I03-Macromolecular Crystallography
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Christopher R.
Wellaway
,
Dominique
Amans
,
Paul
Bamborough
,
Heather
Barnett
,
Rino A.
Bit
,
Jack A.
Brown
,
Neil R.
Carlson
,
Chun-wa
Chung
,
Anthony W. J.
Cooper
,
Peter D.
Craggs
,
Robert P.
Davis
,
Tony W.
Dean
,
John P.
Evans
,
Laurie
Gordon
,
Isobel L.
Harada
,
David J.
Hirst
,
Philip G.
Humphreys
,
Katherine L.
Jones
,
Antonia J.
Lewis
,
Matthew J.
Lindon
,
Dave
Lugo
,
Mahnoor
Mahmood
,
Scott
Mccleary
,
Patricia
Medeiros
,
Darren J.
Mitchell
,
Michael
O’sullivan
,
Armelle
Le Gall
,
Vipulkumar K.
Patel
,
Chris
Patten
,
Darren L.
Poole
,
Rishi R.
Shah
,
Jane E.
Smith
,
Kayleigh A. J.
Stafford
,
Pamela J.
Thomas
,
Mythily
Vimal
,
Ian D.
Wall
,
Robert J.
Watson
,
Natalie
Wellaway
,
Gang
Yao
,
Rab K.
Prinjha
Abstract: The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET–KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
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Jan 2020
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E02-JEM ARM 300CF
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Diamond Proposal Number(s):
[22207]
Abstract: Confining electric fields to a nanoscale region is challenging yet crucial for applications such as high resolution probing of electrical properties of materials and electric-field manipulation of nanoparticles. State-of-the-art techniques involving atomic force microscopy typically have a lateral resolution limit of tens of nanometers due to limitations in the probe geometry and stray electric fields that extend over space. Engineering the probes is the most direct approach to improving this resolution limit. However, current methods to fabricate high-resolution probes, which can effectively confine the electric fields laterally involve expensive and sophisticated probe manipulation, which has limited the use of this approach. Here, we demonstrate that nanoscale phase switching of configurable thin films on probes can result in high-resolution electrical probes. These configurable coatings can be both germanium-antimony-tellurium (GST) as well as amorphous-carbon, materials known to undergo electric field-induced non-volatile, yet reversible switching. By forming a localized conductive filament through phase transition, we demonstrate a spatial resolution of electrical field beyond the geometrical limitations of commercial platinum probes (i.e. an improvement of ~48%). We then utilize these confined electric fields to manipulate nanoparticles with single nanoparticle precision via dielectrophoresis. Our results advance the field of nanomanufacturing and metrology with direct applications for pick and place assembly at the nanoscale.
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Jan 2020
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I12-JEEP: Joint Engineering, Environmental and Processing
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Diamond Proposal Number(s):
[11161]
Open Access
Abstract: We report the synthesis of organometal halide perovskites by milling CH3NH3I and PbI2 directly with an Al2O3 scaffold to create hybrid Al2O3-CH3NH3PbI3 perovskites, without the use of organic capping ligands that otherwise limit the growth of the material in the three dimensions. Not only does this improve the ambient stability of perovskites in air (100 min versus 5 min for dimethylformamide (DMF)-processed material), the method also uses much fewer toxic solvents (terpineol versus dimethylformamide). This has been achieved by solid-state reaction of the perovskite precursors to produce larger perovskite nanoparticles. The resulting hybrid perovskite–alumina particles effectively improve the hydrophobicity of the perovskite phase whilst the increased thermal mass of the Al2O3 increases the thermal stability of the organic cation. Raman data show the incorporation of Al2O3 shifts the perovskite spectrum, suggesting the formation of a hybrid 3D mesoporous stack. Laser-induced current mapping (LBIC) and superoxide generation measurements, coupled to thermogravimetric analysis, show that these hybrid perovskites demonstrate slightly improved oxygen and thermal stability, whilst ultra-fast X-ray diffraction studies using synchrotron radiation show substantial (20×) increase in humidity stability. Overall, these data show considerably improved ambient stability of the hybrid perovskites compared to the solution-processed material.
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Jan 2020
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I12-JEEP: Joint Engineering, Environmental and Processing
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Diamond Proposal Number(s):
[18468]
Open Access
Abstract: There are several mechanisms contributing towards detrimental damage in wind turbine gearbox bearings, with sudden overload events believed to reduce their expected operational life. The generation of subsurface plasticity, followed by rolling contact fatigue, may lead to the initiation of either surface or subsurface cracking. This study presents a novel technique capable of measuring subsurface strain evolution in a rotating roller bearing, using energy dispersive X-ray diffraction. A pre-overloaded bearing was tested dynamically and consequently failed prematurely, supporting the hypothesis that overloads accelerate bearing failure. Throughout the test, an increase in compressive radial strain was observed, indicative of material softening, generally associated with the unstable stage of rolling contact fatigue, which occurs prior to definitive bearing failure.
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Dec 2019
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I11-High Resolution Powder Diffraction
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Diamond Proposal Number(s):
[18206]
Abstract: Pure and Nb-doped zirconium germanate materials of composition K2-xZr1-xNbxGe3O9.H2O where x = 0, 0.1, 0.2 and 0.25 with the structure of the mineral umbite have been successfully synthesised. The parent material displays negligible ion exchange of K+ for Cs+ but the doped materials shows much improved exchange. Synchrotron X-ray diffraction shows substantial peak splitting which varies with increasing niobium content. Preliminary Rietveld refinements suggest a two phase model with a caesium and potassium rich doped umbite phase.
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Dec 2019
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I15-Extreme Conditions
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Diamond Proposal Number(s):
[9902, 8858, 17412]
Abstract: The atomic-scale structural evolution of Ga68.5In21·5Sn10 (wt. %) liquid alloy has been explored utilizing in-situ high-energy synchrotron X-ray diffraction from room temperature (293 K) to around the melting point. During the process of decreasing temperature, bond lengths of dominant atomic pairs decrease, whereas the total coordination numbers of the first nearest neighbor shell increase. This structural transition is ascribed to the redistribution of atoms and/or clusters and the decrease of vacancies induced by decreasing temperature. Our results are supportive for further understanding the atomic-scale structural evolution of liquid alloys at the low-temperature condition.
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Dec 2019
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I18-Microfocus Spectroscopy
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Diamond Proposal Number(s):
[17250]
Abstract: From oxic atmosphere to metallic core, the Earth's components are broadly stratified with respect to oxygen fugacity. A simple picture of reducing oxygen fugacity with depth may be disrupted by the accumulation of oxidised crustal material in the deep lower mantle, entrained there as a result of subduction. While hotspot volcanoes are fed by regions of the mantle likely to have incorporated such recycled material, the oxygen fugacity of erupted hotspot basalts had long been considered comparable to or slightly more oxidised than that of mid-ocean ridge basalt (MORB) and more reduced than subduction zone basalts. Here we report measurements of the redox state of glassy crystal-hosted melt inclusions from tephra and quenched lava samples from the Canary and Cape Verde Islands, that we can independently show were entrapped prior to extensive sulphur degassing. We find high ferric iron to total iron ratios (Fe3+/∑Fe) of up to 0.27–0.30, indicating that mantle plume primary melts are significantly more oxidised than those associated with mid-ocean ridges and even subduction zone. These results, together with previous investigations from the Erebus, Hawaiian and Icelandic hotspots, confirm that mantle upwelling provides a return flow from the deep Earth for components of oxidised subducted lithosphere and suggest that highly oxidised material accumulates or is generated in the lower mantle. The oxidation state of the Earth's interior must therefore be highly heterogeneous and potentially locally inversely stratified.
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Dec 2019
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I12-JEEP: Joint Engineering, Environmental and Processing
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Diamond Proposal Number(s):
[187201]
Abstract: In this study, the polymorphic transitions of mefenamic acid (MA) were studied by synchrotron X-ray powder diffraction combined with differential scanning calorimetry (XRD-DSC). The initial material was found to be phase-pure form I which, when heated, produces two endotherms that can be observed by DSC at 162.72 and 219.55°C. The former was found to correspond to a solid–solid enantiotropic transition from form I to a mixture of forms II and III. The latter is the melting point of form II. As form I is heated, significantly greater unit-cell expansion is seen in the a direction than in b and c, which can be explained by the stronger intermolecular interactions in the bc plane. Refinements of the reported MA structures against the patterns collected during heating revealed that at 175°C there exists a mixture of forms I, II and III, whereas only forms II and III remain at 205°C. However, reflections are observed at both temperatures which cannot be fitted with the known forms of MA. It is hypothesized that a new form of MA is produced upon heating. The stability of MA after the enantiotropic transition temperature is II > III > I, which differs from the previously reported II > I > III.
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Dec 2019
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Krios I-Titan Krios I at Diamond
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Qinrui
Wang
,
Robin A.
Corey
,
George
Hedger
,
Prafulla
Aryal
,
Mariana
Grieben
,
Chady
Nasrallah
,
Agnese
Baronina
,
Ashley C. W.
Pike
,
Jiye
Shi
,
Elisabeth P.
Carpenter
,
Mark S. P.
Sansom
Diamond Proposal Number(s):
[14856]
Open Access
Abstract: Polycystin-2 (PC2) is a transient receptor potential (TRP) channel present in ciliary membranes of the kidney. PC2 shares a transmembrane fold with other TRP channels, in addition to an extracellular domain found in TRPP and TRPML channels. Using molecular dynamics (MD) simulations and cryoelectron microscopy we identify and characterize PIP2 and cholesterol interactions with PC2. PC2 is revealed to have a PIP binding site close to the equivalent vanilloid/lipid binding site in the TRPV1 channel. A 3.0-Å structure reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are characterized by MD simulations. The two classes of lipid binding sites are compared with sites observed in other TRPs and in Kv channels. These findings suggest PC2, in common with other ion channels, may be modulated by both PIPs and cholesterol, and position PC2 within an emerging model of the roles of lipids in the regulation and organization of ciliary membranes.
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Dec 2019
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I16-Materials and Magnetism
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Han Gyeol
Lee
,
Lingfei
Wang
,
Liang
Si
,
Xiaoyue
He
,
Daniel G.
Porter
,
Jeong Rae
Kim
,
Eun Kyo
Ko
,
Jinkwon
Kim
,
Sung Min
Park
,
Bongju
Kim
,
Andrew Thye Shen
Wee
,
Alessandro
Bombardi
,
Zhicheng
Zhong
,
Tae Won
Noh
Diamond Proposal Number(s):
[22181]
Abstract: The metal–insulator transition (MIT) in transition‐metal‐oxide is fertile ground for exploring intriguing physics and potential device applications. Here, an atomic‐scale MIT triggered by surface termination conversion in SrRuO3 ultrathin films is reported. Uniform and effective termination engineering at the SrRuO3(001) surface can be realized via a self‐limiting water‐leaching process. As the surface termination converts from SrO to RuO2, a highly insulating and nonferromagnetic phase emerges within the topmost SrRuO3 monolayer. Such a spatially confined MIT is corroborated by systematic characterizations on electrical transport, magnetism, and scanning tunneling spectroscopy. Density functional theory calculations and X‐ray linear dichroism further suggest that the surface termination conversion breaks the local octahedral symmetry of the crystal field. The resultant modulation in 4d orbital occupancy stabilizes a nonferromagnetic insulating surface state. This work introduces a new paradigm to stimulate and tune exotic functionalities of oxide heterostructures with atomic precision.
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Dec 2019
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