1,035 research outputs found
Ferguson-Smith, Malcolm: transcript of a video interview (06-Jun-2015)
No full textInterview with Professor Malcolm Ferguson-Smith, conducted by Ms Emma M. Jones, for the History of Modern Biomedicine Research Group, 06 June 2015, in Glasgow. Transcribed by Mrs Debra Gee, and edited by Professor Tilli Tansey and Mr Alan Yabsley. The project management was undertaken by Mr Adam Wilkinson. Professor Malcolm Ferguson-Smith (b. 1931) is Emeritus Professor of Pathology, University of Cambridge. He graduated in medicine at Glasgow University in 1955 and, while undertaking postgraduate training there in pathology, was introduced to research on sex chromatin under Bernard Lennox. An interest in Klinefelter’s syndrome in 1957 to 1958 led to his appointment as Fellow in Medicine at Johns Hopkins University, Baltimore, in 1959, where he established the first chromosome diagnostic service in the USA, and undertook cytogenetic research into Turner syndrome. Research interests include molecular cytogenetics, karyotype evolution, vertebrate sex determination and comparative genomics. He is joint author of 'Essential Medical Genetics'.The History of Modern Biomedicine Research Group is funded by the Wellcome Trust, which is a registered charity (no. 210183). The current interview has been funded by the Wellcome Trust Strategic Award entitled “Makers of modern biomedicine: testimonies and legacy” (2012-2017; awarded to Professor Tilli Tansey)
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Proteomics-Based Approaches to Identify and Characterize Molecular Glues
No full textDespite advances in proteomics techniques, the rational discovery of non-degrader molecular glues and their targets remains challenging. In Chapter 1, I describe the BioTAC system, an unbiased ligand-guided proximity labeling method, and showcase its ability to robustly identify small molecule targets and interactomes, including complex partners of non-degrader molecular glues. In Chapter 2, I present a detailed method development guide to implementing the BioTAC system for compounds and proteins of interest. In Chapter 3, I develop a chemoproteomics-based pipeline to identify new covalent ligand-protein binding sites for structure-interactome relationship studies, and characterize a reactive cysteine-containing hub protein as an amenable target for non-degrader molecular glue development
New Zealand Women Traveller Writers : from exile to diaspora
No full textThe focus of this article is a group of New Zealand women traveller writers of the first half of the twentieth century who left their country of origin, and in the encounter with new worlds overseas, reconstructed themselves as deterritorialised, diasporic subjects with new understandings of home and belonging. Their work can be read as both transitional and transnational, reflecting the ambivalence of multiple cultural affiliations and reinflecting literary conventions. Such encounters and new points of reference from transiting through foreign lands inevitably catalyse new and unusual forms of diasporic writing, notable for a heightened consciousness of difference (Kalra et al 2008: 30). This article aims to identify patterns of similarity and contrast in their work, and to determine how they incorporate their varied experiences of loss and liberation into artistic reconciliations with the homeland
Synthesis of Alpha-Synuclein Proteolytic Targeting Chimeras and Selective Tau Tubulin Kinase I Inhibitors
No full textMisfolded alpha-synuclein has been identified as a potential target to developing disease modifying or preventative therapies for Parkinson’s Disease. Proteolytic Targeting Chimeras (PROTACs) have been demonstrated as chemical tools and selective degraders for protein targets in neurodegenerative diseases. PROTACs have already been demonstrated as chemical tools and selective degraders for other neurodegenerative diseases such as targeting tau protein for Frontal Temporal Dementia. Taking previously known binders of alpha-synuclein and proteasomal ligand recruiters a library of PROTACs was synthesized in addition to small molecule degraders with a guanosine-derived autophagy tag, or Autophagy Targeting Chimera (AUTAC), as an alternative form of degradation. Successful development of a selective and potent degrader would allow a better understanding of alpha-synuclein and its role in Parkinson’s Disease. Hyperphosphorylation of Tau is a hallmark of many neurodegenerative diseases. Tau Tubulin Kinase 1 (TTBK1) is involved in tau phosphorylation and has been indicated to phosphorylate tau at pathologically relevant sites making it a promising drug target. Small molecule inhibitors exist that can inhibit TTBK1 with off target affects on TTBK2 which has important functions throughout the nervous system. Utilizing known crystal structures of TTBK1 and TTBK2, selective small molecules were synthesized taking advantage of a peripheral lysine residue which can covalently react with a flour sulfonyl moiety. Using this strategy, separation of TTBK1 and 2 would allow for detailed understanding of their separate and overlapping substrates and biological functions
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Developing a Generalizable Approach to Improve the Blood Brain Barrier Permeability of Proteolysis Targeting Chimeras through Prodrugs
No full textProteolysis targeting chimeras (PROTACs) are a promising class of molecular probes that can elicit degradation of classically undruggable targets. This capability comes with a large size (>1000Da), and thus reduced cell permeability: this extends to the blood brain barrier (BBB), effectively limiting the employment of PROTACs as in vivo probes for pharmacologically relevant targets that lie in the central nervous system. Strategies for small molecule inhibitors generally cannot be applied to PROTACs due to their large size, however one such approach that shows promise is the prodrug approach, in which a labile attachment known as a promoiety is attached to a pharmacologically active site of a drug with the purpose of improving physicochemical properties. To date, no studies exist which utilize the prodrug approach as a means of improving the BBB permeability of PROTACs. The work herein describes our efforts to develop a generalizable strategy to improve the BBB permeability of PROTACs through the prodrug approach, as to expand the degradable proteome into the CNS
"The honor of firing before His Majesty": Patrick Ferguson's will and the Royal Armouries’ Ferguson rifle
No full textPatrick Ferguson (1744-80) designed the first breech-loading rifle to be used by the British Army. In November 2000, the Royal Armouries purchased an early example, formerly in the possession of the Fergusons of Pitfour, descendants of Patrick's younger brother, George. Patrick Ferguson's will has helped the author identify the Royal Armouries' Ferguson Rifle as the one which Patrick Ferguson used when he demonstrated it before George III and Queen Charlotte at Windsor in 1776
Mobile Press-Register sleeve MP0080642
No full textM. A. Le Fleur, J. Grogan, M. E. Ferguson / Bonnie Harper / Grace Wright, Bettie Tanner / Brandee Garrett / Margie Windham, Tessie Ellis, Bonnie Walker / Satsuma children dancing / M. A. Napper and 3 students in pilgrim costumes / Bea Stevens and Jessie Lucas in kitchen / (Saraland; Satsuma; Chickasaw
Increasing the region of attraction in DC microgrids
No full textBased on the port-Hamiltonian framework, this paper proposes a novel control scheme for stabilising the voltage in DC networks affected by (i) unknown ZIP-loads, i.e., nonlinear loads consisting of the parallel combination of constant impedance (Z), current (I) and power (P) load types, and (ii) unknown (but bounded) time-varying disturbances. Differently from the results existing in the literature, where restrictive (sufficient) conditions on the load parameters, voltage trajectory and voltage reference are assumed to be satisfied, this is the first paper (to the best of our knowledge) proposing a controller that relaxes such conditions and guarantees the exponential stability of the desired equilibrium point, whose region of attraction can be increased by simply tuning the control gains. In the case the network is affected by unknown time-varying disturbances, local input-to-state stability (l-ISS) is ensured. Furthermore, if non-ideal P-loads are considered, excluding the unrealistic possibility that the load absorbs infinite current when the voltage approaches zero, the aforementioned stability results hold globally.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
De afsluiting van het Haringvliet
No full textIr. H. A. Ferguson - Ten geleide ** H. J. Stuvel - BoIwerk en hoafdkraan ** Ir. P. Santema - De Haringvlietafsluiting aIs instrument vaor regionalewaterbeheersing in Zuidwest-Nedefland ** Prof. ir. P. A. van de Velde - Het ontwerp in hoofdlijnen vaor de uitwateringssluis ** H. J . Stuvel - De kraan van de Delta ** Ir. J. E. Prins - Haringvlietproject stuwde waterloopkundig ondefzoek naar hager plan ** lr. F. Spaargaren en iT. J. J. Vinje - Waterloopkundig onderzoek ten behoeve van vormgeving kunstwerk, vorm bouwput en vonn sluitgat ** H. J. Stroband, ing. - De'Deltar' ** Ir. P. H. van der Weele- De bodembescherming ter weerszijden van de spuisluizen ** W. Drooger - Mechanisch zinken ** Ir. C. A. ZuMerwijk - 'Grootgrondverzet' in het Haringvliet ** Ir. P. Blokland - De problemen van de schaalvergroting bij het ontwerpen en bouwen van de spnisluis in het Haringvliet ** H. J. Stuvel - De produktie van de nablaliggers ** Ir. A. van Dam en ir. Ph. Diderich - Terugblik op een inspirerende opdracht ** Ir. drs. H. Kuiper - De segmentschuiven met elektro-hydraulische aandrijving ** fr. M. Geleedst en ir. W. A. Venis - OnderLoek naar het dynamisch gedrag van de Haringvlietsluis ** Ir. R.I. Schor - De vervaardiging van de schuiven ** Ir. J. ter Brugge - De montage van de schuiven ** Ir. P. H. van der Weele - De kabelbaan ** Ir. T. G. van der Meer - De sluiling van het Rak van Scheelhoek ** Ir. A. 1. Woestenenk - Bijzondere toerassing van zandasfalt in de waterbouw ** Ir. J.J. Pilon- De Hydrometische begeleiding van de Haringvlietwerken ** W. A. A. van Eyden en ir. F. Langeweg - De functie van de Haringvlietsluizen binnen het waterbeheersingssysteem van het noordelijk Deltabekken ** Prof. ir. P. Ph. Jansen - Een historisch gebeurenDeltawerke
Harnessing Antibody-Mimetic Selectivity for Activation-State-Specific Targeted Degradation of Endogenous K-Ras
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