I12-JEEP: Joint Engineering, Environmental and Processing
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Diamond Proposal Number(s):
[13911]
Abstract: Materials used as electrodes in energy storage devices have been extensively studied with solid-state NMR spectroscopy. Due to the almost ubiquitous presence of transition metals, these systems are also often magnetic. While it is well known that the presence of anisotropic bulk magnetic susceptibility (ABMS) leads to broadening of resonances under MAS, we show that for mono-disperse and non-spherical particle morphologies, the ABMS can also lead to considerable shifts, which vary substantially as a function of particle shape. This, on one hand, complicates the interpretation of the NMR spectrum and the ability to compare the measured shift of different samples of the same system. On the other hand the ABMS shift provides a mechanism with which to derive the particle shape from the NMR spectrum. In this work, we present a methodology to model the ABMS shift, and relate it to the shape of the studied particles. The approach is tested on the $^7$Li NMR spectra of single crystals and powders of LiFePO$_4$. The results show that the ABMS shift can be a major contribution to the total NMR shift in systems with large magnetic anisotropies and small hyperfine shifts, $^7$Li shifts for typical LiFePO$_4$ morphologies varying by as much as 100 ppm. The results are generalised to demonstrate that the approach can be used as a means with which to probe the aspect ratio of particles. The work has implications for the analysis of NMR spectra of all materials with anisotropic magnetic susceptibilities, including diamagnetic materials such as graphite.
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Jul 2019
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[15762]
Open Access
Abstract: Traditionally small-molecule crystallographers have not usually observed or recognized significant radiation damage to their samples during diffraction experiments. However, the increased flux densities provided by third-generation synchrotrons have resulted in increasing numbers of observations of this phenomenon. The diversity of types of small-molecule systems means it is not yet possible to propose a general mechanism for their radiation-induced sample decay, however characterization of the effects will permit attempts to understand and mitigate it. Here, systematic experiments are reported on the effects that sample temperature and beam attenuation have on radiation damage progression, allowing qualitative and quantitative assessment of their impact on crystals of a small-molecule test sample. To allow inter-comparison of different measurements, radiation-damage metrics (diffraction-intensity decline, resolution fall-off, scaling B-factor increase) are plotted against the absorbed dose. For ease-of-dose calculations, the software developed for protein crystallography, RADDOSE-3D, has been modified for use in small-molecule crystallography. It is intended that these initial experiments will assist in establishing protocols for small-molecule crystallographers to optimize the diffraction signal from their samples prior to the onset of the deleterious effects of radiation damage.
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Jul 2019
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B21-High Throughput SAXS
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Diamond Proposal Number(s):
[21470]
Abstract: The self-assembly and biocatalytic activity of the proline-functionalized lipopeptide PRW-NH-C16 are examined, and compared to that of the related PRW-O-C16 lipopeptide, which differs in having an ester linker between the lipid chain and tripeptide headgroup instead of an amide linker. Lipopeptide PRW-NH-C16 self-assembles into spherical micelles above a critical aggregation concentration, similar to the behaviour of PRW-O-C16 reported previously [B.M. Soares et al. Phys. Chem. Chem. Phys., 2017, 19, 1181—1189]. However, PRW-NH-C16 shows improved catalytic activity in a model aldol reaction. In addition, we explore incorporation of the biocatalytic lipopeptide into lipid cubosomes. SAXS shows that increasing lipopeptide concentration leads to an expansion of the monoolein cubosome lattice spacing, and loss of long-range cubic order as the lipopeptide is encapsulated in the cubosomes. At higher loadings of lipopeptide, reduced cubosome formation is observed at the expense of vesicle formation. Our results show that the peptide-lipid chain linker does not influence self-assembly but does impart improved biocatalytic activity. Furthermore, we show that lipopeptides can be incorporated into lipid cubosomes, leading to restructuring into vesicles at high loadings. These findings point the way towards the future development of bioactive lipopeptide assemblies and slow release cubosome-based delivery systems.
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Jul 2019
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I04-Macromolecular Crystallography
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Yan
Xiong
,
Holger
Greschik
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Catrine
Johansson
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Ludwig
Seifert
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Johannes
Bacher
,
Kwang-su
Park
,
Nicolas
Babault
,
Michael L.
Martini
,
Vincent
Fagan
,
Fengling
Li
,
Irene
Chau
,
Thomas
Christott
,
David
Dilworth
,
Dalia
Barsyte-lovejoy
,
Masoud
Vedadi
,
Cheryl H.
Arrowsmith
,
Paul E.
Brennan
,
Oleg
Fedorov
,
Manfred
Jung
,
Gillian
Farnie
,
Jing
Liu
,
Udo C. T.
Oppermann
,
Roland
Schüle
,
Jian
Jin
Abstract: By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (Spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to non-tumorigenic cells. The crystal structure of the SPIN1–compound 3 complex indicated that it selectively binds Tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective and cell-active fragment-like inhibitors can be generated by targeting a single Tudor domain.
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Jul 2019
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[18953]
Abstract: The synthesis of anisotropic redox-active polyoxometalates (POMs) that can switch between multiple states is critical for understanding the mechanism of assembly of structures with a high aspect ratio, as well as for their application in electronic devices. However, a synthetic methodology for the controlled growth of such clusters is lacking. Here we describe a strategy, using the heteroanion-directed assembly, to produce a family of ten multi-layered anisotropic POM cages templated redox-active pyramidal heteroanions with the composition [W16Mo2O54(XO3)]n-,[W21Mo3O75(XO3)2]m-,[W26Mo4O93(XO3)3]o- for the single, double and triple layered clusters respectively. It was found that the introduction of reduced molybdate is essential for self-assembly of and results in mixed-metal (W/Mo) and mixed-valence (WVI/MoV) POM cages, as confirmed by an array of analytical techniques. To probe the archetype in detail, a tetrabutyl ammonium (TBA) salt derivative of a fully oxidized two-layered cage is produced as a model structure to confirm that all the cages are a statistical mixture of isostructures with variable ratios of W/Mo. Finally, it was found that multi-layered POM cages exhibit dipolar relaxations due to the presence of the mixed valence WVI/MoV metal centers, demonstrating their potential use for electronic materials.
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Jul 2019
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Pamela A.
Haile
,
Linda N.
Casillas
,
Bartholomew J.
Votta
,
Gren Z.
Wang
,
Adam K.
Charnley
,
Xiaoyang
Dong
,
Michael J.
Bury
,
Joseph J.
Romano
,
John F.
Mehlmann
,
Bryan W.
King
,
Karl F.
Erhard
,
Charles R.
Hanning
,
David B.
Lipshutz
,
Biva M.
Desai
,
Carol A.
Capriotti
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Michelle C.
Schaeffer
,
Scott B.
Berger
,
Mukesh K.
Mahajan
,
Michael A.
Reilly
,
Rakesh
Nagilla
,
Elizabeth J.
Rivera
,
Helen H.
Sun
,
John K.
Kenna
,
Allison M.
Beal
,
Michael T.
Ouellette
,
Mike
Kelly
,
Gillian
Stemp
,
Máire A.
Convery
,
Anna
Vossenkämper
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Thomas T.
Macdonald
,
Peter J.
Gough
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John
Bertin
,
Robert W.
Marquis
Diamond Proposal Number(s):
[1195, 5799]
Abstract: RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.
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Jul 2019
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Theoretical Physics
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Open Access
Abstract: In 1878, the Dutch physicist Hendrik Antoon Lorentz first addressed the calculation of the local electric field at an atomic site in a ferroelectric material, generated by all the other electric dipoles within the sample. This calculation, which applies equally well to ferromagnets, is taught in Universities around the World. Here we demonstrate that the Lorentz concept can be used to speed up calculations of the local dipolar field in square, circular, and elliptical shaped monolayers and thin films, not only at the center of the film, but across the sample. Calculations show that long elliptical and rectangular films should exhibit the narrowest ferromagnetic resonance linewidth. In addition, discrete dipole calculations show that the Lorentz cavity field does not hold in tetragonal films. Depending on the ratio (b/a), the local field can be either less/greater than : an observation that has implications for ferromagnetic resonance. 3D simple cubic (SC) systems are also examined. For example, while most texts discuss the Lorentz cavity field in terms of a Lorentz sphere, the Lorentz cavity field still holds when a Lorentz sphere is replaced by a the Lorentz cube, but only in cubic SC, FCC and BCC systems. Finally, while the primary emphasis is on the discrete dipole-dipole interaction, contact is made with the continuum model. For example, in the continuous SC dipole model, just one monolayer is required to generate the Lorentz cavity field. This is in marked contrast to the discrete dipole model, where a minimum of five adjacent monolayers is required.
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Jul 2019
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I03-Macromolecular Crystallography
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Abstract: The c-MYC transcription factor is a master regulator of cell growth and proliferation and is an established target for cancer therapy. This basic helix–loop–helix Zip protein forms a heterodimer with its obligatory partner MAX, which binds to DNA via the basic region. Considerable research efforts are focused on targeting the heterodimerization interface and the interaction of the complex with DNA. The only available crystal structure is that of a c-MYC:MAX complex artificially tethered by an engineered disulfide linker and prebound to DNA. We have carried out a detailed structural analysis of the apo form of the c-MYC:MAX complex, with no artificial linker, both in solution using nuclear magnetic resonance (NMR) spectroscopy and by X-ray crystallography. We have obtained crystal structures in three different crystal forms, with resolutions between 1.35 and 2.2 Å, that show extensive helical structure in the basic region. Determination of the α-helical propensity using NMR chemical shift analysis shows that the basic region of c-MYC and, to a lesser extent, that of MAX populate helical conformations. We have also assigned the NMR spectra of the c-MYC basic helix–loop–helix Zip motif in the absence of MAX and showed that the basic region has an intrinsic helical propensity even in the absence of its dimerization partner. The presence of helical structure in the basic regions in the absence of DNA suggests that the molecular recognition occurs via a conformational selection rather than an induced fit. Our work provides both insight into the mechanism of DNA binding and structural information to aid in the development of MYC inhibitors.
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Jul 2019
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B23-Circular Dichroism
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Inna M.
Yasinska
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Svetlana S.
Sakhnevych
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Ludmila
Pavlova
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Anette
Teo Hansen Selnø
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Ana Maria
Teuscher Abeleira
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Ouafa
Benlaouer
,
Isabel
Gonçalves Silva
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Marianne
Mosimann
,
Luca
Varani
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Marco
Bardelli
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Rohanah
Hussain
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Giuliano
Siligardi
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Dietmar
Cholewa
,
Steffen M.
Berger
,
Bernhard F.
Gibbs
,
Yuri A.
Ushkaryov
,
Elizaveta
Fasler-kan
,
Elena
Klenova
,
Vadim V.
Sumbayev
Diamond Proposal Number(s):
[20755]
Open Access
Abstract: Human cancer cells operate a variety of effective molecular and signaling mechanisms which allow them to escape host immune surveillance and thus progress the disease. We have recently reported that the immune receptor Tim-3 and its natural ligand galectin-9 are involved in the immune escape of human acute myeloid leukemia (AML) cells. These cells use the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3, and possibly other ligands) to trigger the pathway. We hypothesized that the Tim-3-galectin-9 pathway may be involved in the immune escape of cancer cells of different origins. We found that studied breast tumors expressed significantly higher levels of both galectin-9 and Tim-3 compared to healthy breast tissues of the same patients and that these proteins were co-localized. Increased levels of LPHN2 and expressions of LPHN3 as well as FLRT3 were also detected in breast tumor cells. Activation of this pathway facilitated the translocation of galectin-9 onto the tumor cell surface, however no secretion of galectin-9 by tumor cells was observed. Surface-based galectin-9 was able to protect breast carcinoma cells against cytotoxic T cell-induced death. Furthermore, we found that cell lines from brain, colorectal, kidney, blood/mast cell, liver, prostate, lung, and skin cancers expressed detectable amounts of both Tim-3 and galectin-9 proteins. The majority of cell lines expressed one of the LPHN isoforms and FLRT3. We conclude that the Tim-3-galectin-9 pathway is operated by a wide range of human cancer cells and is possibly involved in prevention of anti-tumor immunity.
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Jul 2019
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I16-Materials and Magnetism
I22-Small angle scattering & Diffraction
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Diamond Proposal Number(s):
[11687, 14117, 15319]
Abstract: The influence of reaction rate on the evolving polymer structure of photo-activated dimethacrylate biomedical resins was investigated using neutron and in situ synchrotron X-ray scattering with simultaneous Fourier-transform-near-infrared spectroscopy. Previous studies have correlated the degree of reactive group conversion with mechanical properties, but the impact of polymerization rate on the resultant polymer structure is unknown. Here, we demonstrate that the medium-range structural order at the functional end groups of these materials is dependent on the reaction rate. Accelerating polymerization increases correlation lengths in the methacrylate end groups but reduces the medium-range structural order per converted vinyl bond when compared with more slowly polymerized systems. At faster rates of polymerization, the conformation of atoms at the reacting end group can become fixed into the polymer structure at the onset of autodeceleration, storing residual strain. Neutron scattering confirms that the structural differences observed are reproduced at longer length scales. This effect is not as prominent in systems polymerized at slower rates despite similar final degrees of reactive group conversion. Results suggest that current interpretations of these materials, which extrapolate mechanical properties from conversion, may be incomplete. Accelerating polymerization can introduce structural differences, which will dictate residual strain and may ultimately explain the discrepancies in the predictive modeling of the mechanical behavior of these materials using conventional techniques.
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Jul 2019
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