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  • 1. Agostinho, A.
    et al.
    Kouznetsova, A.
    Hernández-Hernández, A.
    Bernhem, Kristoffer
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Blom, Hans
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Höög, C.
    Sexual dimorphism in the width of the mouse synaptonemal complex2018Inngår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 131, nr 5, artikkel-id jcs212548Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sexual dimorphism has been used to describe morphological differences between the sexes, but can be extended to any biologically related process that varies between males and females. The synaptonemal complex (SC) is a tripartite structure that connects homologous chromosomes in meiosis. Here, aided by superresolution microscopy techniques, we show that the SC is subject to sexual dimorphism, in mouse germ cells. We have identified a significantly narrower SC in oocytes and have established that this difference does not arise from a different organization of the lateral elements nor from a different isoform of transverse filament protein SYCP1. Instead, we provide evidence for the existence of a narrower central element and a different integration site for the C-termini of SYCP1, in females. In addition to these female-specific features, we speculate that post-translation modifications affecting the SYCP1 coiled-coil region could render a more compact conformation, thus contributing to the narrower SC observed in females.

  • 2.
    Akkuratov, Evgeny E.
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. St Petersburg State Univ, Inst Translat Biomed, St Petersburg, Russia.
    Gelfand, Mikhail S.
    Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Moscow, Russia.;Russian Acad Sci, Inst Informat Transmiss Problems, Moscow, Russia.;Natl Res Univ, Higher Sch Econ, Fac Comp Sci, Moscow, Russia.;MM Lomonosov Moscow State Univ, Dept Bioengn & Bioinformat, Moscow, Russia..
    Khrameeva, Ekaterina E.
    Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Moscow, Russia.;Russian Acad Sci, Inst Informat Transmiss Problems, Moscow, Russia..
    Neanderthal and Denisovan ancestry in Papuans: A functional study2018Inngår i: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 16, nr 2, artikkel-id 1840011Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sequencing of complete nuclear genomes of Neanderthal and Denisovan stimulated studies about their relationship with modern humans demonstrating, in particular, that DNA alleles from both Neanderthal and Denisovan genomes are present in genomes of modern humans. The Papuan genome is a unique object because it contains both Neanderthal and Denisovan alleles. Here, we have shown that the Papuan genomes contain different gene functional groups inherited from each of the ancient people. The Papuan genomes demonstrate a relative prevalence of Neanderthal alleles in genes responsible for the regulation of transcription and neurogenesis. The enrichment of specific functional groups with Denisovan alleles is less pronounced; these groups are responsible for bone and tissue remodeling. This analysis shows that introgression of alleles from Neanderthals and Denisovans to Papuans occurred independently and retention of these alleles may carry specific adaptive advantages.

  • 3. Arruda, L. C. M.
    et al.
    Gaballa, A.
    Uhlin, Michael
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution2019Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 202, nr 6, s. 1859-1870Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although the impact of donor graft composition on clinical outcomes after hematopoietic stem cell transplantation (HSCT) has been studied, little is known about the role of intragraft γδ TCR repertoire on clinical outcomes following HSCT. Using a high-throughput sequencing platform, we sought to analyze the TCR γ-chain (TRG) repertoire of γδ T cells within donor stem cell grafts and address its potential impact on clinical response in the corresponding patients. A total of 20 peripheral blood stem cell grafts were analyzed, and donors were classified as CMV+/- The respective acute myeloid leukemia recipients were followed for disease relapse and acute graft-versus-host disease (aGvHD) development post-HSCT. In all samples, TRG repertoire showed a reduced diversity and displayed overrepresented clones. This was more prominent in grafts from CMV+ donors, which presented a more private repertoire, lower diversity, skewed distribution, and reduced usage of the V9-JP pairing. Grafts given to nonrelapse patients presented a more public repertoire and increased presence of long sequence clonotypes. Variable-joining gene segment usage was not associated with aGvHD development, but a higher usage of V2-JP1 pairing and lower usage of V4-J2/V5-J2/V8-JP2 were observed in grafts given to nonrelapse patients. Our work identified five private overrepresented and one public CDR3 sequence (CATWDGPYYKKLF) associated with CMV infection, in addition to 12 highly frequent public sequences present exclusively in grafts given to nonrelapse patients. Our findings show that, despite CMV infection reshaping the TRG repertoire, TRG composition is not associated with aGvHD development, and several public sequences are associated with clinical remission.

  • 4. Caceres, R.
    et al.
    Bojanala, N.
    Kelley, L. C.
    Dreier, Jes
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik.
    Manzi, J.
    Di Federico, F.
    Chi, Q.
    Risler, T.
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Sherwood, D. R.
    Plastino, J.
    WASP and WAVE activate the Arp2/3 complex for actin-based force production during basement membrane invasion.2017Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 28Artikkel i tidsskrift (Annet vitenskapelig)
  • 5.
    Fontana, Jacopo M.
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik.
    Khodus, Georgiy R.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Unnersjö Jess, David
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Blom, Hans
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Aperia, Anita
    Karolinska Inst, Sci Life Lab, Dept Womens & Childrens Hlth, Solna, Sweden..
    Brismar, Hjalmar
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney2019Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, nr 3, s. 4089-4096Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The central role of calcium signaling during development of early vertebrates is well documented, but little is known about its role in mammalian embryogenesis. We have used immunofluorescence and time-lapse calcium imaging of cultured explanted embryonic rat kidneys to study the role of calcium signaling for branching morphogenesis. In mesenchymal cells, we recorded spontaneous calcium activity that was characterized by irregular calcium transients. The calcium signals were dependent on release of calcium from intracellular stores in the endoplasmic reticulum. Down-regulation of the calcium activity, both by blocking the sarco-endoplasmic reticulum Ca2+-ATPase and by chelating cytosolic calcium, resulted in retardation of branching morphogenesis and a reduced formation of primitive nephrons but had no effect on cell proliferation. We propose that spontaneous calcium activity contributes with a stochastic factor to the self-organizing process that controls branching morphogenesis, a major determinant of the ultimate number of nephrons in the kidney.Fontana, J. M., Khodus, G. R., Unnersjo-Jess, D., Blom, H., Aperia, A., Brismar, H. Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney.

  • 6.
    Gianti, Eleonora
    et al.
    Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA..
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH Royal Inst Technol, Dept Theoret Phys, Stockholm, Sweden..
    Klein, Michael
    Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA..
    Carnevale, Vincenzo
    Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA..
    Exploiting water density fluctuations in ion channel drug design2017Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253Artikkel i tidsskrift (Annet vitenskapelig)
  • 7.
    Gianti, Eleonora
    et al.
    Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA..
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH Royal Inst Technol, Stockholm, Sweden..
    Klein, Michael
    Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA..
    Carnevale, Vincenzo
    Temple Univ, Inst Computat Mol Sci, Philadelphia, PA 19122 USA..
    Modeling activation states in the voltage-gated proton channel 1 (Hv1) as a strategy for drug discovery2016Inngår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 252Artikkel i tidsskrift (Annet vitenskapelig)
  • 8.
    Groome, J. R.
    et al.
    United States.
    Moreau, A.
    France.
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Gating pore currents in sodium channels2018Inngår i: Handbook of Experimental Pharmacology, ISSN 0171-2004, E-ISSN 1865-0325, s. 371-399Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Voltage-gated sodium channels belong to the superfamily of voltage-gated cation channels. Their structure is based on domains comprising a voltage sensor domain (S1–S4 segments) and a pore domain (S5–S6 segments). Mutations in positively charged residues of the S4 segments may allow protons or cations to pass directly through the gating pore constriction of the voltage sensor domain; these anomalous currents are referred to as gating pore or omega (ω) currents. In the skeletal muscle disorder hypokalemic periodic paralysis, and in arrhythmic dilated cardiomyopathy, inherited mutations of S4 arginine residues promote omega currents that have been shown to be a contributing factor in the pathogenesis of these sodium channel disorders. Characterization of gating pore currents in these channelopathies and with artificial mutations has been possible by measuring the voltage-dependence and selectivity of these leak currents. The basis of gating pore currents and the structural basis of S4 movement through the gating pore has also been studied extensively with molecular dynamics. These simulations have provided valuable insight into the nature of S4 translocation and the physical basis for the effects of mutations that promote permeation of protons or cations through the gating pore.

  • 9.
    Guha, Arnab
    et al.
    Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Epinal Way, Loughborough, Loughborough University, LE11 3TU, UK.
    Sandström, Niklas
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Ostanin, Victor
    Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW , UK.
    van der Wijngaart, Wouter
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Mikro- och nanosystemteknik.
    Klenerman, David
    Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW , UK.
    Ghosh, Sourav
    Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Epinal Way, Loughborough, Loughborough University, LE11 3TU, UK.
    Measurement of protein binding with vastly improved time resolution using a quartz crystal microbalance driven at a fixed frequency2017Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    Introduction: Quartz crystal microbalance (QCM) is commonly used to study biomolecular binding by measuring shifts in resonance frequency of a quartz-crystal-oscillator. However, the currently used methods like impedance analysis or QCM-D, which require repeated sweeps or ringing, are limited in time resolution (~1 second) due to the need for averaging. This restricts our ability to study transient biomolecular processes, which occur in sub-millisecond time scale. A novel technique has been reported here that allows quantification of resonance frequency of a quartz-crystal-oscillator with significantly improved time resolution by driving and measuring continuously at a constant frequency within the resonance bandwidth. 

    Method: The reactive component of the experimentally obtained impedance is utilized for the estimation of resonance frequency from the Butterworth Van-dyke (BVD) model of a quartz-crystal-oscillator, assuming that changes in motional inductance and capacitance around resonance are negligible. Triplicate sets of experiments involving the binding of streptavidin with a biotin functionalized 14.3 MHz quartz oscillator surface were performed. Intermittent frequency sweeps and fixed frequency drives, both of 0.1 second duration and around 14.3 MHz, were taken at intervals of 2 minutes under the flow of phosphate-buffer-saline (PBS buffer) before and after injection of streptavidin. 

    Results: The average shift in resonance frequency from the baseline (measurements before streptavidin injection) due to streptavidin-biotin binding, calculated from the fixed frequency drive or FFD (148 Hz) was within 1% of that estimated from the frequency sweep method by fitting the experimentally recorded impedance employing the BVD model (149 Hz). 

    Discussion: The agreement of the FFD with conventional frequency sweep method suggests that protein binding can be quantified with reasonable accuracy from each impedance data point, which with our set-up is recorded at 30 kHz sampling rate. This gives a time resolution of 0.03 millisecond, which is about 4 orders of magnitude improvement over the state-of-the-art.

  • 10.
    Hess, Berk
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Gong, Jing
    KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Skolan för datavetenskap och kommunikation (CSC), Centra, Parallelldatorcentrum, PDC.
    Pall, Szilard
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Schlatter, Philipp
    KTH, Skolan för teknikvetenskap (SCI), Mekanik. KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Skolan för teknikvetenskap (SCI), Centra, Linné Flow Center, FLOW.
    Peplinski, Adam
    KTH, Skolan för teknikvetenskap (SCI), Mekanik, Stabilitet, Transition, Kontroll.
    Highly Tuned Small Matrix Multiplications Applied to Spectral Element Code Nek50002016Konferansepaper (Fagfellevurdert)
  • 11.
    Howard, R. J.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Heusser, S. A.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Zhuang, Y.
    Uppsala Univ, Sect Chem, Uppsala, Sweden..
    Lycksell, M.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Klement, Göran
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Orellana, L.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    ALCOHOL MODULATION VIA ALLOSTERIC TRANSMEMBRANE SITES IN PENTAMERIC LIGAND-GATED ION CHANNELS2018Inngår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, s. 60A-60AArtikkel i tidsskrift (Fagfellevurdert)
  • 12.
    Jess, David Unnersjö
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    High-resolution Imaging of Cleared and Expanded Kidney Tissue Samples2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The kidney is one of the most important and complex organs in the humanbody with the task of filtering hundreds of litres of blood daily. It is responsiblefor the salt and acid/base balance in the body, as well as secretinghormones important for red blood cell production and blood pressure regulation. Kidney disease is one of the fastest growing causes of death in the modern world, and this motivates extensive research for better understandingthe function of the kidney in both health and disease. Kidney failure or end stage renal disease (ESRD) is irreversible and requires treatment with dialysisor transplantation. Some of the most important cellular structures for blood filtration in the kidney are of very small dimensions (below 200 nanometers), and thus electron microscopy has previously been the only method with high enough resolution to study the morphology and topology of these minute structures. In three studies included in this thesis, we show that the finest elements of the kidney can now be resolved using different light microscopy techniques. In study 1, we show that by combining optical clearing with STED microscopy, protein localizations in the slit diaphragm of the kidney can be resolved, with widths around 75 nanometers. In study 3, a novel sample preparation method, expansion microscopy, is utilized to isotropically expand kidney tissue samples in space. Expansion improves the effective resolution by a factor of 5, making it possible to resolve podocyte foot processes and the slit diaphragmusing diffraction-limited confocal microscopy. We also show that by combining expansion microscopy and STED microscopy, the effective resolution can be improved even further (<20 nm). In our most recent work, study 5, we apply a simplified, moderate tissue swelling protocol which together with optimization of the confocal imaging provides sufficient resolution to resolve foot processes and parts of the filtration barrier. This new protocol is fast and technically simple, making it ideal for routine use, such as for future clinical pathology. In collaboration with kidney researchers, we have applied both STED microscopy and expansion microscopy to various disease models, showing that these tools can be used to both visualize and quantify pathologies occurring in different parts of the glomerular filtration barrier (GFB). In study 2, STED microscopy in combination with optical clearing is used to study the localization of Coro2b in secondary foot processes in both mouse and human tissue. In two ongoing studies with preliminary results presented in the thesis, we use STED microscopy and optical clearing to study the pathogenesis of focal segmental glomerulosclerosis (FSGS) by the use of genetic mouse models. Based on STED images, we extract different morphological parameters from foot processes and the glomerular filtration barrier (GFB) at different stages of the disease. In study 4, we apply a tissue expansion protocol to answer questions about the phenotype seen in podocytes where the mediator complex subunit 22 (Med22) is inactivated. By inactivating Med22 in a transgenic mouse line with cytosolic expression of tdTomato in podocytes, we saw strong indications that the vesicle-like structures seen in EM micrographs were indeed intracellular vesicles and not dilated sub-podocyte space. In summary, the work presented in this thesis has contributed to the development of a new toolbox for imaging renal ultra-structure using light microscopy, a field previously reserved for electron microscopy.

  • 13.
    Johansson, Petter
    et al.
    KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Hess, Berk
    KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Molecular origin of contact line friction in dynamic wetting2018Inngår i: Physical Review Fluids, E-ISSN 2469-990X, Vol. 3, nr 7, artikkel-id 074201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A hydrophilic liquid, such as water, forms hydrogen bonds with a hydrophilic substrate. The strength and locality of the hydrogen bonding interactions prohibit slip of the liquid over the substrate. The question then arises how the contact line can advance during wetting. Using large-scale molecular dynamics simulations we show that the contact line advances by single molecules moving ahead of the contact line through two distinct processes: either moving over or displacing other liquid molecules. In both processes friction occurs at the molecular scale. We measure the energy dissipation at the contact line and show that it is of the same magnitude as the dissipation in the bulk of a droplet. The friction increases significantly as the contact angle decreases, which suggests suggests thermal activation plays a role. We provide a simple model that is consistent with the observations.

  • 14.
    Kasimova, Marina A.
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Lindahl, Erik
    KTH.
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Detection of Voltage-Sensing Residues in Membrane Proteins2018Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, nr 3, s. 476A-476AArtikkel i tidsskrift (Annet vitenskapelig)
  • 15.
    Marsavelski, Aleksandra
    et al.
    Rudjer Boskovic Inst, Div Organ Chem & Biochem, Computat Organ Chem & Biochem Grp, Bijenicka Cesta 54, Zagreb 10000, Croatia.;Univ Zagreb, Fac Sci, Dept Chem, Horvatovac 102a, Zagreb 10000, Croatia.;Uppsala Univ, Dept Cell & Mol Biol, BMC Box 596, S-75124 Uppsala, Sweden..
    Petrovic, Dusan
    Uppsala Univ, Dept Cell & Mol Biol, BMC Box 596, S-75124 Uppsala, Sweden..
    Bauer, Paul
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Cell & Mol Biol, BMC Box 596, S-75124 Uppsala, Sweden.
    Vianello, Robert
    Rudjer Boskovic Inst, Div Organ Chem & Biochem, Computat Organ Chem & Biochem Grp, Bijenicka Cesta 54, Zagreb 10000, Croatia..
    Kamerlin, Shina Caroline Lynn
    Uppsala Univ, Dept Cell & Mol Biol, BMC Box 596, S-75124 Uppsala, Sweden..
    Empirical Valence Bond Simulations Suggest a Direct Hydride Transfer Mechanism for Human Diamine Oxidase2018Inngår i: ACS OMEGA, ISSN 2470-1343, Vol. 3, nr 4, s. 3665-3674Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diamine oxidase (DAO) is an enzyme involved in the regulation of cell proliferation and the immune response. This enzyme performs oxidative deamination in the catabolism of biogenic amines, including, among others, histamine, putrescine, spermidine, and spermine. The mechanistic details underlying the reductive half-reaction of the DAO-catalyzed oxidative deamination which leads to the reduced enzyme cofactor and the aldehyde product are, however, still under debate. The catalytic mechanism was proposed to involve a prototropic shift from the substrateSchiff base to the product-Schiff base, which includes the ratelimiting cleavage of the C alpha-H bond by the conserved catalytic aspartate. Our detailed mechanistic study, performed using a combined quantum chemical cluster approach with empirical valence bond simulations, suggests that the rate-limiting cleavage of the C alpha-H bond involves direct hydride transfer to the topaquinone cofactor. a mechanism that does not involve the formation of a Schiff base. Additional investigation of the D373E and D373N variants supported the hypothesis that the conserved catalytic aspartate is indeed essential for the reaction; however, it does not appear to serve as the catalytic base, as previously suggested. Rather, the electrostatic contributions of the most significant residues (including D373), together with the proximity of the Cu2+ cation to the reaction site, lower the activation barrier to drive the chemical reaction.

  • 16.
    Maurer, Dirk
    et al.
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden..
    Enugala, Thilak Reddy
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden..
    Hamnevik, Emil
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden..
    Bauer, Paul
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. Uppsala Univ, Dept Cell & Mol Biol, Box 596, SE-75124 Uppsala, Sweden.;.
    Lüking, Malin
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden.;Uppsala Univ, Dept Cell & Mol Biol, Box 596, SE-75124 Uppsala, Sweden..
    Petrovic, Dusan
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden.;Uppsala Univ, Dept Cell & Mol Biol, Box 596, SE-75124 Uppsala, Sweden..
    Hillier, Heidi
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden..
    Kamerlin, Shina C. L.
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden.;Uppsala Univ, Dept Cell & Mol Biol, Box 596, SE-75124 Uppsala, Sweden..
    Dobritzsch, Doreen
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden..
    Widersten, Mikael
    Uppsala Univ, BMC, Dept Chem, Box 576, SE-751236 Uppsala, Sweden..
    Stereo- and Regioselectivity in Catalyzed Transformation of a 1,2-Disubstituted Vicinal Diol and the Corresponding Diketone by Wild Type and Laboratory Evolved Alcohol Dehydrogenases2018Inngår i: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 8, nr 8, s. 7526-7538Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ADH-A from Rhodococcus ruber DSM 44541 catalyzes the oxidation of (S)-1-phenylethanol 3000-fold more efficiently as compared with the 2-hydroxylated derivative (R)-phenylethane-1,2-diol. The enzyme is also highly selective for sec-alcohols with comparably low activities with the corresponding primary alcohols. When challenged with a substrate containing two secondary alcohols, such as 1-phenylpropane-(1R,2S)-diol, ADH-A favors the oxidation of the benzylic carbon of this alcohol. The catalytic efficiency, however, is modest in comparison to the activity with (S)-1-phenylethanol. To investigate the structural requirements for improved oxidation of vicinal diols, we conducted iterative saturation mutagenesis combined with activity screening. A first-generation variant, B1 (Y54G, L119Y) displays a 2-fold higher k(cat) value with 1-phenylpropane-(1R,25)-diol and a shift in the cooperative behavior in alcohol binding, from negative in the wild type, to positive in B1, suggesting a shift from a less active enzyme form (T) in the wild type to a more active form (R) in the B1 variant. Also, the regiopreference changed to favor oxidation of C-2. A second-generation variant, B1F4 (F43T, Y54G, L119Y, F282W), shows further improvement in the turnover and regioselectivity in oxidation of 1-phenylpropane-(1R,2S)-diol. The crystal structures of the B1 and B1F4 variants describe the structural alterations to the active site, the most significant of which is a repositioning of a Tyr side-chain located distal to the coenzyme and the catalytic zinc ion. The links between the changes in structures and stereoselectivities are rationalized by molecular dynamics simulations of substrate binding at the respective active sites.

  • 17.
    Nair, Deepika
    et al.
    Karolinska Inst, Dept Med Huddinge, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Biochem, Stockholm, Sweden..
    Radestad, Emelie
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Khalkar, Prajakta
    Karolinska Inst, Dept Med Biochem & Biophys, Div Biochem, Stockholm, Sweden..
    Diaz-Argelich, Nuria
    Karolinska Inst, Dept Med Biochem & Biophys, Div Biochem, Stockholm, Sweden.;Univ Navarra, Dept Organ & Pharmaceut Chem, Pamplona, Spain..
    Schroder, Axel
    Karolinska Inst, Dept Med Biochem & Biophys, Div Biochem, Stockholm, Sweden..
    Klynning, Charlotte
    Karolinska Univ Hosp, Dept Gynecol Oncol, Stockholm, Sweden..
    Ungerstedt, Johanna
    Karolinska Inst, Dept Med Huddinge, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Uhlin, Michael
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Fernandes, Aristi P.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Biochem, Stockholm, Sweden..
    Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels2018Inngår i: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 8, artikkel-id 407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Redox active selenium (Se) compounds at sub toxic doses act as pro-oxidants with cytotoxic effects on tumor cells and are promising future chemotherapeutic agents. However, little is known about how Se compounds affect immune cells in the tumor microenvironment. We demonstrate that the inorganic Se compound selenite and the organic methylseleninic acid (MSA) do not, despite their pro-oxidant function, influence the viability of immune cells, at doses that gives cytotoxic effects in ovarian cancer cell lines. Treatment of the ovarian cancer cell line A2780 with selenite and MSA increases NK cell mediated lysis, and enhances the cytolytic activity of T cells. Increased T cell function was observed after incubation of T cells in preconditioned media from tumor cells treated with MSA, an effect that was coupled to decreased levels of PDL1, HIF-1 alpha, and VEGF. In conclusion, redox active selenium compounds do not kill or inactivate immune cells at doses required for anti-cancer treatment, and we demonstrate that MSA enhances T cell-mediated tumor cell killing via PDL1 and VEGF inhibition.

  • 18.
    Nilsson, Linnéa
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Studies on the Role of Apoptosis in Kidney Diseases2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Apoptosis is one of the most common types of cell death. Under physiological conditions, it plays an essential role in removal of damaged and potentially harmful cells. Excessive apoptosis has however been linked to a number of diseases including proteinuric kidney disease and DKD, and is believed to enhance the disease progression. Albuminuria and hyperglycemia are common symptoms of these diseases and albumin and high glucose have been seen to trigger intrinsic apoptosis in renal cells. Ouabain, a cardiotonic steroid, has previously been identified as an antiapoptotic agent that in subsaturating concentrations protect from intrinsic apoptosis. The mechanism of the protective effect of ouabain is still not fully understood and it remains to be concluded whether ouabain can protect from albumin and/or glucotoxic-triggered apoptosis.

    In study I we investigated the protective effects of ouabain in albumin-exposed primary rat PTC and podocytes and in the proteinuric kidney disease animal model passive Heymann nephritis. By reestablishing the balance between the proapoptotic protein BAX and the antiapoptotic protein BCL-XL, ouabain averted the albumin-triggered apoptosis in vitro and in vivo and protected from podocytes loss and glomerular-tubular disconnection.

    In study II we investigated the relationship between the glucose transporters renal cells express and their susceptibility of glucotoxic-triggered apoptosis. We identified the SGLT expressing cells, PTC and MC, to be more susceptible to high glucose-induced apoptosis than cells without SGLT. The apoptosis was mediated by BAX and BCL-XL imbalance and mitochondrial dysfunction, and was abolished when treated with ouabain or SGLT inhibitors. Podocytes, which lack SGLT, did not respond to short-term high glucose exposure.

    In study III we used super-resolution microscopy to investigate at which stage of the apoptotic process ouabain start to intervene. Ouabain interfered early in the apoptotic process, where it prevented activation of the sensitizer protein BAD. This allowed BCL-XL to avert BAX activation and translocation to mitochondria and thereby protected from mitochondrial dysfunction and apoptosis.

    In study IV we investigated differentially expressed genes between renal cortex and primary short-term PTC cultures and between PTC exposed to control and high glucose. The mRNA expression level of most genes was significantly up- or downregulated in PTC compared to renal cortex, with the biggest differences in mitochondria and metabolism related genes. Early state glucotoxicity did not significantly alter mRNA expression levels in PTC.

  • 19.
    Nilsson, Linnéa
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Scott, Lena
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    RNA-seq reveals altered gene expression levels in PTC cultures compared to renal cortex but not in early state glucotoxic PTCManuskript (preprint) (Annet vitenskapelig)
  • 20.
    Nilsson, Linnéa
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Zhang, Liang
    Alexander, Bondar
    Svensson, Daniel
    Wernerson, Annika
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Scott, Lena
    Aperia, Anita
    Prompt apoptotic response to high glucose in SGLT expressing cells2019Inngår i: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is generally believed that cells that are unable to downregulate glucose transport are particularly vulnerable to hyperglycemia. Yet little is known about the relation between expression of glucose transporters and acute toxic effects of high glucose exposure.Here we have, in an ex vivo study on rat renal cells, compared the apoptotic response to a moderate increase in glucose concentration. We have studied the cell types that commonly are targeted in diabetic kidney disease (DKD): proximal tubule cells (PTC) that express SGLT2, mesangial cells (MC) that express SGLT1, and podocytes that lack SGLT and take up glucose via the insulin dependent GLUT4.PTC and MC responded within 4-8 h exposure to 15 mM glucose with translocation of the apoptotic protein Bax to mitochondria and increased apoptotic index. SGLT down-regulation and exposure to SGLT inhibitors abolished the apoptotic response. Onset of overt DKD generally coincides with onset of albuminuria. Albumin had an additive effect on the apoptotic response. Ouabain, which interferes with apoptotic onset, rescued from the apoptotic response. Insulin supplemented podocytes remained resistant to 15 and 30 mM glucose for at least 24 h.Our study points to a previously unappreciated role of SGLT dependent glucose uptake as a risk-factor for diabetic complications and highlights the importance of therapeutic approaches that specifically target the different cell types in DKD.

  • 21.
    Pudelko, Linda
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
    Edwards, Steven
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. Royal Inst Technol, Sci Life Lab, Dept Appl Phys, Stockholm, Sweden..
    Balan, Mirela
    Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Nyqvist, Daniel
    Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Al-Saadi, Jonathan
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
    Dittmer, Johannes
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
    Almlof, Ingrid
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
    Helleday, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
    Brautigam, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
    An orthotopic glioblastoma animal model suitable for high-throughput screenings2018Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, nr 11, s. 1475-1484Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Glioblastoma (GBM) is an aggressive form of brain cancer with poor prognosis. Although murine animal models have given valuable insights into the GBM disease biology, they cannot be used in high-throughput screens to identify and profile novel therapies. The only vertebrate model suitable for large-scale screens, the zebrafish, has proven to faithfully recapitulate biology and pathology of human malignancies, and clinically relevant orthotopic zebrafish models have been developed. However, currently available GBM orthotopic zebrafish models do not support high-throughput drug discovery screens. Methods. We transplanted both GBM cell lines as well as patient-derived material into zebrafish blastulas. We followed the behavior of the transplants with time-lapse microscopy and real-time in vivo light-sheet microscopy. Results. We found that GBM material transplanted into zebrafish blastomeres robustly migrated into the developing nervous system, establishing an orthotopic intracranial tumor already 24 hours after transplantation. Detailed analysis revealed that our model faithfully recapitulates the human disease. Conclusion. We have developed a robust, fast, and automatable transplantation assay to establish orthotopic GBM tumors in zebrafish. In contrast to currently available orthotopic zebrafish models, our approach does not require technically challenging intracranial transplantation of single embryos. Our improved zebrafish model enables transplantation of thousands of embryos per hour, thus providing an orthotopic vertebrate GBM model for direct application in drug discovery screens.

  • 22.
    Radestad, Emelie
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Sundin, Mikael
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Pediat, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Hematol Immunol HSCT Sect, Stockholm, Sweden..
    Torlen, Johan
    Karolinska Univ Hosp, Cell Therapy & Allogene Stem Cell Transplantat, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Thunberg, Sara
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik.
    Önfelt, Björn
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ljungman, Per
    Karolinska Univ Hosp, Cell Therapy & Allogene Stem Cell Transplantat, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Watz, Emma
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Transplantat Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Mattsson, Jonas
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Uhlin, Michael
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion2019Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, artikkel-id 189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with several potentially lethal complications. Higher levels of CD3+ T-cells in the graft have been associated with increased risk of graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia effect and reduced infections. To tackle post-transplant complications, donor lymphocyte infusions have been used but with an increased risk of GVHD. To reduce this risk, we performed depletion of alpha beta T-cells and treated 12 patients post-HSCT suffering from infections and/or poor immune reconstitution. The alpha beta T-cell depleted cell products were characterized by flow cytometry. The median log depletion of alpha beta T-cells was -4.3 and the median yield of gamma delta T-cells was 73.5%. The median CD34+ cell dose was 4.4 x 10(6)/kg. All 12 patients were alive 3 months after infusion and after 1 year, two patients had died. No infusion-related side effects were reported and no severe acute GVHD (grade III-IV) developed in any patient post-infusion. Overall, 3 months after infusion 11 out of 12 patients had increased levels of platelets and/or granulocytes. In conclusion, we describe the use of alpha beta T-cell depleted products as stem cell boosters with encouraging results.

  • 23.
    Ravi shankar, Harsha
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Tracking active transport intermediates in real – timeArtikkel i tidsskrift (Fagfellevurdert)
  • 24.
    Ravishankar, Harsha
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Characterization of membrane protein active transport under native-like conditions2018Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    P-type ATPase proteins are a family of membrane proteins that maintain concentration gradients of e.g. ions by ATP-driven transport across the membrane. While these transporters share many features in their molecular architecture, structural differences are required to convey ion specificity. In addition, the transport dynamics accomplished by conformational changes may also differ in-between ATPase subtypes. Therefore, resolving P-type ATPase temporal and spatial structural dynamics is crucial to understand how these proteins function. 

     

    To pave way for time-resolved X-ray characterization of conformational changes during P-type ATPase transport in solution, it was necessary to identify optimal conditions for triggering the protein reaction. Therefore, ATP activation of a recombinant Zn2+-transporting ATPase was studied using a biochemical activity assay and infrared spectroscopic techniques. Specifically, time-dependent Fourier-Transform Infra-Red (FTIR) spectroscopy was used to study activation using photolysis of caged ATP. The highest protein activity was obtained at a protein concentration of 25 mg/mL at 310 K and pH 7, and this required the presence of 20% glycerol as a stabilizing agent. It was also observed that neither the presence of caged ATP nor higher lipid concentrations affected protein activity significantly. 

     

    The Ca2+-transporting sarcoplasmic reticulum ATPase (SERCA), found abundantly in skeletal muscle native membranes, was used to develop the time-resolved Wide-Angle X-ray Scattering (TR-WAXS) technique for irreversible caged ATP activation and subsequent structural refinement. Several SERCA intermediate states and protein-lipid interactions have been characterized by X-ray crystallography, rendering the SERCA protein an ideal proof-of-principle target system. In the native membrane, fast single-cycle dynamics were registered followed by steady state accumulation. The structural refinement procedure starting from existing intermediate crystal structures indicated that the accumulated state represented a phosphorylated state (E2-P) or possibly a Ca2+ bound E2 state (Ca2E2P), which has so far eluded X-ray crystallographic characterization. The results also showed that the corresponding ground state (Ca2E1) underwent significant rearrangements of the cytosolic domains, which implies that the Ca2E1 crystal structure might be one of several possible structures and might not represent the dominant structure in solution. Additionally, the TR-WAXS models indicated that the rocking motion of the soluble domains observed in a detergent/lipid mixture is also present in the native membrane.

  • 25.
    Ravishankar, Harsha
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Barth, Andreas
    Andersson, Magnus
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Probing the activity of a recombinant Zn2+-transporting P-type ATPase2017Inngår i: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282Artikkel i tidsskrift (Fagfellevurdert)
  • 26. Rodriguez, Patricia Q.
    et al.
    Chen, Ping
    Jess, David Unnersjö
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zambrano, Sonia S.
    Guo, Jing
    Schwarz, Angelina
    Möller-Hackbarth, Katja
    Axelsson, Jonas
    Blom, Hans
    Sandberg, Rickard
    Jahnukainen, Timo
    Ebarasi, Lwaki
    Patrakka, Jaakko
    Mediator complex subunit 22 is necessary for glomerular homeostasis by regulation of podocyte vesicular traffickingManuskript (preprint) (Annet vitenskapelig)
  • 27.
    Roose, Benjamin W.
    et al.
    Univ Penn, Dept Chem, 231 S 34th St, Philadelphia, PA 19104 USA..
    Zemerov, Serge D.
    Univ Penn, Dept Chem, 231 S 34th St, Philadelphia, PA 19104 USA..
    Wang, Yanfei
    Harvard Med Sch, 300 Longwood Ave, Boston, MA 02115 USA..
    Kasimova, Marina A.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Carnevale, Vincenzo
    Temple Univ, Coll Sci & Technol, Inst Computat Mol Sci, 1925 N 12th St, Philadelphia, PA 19122 USA..
    Dmochowski, Ivan J.
    Univ Penn, Dept Chem, 231 S 34th St, Philadelphia, PA 19104 USA..
    A Structural Basis for Xe-129 Hyper-CEST Signal in TEM-1 beta-Lactamase2019Inngår i: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 20, nr 2, s. 260-267Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetically encoded (GE) contrast agents detectable by magnetic resonance imaging (MRI) enable non-invasive visualization of gene expression and cell proliferation at virtually unlimited penetration depths. Using hyperpolarized Xe-129 in combination with chemical exchange saturation transfer, an MR contrast approach known as hyper-CEST, enables ultrasensitive protein detection and biomolecular imaging. GE MRI contrast agents developed to date include nanoscale proteinaceous gas vesicles as well as the monomeric bacterial proteins TEM-1 beta-lactamase (bla) and maltose binding protein (MBP). To improve understanding of hyper-CEST NMR with proteins, structural and computational studies were performed to further characterize the Xe-bla interaction. X-ray crystallography validated the location of a high-occupancy Xe binding site predicted by MD simulations, and mutagenesis experiments confirmed this Xe site as the origin of the observed CEST contrast. Structural studies and MD simulations with representative bla mutants offered additional insight regarding the relationship between local protein structure and CEST contrast.

  • 28.
    Seplyarskiy, Vladimir B.
    et al.
    Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA USA.;Harvard Med Sch, Dept Biomed Informat, Boston, MA USA.;Russian Acad Sci, Inst Informat Transmiss Problems, Kharkevich Inst, Moscow, Russia..
    Akkuratov, Evgeny E.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. St Petersburg State Univ, Inst Translat Biomed, St Petersburg, Russia.;Royal Inst Technol, Dept Appl Phys, Sci Life Lab, Stockholm, Sweden..
    Akkuratova, Natalia
    St Petersburg State Univ, Inst Translat Biomed, St Petersburg, Russia..
    Andrianova, Maria A.
    Skolkovo Inst Sci & Technol, Skolkovo, Russia..
    Nikolaev, Sergey I.
    Univ Paris Saclay, INSERM, U981, Gustave Roussy Canc Campus, Villejuif, France.;Univ Paris 07, St Louis Hosp, Dept Dermatol & Venereol, Paris, France..
    Bazykin, Georgii A.
    Russian Acad Sci, Inst Informat Transmiss Problems, Kharkevich Inst, Moscow, Russia.;Skolkovo Inst Sci & Technol, Skolkovo, Russia..
    Adameyko, Igor
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.;Med Univ Vienna, Ctr Brain Res, Vienna, Austria..
    Sunyaev, Shamil R.
    Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA USA.;Harvard Med Sch, Dept Biomed Informat, Boston, MA USA..
    Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations2019Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, nr 1, s. 36-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Transcription-coupled DNA repair removes lesions on the transcribed strand; lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between mutation types predominant on the non-transcribed strand and on the strand lagging during replication. Moreover, damage-induced mutations in cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are resolved asymmetrically. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of ultraviolet irradiation, confirming that replication converts DNA damage into mutations. We estimate that at least 10% of human mutations arise due to DNA damage.

  • 29.
    Sohlberg, Ebba
    et al.
    Karolinska Inst, CIM, Stockholm, Sweden..
    Haroun-Izquierdo, Alvaro
    Ctr Infect Med, Dept Med, Huddinge, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Bjorklund, Andreas T.
    Karolinska Univ Hosp, Karolinska Inst, Sollentuna, Sweden..
    Cooley, Sarah
    Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Box 736 UMHC, Minneapolis, MN 55455 USA..
    Wiiger, Merete Thune
    Oslo Univ Hosp, Dept Canc Immunol, Oslo, Norway..
    Goodridge, Peter
    Oslo Univ Hosp, Oslo, Norway..
    Hoel, Hanna Julie
    Oslo Univ Hosp, Oslo, Norway..
    Pfefferle, Aline
    Karolinska Inst, Stockholm, Sweden..
    Chrobook, Michael
    Karolinska Inst, Dept Med Huddinge, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Kremer, Veronika
    Karolinska Inst, Ctr Infectous Med, Stockholm, Sweden..
    Hellström-Lindberg, Eva
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Ask, Eivind Heggernes
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway..
    Pontus, Blomberg
    Karolinska Univ Hosp, Vecura, Stockholm, Sweden..
    Valamehr, Bahram
    Fate Therapeut Inc, San Diego, CA USA..
    Guldevall, Karolin
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    van Ooijen, Hanna
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Önfelt, Björn
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Alici, Evren
    Karolinska Inst, Stockholm, Sweden..
    Ljunggren, Hans-Gustaf
    Karolinska Inst, CIM, Stockholm, Sweden..
    Miller, Jeffrey S.
    Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA..
    Malmberg, Karl-Johan
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway..
    Efficient Scale-up and Pre-Clinical Evaluation of NKG2C+Adaptive NK Cell Expansion for Therapy Against High-Risk AML/MDS2018Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Artikkel i tidsskrift (Annet vitenskapelig)
  • 30. Törlén, J.
    et al.
    Gaballa, A.
    Remberger, M.
    Mörk, L. -M
    Sundberg, B.
    Mattsson, J.
    Uhlin, Michael
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation2019Inngår i: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lymphocyte reconstitution is pivotal for successful long-term outcome after allogeneic hematopoietic stem cell transplantation (HSCT), and conditioning regimen and post-transplantation immunosuppression are risk factors for prolonged immunodeficiency. Nevertheless, the effects of different immunosuppressive protocols on lymphocyte output and replicative capacity have not been investigated. Here we assessed T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and T cell telomere length (TL) as proxy markers for immune reconstitution in patients in a prospective randomized trial comparing graft-versus-host disease (GVHD) prophylaxis after transplantation (cyclosporine/methotrexate versus tacrolimus/sirolimus; n = 200). Results showed that medians of TREC, KREC, and TL were not significantly different between the prophylaxis groups at any assessment time point during follow-up (24 months), but the kinetics of TREC, KREC, and TL were significantly influenced by other transplantation-related factors. Older recipient age, the use of antithymocyte globulin before graft infusion, and use of peripheral blood stem cell grafts were associated with lower TREC levels, whereas acute GVHD transiently affected KREC levels. Patients with lymphocyte excision circle levels above the median at ≤6 months post-transplantation had reduced transplantation-related mortality and superior 5-year overall survival (P <.05). We noticed significant T cell telomere shortening in the patient population as a whole during follow-up. Our results suggest that lymphocyte reconstitution after transplantation is not altered by different immunosuppressive protocols. This study has been registered at ClinicalTrials.gov (identifier: NCT00993343). 

  • 31.
    Uhlin, Michael
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.
    Abumaree, Mohamed
    King Abdul Aziz Med City, King Abdullah Int Med Res Ctr, Stem Cells & Regenerat Med Dept, POB 22490, Riyadh 11426, Saudi Arabia.;Minist Natl Guard Hlth Affairs, POB 22490, Riyadh 11426, Saudi Arabia.;King Saud Bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City, Coll Sci & Hlth Profess, POB 3660, Riyadh 11481, Saudi Arabia.;Minist Natl Guard Hlth Affairs, POB 3660, Riyadh 11481, Saudi Arabia..
    Abdelalim, Essam M.
    Hamad Bin Khalifa Univ, Qatar Fdn, Qatar Biomed Res Inst, Diabet Res Ctr, Doha, Qatar..
    Therapeutic Use of Extraembryonic-Derived Tissues2018Inngår i: Stem Cells International, ISSN 1687-966X, artikkel-id 6082698Artikkel i tidsskrift (Fagfellevurdert)
  • 32.
    Unnersjö-Jess, David
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Butt, Linus
    Höhne, Martin
    Patrakka, Jaakko
    Schermer, Bernhard
    Benzing, Thomas
    Scott, Lena
    Blom, Hans
    Brismar, Hjalmar
    Renal diagnostics using a simplified optical clearing and swelling protocolManuskript (preprint) (Annet vitenskapelig)
  • 33.
    Wang, T.
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Remberger, M.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat CAST, Huddinge, Sweden..
    Nygell, U. Axdorph
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Haematol, Huddinge, Sweden..
    Sundin, M.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Björklund, A.
    Karolinska Univ Hosp, Dept Haematol, Huddinge, Sweden..
    Mattsson, J.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat CAST, Huddinge, Sweden..
    Uhlin, Michael
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.
    Watz, E.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Change of apheresis device decreased the incidence of severe acute graft-versus-host disease among patients after allogeneic stem cell transplantation with sibling donors2018Inngår i: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 58, nr 6, s. 1442-1451Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The composition of the graft used for allogeneic hematopoietic stem cell transplantation (HSCT) is important for the treatment outcome. Different apheresis devices may yield significant differences in peripheral blood stem cell graft cellular composition. We compared stem cell grafts produced by Cobe Spectra (Cobe) and Spectra Optia (Optia) with use of the mononuclear cell (MNC) protocol, and evaluated clinical outcome parameters such as graft-versus-host disease (GvHD), transplant-related mortality (TRM), relapse, and overall survival.

    STUDY DESIGN AND METHODS: During 5 years, 31 Cobe Spectra and 40 Spectra Optia grafts were analyzed for CD34, CD3, CD4, CD8, CD19, and CD56 cell content. Clinical outcome parameters were correlated and compared between the two patient groups using different apheresis devices.

    RESULTS: Optia grafts contained fewer lymphocytes compared to Cobe (p<0.001). Optia grafts had a significantly lower incidence of acute GvHD Grades II through IV (Cobe 45% vs. Optia 23%; p=0.039) and TRM (16% vs. 2.5%; p<0.05) but higher chronic GvHD (32% vs. 67%; p=0.005) compared to Cobe grafts. Finally, the multivariate analysis showed a significant correlation among the different apheresis devices and both acute GvHD II through IV and severe chronic GvHD. The multivariate analysis also showed a significant correlation between the CD3+ cell dose and the incidence of severe acute GvHD.

    CONCLUSION: Optia-obtained grafts yielded a lower acute GvHD Grades II-IV and TRM risk, but had no impact on relapse or overall survival in this study. Understanding and further improvement of peripheral blood stem cell (PBSC) apheresis techniques may be used in the future to personalize HSCT by, for example, fine-tuning the GvHD incidence.

  • 34.
    Westerlund, Annie M.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Computational Study of Calmodulin’s Ca2+-dependent Conformational Ensembles2018Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Ca2+ and calmodulin play important roles in many physiologically crucial pathways. The conformational landscape of calmodulin is intriguing. Conformational changes allow for binding target-proteins, while binding Ca2+ yields population shifts within the landscape. Thus, target-proteins become Ca2+-sensitive upon calmodulin binding. Calmodulin regulates more than 300 target-proteins, and mutations are linked to lethal disorders. The mechanisms underlying Ca2+ and target-protein binding are complex and pose interesting questions. Such questions are typically addressed with experiments which fail to provide simultaneous molecular and dynamics insights. In this thesis, questions on binding mechanisms are probed with molecular dynamics simulations together with tailored unsupervised learning and data analysis.

    In Paper 1, a free energy landscape estimator based on Gaussian mixture models with cross-validation was developed and used to evaluate the efficiency of regular molecular dynamics compared to temperature-enhanced molecular dynamics. This comparison revealed interesting properties of the free energy landscapes, highlighting different behaviors of the Ca2+-bound and unbound calmodulin conformational ensembles.

    In Paper 2, spectral clustering was used to shed light on Ca2+ and target protein binding. With these tools, it was possible to characterize differences in target-protein binding depending on Ca2+-state as well as N-terminal or C-terminal lobe binding. This work invites data-driven analysis into the field of biomolecule molecular dynamics, provides further insight into calmodulin’s Ca2+ and targetprotein binding, and serves as a stepping-stone towards a complete understanding of calmodulin’s Ca2+-dependent conformational ensembles.

  • 35.
    Westerlund, Annie M.
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    On the Selective Promiscuity of Calmodulin2018Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, nr 3, s. 7A-8AArtikkel i tidsskrift (Annet vitenskapelig)
  • 36.
    Westerlund, Annie M.
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH Royal Inst Technol, Phys, Stockholm, Sweden..
    Harpole, Tyler J.
    KTH, Skolan för teknikvetenskap (SCI), Fysik.
    Blau, Christian
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Delemotte, Lucie
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Inference of Calmodulin's Ca2+: Dependent Free Energy Landscapes via Gaussian Mixture Model Validation2018Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, nr 3, s. 675A-675AArtikkel i tidsskrift (Fagfellevurdert)
  • 37. Zhang, Liang
    et al.
    Fontana, Jacopo
    Bernhem, Kristoffer
    Nilsson, Linnéa
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Scott, Lena
    Blom, Hans
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Aperia, Anita
    Ouabain intervenes early in the apoptotic process by preventing BAD activationManuskript (preprint) (Annet vitenskapelig)
1 - 37 of 37
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