, Martin
    Snyder, Michael
    Stoevesandt, Oda
    Taussig, Michael J.
    Templin, Markus
    Uhlén, Matthias
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    van der Maarel, Silvere
    Wingren, Christer
    Hermjakob, Henning
    Sherman, David
    Minimum information about a protein affinity reagent (MIAPAR)2010In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 28, no 7, p. 650-653Article in journal (Other academic)
  • 15.
    Burgess, J. Michael
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Engineering Sciences (SCI), Physics. Oskar Klein Ctr Cosmoparticle Phys, SE-10691 Stockholm, Sweden..
    Yu, Hoi-Fung
    Max Planck Inst Extraterr Phys, D-85748 Garching, Germany..
    Greiner, Jochen
    Max Planck Inst Extraterr Phys, D-85748 Garching, Germany..
    Mortlock, Daniel J.
    Imperial Coll London, Stat Sect, Dept Math, London SW7 2AZ, England.;Imperial Coll London, Blackett Lab, Astrophys Grp, Prince Consort Rd, London SW7 2AZ, England.;Stockholm Univ, Dept Astron, AlbaNova, SE-10691 Stockholm, Sweden..
    Awakening the BALROG: BAyesian Location Reconstruction Of GRBs2018In: Monthly notices of the Royal Astronomical Society, ISSN 0035-8711, E-ISSN 1365-2966, Vol. 476, no 2, p. 1427-1444Article in journal (Refereed)
    Abstract [en]

    The accurate spatial location of gamma-ray bursts (GRBs) is crucial for both accurately characterizing their spectra and follow-up observations by other instruments. The Fermi Gamma-ray Burst Monitor (GBM) has the largest field of view for detecting GRBs as it views the entire unocculted sky, but as a non-imaging instrument it relies on the relative count rates observed in each of its 14 detectors to localize transients. Improving its ability to accurately locate GRBs and other transients is vital to the paradigm of multimessenger astronomy, including the electromagnetic follow-up of gravitational wave signals. Here we present the BAyesian Location Reconstruction Of GRBs (BALROG) method for localizing and characterizing GBM transients. Our approach eliminates the systematics of previous approaches by simultaneously fitting for the location and spectrum of a source. It also correctly incorporates the uncertainties in the location of a transient into the spectral parameters and produces reliable positional uncertainties for both well-localized sources and those for which the GBM data cannot effectively constrain the position. While computationally expensive, BALROG can be implemented to enable quick follow-up of all GBM transient signals. Also, we identify possible response problems that require attention and caution when using standard, public GBM detector response matrices. Finally, we examine the effects of including the uncertainty in location on the spectral parameters of GRB080916C. We find that spectral parameters change and no extra components are required when these effects are included in contrast to when we use a fixed location. This finding has the potential to alter both the GRB spectral catalogues and the reported spectral composition of some well-known GRBs.

  • 16.
    Burvall, Anna
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Lundström, Ulf
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Takman, Per
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Larsson, Daniel
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hertz, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    X-ray in-line phase retrieval for tomography2012In: Progress in Biomedical Optics and Imaging - Proceedings of SPIE, SPIE - International Society for Optical Engineering, 2012, Vol. 8313, p. 83136A-Conference paper (Refereed)
    Abstract [en]

    Phase contrast in X-ray imaging offers imaging of fine features at lower doses than absorption. Of the phasecontrast methods in use in-line phase contrast is interesting due to its experimental simplicity, but to extract information on absorption and phase distributions from the resulting images, phase retrieval is needed. Many phase-retrieval methods suitable for different situations have been developed, but few comparisons of those methods done. We consider a sub-group of phase-retrieval methods that are suitable for tomography, i.e., that use only one exposure (for practical experimental reasons) and are non-iterative (for speed). In total we have found seven suitable methods in the literature. All, though derived in different ways under different assumptions, follow the same pattern and can be outlined as a single method where each specific version is marked by variations in particular steps. We summarize this unified approach, and give the variations of the individual methods. In addition, we outline approximations and assumptions of each method. Using this approach it is possible to conclude which specific algorithms are most suitable in specific situations and to test this based on simulated and experimental data. Ultimately, this leads to conclusions on which methods are the most suitable in different situations.

  • 17.
    Cunha, Ana Gisela
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Zhou, Qi
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Larsson, Per Tomas
    KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center. INNVENTIA AB, Sweden.
    Berglund, Lars A.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Topochemical acetylation of cellulose nanopaper structures for biocomposites: mechanisms for reduced water vapour sorption2014In: Cellulose (London), ISSN 0969-0239, E-ISSN 1572-882X, Vol. 21, no 4, p. 2773-2787Article in journal (Refereed)
    Abstract [en]

    Moisture sorption decreases dimensional stability and mechanical properties of polymer matrix biocomposites based on plant fibers. Cellulose nanofiber reinforcement may offer advantages in this respect. Here, wood-based nanofibrillated cellulose (NFC) and bacterial cellulose (BC) nanopaper structures, with different specific surface area (SSA), ranging from 0.03 to 173.3 m(2)/g, were topochemically acetylated and characterized by ATR-FTIR, XRD, solid-state CP/MAS C-13-NMR and moisture sorption studies. Polymer matrix nanocomposites based on NFC were also prepared as demonstrators. The surface degree of substitution (surface-DS) of the acetylated cellulose nanofibers is a key parameter, which increased with increasing SSA. Successful topochemical acetylation was confirmed and significantly reduced the moisture sorption in nanopaper structures, especially at RH = 53 %. BC nanopaper sorbed less moisture than the NFC counterpart, and mechanisms are discussed. Topochemical NFC nanopaper acetylation can be used to prepare moisture-stable nanocellulose biocomposites.

  • 18.
    Edfors, Fredrik
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Forsström, Björn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Boström, Tove
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. Atlas Antibodies AB.
    Maddalo, Gianluca
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Svensson, Anne-Sophie
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Tegel, Hanna
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Jochen, Schwenk
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. Technical University of Denmark, Denmark.
    A recombinant protein standard resource for targeted proteomicsManuscript (preprint) (Other academic)
    Abstract [en]

    Here, we have used a resource of 26,000 recombinant protein fragments to create custom libraries of standards for targeted proteomics based on parallel reaction monitoring (PRM). The recombinant fragments can be produced in a bacterial cell factory to generate heavy isotope labeled standards for absolute quantification of the corresponding protein targets and be used to produce high- quality spectral libraries. Altogether, coordinates for 25,684 unique proteotypic peptide assays have been experimentally defined covering 10,163 human proteins. The protocol allows for precise monitoring of digestion kinetics and thus enables to select peptides that behave quantitative during the sample preparation process. We show that the quantification tag of each recombinant protein fragment can be used for accurate retention time prediction and allows for assay standardization across different method parameters. The use of this resource was illustrated by determining the absolute concentrations of selected protein targets using multiplex targeted proteomics assays for determination of quantitative assessment of 49 protein targets in serum samples. 

  • 19. Ehlén, Å.
    et al.
    Nodin, B.
    Rexhepaj, E.
    Brändstedt, J.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Alvarado-Kristensson, M.
    Pontén, F.
    Brennan, D. J.
    Jirström, K.
    RBM3-regulated genes promote DNA integrity and affect clinical outcome in epithelial ovarian cancer2011In: Translational Oncology, ISSN 1936-5233, Vol. 4, no 4, p. 202-211Article in journal (Refereed)
    Abstract [en]

    The RNA-binding motif protein 3 (RBM3) was initially discovered as a putative cancer biomarker based on its differential expression in various cancer forms in the Human Protein Atlas (HPA). We previously reported an association between high expression of RBM3 and prolonged survival in breast and epithelial ovarian cancer (EOC). Because the function of RBM3 has not been fully elucidated, the aim of this study was to use gene set enrichment analysis to identify the underlying biologic processes associated with RBM3 expression in a previously analyzed EOC cohort (cohort 1, n = 267). This revealed an association between RBM3 expression and several cellular processes involved in the maintenance of DNA integrity. RBM3-regulated genes were subsequently screened in the HPA to select for putative prognostic markers, and candidate proteins were analyzed in the ovarian cancer cell line A2780, whereby an up-regulation of Chk1, Chk2, and MCM3 was demonstrated in siRBM3-treated cells compared to controls. The prognostic value of these markers was assessed at the messenger RNA level in cohort 1 and the protein level in an independent EOC cohort (cohort 2, n = 154). High expression levels of Chk1, Chk2, and MCM3 were associated with a significantly shorter survival in both cohorts, and phosphorylated Chk2 was an adverse prognostic marker in cohort 2. These results uncover a putative role for RBM3 in DNA damage response, which might, in part, explain its cisplatin-sensitizing properties and good prognostic value in EOC. Furthermore, it is demonstrated that Chk1, Chk2, and MCM3 are poor prognostic markers in EOC.

  • 20.
    Fognini, A.
    et al.
    Delft Univ Technol, Kavli Inst Nanosci Delft, NL-2628 CJ Delft, Netherlands..
    Ahmadi, A.
    Univ Waterloo, Inst Quantum Comp, Waterloo, ON N2L 3G1, Canada.;Univ Waterloo, Dept Phys & Astron, Waterloo, ON N2L 3G1, Canada..
    Daley, S. J.
    Univ Waterloo, Inst Quantum Comp, Waterloo, ON N2L 3G1, Canada.;Univ Waterloo, Dept Elect & Comp Engn, Waterloo, ON N2L 3G1, Canada..
    Reimer, M. E.
    Univ Waterloo, Inst Quantum Comp, Waterloo, ON N2L 3G1, Canada.;Univ Waterloo, Dept Elect & Comp Engn, Waterloo, ON N2L 3G1, Canada..
    Zwiller, V
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Engineering Sciences (SCI), Applied Physics. Delft Univ Technol, Kavli Inst Nanosci Delft, NL-2628 CJ Delft, Netherlands..
    Universal fine-structure eraser for quantum dots2018In: Optics Express, ISSN 1094-4087, E-ISSN 1094-4087, Vol. 26, no 19, p. 24487-24496Article in journal (Refereed)
    Abstract [en]

    We analyze the degree of entanglement measurable from a quantum dot via the biexciton-exciton cascade as a function of the exciton fine-structure splitting and the detection time resolution. We show that the time-energy uncertainty relation provides means to measure a high entanglement even in presence of a finite fine-structure splitting when a detection system with high temporal resolution is employed. Still, in many applications it would be beneficial if the fine-structure splitting could be compensated to zero. To solve this problem, we propose an all-optical approach with rotating waveplates to erase this fine-structure splitting completely which should allow obtaining a high degree of entanglement with near-unity efficiency. Our optical approach is possible with current technology and is also compatible with any quantum dot showing fine-structure splitting. This bears the advantage that for example the fine-structure splitting of quantum dots in nanowires and micropillars can be directly compensated without the need for further sample processing. 

  • 21.
    Fransson, Linda
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry. KTH, School of Biotechnology (BIO), Biochemistry. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Laurell, Anna
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Widyan, Khalid
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Wingstrand, Erica
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Hult, Karl
    KTH, School of Biotechnology (BIO), Biochemistry. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Moberg, Christina
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Minor Enantiomer Recycling-Effect of Two Reinforcing Catalysts on Product Yield and Enantiomeric Excess2010In: ChemCatChem, ISSN 1867-3880, E-ISSN 1867-3899, Vol. 2, no 6, p. 683-693Article in journal (Refereed)
    Abstract [en]

    Kinetic modeling of a recycling procedure in which the minor product enantiomer from an enantioselective catalytic reaction is selectively retransformed to starting material by a second chiral catalyst demonstrates that the enantiomeric excess of the product is not affected by the relative amounts of the two catalysts, but that the yield increases when the amount of the catalyst for the product-forming reaction is increased. The yield, but not the enantiomeric excess, is also affected by the initial substrate concentration. The recycling process is compared to sequential processes in which either the second catalyst is added after completion of the first reaction or in which the two catalysts are added simultaneously. In the sequential processes, high enantioselectivity can be obtained at the expense of product yield, whereas under recycling conditions both high enantiomeric excess and high yield can be achieved. Experimental data from a recycling procedure providing qualitative support for results from kinetic modeling are presented.

  • 22.
    Fransson, Linda
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Moberg, Christina
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Gaining Selectivity by Combining Catalysts: Sequential versus Recycling Processes2010In: CHEMCATCHEM, ISSN 1867-3880, Vol. 2, no 12, p. 1523-1532Article, review/survey (Refereed)
    Abstract [en]

    Highly enantioenriched chiral products may be obtained by using a combination of two moderately selective catalysts. Sequential enantioselective transformations comprising an asymmetric reaction followed by a kinetic resolution of the scalemic product mixture obtained in the first step are well known. In such processes, the minor, undesired enantiomer is transformed to a compound that can be more easily separated from the major enantiomer. Although chiral compounds may be obtained with high enantiopurity by such coupled processes, the yield of the desired product necessarily suffers. Recycling processes, whereby the minor enantiomer is transformed to prochiral starting material, avoid this limitation. In this Mini-review, different types of sequential catalytic processes using two reinforcing catalysts are surveyed and their advantages and limitations discussed in relation to recycling processes.

  • 23. Garousi, J.
    et al.
    Lindbo, Sarah
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Orlova, A.
    Åstrand, Mikael
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Nilvebrant, Johan
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Buijs, J.
    Sandstrom, M.
    Honarvar, H.
    Tolmachev, V.
    Hober, Sophia
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Development of ADAPT6 as a new scaffold protein for radionuclide molecular imaging2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, p. S309-S309Article in journal (Refereed)
  • 24. Gloriam, David E.
    et al.
    Orchard, Sandra
    Bertinetti, Daniela
    Björling, Erik
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Bongcam-Rudloff, Erik
    Borrebaeck, Carl A. K.
    Bourbeillon, Julie
    Bradbury, Andrew R. M.
    de Daruvar, Antoine
    Duebel, Stefan
    Frank, Ronald
    Gibson, Toby J.
    Gold, Larry
    Haslam, Niall
    Herberg, Friedrich W.
    Hiltke, Tara
    Hoheisel, Joerg D.
    Kerrien, Samuel
    Koegl, Manfred
    Konthur, Zoltan
    Korn, Bernhard
    Landegren, Ulf
    Montecchi-Palazzi, Luisa
    Palcy, Sandrine
    Rodriguez, Henry
    Schweinsberg, Sonja
    Sievert, Volker
    Stoevesandt, Oda
    Taussig, Michael J.
    Ueffing, Marius
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics.
    van der Maarel, Silvere
    Wingren, Christer
    Woollard, Peter
    Sherman, David J.
    Hermjakob, Henning
    A Community Standard Format for the Representation of Protein Affinity Reagents2010In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 9, no 1, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Protein affinity reagents (PARs), most commonly antibodies, are essential reagents for protein characterization in basic research, biotechnology, and diagnostics as well as the fastest growing class of therapeutics. Large numbers of PARs are available commercially; however, their quality is often uncertain. In addition, currently available PARs cover only a fraction of the human proteome, and their cost is prohibitive for proteome scale applications. This situation has triggered several initiatives involving large scale generation and validation of antibodies, for example the Swedish Human Protein Atlas and the German Antibody Factory. Antibodies targeting specific subproteomes are being pursued by members of Human Proteome Organisation (plasma and liver proteome projects) and the United States National Cancer Institute (cancer-associated antigens). ProteomeBinders, a European consortium, aims to set up a resource of consistently quality-controlled protein-binding reagents for the whole human proteome. An ultimate PAR database resource would allow consumers to visit one online warehouse and find all available affinity reagents from different providers together with documentation that facilitates easy comparison of their cost and quality. However, in contrast to, for example, nucleotide databases among which data are synchronized between the major data providers, current PAR producers, quality control centers, and commercial companies all use incompatible formats, hindering data exchange. Here we propose Proteomics Standards Initiative (PSI)-PAR as a global community standard format for the representation and exchange of protein affinity reagent data. The PSI-PAR format is maintained by the Human Proteome Organisation PSI and was developed within the context of ProteomeBinders by building on a mature proteomics standard format, PSI-molecular interaction, which is a widely accepted and established community standard for molecular interaction data. Further information and documentation are available on the PSI-PAR web site. Molecular & Cellular Proteomics 9: 1-10, 2010.

  • 25.
    Haviland, David
    KTH, School of Engineering Sciences (SCI), Applied Physics, Nanostructure Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    SUPERCONDUCTING CIRCUITS Quantum phase slips2010In: Nature Physics, ISSN 1745-2473, E-ISSN 1745-2481, Vol. 6, no 8, p. 565-566Article in journal (Refereed)
  • 26.
    Hjelm, Barbara
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Fernandez, Carmen Diez
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Löfblom, John
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Ståhl, Stefan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Johannesson, Henrik
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Rockberg, Johan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Uhlen, Mathias
    KTH, School of Biotechnology (BIO), Proteomics.
    Exploring epitopes of antibodies toward the human tryptophanyl-tRNA synthetase2010In: NEW BIOTECHNOL, ISSN 1871-6784, Vol. 27, no 2, p. 129-137Article in journal (Refereed)
    Abstract [en]

    There is a need to characterize the epitopes of affinity reagents to develop high quality affinity reagents for research, diagnostics and therapy. Here, we describe the analysis of epitopes of antibodies generated toward human tryptophanyl-tRNA synthetase (WARS) using both combinatorial bacterial display and suspension bead array. The bacterial display revealed that the polyclonal antibody binds to three separate epitopes and peptide scanning using 15-mers revealed binding to a 13 amino acid consensus sequence (ELINRIERATGQR). A mouse monoclonal antibody was generated and the mapping approach revealed binding toward a slightly shifted position of the same epitope. Structural analysis showed that the antibodies bind to a-helical regions on the surface of the target protein. An alanine-scanning experiment showed binding to four specific residues. The implications for the systematic analysis of antibody epitopes on the basis of these results are discussed.

  • 27.
    Hjelm, Barbara
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Forsström, Björn
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Igel, Ulrika
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Johannesson, Henrik
    Stadler, Charlotte
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Sjoberg, Anna
    Rockberg, Johan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Schwenk, Jochen M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Johansson, Christine
    Uhlen, Mathias
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Generation of monospecific antibodies based on affinity capture of polyclonal antibodies2011In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 20, no 11, p. 1824-1835Article in journal (Refereed)
    Abstract [en]

    A method is described to generate and validate antibodies based on mapping the linear epitopes of a polyclonal antibody followed by sequential epitope-specific capture using synthetic peptides. Polyclonal antibodies directed towards four proteins RBM3, SATB2, ANLN, and CNDP1, potentially involved in human cancers, were selected and antibodies to several non-overlapping epitopes were generated and subsequently validated by Western blot, immunohistochemistry, and immunofluorescence. For all four proteins, a dramatic difference in functionality could be observed for these monospecific antibodies directed to the different epitopes. In each case, at least one antibody was obtained with full functionality across all applications, while other epitope-specific fractions showed no or little functionality. These results present a path forward to use the mapped binding sites of polyclonal antibodies to generate epitope-specific antibodies, providing an attractive approach for large-scale efforts to characterize the human proteome by antibodies.

  • 28. Hu, Francis Jingxin
    et al.
    Lundqvist, Magnus
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Rockberg, Johan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    SAMURAI (Solid-phase Assisted Mutagenesis by Uracil Restricted Ablation In vitro) for Antibody Affinity Maturation and Paratope MappingManuscript (preprint) (Other academic)
    Abstract [en]

    Mutagenesis libraries are essential for combinatorial protein engineering. Despite improve- ments in gene synthesis and directed mutagenesis, current methodologies still have limitations regarding the synthesis of intact antibody scFv genes and simultaneous diversification of all six CDRs. Here, we de- scribe the generation of mutagenesis libraries for antibody affinity maturation, using a cell-free solid-phase technique for annealing of single-strand mutagenic oligonucleotides. This procedure consists of PCR-based incorporation of uracil into a wild-type template, bead-based capture, and elution of single-strand DNA, and in vitro uracil excision enzyme based degradation of the template DNA. Our approach enabled rapid (8 hours) mutagenesis and automated cloning of 50 position specific alanine mutants for mapping of a scFv antibody paratope. We further exemplify our method by generating affinity maturation libraries with di- versity introduced in critical, nonessential, or all CDR positions randomly. Assessment with Illumina deep sequencing showed >99% functional diversity in two libraries and the ability to diversify all CDR positions simultaneously. Selections of the libraries with bacterial display and deep sequencing evaluation of the selection output showed that diversity introduced in non-essential positions allowed quicker enrichment of improved binders compared to the other two diversification strategies.

  • 29.
    Hultin, Emelie
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Käller, Max
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Ahmadian, Afshin
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Competitive enzymatic reaction to control allele-specific extensions2005In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 33, no 5, p. e48:1-e48:10Article in journal (Refereed)
    Abstract [en]

    Here, we present a novel method for SNP genotyping based on protease-mediated allele-specific primer extension (PrASE), where the two allele-specific extension primers only differ in their 3'-positions. As reported previously [Ahmadian, A., Gharizadeh, B., O'Meara, D., Odeberg, J. and Lundeberg, J. (2001), Nucleic Acids Res., 29, e121], the kinetics of perfectly matched primer extension is faster than mismatched primer extension. In this study, we have utilized this difference in kinetics by adding protease, a protein-degrading enzyme, to discriminate between the extension reactions. The competition between the polymerase activity and the enzymatic degradation yields extension of the perfectly matched primer, while the slower extension of mismatched primer is eliminated. To allow multiplex and simultaneous detection of the investigated single nucleotide polymorphisms (SNPs), each extension primer was given a unique signature tag sequence on its 50 end, complementary to a tag on a generic array. A multiplex nested PCR with 13 SNPs was performed in a total of 36 individuals and their alleles were scored. To demonstrate the improvements in scoring SNPs by PrASE, we also genotyped the individuals without inclusion of protease in the extension. We conclude that the developed assay is highly allele-specific, with excellent multiplex SNP capabilities.

  • 30.
    Kaewthai, Nomchit
    et al.
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Gendre, Delphine
    Eklöf, Jens M.
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Ibatullin, Farid M.
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Ezcurra, Ines
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Bhalerao, Rishikesh P
    Brumer, Harry
    KTH, School of Biotechnology (BIO), Glycoscience. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Group III-A XTH Genes of Arabidopsis Encode Predominant Xyloglucan Endohydrolases That Are Dispensable for Normal Growth2013In: Plant Physiology, ISSN 0032-0889, E-ISSN 1532-2548, Vol. 161, no 1, p. 440-454Article in journal (Refereed)
    Abstract [en]

    The molecular basis of primary wall extension endures as one of the central enigmas in plant cell morphogenesis. Classical cell wall models suggest that xyloglucan endo-transglycosylase activity is the primary catalyst (together with expansins) of controlled cell wall loosening through the transient cleavage and religation of xyloglucan-cellulose cross links. The genome of Arabidopsis (Arabidopsis thaliana) contains 33 phylogenetically diverse XYLOGLUCAN ENDO-TRANSGLYCOSYLASE/HYDROLASE (XTH) gene products, two of which were predicted to be predominant xyloglucan endohydrolases due to clustering into group III-A. Enzyme kinetic analysis of recombinant AtXTH31 confirmed this prediction and indicated that this enzyme had similar catalytic properties to the nasturtium (Tropaeolum majus) xyloglucanase1 responsible for storage xyloglucan hydrolysis during germination. Global analysis of Genevestigator data indicated that AtXTH31 and the paralogous AtXTH32 were abundantly expressed in expanding tissues. Microscopy analysis, utilizing the resorufin beta-glycoside of the xyloglucan oligosaccharide XXXG as an in situ probe, indicated significant xyloglucan endohydrolase activity in specific regions of both roots and hypocotyls, in good correlation with transcriptomic data. Moreover, this hydrolytic activity was essentially completely eliminated in AtXTH31/AtXTH32 double knockout lines. However, single and double knockout lines, as well as individual overexpressing lines, of AtXTH31 and AtXTH32 did not demonstrate significant growth or developmental phenotypes. These results suggest that although xyloglucan polysaccharide hydrolysis occurs in parallel with primary wall expansion, morphological effects are subtle or may be compensated by other mechanisms. We hypothesize that there is likely to be an interplay between these xyloglucan endohydrolases and recently discovered apoplastic exo-glycosidases in the hydrolytic modification of matrix xyloglucans.

  • 31.
    Kanje, Sara
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH).
    Venskutonytė, Raminta
    Lund University.
    Scheffel, Julia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH).
    Nilvebrant, Johan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH). KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Lindkvist-Petersson, Karin
    Hober, Sophia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH). KTH, School of Biotechnology (BIO), Centres, Centre for Bioprocess Technology, CBioPT. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Protein engineering allows for mild affinity-based elution of therapeutic antibodies2018In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 18, p. 3427-3438Article in journal (Refereed)
    Abstract [en]

    Presented here is an engineered protein domain, based on Protein A, that displays a calcium-dependent binding to antibodies. This protein, ZCa, is shown to efficiently function as an affinity ligand for mild purification of antibodies through elution with ethylenediaminetetraacetic acid. Antibodies are commonly used tools in the area of biological sciences and as therapeutics, and the most commonly used approach for antibody purification is based on Protein A using acidic elution. Although this affinity-based method is robust and efficient, the requirement for low pH elution can be detrimental to the protein being purified. By introducing a calcium-binding loop in the Protein A-derived Z domain, it has been re-engineered to provide efficient antibody purification under mild conditions. Through comprehensive analyses of the domain as well as the ZCa–Fc complex, the features of this domain are well understood. This novel protein domain provides a very valuable tool for effective and gentle antibody and Fc-fusion protein purification

  • 32. Kuklin, A. V.
    et al.
    Baryshnikov, Gleb V.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Minaev, B. F.
    Ignatova, Nina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Strong Topological States and High Charge Carrier Mobility in Tetraoxa[8]circulene Nanosheets2018In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 122, no 38, p. 22216-22222Article in journal (Refereed)
    Abstract [en]

    Here we report structural and electronic properties of a new family of two-dimensional covalent metal-free organic frameworks based on tetraoxa[8]circulene with different types of fusing. All nanosheets demonstrate high thermodynamic stability and unique electronic properties depending on the fusing type. Among three types of nanosheets, only two demonstrate semiconducting properties exhibiting 1.37 and 1.84 eV direct band gaps, while another one is found to be a semimetal, which hosts strong topological states and enhances the band gap (∼87 meV) induced by spin-orbit coupling that exceeds by several orders of magnitude that gap in graphene. Tetraoxa[8]circulene-based nanosheets are also predicted to be good organic semiconductors due to a clearly observable quantum confinement effect on the band gap size in oligomers and relatively low effective masses, which result in high carrier mobility. Owing to the versatility of chemical design, these materials have the potential to expand applications beyond those of graphene.

  • 33.
    Käller, Max
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hultin, Emilie
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Holmberg, Kristina
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Persson, Marie-Louise
    Clinical Chemistry Laboratory, Blekinge Hospital, Karlskrona.
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Ahmadian, Afshin
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Comparison of PrASE and Pyrosequencing for SNP Genotyping2006In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 7, p. 291-Article in journal (Refereed)
    Abstract [en]

    Background: There is an imperative need for SNP genotyping technologies that are cost-effective per sample with retained high accuracy, throughput and flexibility. We have developed a microarray-based technique and compared it to Pyrosequencing. In the protease-mediated allele-specific extension (PrASE), the protease constrains the elongation reaction and thus prevents incorrect nucleotide incorporation to mismatched 3'-termini primers.

    Results: The assay is automated for 48 genotyping reactions in parallel followed by a tag-microarray detection system. A script automatically visualizes the results in cluster diagrams and assigns the genotypes. Ten polymorphic positions suggested as prothrombotic genetic variations were analyzed with Pyrosequencing and PrASE technologies in 442 samples and 99.8 % concordance was achieved. In addition to accuracy, the robustness and reproducibility of the technique has been investigated.

    Conclusion: The results of this study strongly indicate that the PrASE technology can offer significant improvements in terms of accuracy and robustness and thereof increased number of typeable SNPs.

  • 34.
    Lindberg, Johan
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Wijbrandts, Carla A.
    van Baarsen, Lisa G.
    Nader, Gustavo
    Klareskog, Lars
    Catrina, Anca
    Thurlings, Rogier
    Vervoordeldonk, Margriet
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Tak, Paul P.
    The Gene Expression Profile in the Synovium as a Predictor of the Clinical Response to Infliximab Treatment in Rheumatoid Arthritis2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 6, p. e11310-Article in journal (Refereed)
    Abstract [en]

    Background: Although the use of TNF inhibitors has fundamentally changed the way rheumatoid arthritis (RA) is treated, not all patients respond well. It is desirable to facilitate the identification of responding and non-responding patients prior to treatment, not only to avoid unnecessary treatment but also for financial reasons. In this work we have investigated the transcriptional profile of synovial tissue sampled from RA patients before anti-TNF treatment with the aim to identify biomarkers predictive of response. Methodology/Principal Findings: Synovial tissue samples were obtained by arthroscopy from 62 RA patients before the initiation of infliximab treatment. RNA was extracted and gene expression profiling was performed using an in-house spotted long oligonucleotide array covering 17972 unique genes. Tissue sections were also analyzed by immunohistochemistry to evaluate cell infiltrates. Response to infliximab treatment was assessed according to the EULAR response criteria. The presence of lymphocyte aggregates dominated the expression profiles and a significant overrepresentation of lymphocyte aggregates in good responding patients confounded the analyses. A statistical model was set up to control for the effect of aggregates, but no differences could be identified between responders and non-responders. Subsequently, the patients were split into lymphocyte aggregate positive-and negative patients. No statistically significant differences could be identified except for 38 transcripts associated with differences between good- and non-responders in aggregate positive patients. A profile was identified in these genes that indicated a higher level of metabolism in good responding patients, which indirectly can be connected to increased inflammation. Conclusions/Significance: It is pivotal to account for the presence of lymphoid aggregates when studying gene expression patterns in rheumatoid synovial tissue. In spite of our original hypothesis, the data do not support the notion that microarray analysis of whole synovial biopsy specimens can be used in the context of personalized medicine to identify non-responders to anti-TNF therapy before the initiation of treatment.

  • 35.
    Lindbo, Sarah
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Garousi, Javad
    Uppsala university.
    Mitran, Bogdan
    Uppsala university.
    Vorobyeva, Anzhelika
    Uppsala university.
    Oroujeni, Maryam
    Uppsala university.
    Orlova, Anna
    Uppsala university.
    Hober, Sophia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH). KTH, School of Biotechnology (BIO), Centres, Centre for Bioprocess Technology, CBioPT. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Tolmachev, Vladimir
    Uppsala university.
    Optimized molecular design of ADAPT-based HER2-imaging probes labelled with 111In and 68Ga2018In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 7, p. 2674-2683Article in journal (Refereed)
    Abstract [en]

    Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE)3DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C59-DEAVDANS-ADAPT6-GSSC and DOTA-C61-(HE)3DANS-ADAPT6-GSSC) were stably labeled with 111In for SPECT and 68Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68Ga-labeled counterparts. The best performing variant was DOTA-C61-(HE)3DANS-ADAPT6-GSSC, which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111In and 68Ga labels, respectively.

  • 36. Lindfors, Charlotte
    et al.
    Nilsson, Ida A. K.
    Garcia-Roves, Pablo M.
    Zuberi, Aamir R.
    Karimi, Mohsen
    Donahue, Leah Rae
    Roopenian, Derry C.
    Mulder, Jan
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Ekstrom, Tomas J.
    Davisson, Muriel T.
    Hokfelt, Tomas G. M.
    Schalling, Martin
    Johansen, Jeanette E.
    Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 44, p. 18108-18113Article in journal (Refereed)
    Abstract [en]

    The anorectic anx/anx mouse exhibits disturbed feeding behavior and aberrances, including neurodegeneration, in peptidergic neurons in the appetite regulating hypothalamic arcuate nucleus. Poor feeding in infants, as well as neurodegeneration, are common phenotypes in human disorders caused by dysfunction of the mitochondrial oxidative phosphorylation system (OXPHOS). We therefore hypothesized that the anorexia and degenerative phenotypes in the anx/anx mouse could be related to defects in the OXPHOS. In this study, we found reduced efficiency of hypothalamic OXPHOS complex I assembly and activity in the anx/anx mouse. We also recorded signs of increased oxidative stress in anx/anx hypothalamus, possibly as an effect of the decreased hypothalamic levels of fully assembled complex I, that were demonstrated by native Western blots. Furthermore, the Ndufaf1 gene, encoding a complex I assembly factor, was genetically mapped to the anx interval and found to be down-regulated in anx/anx mice. These results suggest that the anorexia and hypothalamic neurodegeneration of the anx/anx mouse are associated with dysfunction of mitochondrial complex I.

  • 37.
    Lindgren, Joel
    et al.
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101). KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Wahlstrom, Anna
    Danielsson, Jens
    Markova, Natalia
    Ekblad, Caroline
    Graslund, Astrid
    Abrahmsen, Lars
    Eriksson Karlström, Amelie
    KTH, School of Biotechnology (BIO), Molecular Biotechnology (closed 20130101). KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Warmlander, Sebastian K. T. S.
    N-terminal engineering of amyloid-beta-binding Affibody molecules yields improved chemical synthesis and higher binding affinity2010In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 19, no 12, p. 2319-2329Article in journal (Refereed)
    Abstract [en]

    The aggregation of amyloid-beta (A beta) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease Molecules binding with high affinity and selectivity to A beta-peptides are important tools for investigating the aggregation process An A beta-binding Affibody molecule, Z(A beta 3), has earlier been selected by phage display and shown to bind A beta(1-40) with nanomolar affinity and to inhibit A beta-peptide aggregation In this study, we create truncated functional versions of the Z(A beta 3) Affibody molecule better suited for chemical synthesis production Engineered Affibody molecules of different length were produced by solid phase peptide synthesis and allowed to form covalently linked homodimers by S-S-bridges The N-terminally truncated Affibody molecules Z(A beta 3)(12-58), Z(A beta 3)(15-58), and Z(A beta 3)(18-58) were produced in considerably higher synthetic yield than the corresponding full-length molecule Z(A beta 3)(1-58) Circular dichroism spectroscopy and surface plasmon resonance-based biosensor analysis showed that the shortest Affibody molecule, Z(A beta 3)(18-58), exhibited complete loss of binding to the A beta(1-40)-peptide, while the Z(A beta 3)(12-58) and Z(A beta 3)(15-58) Affibody molecules both displayed approximately one order of magnitude higher binding affinity to the A beta(1-40)-peptide compared to the full-length Affibody molecule Nuclear magnetic resonance spectroscopy showed that the structure of A beta(1-40) in complex with the truncated Affibody dimers is very similar to the previously published solution structure of the A beta(1-40)-peptide in complex with the full-length Z(A beta 3) Affibody molecule This indicates that the N-terminally truncated Affibody molecules Z(A beta 3)(12-58) and Z(A beta 3)(15-58) are highly promising for further engineering and future use as binding agents to monomeric A beta(1-40)

  • 38. Lindström, Sara
    et al.
    Andersson-Svahn, Helene
    KTH, School of Biotechnology (BIO), Proteomics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Overview of single-cell analyses: microdevices and applications2010In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 10, no 24, p. 3363-3372Article, review/survey (Refereed)
    Abstract [en]

    Numerous microdevices developed for single-cell analyses have been presented in the last decades. Practical usefulness in biological and clinical settings has become an important focus during the development and implementation of new structures and assays. Single-cell analysis has been applied in intracellular research, gene-and protein content and expression, PCR, cell culture and division, clone formation, differentiation, morphology, lysis, separation, sorting, cytotoxicity and fluorescence screens, antibody secretion, etc. as discussed here along with brief descriptions of the technical devices used for the studies, e. g. well-, trap-, pattern-, and droplet-based structures. This review aims to serve as an overview of available techniques for single-cell analysis by describing the different biological single-cell assays that have been performed to date and how each individual application requires a particular device design.

  • 39.
    Liu, Jun
    et al.
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Wood & Paper Chem, Porthansgatan 3-5, FI-20500 Turku, Finland.;Jiangsu Univ, Dept Environm & Safety, Biofuels Inst, Zhenjiang 212013, Peoples R China..
    Leppanen, Ann-Sofie
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Wood & Paper Chem, Porthansgatan 3-5, FI-20500 Turku, Finland..
    Kisonen, Victor
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Wood & Paper Chem, Porthansgatan 3-5, FI-20500 Turku, Finland..
    Willfor, Stefan
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Wood & Paper Chem, Porthansgatan 3-5, FI-20500 Turku, Finland..
    Xu, Chunlin
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Wallenberg Wood Science Center. Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Wood & Paper Chem, Porthansgatan 3-5, FI-20500 Turku, Finland..
    Vilaplana, Francisco
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Wallenberg Wood Science Center. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Glycoscience.
    Insights on the distribution of substitutions in spruce galactoglucomannan and its derivatives using integrated chemo-enzymatic deconstruction, chromatography and mass spectrometry2018In: International Journal of Biological Macromolecules, ISSN 0141-8130, E-ISSN 1879-0003, Vol. 112, p. 616-625Article in journal (Refereed)
    Abstract [en]

    Accurate determination of the distribution of substitutions in the primary molecular structure of heteropolysaccharides and their derivatives is a prerequisite for their increasing application in the pharmaceutical and biomedical fields, which is unfortunately hindered due to the lack of effective analytical techniques. Acetylated galactoglucomannan (GGM) is an abundant plant polysaccharide as the main hemicellulose in softwoods, and therefore constitutes an important renewable resource from lignocellulosic biomass for the development of bioactive and functional materials. Here we present a methodology for profiling the intramolecular structure of spruce GGM and its chemical derivatives (cationic, anionic, and benzoylated) by combining chemo-enzymatic hydrolysis, liquid chromatography, and mass spectrometry. Fast identification and qualitative mass profiling of GGM and its derivatives was conducted using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS) and electrospray ionization mass spectrometry (ESI-MS). Tandem mass fragmentation analysis and its hyphenation with hydrophilic interaction liquid chromatography (HILIC-ESI-MS/MS) provide further insights on the substitution placement of the GGM oligosaccharides and its derivatives. This method will be useful in understanding the structure-function relationships of native GGM and their derivatives, and therefore facilitate their potential application. 

  • 40. Liu, Zihe
    et al.
    Liu, Lifang
    Osterlund, Tobias
    Hou, Jin
    Huang, Mingtao
    Fagerberg, Linn
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Petranovic, Dina
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Denmark .
    Nielsen, Jens
    Improved Production of a Heterologous Amylase in Saccharomyces cerevisiae by Inverse Metabolic Engineering2014In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 80, no 17, p. 5542-5550Article in journal (Refereed)
    Abstract [en]

    The increasing demand for industrial enzymes and biopharmaceutical proteins relies on robust production hosts with high protein yield and productivity. Being one of the best-studied model organisms and capable of performing posttranslational modifications, the yeast Saccharomyces cerevisiae is widely used as a cell factory for recombinant protein production. However, many recombinant proteins are produced at only 1% (or less) of the theoretical capacity due to the complexity of the secretory pathway, which has not been fully exploited. In this study, we applied the concept of inverse metabolic engineering to identify novel targets for improving protein secretion. Screening that combined UV-random mutagenesis and selection for growth on starch was performed to find mutant strains producing heterologous amylase 5-fold above the level produced by the reference strain. Genomic mutations that could be associated with higher amylase secretion were identified through whole-genome sequencing. Several single-point mutations, including an S196I point mutation in the VTA1 gene coding for a protein involved in vacuolar sorting, were evaluated by introducing these to the starting strain. By applying this modification alone, the amylase secretion could be improved by 35%. As a complement to the identification of genomic variants, transcriptome analysis was also performed in order to understand on a global level the transcriptional changes associated with the improved amylase production caused by UV mutagenesis.

  • 41.
    Lopes, Denise Adorno
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Uygur, Selim
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Johnson, Kyle
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Degradation of UN and UN-U3Si2 pellets in steam environment2017In: Journal of Nuclear Science and Technology, ISSN 0022-3131, E-ISSN 1881-1248, Vol. 54, no 4, p. 405-413Article in journal (Refereed)
    Abstract [en]

    In this work, a systematic study of the degradation of UN pellets (density range 96%-99.9% and grain size of 6-24 mu m) and UN-10%U3Si2 (wt%) composite in a steam environment is presented. Static steam autoclave tests were performed at 300 degrees C and 9 MPa for period of 0.5-1.5 hours. Microstructural analyses of UN pellets show that, in a high-pressure atmosphere, the fuel collapses principally by intergranular cracking generated by the precipitation of an oxide phase in the grain boundaries. This mechanism leads to a premature mechanical collapse of the fuel pellet, exposing fresh surfaces to steam, and ultimately accelerating the oxidation process. Increasing density (specifically eliminating open porosity) was found to delay the oxidation process, while increasing grain size was found to accelerate the degradation process due to a greater susceptibility to mechanical fracture by way of intergranular oxidation. The performance of the UN-10%U3Si2 composite proved to be better when compared to UN. The U3Si2 phase served to stabilize the UN grain boundary interface and reacted preferentially with the steam, thereby altering the failure mechanism. In this composite material, the cracking was predominantly intra-granular and the exposure of fresh surfaces was limited, resulting in a slower degradation process.

  • 42. Lundin, P.
    et al.
    Gurell, J.
    Mannervik, S.
    Royen, P.
    Norlin, Lars-Olov
    KTH, School of Engineering Sciences (SCI), Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hartman, H.
    Hibbert, A.
    Metastable levels in ScII: lifetime measurements and calculations2008In: Physica Scripta, ISSN 0031-8949, E-ISSN 1402-4896, Vol. 78, no 1, p. 015301-Article in journal (Refereed)
    Abstract [en]

    The lifetime of the metastable level 3d(21)G(4) in a singly charged scandium has been experimentally investigated at the ion storage ring CRYRING. A laser probing technique has been used for the studies. We also report calculated lifetimes and transition rates for 10 metastable levels in Sc II, including the 3d(21)G(4) state, by calculations using configuration interaction wave functions. The lifetime of the (1)G(4) level is experimentally determined to be tau(exp) = 2.64 +/- 0.18 s and is in good agreement with the theoretical calculation tau(th) = 2.84 s.

  • 43.
    Lundman, Christoffer
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Engineering Sciences (SCI), Physics. Columbia Univ, Phys Dept, 538 West 120th St, New York, NY 10027 USA.;Columbia Univ, Columbia Astrophys Lab, 538 West 120th St, New York, NY 10027 USA.;AlbaNova, Oskar Klein Ctr Cosmoparticle Phys, SE-10691 Stockholm, Sweden..
    Beloborodov, Andrei M.
    Columbia Univ, Phys Dept, 538 West 120th St, New York, NY 10027 USA.;Columbia Univ, Columbia Astrophys Lab, 538 West 120th St, New York, NY 10027 USA..
    Vurm, Indrek
    Columbia Univ, Phys Dept, 538 West 120th St, New York, NY 10027 USA.;Columbia Univ, Columbia Astrophys Lab, 538 West 120th St, New York, NY 10027 USA.;Tartu Observ, EE-61602 Toravere, Tartumaa, Estonia..
    Radiation-mediated Shocks in Gamma-Ray Bursts: Pair Creation2018In: Astrophysical Journal, ISSN 0004-637X, E-ISSN 1538-4357, Vol. 858, no 1, article id 7Article in journal (Refereed)
    Abstract [en]

    Relativistic sub-photospheric shocks are a possible mechanism for producing prompt gamma-ray burst (GRB) emission. Such shocks are mediated by scattering of radiation. We introduce a time-dependent, special relativistic code which dynamically couples Monte Carlo radiative transfer to the flow hydrodynamics. The code also self-consistently follows electron-positron pair production in photon-photon collisions. We use the code to simulate shocks with properties relevant to GRBs. We focus on plane-parallel solutions, which are accurate deep below the photosphere. The shock generates a power-law photon spectrum through the first-order Fermi mechanism, extending upward from the typical upstream photon energy. Strong (high Mach number) shocks produce rising nu F-nu spectra. We observe that in non-relativistic shocks the spectrum extends to E-max similar to m(e)v(2), where v is the speed difference between the upstream and downstream. In relativistic shocks the spectrum extends to energies E > 0.1 m(e)c(2) where its slope softens due to Klein-Nishina effects. Shocks with Lorentz factors gamma > 1.5 are prolific producers of electron-positron pairs, yielding hundreds of pairs per proton. The main effect of pairs is to reduce the shock width by a factor of similar to Z(+/-)(-1). Most pairs annihilate far downstream of the shock, and the radiation spectrum relaxes to a Wien distribution, reaching equilibrium with the plasma at a temperature determined by the shock jump conditions and the photon number per proton. We discuss the implications of our results for observations of radiation generated by sub-photospheric shocks.

  • 44.
    Lundow, Per Håkan
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Condensed Matter Theory. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Markstrom, Klas
    EXACT AND APPROXIMATE COMPRESSION OF TRANSFER MATRICES FOR GRAPH HOMOMORPHISMS2008In: LMS Journal of Computation and Mathematics, ISSN 1461-1570, E-ISSN 1461-1570, Vol. 11, p. 1-14Article in journal (Refereed)
    Abstract [en]

    The aim of this paper is to extend the previous work on transfer matrix compression in the case of graph homomorphisms. For H-homomorphisms of lattice-like graphs we demonstrate how the automorphisms of H, as well as those of the underlying lattice, can be used to reduce the size of the relevant transfer matrices. As applications of this method we give currently best known bounds for the number of 4- and 5-colourings of the square grid, and the number of 3- and 4-colourings of the three-dimensional cubic lattice. Finally, we also discuss approximate compression of transfer matrices.

  • 45.
    McGlynn, Sinead
    et al.
    KTH, School of Engineering Sciences (SCI), Physics. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Foley, S.
    McBreen, S.
    Hanlon, L.
    O'Connor, R.
    Carrillo, A. Martin
    McBreen, B.
    GRB 070707: the first short gamma-ray burst observed by INTEGRAL2008In: Astronomy and Astrophysics, ISSN 0004-6361, E-ISSN 1432-0746, Vol. 486, no 2, p. 405-410Article in journal (Refereed)
    Abstract [en]

    Context. INTEGRAL has observed 47 long-duration GRBs (T-90 greater than or similar to 2 s) and 1 short-duration GRB (T-90 less than or similar to 2 s) in five years of observation since October 2002. Aims. This work presents the properties of the prompt emission of GRB 070707, which is the first short hard GRB observed by INTEGRAL. Methods. The spectral and temporal properties of GRB 070707 were determined using the two sensitive coded-mask gamma-ray instruments on board INTEGRAL, IBIS and SPI. Results. The T-90 duration was 0.8 s, and the spectrum of the prompt emission was obtained by joint deconvolution of IBIS and SPI data to yield a best fit power-law with photon index alpha = -1.19(-0.13)(+0.14) , which is consistent with the characteristics of short-hard gamma-ray bursts. The peak flux over 1 s was 1.79(-0.21)(+0.06) photons cm(-2) s(-1) and the fluence over the same interval was (2.07(-0.32)(+0.06) ) x 10(-7) erg cm(-2) in the energy range 20-200 keV. The spectral lag measured between 25-50 keV and 100-300 keV is 20 +/- 5 ms, consistent with the small or negligible lags measured for short bursts. Conclusions. The spectral and temporal properties of GRB 070707 are comparable to those of the short hard bursts detected by other gamma-ray satellites, including BATSE and Swift. We estimate a lower limit on the Lorentz factor Gamma greater than or similar to 25 for GRB 070707, assuming the typical redshift for short GRBs of z = 0.35. This limit is consistent with previous estimates for short GRBs and is smaller than the lower limits of Gamma greater than or similar to 100 calculated for long GRBs. If GRB 070707 is a member of the recently postulated class of short GRBs at z similar to 1, the lower limit on Gamma increases to Gamma greater than or similar to 35.

  • 46. Mersmann, Michael
    et al.
    Meier, Doris
    Mersmann, Jana
    Helmsing, Saskia
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Graslund, Susanne
    Colwill, Karen
    Hust, Michael
    Duebel, Stefan
    Towards proteome scale antibody selections using phage display2010In: NEW BIOTECHNOL, ISSN 1871-6784, Vol. 27, no 2, p. 118-128Article in journal (Refereed)
    Abstract [en]

    In vitro antibody generation by panning a large universal gene library with phage display was employed to generate antibodies to more than 60 different antigens. Of particular interest was a comparison of pannings on 20 different SH2 domains provided by the Structural Genomics Consortium (SGC). Streamlined methods for high throughput antibody generation developed within the 'Antibody Factory' of the German National Genome Research Network (NGFN) were demonstrated to minimise effort and provide a reliable and robust source for antibodies. For the SH2 domains, in two successive series of selections, 2668 clones were analysed, resulting in 347 primary hits in ELISA. Half of these hits were further analysed, and more than 90 different scFv antibodies to all antigens were identified. The validation of selected antibodies by cross-reactivity ELISA, western blot and on protein microarrays demonstrated the versatility of the in vitro antibody selection pipeline to generate a renewable resource of highly specific monoclonal binders in proteome scale numbers with substantially reduced effort and time.

  • 47. Moore, R. G.
    et al.
    Nascimento, V. B.
    Zhang, Jiandi
    Rundgren, John
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theory of Materials. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Jin, R.
    Mandrus, D.
    Plummer, E. W.
    Manifestations of broken symmetry: The surface phases of Ca2-xSrxRuO42008In: Physical Review Letters, ISSN 0031-9007, E-ISSN 1079-7114, Vol. 100, no 6, p. 066102-Article in journal (Refereed)
    Abstract [en]

    The surface structural phases of Ca2-xSrxRuO4 are investigated using quantitative low energy electron diffraction. The broken symmetry at the surface enhances the structural instability against the RuO6 rotational distortion while diminishing the instability against the RuO6 tilt distortion occurring within the bulk crystal. As a result, suppressed structural and electronic surface phase transition temperatures are observed, including the appearance of an inherent Mott metal-to-insulator transition for x=0.1 and possible modifications of the surface quantum critical point near x(c)similar to 0.5.

  • 48.
    Mudedla, Sathish Kumar
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH). AlbaNova Univ Ctr, Royal Inst Technol KTH, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Natarajan Arul, Murugan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. AlbaNova Univ Ctr, Royal Inst Technol KTH, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. AlbaNova Univ Ctr, Royal Inst Technol KTH, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.;Uppsala Univ, Dept Phys & Astron, Box 516, SE-75120 Uppsala, Sweden..
    Free Energy Landscape for Alpha-Helix to Beta-Sheet Interconversion in Small Amyloid Forming Peptide under Nanoconfinement2018In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 122, no 42, p. 9654-9664Article in journal (Refereed)
    Abstract [en]

    Understanding the mechanism of fibrillization of amyloid forming peptides could be useful for the development of therapeutics for Alzheimer's disease (AD). Taking this standpoint, we have explored in this work the free energy profile for the interconversion of monomeric and dimeric forms of amyloid forming peptides into different secondary structures namely beta-sheet, helix, and random coil in aqueous solution using umbrella sampling simulations and density functional theory calculations. We show that the helical structures of amyloid peptides can form beta sheet rich aggregates through random coil conformations in aqueous condition. Recent experiments (Chem. Eur. J. 2018, 24, 3397-3402 and ACS Appl. Mater. Interfaces 2017, 9, 21116-21123) show that molybdenum disulfide nanosurface and nanoparticles can reduce the fibrillization process of amyloid beta peptides. We have unravelled the free energy profile for the interconversion of helical forms of amyloid forming peptides into beta-sheet and random coil in the presence of a two-dimensional nanosurface of MoS2. Results indicate that the monomer and dimeric forms of the peptides adopt the random coil conformation in the presence of MoS2 while the helical form is preferable for the monomeric form and that the beta-sheet and helix forms are the preferable forms for dimers in aqueous solution. This is due to strong interaction with MoS2 and intramolecular hydrogen bonds of random coil conformation. The stabilization of random coil conformation does not lead to a beta sheet like secondary structure for the aggregate. Thus, the confinement of MoS2 promotes deaggregation of amyloid beta peptides rather than aggregation, something that could be useful for the development of therapeutics for AD.

  • 49.
    Natarajan Arul, Murugan
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Nordberg, Agneta
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry.
    Different Positron Emission Tomography Tau Tracers Bind to Multiple Binding Sites on the Tau Fibril: Insight from Computational Modeling2018In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 7, p. 1757-1767Article in journal (Refereed)
    Abstract [en]

    Using the recently reported cryo-EM structure for the tau fibril [Fitzpatrick et al. (2017) Nature 547, 185-190], which is a potential target concerning Alzheimer's disease, we present the first molecular modeling studies on its interaction with various positron emission tomography (PET) tracers. Experimentally, based on the binding assay studies, at least three different high affinity binding sites have been reported for tracers in the tau fibril. Herein, through integrated modeling using molecular docking, molecular dynamics, and binding free energy calculations, we provide insight into the binding patterns of various tracers to the tau fibril. We suggest that there are four different high affinity binding sites available for many of the studied tracers showing varying binding affinity to different binding sites. Thus, PBB3 binds most strongly to site 4, and interestingly, this site is not a preferable site for any other tracers. For THIC5351, our data show that it strongly binds to sites 3 and 1, the former one being more preferable. We also find that MK6240 and T807 bind to site 1 specifically. The modeling data also give some insight into whether a tracer bound to a specific site can be replaced by others or not. For example, the displacement of T807 by PBB3 as reported experimentally can also be explained and attributed to the larger binding affinity of the latter compound in all binding sites. The binding free energy results explain very well the small binding affinity of THK523 compared to all the aryl quinoline moieties containing THK tracers. The ability of certain tau tracers, like FDDNP and THK523, to bind to amyloid fibrils has also been investigated. Furthermore, such off-target interaction of tau tracers with amyloid beta fibrils has been validated using a quantum mechanical fragmentation approach.

  • 50.
    Natarajan Arul, Murugan
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Zalesny, Robert
    Wroclaw Univ Sci & Technol, Fac Chem, Dept Phys & Quantum Chem, Wyb Wyspianskiego 27, PL-50370 Wroclaw, Poland..
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Unusual binding-site-specific photophysical properties of a benzothiazole-based optical probe in amyloid beta fibrils2018In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 31, p. 20334-20339Article in journal (Refereed)
    Abstract [en]

    Optical imaging of amyloid fibrils serves as a cost-effective route for the diagnosis of Alzheimer-like conformational diseases. However, the challenge here is to optimize the binding affinity and photophysical properties of the optical imaging agents in a way specific to certain types of amyloids. In a few occasions it is shown that novel optical imaging agents can be designed to bind to a particular type of amyloid fibril with larger binding affinity and specificity. There is also a recent report on photoluminescent polythiophenes which display photophysical properties that can be used to distinguish the variants or subtypes of amyloids (J. Rasmussen et al., Proc. Natl. Acad. Sci. U. S. A., 2017, 114(49), 13018-13023). Based on a multiscale modeling approach, here, we report on the complementary aspect that the photophysical properties of a benzothiazole based optical probe (referred to as BTA-3) can be specific to the binding sites in the same amyloid fibrils and we attribute this to its varying electronic structure in different sites. As reported experimentally from competitive binding assay studies for many amyloid staining molecules and tracers, we also show multiple binding sites in amyloid fibrils for this probe. In particular, BTA-3 displayed a red-shift in its low-frequency absorption band only in site-4, a surface site of amyloid fibrils when compared to the spectra in water solvent. In the remaining sites, it exhibited a less significant blue shift for the same absorption band.

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