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Dissertations / Theses on the topic 'Protein; Ligands'

Author: Grafiati

Published: 4 June 2021

Last updated: 16 February 2022

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1

Almeida, T. B. "Identification and optimisation of ligands to target protein-protein interactions : EB1-SxIP proteins." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3004877/.

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End binding protein 1 (EB1) is a key element in the complex network of protein-protein interactions at microtubule growing ends which has a fundamental role in microtubule polymerisation. EB1 regulates the microtubule dynamic behaviour, through protein recruitment, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved SxIP motif within an intrinsically disordered region enriched with basic, serine and proline residues. Crystal structure of EB1 in complex with a peptide containing the SxIP motif

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2

Hassan, Hani Mutlak Abdullah. "Chemical Synthesis of Protein Ligands." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501975.

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3

Larsson, Emma. "Calcium-dependent affinity ligands for protein purification." Thesis, KTH, Skolan för kemi, bioteknologi och hälsa (CBH), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-278695.

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The rapid growth of the biopharmaceutical industry has led to increasing demands on the protein production process. An important aspect is the yield of functional protein, which can be greatly affected by the choice of downstream purification. Purification based on acidic elution can be an issue for pH-sensitive proteins, since dramatic changes in pH can lead to protein aggregation and loss of function. The harsh, acidic elution conditions used in conventional purification of antibodies by Protein A affinity chromatography can thus be problematic. To address this, a calcium-dependent protein d

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4

Street, Ian Philip. "Protein - carbohydrate interactions in glycogen phosphorylase." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/25049.

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It has long been observed that some organo-fluorine compounds exhibit enhanced biological activity over their non-fluorinated precursors, however reasons for these unusual properties still remain poorly understood. An explanation which has been widely used relates to the ability of the C-F fragment of the analog to participate in hydrogen-bonding interactions with its protein receptor. For this reason, fluorinated carbohydrates have been used as hydrogen-bonding probes with a number of proteins. Thus there exists a need for a systematic investigation into the hydrogen-bonding ability of the C

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5

Linhult, Martin. "Protein engineering to explore and improve affinity ligands." Doctoral thesis, KTH, Biotechnology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-3632.

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<p>In order to produce predictable and robust systems forprotein purification and detection, well characterized, small,folded domains descending from bacterial receptors have beenused. These bacterial receptors, staphylococcal protein A (SPA)and streptococcal protein G (SPG), possess high affinity to IgGand / or HSA. They are composed of repetitive units in whicheach one binds the ligand independently. The domains foldindependently and are very stable. Since the domains also havewellknown three-dimensional structures and do not containcysteine residues, they are very suitable as frameworks for

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6

Georgiou, Charis. "Rational design of isoform specific ligands." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28713.

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Cyclophilins (Cyp) are proteins that catalyze the interconversion of trans/cis isomers of proline belonging to the peptidyl-prolyl isomerases family (PPIase). In addition to their PPIase activity, Cyps have diverse biological roles and have been implicated in a number of different diseases such as HIV-1 and HCV. Although several Cyp inhibitors have been reported in the literature, none are able to inhibit with high specificity various Cyp isoforms. To facilitate the development of isoform-specific Cyp ligands, we have pursued detailed studies of Cyp dynamics and ligand binding thermodynamics u

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7

Duraj-Thatte, Anna. "Fluorescent GFP chromophores as potential ligands for various nuclear receptors." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/44764.

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Nuclear receptors are ligand activated transcription factors, where upon binding with small molecule ligands, these proteins are involved in the regulation of gene expression. To date there are approximately 48 human nuclear receptors known, involved in multiple biological and cellular processes, ranging from differentiation to maintenance of homeostasis. Due to their critical role in transcriptional regulation, these receptors are implicated in several diseases. Currently, 13% of prescribed drugs in the market are NR ligands for diseases such as cancer, diabetes and osteoporosis. In addition

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8

Tosch, Paul. "Investigations of ephrin ligands during development." Title page, abstract and table of contents only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09pht713.pdf.

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"May 2002." Addendum inside back cover. Bibliography: p. 139-157. Aims to isolate ephrin ligands from Drosophila melanogaster and analyse their involvement in Drosophila deveopment. Also investigates the potential of ephrin B-1 as a causative gene in the human condition Aicardi's syndrome.

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9

Robinson, Daniel D. "Applications of pattern recognition and pattern analysis to molecule design." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343465.

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10

Boussert, Stéphanie Van Dorsselaer Alain Giralt Ernest. "Structural studies of proteins and protein complexes by mass spectrometry and atomic force microscopy." Strasbourg : Université Louis Pasteur, 2008. http://eprints-scd-ulp.u-strasbg.fr:8080/977/01/BOUSSERT_Stephanie_2008.pdf.

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11

Soto, Renou Emma Nadia. "Design, synthesis and selection of prion protein affinity ligands." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619972.

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12

Macleod, Charlotte Victoria. "Investigating TLR-4 signalling in response to protein ligands." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/274540.

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Toll-like receptor (TLR)-4 is a pattern recognition receptor (PRR) that recognises the pathogen-associated molecular pattern (PAMP) lipopolysaccharide (LPS) produced by Gram-negative bacteria. LPS binds to Myeloid differentiation 2 (MD-2)/TLR-4 heterodimers, driving their dimerisation and inducing a conformational change of the intracellular TLR-4 toll/interleukin-1 receptor (TIR) domains. The adaptor protein Myeloid differentiation primary response gene 88 (MyD88)-adaptor-like (Mal)/TIR domain-containing adaptor protein (TIRAP) then binds to the TIR domains of TLR-4 and acts as a bridge for M

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13

Nikbin, Nikzad. "Bivalent ligands for the Î²â‚‚ adrenergic receptor." Thesis, University of Essex, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274301.

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14

Bailey, Jenna Clair. "Complementary structural studies of C-reactive protein with natural ligands." Thesis, Keele University, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679591.

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15

Gülich, Susanne. "Engineering Proteinaceous Ligands for Improved Performance in Affinity Chromatography Applications." Doctoral thesis, KTH, Biotechnology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-3327.

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16

Stamp, Anna Louise Elizabeth. "Structural studies of protein - ligand interactions : potential biomedical implications." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670175.

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17

Enekwa, C. Denise. "In silico design of novel binding ligands for biological targets." Thesis, Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/41067.

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An in silico design algorithm has been developed to design binding ligands for protein targets of known three-dimensional structure. In this method, the binding energy of a candidate ligand is used to ascribe it a probability of binding. A sample of a virtual library of candidate ligands is then used to ascribe implicit weights to all the ligands in the library. These weights are used to obtain virtual sub-libraries which collectively carry a greater probability to bind to the target. This algorithm is presented along with validation studies on the different algorithmic components, demonstrati

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18

Lapins, Maris. "Development of Proteochemometrics—A New Approach for Analysis of Protein-Ligand Interactions." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7211.

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19

Neels, Jacobus Gerardus. "LDL receptor-related protein molecular analysis and identification of new ligands /." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2001. http://dare.uva.nl/document/60201.

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20

Lachmann, Daniel [Verfasser], and Burkhard [Akademischer Betreuer] König. "Photochromic G-Protein Coupled Receptor Ligands / Daniel Lachmann ; Betreuer: Burkhard König." Regensburg : Universitätsbibliothek Regensburg, 2020. http://d-nb.info/1206415312/34.

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21

Joce, Catherine Maria. "Applications of bivalent ligands for modulating the function of protein complexes." Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493303.

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Studies towards the development of novel chemical tools for the investigation of protein - protein interactions are described. The E. coli methionine repressor dimer protein (MetJ) was employed as a model system. An improved synthesis of a ligand for MetJ, aza-SAM, is reported.

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22

Lindquist, Charlotta. "Design & synthesis of protein interacting affinity ligands and protease inhibitors /." Stockholm : Department of Organic Chemistry, Stockholm University, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-35292.

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Diss. (sammanfattning) Stockholm : Stockholms universitet, 2010.<br>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript. Härtill 4 uppsatser.

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23

Yu, Shun. "Protein interaction with polyelectrolytes and ligands: A structural and thermodynamic investigation." Doctoral thesis, Humboldt-Universität zu Berlin, 2017. http://dx.doi.org/10.18452/18197.

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Der erste Teil dieser Arbeit untersucht die Ladungswechselwirkung zwischen Proteinen und Polyelektrolyten. Dabei wird die Bindung von Polyakrylsäure (PAA) als kurzes Modell-Polyelektrolyt an Humanalbumin (HSA) in einer umfassenden experimentellen und theoretischen Studie untersucht und sehr gute Übereinstimmung der Resultate konnte festgestellt werden. Die Computersimulationen in dieser Arbeit wurden von Xiao Xu im Rahmen seiner Promotion durchgeführt. Thermodynamische Daten wurden mit Hilfe von Isothermer Titrationskalorimetrie (ITC) gesammelt und strukturelle Untersuchungen wurden mit Hilfe

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24

Mbianda, Johanne. "Protein Surface Recognition with Urea-based foldamers : application to the design of ligands targeting histone chaperone proteins." Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0184.

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Avec 8,8 millions de décès dénombrés en 2015, le cancer est l’une des plus grandes causes de mortalité dans le monde. De nouvelles stratégies thérapeutiques ont émergé et l’identification de nouvelles cibles biologiques comme notamment la protéine Asf1, un chaperon d’histone H3-H4 surexprimée dans les cellules cancéreuses et en particulier le cancer du sein. Cette protéine possède différentes fonctions dans la cellule et agit à plusieurs endroits par des interactions protéine-protéines. Au cours de cette thèse de doctorat, nous avons développé une stratégie originale de design d’inhibiteurs d’

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25

James, Marion Clare. "The role of the La antigen and associated RNAs in the regulation of protein synthesis." Thesis, St George's, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243864.

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26

Schreyer, Adrian Michael. "Characterisation of protein-ligand interactions and their application to drug discovery." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609324.

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27

da, Silva Ruben Filipe. "Structural studies of surfactant protein D in complex with bacterial lipopolysaccharide ligands." Thesis, Keele University, 2017. http://eprints.keele.ac.uk/4177/.

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This work is focused on the recognition of natural lipopolysaccharide (LPS) by the innate immune protein human lung surfactant protein D (hSP-D) in the form of a biologically active recombinant fragment (rfhSP-D), containing the α-helical coiled-coil and three carbohydrate recognition domains (CRD). Intact LPS from two bacterial strains, S. minnesota (R5 mutant) and H. influenzae type b Eagan (CA7 mutant), were delipidated by means of mild acid hydrolysis, leaving the purified polysaccharide (PS) to be used in X-ray diffraction studies by means of co-crystallisation with rfhSP-D. S. minnesota

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28

Walker, Tia Louise. "Synthesis and Complexation of Thia-Aza Mixed-Donor Ligands." University of Akron / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=akron1353441271.

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29

Taylor, Richard David. "Novel simulation methods for flexible docking." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368873.

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30

Farhang-Fallah, Janet Rozakis-Adcock Maria. "Cloning and characterization of PHIP, a novel protein ligand of the PH domain of IRS-1 /." *McMaster only, 2002.

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31

Zhang, Xiaochen 1969. "The binding modes of maltose binding protein with different ligands studied by NMR /." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=27438.

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Maltose Binding Protein (MBP) of Escherichia Coli, a kind of periplasmic protein, can bind its ligands interacting predominantly either with their anomeric end (end-on binding) or with the middle of the maltodextrin chain (middle binding). Using NMR spectroscopy, we have studied the modes by which maltose, linear maltodextrin and some derivatives like $ beta$-cyclodextrin bind to MBP. 1D proton difference spectra and 2D HSQC proton-nitrogen correlation spectra were acquired of MBP in the presence of different ligands. Spectra with linear maltodextrins showed many common features and were disti

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32

Zhang, Xiaochen. "The binding modes of maltose binding protein with different ligands studied by NMR." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq29813.pdf.

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33

Khine, Aye Aye. "The role of globotriaosylceramide in internalization and functions of globotriaosylceramide-bound protein ligands." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0025/NQ49923.pdf.

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34

Salman, Asma. "Semi-rational design and characterisation of peptide ligands to manipulate ID protein function." Thesis, University of Essex, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.617060.

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ID helix-loop-helix (HLH) proteins play a central role in the regulation of mammalian cell growth, differentiation and tumourigenesis. In many human cancer types, the expression of one or more of the four 10 family members (ID1 to ID4) is deregulated. Extensive data supports a direct role for deregulated ID protein expression in conferring malignant properties on tumour cells, through their inhibition of basic HLH (bHLH) transcription factors, which highlights the ID proteins as candidate therapeutic targets. This research aimed to develop peptides capable of inhibiting ID protein function, an

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35

Klingstedt, Therése. "Fluorescent thiophene-based ligands for detection and characterization of disease-associated protein aggregates." Doctoral thesis, Linköpings universitet, Kemi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-92772.

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In this thesis the unique optical properties of fluorescent ligands termed luminescent conjugated oligothiophenes (LCOs) have been used to study a variety of protein aggregates associated with human protein misfolding disease. This heterogeneous group of diseases contains well known and fatal members such as Alzheimer´s and Huntington´s disease and the development of sensitive tools for the detection and characterization of protein aggregates is crucial for unravelling the complexity of these pathologies. Conventionally, the molecular dyes Congo red and thioflavin T (ThT) have been the primary

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36

Newby, Linda Jane. "Identification of ligands to the PKD1 protein, polycistin-1, using genetically modified cells." Thesis, University of Sheffield, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425192.

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37

Wang, Peng. "Screening Combinatorial Peptide Library for Optimal Enzyme Substrates and High Affinity Protein Ligands." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1039797438.

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38

Onel, Buket, and Buket Onel. "Promoter G-quadruplexes and their Interactions with Ligands and Proteins." Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/621857.

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G-quadruplex secondary structures are four-stranded globular nucleic acid structures that form in specific DNA and RNA G-rich sequences with biological significance, such as those found in human telomeres, oncogene promoter regions, replication initiation sites, and 5’- and 3’-untranslated (UTR) regions, which have been identified as novel drug targets. The non-canonical G-quadruplex secondary structures readily form under physiologically relevant ionic conditions, and exhibit great diversity in their topologies and loop conformations depending on the DNA or RNA sequences at hand. The structur

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39

Swanepoel, C. C. A. "Investigating ligands of cardiac Myosin-Binding Protein C (cMyBPC) as potential regulators of contractility and modifiers of hypertrophy." Thesis, Stellenbosch : Stellenbosch University, 2011. http://hdl.handle.net/10019.1/18072.

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Thesis (PhD ) -- Stellenbosch University, 2011.<br>Bibliography<br>ENGLISH ABSTRACT: The regulation of cardiac contractility is dependent on cooperative interaction between the thick and thin filaments, as well as their accessory proteins, within the cardiac sarcomere. Alteration in cardiac contractility due to a defective sarcomere typically results in cardiomyopathies, such as hypertrophic cardiomyopathy (HCM). One of the sarcomeric genes frequently mutated and which accounts for the second most common form of HCM encodes cardiac myosin binding protein C (cMyBPC), a thick filament accessory

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40

Kolli, Ramya. "Effect of Leaving Ligands of Platinum(II) Diamine Complexes on DNA and Protein Residues." TopSCHOLAR®, 2013. http://digitalcommons.wku.edu/theses/1268.

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Platinum compounds are widely used drugs in cancer treatments. Although DNA is the biological target, reaction of platinum compounds with proteins is also potentially significant. Our objective is to study the effects of leaving ligands on the relative reactivity between 5'-GMP (guanosine 5' phosphate), a key DNA target, and N-Acetyl - L-Methionine (N-AcMet), a key protein target. We have used NMR spectroscopy to monitor reactions with N-AcMet and 5'-GMP added to a platinum complex to see which products are formed preferentially. Previous research showed that both a non-bulky complex such as [

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41

Cain, James Patrick. "Design, Synthesis, and Evaluation of New Ligands for G Protein-Coupled Receptors and Kinases." Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/204272.

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Peptidergic G Protein-Coupled Receptors (GPCRs) play a role in many of the most important biological functions, and the ability to modulate the activity of these critical proteins has tremendous potential to increase our understanding of biology and allow the development of new therapeutics. In some cases this knowledge will point towards the importance of interconnected proteins of the same or different classes, such as kinases, which interact in a complex and dynamic network in vivo. Understanding these systems will be crucial for addressing unmet therapeutic needs, and new chemical structur

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42

Rahman, Ishrat. "Functional analysis of the G-protein coupled chemokine receptor CXCR3-A and its ligands." Thesis, University of Reading, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578079.

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CXCR3 is a G-protein coupled chemokine receptor. Chemokine receptors play a key part in orchestrating immune responses. CXCR3 in particular has attracted attention owing to its abundant expression in activated T-cells and its role in the trafficking of Thl cells to sites of inflammation, and thus may potentially be involved in the pathogenesis of many chronic inflammatory diseases, such as Multiple Sclerosis (MS) and Rheumatoid arthritis (RA). CXCR3 is known to exist as two functional variants; CXCR3-A and CXCR3-B, both associated with diverse signalling events and exert contrasting functional

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43

Rice, Heather Caroline. "Regulation of the Proteolytic Processing and Function of Amyloid Precursor Protein by Candidate Ligands." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11014.

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Despite intense interest in the proteolysis of Amyloid Precursor Protein (APP) in Alzheimer’s disease (AD), how the normal processing and function of this type I receptor-like glycoprotein is regulated remains ill-defined. APP is reported to function in neurodevelopment, including migration of neuronal precursor cells into the cortical plate. In recent years, several candidate ligands for APP, including F-spondin, Reelin, \(\beta1\) Integrin, Contactins, and Lingo-1 have been reported. However, a cognate ligand for APP that regulates its function or processing has yet to be widely confirmed in

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44

Shearer, Lee. "Design and synthesis of ligands to probe the interactions of retinol binding protein (RBP)." Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713694.

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Retinol binding protein (RBP) is a member of the lipocalin family of proteins that is responsible for transporting vitamin A (retinol) in the blood to the target cells of the body. RBP is released from the liver as a complex with transthyretin (TTR) and the role of the complex is to prevent RBP being excreted by the kidney. RBP binds to a specific cell receptor (STRA6) which facilitates the uptake of retinol into the cell. Studies have suggested that elevated levels of serum RBP may be involved in preventing cellular responses to insulin which in turn leads to insulin resistance and eventually

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45

Prischich, Davia. "Development and applications of photoswitchable small molecules and peptides to control protein-protein interactions and GPCR activity." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/671019.

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Photopharmacology is an emerging field that relies on the development of photosensitive compounds to enable precise spatiotemporal control over endogenous proteins. Photochromic ligands· are designed to respond to specific wavelengths of light with a reversible change of structure that enhances or diminishes their activity or affinity towards the desired target. Applications are expected to lead to safer treatments in medicine and to innovative tools to investigate complex signalling networks in biology. Thus, in this thesis we aimed at further expanding the spec

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46

Huggins, David John. "Multiscale docking using evolutionary optimisation." Thesis, University of Oxford, 2005. http://ora.ox.ac.uk/objects/uuid:f166d5ec-5085-48b9-838a-626f754f73fb.

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Molecular docking algorithms are computational methods that predict the binding site and docking pose of specified ligands with a protein target. They have proliferated in recent years, due to the explosion of structural data in biology. Oxdock is an algorithm that uses various techniques to simplify this complex task, the most significant being the use of a multiscale approach to analyse the problem using a simple representation in the early stages. Oxdock is shown to be a very useful tool in computational biology, as exemplified by two cases. The first case is the analysis of the NMDA subcla

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47

Weinberg, Justin B. "Competitive IgG Adsorption on Protein A Chromatography Resins and Improving Resin Performance with PEGylated Ligands." Research Showcase @ CMU, 2017. http://repository.cmu.edu/dissertations/1075.

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Protein A (ProA) chromatography is a bioseparations technique employed throughout the biopharmaceutical industry for the selective capture and purification of IgG-class monoclonal antibodies (mAbs) and Fc-fusion proteins. The rapid growth of mAbs as commercial therapeutics has motivated the need for improved, efficient, and high-throughput purification processes during manufacturing. In direct response, the work presented in thesis aims to 1) increase the scientific community’s understanding of IgG adsorption behavior on ProA chromatography resins and 2) improve the performance of ProA chromat

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48

Bursby, Timothy Patrick. "Investigations of the mitochondrial #beta#-oxidation trifunctional protein and its association with complex 1 of the respiratory chain." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364807.

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49

Boussert, Stéphanie. "Structural studies of proteins and protein complexes by mass spectrometry and atomic force microscopy." Université Louis Pasteur (Strasbourg) (1971-2008), 2008. https://publication-theses.unistra.fr/public/theses_doctorat/2008/BOUSSERT_Stephanie_2008.pdf.

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50

Vestergaard, Henrik Tang. "Diversity in competitive ligand-receptor interactions : electrophysiological studies of ligand-receptor interactions at native and recombinant GABAA receptors /." Cph. : Department of Pharmacology, The Danish University of Pharmaceutical Sciences, 2003. http://www.dfh.dk/phd/defences/henriktangvestergaard.htm.

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