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  • 1. Agostinho, A.
    et al.
    Kouznetsova, A.
    Hernández-Hernández, A.
    Bernhem, Kristoffer
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Höög, C.
    Sexual dimorphism in the width of the mouse synaptonemal complex2018In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 131, no 5, article id jcs212548Article in journal (Refereed)
    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, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, 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 study2018In: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 16, no 2, article id 1840011Article in journal (Refereed)
    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. Caceres, R.
    et al.
    Bojanala, N.
    Kelley, L. C.
    Dreier, Jes
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Manzi, J.
    Di Federico, F.
    Chi, Q.
    Risler, T.
    Testa, Ilaria
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Sherwood, D. R.
    Plastino, J.
    WASP and WAVE activate the Arp2/3 complex for actin-based force production during basement membrane invasion.2017In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 28Article in journal (Other academic)
  • 4.
    Groome, J. R.
    et al.
    United States.
    Moreau, A.
    France.
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Gating pore currents in sodium channels2018In: Handbook of Experimental Pharmacology, ISSN 0171-2004, E-ISSN 1865-0325, p. 371-399Article in journal (Refereed)
    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.

  • 5.
    Hess, Berk
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Gong, Jing
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Pall, Szilard
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Schlatter, Philipp
    KTH, School of Engineering Sciences (SCI), Mechanics. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Peplinski, Adam
    KTH, School of Engineering Sciences (SCI), Mechanics, Stability, Transition and Control.
    Highly Tuned Small Matrix Multiplications Applied to Spectral Element Code Nek50002016Conference paper (Refereed)
  • 6.
    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, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Orellana, L.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden..
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    ALCOHOL MODULATION VIA ALLOSTERIC TRANSMEMBRANE SITES IN PENTAMERIC LIGAND-GATED ION CHANNELS2018In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, p. 60A-60AArticle in journal (Refereed)
  • 7.
    Johansson, Petter
    et al.
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Hess, Berk
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Molecular origin of contact line friction in dynamic wetting2018In: PHYSICAL REVIEW FLUIDS, ISSN 2469-990X, Vol. 3, no 7, article id 074201Article in journal (Refereed)
    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.

  • 8.
    Kasimova, Marina A.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Lindahl, Erik
    KTH.
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Detection of Voltage-Sensing Residues in Membrane Proteins2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 476A-476AArticle in journal (Other academic)
  • 9.
    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, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, 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 Oxidase2018In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 4, p. 3665-3674Article in journal (Refereed)
    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.

  • 10.
    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, School of Engineering Sciences (SCI), Applied Physics, Biophysics. 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 Dehydrogenases2018In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 8, no 8, p. 7526-7538Article in journal (Refereed)
    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.

  • 11.
    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, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    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 Levels2018In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 8, article id 407Article in journal (Refereed)
    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.

  • 12.
    Pudelko, Linda
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
    Edwards, Steven
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. 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 screenings2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1475-1484Article in journal (Refereed)
    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.

  • 13.
    Ravi shankar, Harsha
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Tracking active transport intermediates in real – timeArticle in journal (Refereed)
  • 14.
    Ravishankar, Harsha
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Characterization of membrane protein active transport under native-like conditions2018Licentiate thesis, comprehensive summary (Other academic)
    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.

  • 15.
    Ravishankar, Harsha
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Barth, Andreas
    Andersson, Magnus
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Probing the activity of a recombinant Zn2+-transporting P-type ATPase2017In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282Article in journal (Refereed)
  • 16.
    Uhlin, Michael
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. 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 Tissues2018In: Stem Cells International, ISSN 1687-966X, article id 6082698Article in journal (Refereed)
  • 17.
    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, School of Engineering Sciences (SCI), Applied Physics, Biophysics. 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 donors2018In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 58, no 6, p. 1442-1451Article in journal (Refereed)
    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.

  • 18.
    Westerlund, Annie M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Computational Study of Calmodulin’s Ca2+-dependent Conformational Ensembles2018Licentiate thesis, comprehensive summary (Other academic)
    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.

  • 19.
    Westerlund, Annie M.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    On the Selective Promiscuity of Calmodulin2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 7A-8AArticle in journal (Other academic)
  • 20.
    Westerlund, Annie M.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH Royal Inst Technol, Phys, Stockholm, Sweden..
    Harpole, Tyler J.
    KTH, School of Engineering Sciences (SCI), Physics.
    Blau, Christian
    Stockholm Univ, Biochem & Biophys, Stockholm, Sweden..
    Delemotte, Lucie
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Inference of Calmodulin's Ca2+: Dependent Free Energy Landscapes via Gaussian Mixture Model Validation2018In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 675A-675AArticle in journal (Refereed)
1 - 20 of 20
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