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SPIDER VENOMS AND CHRONIC PAIN – Developing Novel Pharmacological Tools from the Spider Venoms to Target P2X4 in Microglia Lučka Bibič Faculty of Science School of Pharmacy Ph.D. January 2020 Thesis submitted to the School of Pharmacy, University of East Anglia, in fulfilment of the requirement for the degree of Doctor of Philosophy. 1 2 “I wonder,” said Frodo, “But I don’t know. And that’s the way of a real tale.” – J.R.R. Tolkien, The Lord of the Rings 3 Intellectual Property and Publication Statements The candidate confirms that the work submitted is her own, except where work which has formed part of co-authored publications has been included. The contributions of the candidate to this work has been explicitly indicated below. The Chapter 1 on “No Pain, All Gain” was adapted from various sources, including from our review article on the subjects, which was published in 2017: “P2X4 receptor function in the nervous system and current breakthroughs in pharmacology,” Stokes L., Layhadi J. A., Bibic L., Dhuna K., and Fountain S.J., Frontiers of Pharmacology. 2017, 8, 291. The contribution of LB (the candidate) were to co-write the corresponding section of the review and produced the related figures. The work described in Chapter 3 on “Development of high-throughput fluorescent-based screens to accelerate discovery of P2X inhibitors from animal venoms” formed the basis for a research article published in 2019 as “Development of high-throughput fluorescent-based screens to accelerate discovery of P2X inhibitors from animal venoms,” Bibic L., Herzig V., King G. F., and Stokes L., Journal of Natural Products. 2019, 82.9., p.2559-2567. The contribution of LB (the candidate) were to conduct the experiments, analyse the data, prepare the figures, co-write the initial manuscript draft and edit the final drafts. Chapters 4 and 5 are based on a manuscript with a running title of “Discovery of a novel spider toxin that selectively inhibits P2X4 receptor,” Bibic L., et al. and is currently in preparation. Part of the study described in Chapter 6 found its home as a research paper titled ‘Bug Off Pain: educational virtual reality game on spider venoms and chronic pain for public engagement,’ Bibic L.*, Druskis J., Walpole S., Angulo J., and Stokes L., Journal of Chemical Education. 2019, 96, 7, 1486-1490. The contribution of LB (the candidate) were to direct the program of research, designed the game, produced the educational videos, prepared the figures, initiated, wrote, and edited the article. The candidate (LB) owns, together with the University of East Anglia, a copyright protection of the virtual reality game Bug Off Pain©. 4 The copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise than its copyright rests with the author and that use of any information derived there must be in accordance with current UK Copyright Law. In addition, any quotation or extract must include full attribution. © 2020 University of East Anglia and Lucka Bibic 5 Publication Record List Peer-reviewed publications (academic): 1. Bibic, L., Stokes L., Revisiting the idea that amyloid-β peptide acts as an agonist for P2X7. In review. 2. Stokes L., Bidula S., Bibic L., Allum E., “To inhibit or enhance? Is there a benefit to positive allosteric modulation of P2X receptors?” In review. 3. Bibic, L., Herzig V., King G., Stokes L., 2019. Development of high-throughput fluorescent-based screens to accelerate discovery of P2X inhibitors from animal venoms. J Nat Prod. 82, 9, 2559-2567. DOI: 10.1021/acs.jnatprod.9b00410 4. Bibic, L.*, Druskis J., Walpole S., Angulo J., and Stokes L., 2019. “Bug Off Pain: educational virtual reality game on spider venoms and chronic pain for public engagement.” J Chem Educ. 96, 7, 1486- 1490. DOI: 10.1021/acs.jchemed.8b00905 (*corresponding author) 5. Cook, A.B.* and Bibic L.*, 2019. Macromolecules, actually: from Plastics to DNA.” Front Young Minds. 7:126. DOI: 10.3389/frym.2019.00126 (*co-corresponding author) 6. Botta J., Bibic L., Howell L.A., McCormick P.J., 2019. Staple peptides for the G-protein coupled dimers. J Biol Chem. Ahead of print. DOI: 10.1074/jbc.RA119.009160 7. Blasco-Benito et al. Therapeutic targeting of HER2-CB2 heteromers in HER-2 positive breast cancer. 2019. Proc Natl Acad Sci. 116.9: 3863-3872. DOI: 10.1073/pnas.1815034116 8. Dhuna, K., Felgate, M., Bidula, S.M., Walpole, S., Bibic, L., Cromer, B.A., Angulo, J., Sanderson, J., Stebbing, M.J. and Stokes, L., 2019. Ginsenosides act as positive modulators of P2X4 receptors. Mol. Pharmacol. 95(2), pp.210-221. DOI: 10.1124/mol.118.113696 9. Moreno, E., Mireia M., Chiarlone A., Puigdellívol M., Bibic L., Howell L.A., et al. Singular location and signaling profile of adenosine A 2A-Cannabinoid CB 1 receptor heteromers in the dorsal striatum. 2018. Nat Neuropsychopharmacology. 43.5, 964. DOI: 10.1038/npp.2017.12 10. Stokes L., Layhadi J. A., Bibic L., Dhuna K., and Fountain S.J. 2017. P2X4 receptor function in the nervous system and current breakthroughs in pharmacology. Front Pharmacol. 8, 291. DOI: 10.3389/fphar.2017.00291 11. Busnelli M., Kleinau G., Muttenthaler M., Stoev S., Manning M., Bibic L., Howell L. A., et al. 2016. Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure. J Med Chem. 59.15, 7152-7166. DOI: 10.1021/acs.jmedchem.6b00564 6 Other academic publications: 12. Bibic, L.* 2018. Learning to lead. Science. 361: 6407. DOI: 10.1126/science.361.6407.1158 (Working Life article, *corresponding author) 13. Bibic, L. 2018. “Sustainable Electrochemical Functionalization of Alkenes”. J. Am. Chem. Soc. 140: 48. DOI: 10.1021/jacs.8b12638 (Spotlight feature) 14. Bibic, L. 2019. Common Metals, Cheaper Catalysts in Fuel Cells”. J. Am. Chem. Soc. 141: 4. DOI: 10.1021/jacs.9b00602 (Spotlight feature) 15. Bibic, L. 2019. Small but Mighty: Clickable Fluorescent Probe for Bioimaging. J. Am. Chem. Soc. 141: 7. DOI: 10.1021/jacs.9b01585 (Spotlight feature) 16. Bibic, L. 2019. “Spongy yet Sturdy: MOF Harvests Water from Air”. J. Am. Chem. Soc. 141: 12 DOI: 10.1021/jacs.9b02969 (Spotlight feature) 17. Bibic, L. 2019. “Playing with Fire Recovers an Unusual Carbon Compound”. J. Am. Chem. Soc. 141: 15. DOI: 10.1021/jacs.9b03757 (Spotlight feature) 18. Bibic, L. 2019. “Getting a Grip on Protein–Protein Interactions”. J. Am. Chem. Soc. 141: 20. DOI: 10.1021/jacs.9b05138 (Spotlight feature) 19. Bibic, L. 2019. “Triangular Prism Sorts Natural Products”. J. Am. Chem. Soc. 141: 22. DOI: 10.1021/jacs.9b05712 (Spotlight feature) 20. Bibic, L. 2019. “Lighting the Way for Photonic Devices”. J. Am. Chem. Soc. 141: 34. DOI: 10.1021/jacs.9b09008 (Spotlight feature) 21. Bibic, L. 2019. “Under Pressure: Analyzing Amyloid-Beta Peptides as They Fold”. J. Am. Chem. Soc. 141: 37. DOI: 10.1021/jacs.9b09762 (Spotlight feature) 22. Bibic L. 2019. “Pushing the Triple-Phase Boundary for Fuel Cells”. J. Am. Chem. Soc. 141: 48. DOI: 10.1021/jacs.9b12613 (Spotlight feature) 7 Conference Abstracts, Presentations, Travel Awards and a Peer-Review 1. Discovery of a small molecule toxin with inhibitory activity at human P2X4 ion channel. Oral presentation at the “Pharmacology 2019” conference (Edinburgh, UK, December 2019) and at the “Venoms and Toxins 2019” meeting (Oxford, UK, August 2019). 2. Bug Off Pain: Educational VR game about spider venoms and chronic pain for public engagement. Invited speaker for the Gamification: Pedagogy and Practice (Norwich, UK, May 2019) and BISON Conference (Norwich, UK, November 2018). Oral presentations. 3. No Pain, All Gain: Discovery of a novel spider toxin that selectively inhibits hP2X4 Receptor. Poster presentation at the 156th National meeting (Boston, USA, August 2018). Part of CAS Future Leaders Award. 4. Bug Off Pain: Probing P2X Channels with Animal Venoms. Oral presentation at the Purines 2018 (Foz do Iguacu, Brazil, June 2018). Awarded with UEA Pharmacy travel grant (£1000). Poster and flash presentation at the Gordon Research Conference "Venom evolution, structure and biomedical application" (Vermont, USA, August 2018). Awarded with the travel grants from RSC and the Biochemical Society (£1000). 5. Disruption of G-protein coupled receptor dimers by cell-penetrating interference peptides in vitro. Poster and flash presentation at the XXIV EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC 2016, Manchester, UK, 2016). Awarded with the Royal Society Travel Grant (£500). 6. It takes two to tango and one to dip: Disruption of GPCR heteromers by cell-penetrating peptides. Poster presentation at the Peptide and Protein Science Group RSC (Durham, UK, November 2015) and at the GPCRS: Beyond Structure towards Therapy (Prato, Italy, September 2015). 7. Invitation to undertake a peer-review as offered by the Journal of Chemical Education (June 2019) – accepted 8 Awards The list of awards and a certificate obtained during my doctoral studies include: Honours certificate in Writing in the Sciences by Stanford University (2019) – Credential ID K266YN4V5PB8, grade: 95.6%. International CAS Future Leaders Award (2018) – a leadership program organized by Chemical Abstract Service (CAS) and American Chemical Society (ACS) that recognize the top postgraduate and postdoctoral students in chemical sciences. UEA Engagement Award (2018) – a university-based award that recognizes outreach efforts to the local community. Presentation Award “Best 3-minute thesis” (2017) at the UEA, School of Pharmacy’s Research Day. Winners of the Biotechnology YES2017 (2017) entrepreneurship competition and People’s Choice Awards. Best start-up business plan branded as CryoThaw Heart. Finalist pitch at the GlaxoSmith Kline (GSK) at Stevenage (UK). Best Biotechnology pitch for the venture capitalists and judges at the finals in the Royal Society (London, UK).
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    VKM Report 2016: 36 Assessment of the risks to Norwegian biodiversity from the import and keeping of terrestrial arachnids and insects Opinion of the Panel on Alien Organisms and Trade in Endangered species of the Norwegian Scientific Committee for Food Safety Report from the Norwegian Scientific Committee for Food Safety (VKM) 2016: Assessment of risks to Norwegian biodiversity from the import and keeping of terrestrial arachnids and insects Opinion of the Panel on Alien Organisms and Trade in Endangered species of the Norwegian Scientific Committee for Food Safety 29.06.2016 ISBN: 978-82-8259-226-0 Norwegian Scientific Committee for Food Safety (VKM) Po 4404 Nydalen N – 0403 Oslo Norway Phone: +47 21 62 28 00 Email: [email protected] www.vkm.no www.english.vkm.no Suggested citation: VKM (2016). Assessment of risks to Norwegian biodiversity from the import and keeping of terrestrial arachnids and insects. Scientific Opinion on the Panel on Alien Organisms and Trade in Endangered species of the Norwegian Scientific Committee for Food Safety, ISBN: 978-82-8259-226-0, Oslo, Norway VKM Report 2016: 36 Assessment of risks to Norwegian biodiversity from the import and keeping of terrestrial arachnids and insects Authors preparing the draft opinion Anders Nielsen (chair), Merethe Aasmo Finne (VKM staff), Maria Asmyhr (VKM staff), Jan Ove Gjershaug, Lawrence R. Kirkendall, Vigdis Vandvik, Gaute Velle (Authors in alphabetical order after chair of the working group) Assessed and approved The opinion has been assessed and approved by Panel on Alien Organisms and Trade in Endangered Species (CITES). Members of the panel are: Vigdis Vandvik (chair), Hugo de Boer, Jan Ove Gjershaug, Kjetil Hindar, Lawrence R.
  • Gil Ylc Me Sjrp Par.Pdf (846.1Kb)

    Gil Ylc Me Sjrp Par.Pdf (846.1Kb)

    RESSALVA Atendendo solicitação do(a) autor(a), o texto completo desta dissertação será disponibilizado somente a partir de 22/02/2020. Yeimy Lizeth Cifuentes Gil Revisão taxonômica e análise cladística dos gêneros de tarântulas arborícolas Psalmopoeus Pocock, 1985 e Tapinauchenius Ausserer, 1871 (Araneae: Theraphosidae: Aviculariinae). São José do Rio Preto 2018 Yeimy Lizeth Cifuentes Gil Revisão taxonômica e análise cladística dos gêneros de tarântulas arborícolas Psalmopoeus Pocock, 1985 e Tapinauchenius Ausserer, 1871 (Araneae: Theraphosidae: Aviculariinae). Dissertação apresentada como parte dos requisitos para obtenção do título de Mestre em Biologia Animal, junto ao Programa de Pós-Graduação em Biologia Animal, do Instituto de Biociências, Letras e Ciências Exatas da Universidade Estadual Paulista “Júlio de Mesquita Filho”, Câmpus de São José do Rio Preto. Orientador: Prof. Dr. Rogério Bertani. São José do Rio Preto 2018 Gil, Yeimy Lizeth Cifuentes Revisão taxonômica e análise cladística dos gêneros de tarântulas arborícolas Psalmopoeus Pocock, 1985 e Tapinauchenius Ausserer, 1871 (Araneae: Theraphosidae: Aviculariinae) / Yeimy Lizeth Cifuentes Gil. -- São José do Rio Preto, 2018 132 f. : il. Orientador: Rogério Bertani Dissertação (mestrado) – Universidade Estadual Paulista “Júlio de Mesquita Filho”, Instituto de Biociências, Letras e Ciências Exatas 1. Ecologia animal. 2. Aranha. 3. Biologia – Classificação. I. Universidade Estadual Paulista "Júlio deMesquita Filho". Instituto de Biociências, Letras e Ciências Exatas. II. Título.