B18-Core EXAFS
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Diamond Proposal Number(s):
[17782]
Open Access
Abstract: Portland cement-based grouts used for radioactive waste immobilisation contain a Ca- and Si-rich binder phase, known as calcium–silicate–hydrate (C–S–H). Depending on the blend of cement used, the Ca/Si ratio can vary considerably. A range of C–S–H minerals with Ca/Si ratios from 0.6 to 1.6 were synthesised and contacted with aqueous U(VI) at 0.5 mM and 10 mM concentrations. Solid-state 29Si MAS-NMR spectroscopy was applied to probe the Si coordination environment in U(VI)-contacted C–S–H minerals and, in conjunction with U LIII-edge X-ray absorption spectroscopy analysis, inferences of the fate of U(VI) in these systems were made. At moderate or high Ca/Si ratios, uranophane-type uranyl silicates or Ca-uranates dominated, while at the lowest Ca/Si ratios, the formation of a Ca-bearing uranyl silicate mineral, similar to haiweeite (Ca[(UO2)2Si5O12(OH)2]·3H2O) or Ca-bearing weeksite (Ca2(UO2)2Si6O15·10H2O) was identified. This study highlights the influence of Ca/Si ratio on uranyl sequestration, of interest in the development of post-closure safety models for U-bearing radioactive waste disposal.
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Feb 2023
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I13-2-Diamond Manchester Imaging
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Diamond Proposal Number(s):
[28574]
Open Access
Abstract: We present a flyscan compatible acquisition scheme for three-modal X-Ray Computed Tomography (CT) with two-dimensional phase sensitivity. Our approach is demonstrated using a “beam tracking” setup, through which a sample’s attenuation, phase (refraction) and scattering properties can be measured from a single frame, providing three complementary contrast channels. Up to now, such setups required the sample to be stepped at each rotation angle to sample signals at an adequate rate, to prevent resolution losses, anisotropic resolution, and under-sampling artefacts. However, the need for stepping necessitated a step-and-shoot implementation, which is affected by motors’ overheads and increases the total scan time. By contrast, our proposed scheme, by which continuous horizontal and vertical translations of the sample are integrated with its rotation (leading to a “cycloidal-spiral” trajectory), is fully compatible with continuous scanning (flyscans). This leads to greatly reduced scan times while largely preserving image quality and isotropic resolution.
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Dec 2022
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Open Access
Abstract: Disadvantaged socio-economic position (SEP) is associated with greater biological age, relative to chronological age, measured by DNA methylation (positive ‘age acceleration’, AA). Social mobility has been proposed to ameliorate health inequalities. This study aimed to understand the association of social mobility with positive AA. Diagonal reference modelling and ordinary least square regression techniques were applied to explore social mobility and four measures of age acceleration (first-generation: ‘Horvath’, ‘Hannum’ and second-generation: ‘Phenoage’, DunedinPoAm) in n = 3140 participants of the UK Household Longitudinal Study. Disadvantaged SEP in early life is associated with positive AA for three (Hannum, Phenoage and DunedinPoAm) of the four measures examined while the second generation biomarkers are associated with SEP in adulthood (p < 0.01). Social mobility was associated with AA measured with Hannum only such that compared to no mobility, upward mobility was associated with greater age independently of origin and destination SEP. Compared to continuously advantaged groups, downward mobility was associated with positive Phenoage (1.06y [− 0.03, 2.14]) and DunedinPoAm assessed AA (0.96y [0.24, 1.68]). For these two measures, upward mobility was associated with negative AA (Phenoage, − 0.65y [− 1.30, − 0.002]; DunedinPoAm, − 0.96y [− 1.47, − 0.46]) compared to continually disadvantaged groups. While we find some support for three models of lifecourse epidemiology with early life as a sensitive period, SEP across the lifecourse and social mobility for age acceleration measured with DNA methylation, our findings suggest that disadvantaged SEP across the lifecourse is most consistently associated with positive AA.
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Dec 2022
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I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
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Olivier A.
Pierrat
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Manjuan
Liu
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Gavin W.
Collie
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Kartika N.
Shetty
,
Matthew J.
Rodrigues
,
Yann-Vai
Le Bihan
,
Emma A.
Gunnell
,
P. Craig
Mcandrew
,
Mark
Stubbs
,
Martin G.
Rowlands
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Norhakim
Yahya
,
Erald
Shehu
,
Rachel
Talbot
,
Lisa
Pickard
,
Benjamin R.
Bellenie
,
Kwai-Ming J.
Cheung
,
Ludovic
Drouin
,
Paolo
Innocenti
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Hannah
Woodward
,
Owen A.
Davis
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Matthew G.
Lloyd
,
Ana
Varela
,
Rosemary
Huckvale
,
Fabio
Broccatelli
,
Michael
Carter
,
David
Galiwango
,
Angela
Hayes
,
Florence I.
Raynaud
,
Christopher
Bryant
,
Steven
Whittaker
,
Olivia W.
Rossanese
,
Swen
Hoelder
,
Rosemary
Burke
,
Rob L. M.
Van Montfort
Open Access
Abstract: By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein–protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.
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Nov 2022
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B23-Circular Dichroism
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Diamond Proposal Number(s):
[31392]
Open Access
Abstract: Designing the architecture of L-lysine-based polymeric structures is a highly challenging task that requires careful control of the amino acid reactive groups. Conventional processes to obtain branched polylysine need several steps and the addition of specific catalysts. In the present work, to gain a better understanding and control of the formation of L-lysine-based polymers, we have investigated the correlation between the protonation state of L-lysine and the corresponding hydrothermally grown structures. The samples have been characterized by combining optical spectroscopies, such as UV–Vis, fluorescence, and synchrotron radiation circular dichroism with structural analysis by Nuclear Magnetic Resonance, Fourier Transform Infrared spectroscopy, and dynamic light scattering. We have observed that aqueous precursor solutions with alkaline pHs promote the formation of branched structures. In contrast, high pHs favour the reactivity of the ε-amino groups leading to linear structures, as shown by circular dichroism analyses. On the other hand, acidic conditions trigger the branching of the amino acid. Interestingly, the polymeric forms of L-lysine emit in the blue because the increasing number of intermolecular hydrogen bonds promote the intermolecular charge transfer responsible for the emission. Understanding the correlation between the L-lysine charged states and the polymeric structures that could form controlling the protonation–deprotonation states of the amino acid opens the route to a refined design of polypeptide systems based on L-lysine.
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Nov 2022
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I02-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
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Diamond Proposal Number(s):
[9306]
Open Access
Abstract: JmjC (Jumonji-C) domain-containing 5 (JMJD5) plays important roles in circadian regulation in plants and humans and is involved in embryonic development and cell proliferation. JMJD5 is a 2-oxoglutarate (2OG) and Fe(II) dependent oxygenase of the JmjC subfamily, which includes histone Nε-methyl lysine-demethylases (KDMs) and hydroxylases catalysing formation of stable alcohol products. JMJD5 is reported to have KDM activity, but has been shown to catalyse C-3 hydroxylation of arginine residues in sequences from human regulator of chromosome condensation domain-containing protein 1 (RCCD1) and ribosomal protein S6 (RPS6) in vitro. We report crystallographic analyses of human JMJD5 complexed with 2OG analogues, including the widely used hypoxia mimic pyridine-2,4-dicarboxylate, both D- and L-enantiomers of the oncometabolite 2-hydroxyglutarate, and a cyclic N-hydroxyimide. The results support the assignment of JMJD5 as a protein hydroxylase and reveal JMJD5 has an unusually compact 2OG binding pocket suitable for exploitation in development of selective inhibitors. They will be useful in the development of chemical probes to investigate the physiologically relevant roles of JMJD5 in circadian rhythm and development and explore its potential as a medicinal chemistry target.
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Nov 2022
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NONE-No attached Diamond beamline
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Open Access
Abstract: The substantial cost of new drug research and development has consistently posed a huge burden for both pharmaceutical companies and patients. In order to lower the expenditure and development failure rate, repurposing existing and approved drugs by identifying interactions between drug molecules and target proteins based on computational methods have gained growing attention. Here, we propose the DeepLPI, a novel deep learning-based model that mainly consists of ResNet-based 1-dimensional convolutional neural network (1D CNN) and bi-directional long short term memory network (biLSTM), to establish an end-to-end framework for protein–ligand interaction prediction. We first encode the raw drug molecular sequences and target protein sequences into dense vector representations, which go through two ResNet-based 1D CNN modules to derive features, respectively. The extracted feature vectors are concatenated and further fed into the biLSTM network, followed by the MLP module to finally predict protein–ligand interaction. We downloaded the well-known BindingDB and Davis dataset for training and testing our DeepLPI model. We also applied DeepLPI on a COVID-19 dataset for externally evaluating the prediction ability of DeepLPI. To benchmark our model, we compared our DeepLPI with the baseline methods of DeepCDA and DeepDTA, and observed that our DeepLPI outperformed these methods, suggesting the high accuracy of the DeepLPI towards protein–ligand interaction prediction. The high prediction performance of DeepLPI on the different datasets displayed its high capability of protein–ligand interaction in generalization, demonstrating that the DeepLPI has the potential to pinpoint new drug-target interactions and to find better destinations for proven drugs.
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Oct 2022
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B21-High Throughput SAXS
I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
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Diamond Proposal Number(s):
[8423]
Open Access
Abstract: Sizzled (Szl) is both a secreted frizzled related protein (sFRP) and a naturally occurring inhibitor of the zinc metalloproteinase bone morphogenetic protein-1 (BMP-1), a key regulator of extracellular matrix assembly and growth factor activation. Here we present a new crystal structure for Szl which differs from that previously reported by a large scale (90°) hinge rotation between its cysteine-rich and netrin-like domains. We also present results of a molecular docking analysis showing interactions likely to be involved in the inhibition of BMP-1 activity by Szl. When compared with known structures of BMP-1 in complex with small molecule inhibitors, this reveals features that may be helpful in the design of new inhibitors to prevent the excessive accumulation of extracellular matrix that is the hallmark of fibrotic diseases.
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Sep 2022
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I19-Small Molecule Single Crystal Diffraction
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Bernhard
Kepplinger
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Lina
Mardiana
,
Joseph
Cowell
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Stephanie
Morton-Laing
,
Yousef
Dashti
,
Corinne
Wills
,
Emma C. L.
Marrs
,
John D.
Perry
,
Joe
Gray
,
Michael
Goodfellow
,
Jeff
Errington
,
Michael R.
Probert
,
William
Clegg
,
Jonathan
Bogaerts
,
Wouter
Herrebout
,
Nick E. E.
Allenby
,
Michael J.
Hall
Diamond Proposal Number(s):
[6749, 11145]
Open Access
Abstract: A genomic and bioactivity informed analysis of the metabolome of the extremophile Amycolatopsis sp. DEM30355 has allowed for the discovery and isolation of the polyketide antibiotic tatiomicin. Identification of the biosynthetic gene cluster was confirmed by heterologous expression in Streptomyces coelicolor M1152. Structural elucidation, including absolute stereochemical assignment, was performed using complementary crystallographic, spectroscopic and computational methods. Tatiomicin shows antibiotic activity against Gram‑positive bacteria, including methicillin‑resistant Staphylococcus aureus (MRSA). Cytological profiling experiments suggest a putative antibiotic mode‑of‑action, involving membrane depolarisation and chromosomal decondensation of the target bacteria.
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Sep 2022
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I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[31420]
Open Access
Abstract: A 1494 Dalton hemoglycin space polymer of Glycine18 Hydroxy-glycine4 Fe2O4 termed the “core unit” is part of a polymer of Glycine, Si, Fe and O that forms tubes, vesicles and a lattice structure. It has been isolated from four different CV3 meteorites and characterized by mass spectrometry, FIB/SIMS and X-ray analysis. In quantum calculations (HF and DF wB97X-D 6-31G) the polymer has an absorption at 480 nm that is dependent on rectus “R” (= dextro D) chirality in a hydroxy glycine residue whose C-terminus is bonded to an iron atom. The absorption originates in the Fe II state as a consequence of chiral symmetry breaking. In confirmation of theory, measurements at Diamond Light Source UK, on crystals of hemoglycin derived from Acfer-086 and Sutter’s Mill meteorites have shown a strong 483 ± 3 nm absorption that confirms the proposed location of hydroxy glycine residues within the polymer. A high 483 nm to 580 nm absorption ratio points to an “R” chirality excess in hemoglycin, suggesting that 480 nm photons could have provided the energy for its replication in the protoplanetary disc.
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Sep 2022
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