B22-Multimode InfraRed imaging And Microspectroscopy
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James M.
Cameron
,
Justin J. A.
Conn
,
Christopher
Rinaldi
,
Alexandra
Sala
,
Paul M.
Brennan
,
Michael D.
Jenkinson
,
Helen
Caldwell
,
Gianfelice
Cinque
,
Khaja
Syed
,
Holly J.
Butler
,
Mark G.
Hegarty
,
David S.
Palmer
,
Matthew J.
Baker
Diamond Proposal Number(s):
[23417]
Open Access
Abstract: Mutations in the isocitrate dehydrogenase 1 (IDH1) gene are found in a high proportion of diffuse gliomas. The presence of the IDH1 mutation is a valuable diagnostic, prognostic and predictive biomarker for the management of patients with glial tumours. Techniques involving vibrational spectroscopy, e.g., Fourier transform infrared (FTIR) spectroscopy, have previously demonstrated analytical capabilities for cancer detection, and have the potential to contribute to diagnostics. The implementation of FTIR microspectroscopy during surgical biopsy could present a fast, label-free method for molecular genetic classification. For example, the rapid determination of IDH1 status in a patient with a glioma diagnosis could inform intra-operative decision-making between alternative surgical strategies. In this study, we utilized synchrotron-based FTIR microanalysis to probe tissue microarray sections from 79 glioma patients, and distinguished the positive class (IDH1-mutated) from the IDH1-wildtype glioma, with a sensitivity and specificity of 82.4% and 83.4%, respectively. We also examined the ability of attenuated total reflection (ATR)-FTIR spectroscopy in detecting the biomolecular events and global epigenetic and metabolic changes associated with mutations in the IDH1 enzyme, in blood serum samples collected from an additional 72 brain tumour patients. Centrifugal filtration enhanced the diagnostic ability of the classification models, with balanced accuracies up to ~69%. Identification of the molecular status from blood serum prior to biopsy could further direct some patients to alternative treatment strategies.
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Dec 2020
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I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[19800]
Open Access
Abstract: Energy-coupling factor (ECF) transporters mediate import of micronutrients in prokaryotes. They consist of an integral membrane S-component (that binds substrate) and ECF module (that powers transport by ATP hydrolysis). It has been proposed that different S-components compete for docking onto the same ECF module, but a minimal liposome-reconstituted system, required to substantiate this idea, is lacking. Here, we co-reconstituted ECF transporters for folate (ECF-FolT2) and pantothenate (ECF-PanT) into proteoliposomes, and assayed for crosstalk during active transport. The kinetics of transport showed that exchange of S-components is part of the transport mechanism. Competition experiments suggest much slower substrate association with FolT2 than with PanT. Comparison of a crystal structure of ECF-PanT with previously determined structures of ECF-FolT2 revealed larger conformational changes upon binding of folate than pantothenate, which could explain the kinetic differences. Our work shows that a minimal in vitro system with two reconstituted transporters recapitulates intricate kinetics behaviour observed in vivo.
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Dec 2020
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I13-1-Coherence
I18-Microfocus Spectroscopy
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Diamond Proposal Number(s):
[18762, 19399]
Open Access
Abstract: Aims: We sought to develop a novel experimental system which enabled application of iodinated contrast media to in vivo plant roots intact in soil and was compatible with time-resolved synchrotron X-ray computed tomography imaging. The system was developed to overcome issues of low contrast to noise within X-ray computed tomography images of plant roots and soil environments, the latter of which can complicate image processing and result in the loss of anatomical information. Methods: To demonstrate the efficacy of the system we employ the novel use of both synchrotron X-ray computed tomography and synchrotron X-ray fluorescence mapping to capture the translocation of the contrast media through root vasculature into the leaves. Results: With the application of contrast media we identify fluid flow in root vasculature and visualise anatomical features, which are otherwise often only observable in ex vivo microscopy, including: the xylem, metaxylem, pith, fibres in aerenchyma and leaf venation. We are also able to observe interactions between aerenchyma cross sectional area and solute transport in the root vasculature with depth. Conclusions: Our novel system was capable of successfully delivering sufficient contrast media into root and leaf tissues such that anatomical features could be visualised and internal fluid transport observed. We propose that our system could be used in future to study internal plant transport mechanisms and parameterise models for fluid flow in plants.
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Dec 2020
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I21-Resonant Inelastic X-ray Scattering (RIXS)
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Roberto
Fumagalli
,
Abhishek
Nag
,
Stefano
Agrestini
,
Mirian
Garcia-fernandez
,
Andrew C.
Walters
,
Davide
Betto
,
Nicholas B.
Brookes
,
Lucio
Braicovich
,
Kejin
Zhou
,
Giacomo
Ghiringhelli
,
Marco Moretti
Sala
Diamond Proposal Number(s):
[23413]
Abstract: Motivated by the recent synthesis of Ba
CuO
(BCO), a high temperature superconducting cuprate with putative
ground state symmetry, we investigated its electronic structure by means of Cu
x-ray absorption (XAS) and resonant inelastic x-ray scattering (RIXS) at the Cu
edge on a polycrystalline sample. We show that the XAS profile of BCO is characterised by two peaks associated to inequivalent Cu sites, and that its RIXS response features a single, sharp peak associated to crystal-field excitations. We argue that these observations are only partially compatible with the previously proposed crystal structure of BCO. Based on our spectroscopic results and on previously published powder diffraction measurements, we propose a crystalline structure characterized by two inequivalent Cu sites located at alternated planes along the
axis: nominally trivalent Cu(1) belonging to very short Cu-O chains, and divalent Cu(2) in the oxygen deficient CuO
planes. We also analyze the low-energy region of the RIXS spectra to estimate the magnitude of the magnetic interactions in BCO and find that in-plane nearest neighbor superexchange exceeds 120 meV, similarly to that of other layered cuprates. Although these results do not support the pure
ground state scenario, they hint at a significant departure from the common quasi-2D electronic structure of superconducting cuprates of pure
symmetry.
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Dec 2020
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I12-JEEP: Joint Engineering, Environmental and Processing
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Diamond Proposal Number(s):
[22178]
Abstract: Fluid release from dehydration reactions is considered to have significant effects on the strength and dynamics of tectonic faults at convergent plate boundaries. It is classically assumed that the production of fluid leads to increased pore fluid pressures that perturb a fault's stress state and thereby facilitates and enhances deformation. This important assumption has never been supported by direct microstructural observations. Here, we investigate the role of gypsum dehydration in the deformation of evaporitic rocks using synchrotron-based time-resolved X-ray computed microtomography (4D) imaging. This approach enables the documentation of coupled chemical, hydraulic and mechanical processes on the grain scale. In our experiments with deforming halite-gypsum-halite sandwiches we observe that the fluid released by dehydrating gypsum accumulates at the gypsum-halite interface before a distributed hydraulic failure of the halite layer drains the fluid. From our observations we conclude that perceivedly impermeable halite layers in evaporites are unlikely to trap overpressured fluid, e.g., in thin-skinned tectonic detachment horizons. Moreover, as the hydraulic failure is diffuse and not localized, our experiments suggest that dehydration reactions alone may not explain intermediate depth seismicity in subduction zones. Our data demonstrate the significant potential that in-situ 4D imaging has for the grain-scale investigation of fundamental tectonic processes.
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Dec 2020
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Abstract: Optical fiber technology has revolutionized the telecommunications industry, though is still under‐utilized in chemistry. Optical fibers open many avenues for introducing, and containing, light in chemical reactions, as part of a photoreactor. This work shows, for the first time, a design strategy for incorporating a photocatalytic, nanoporous framework (Co ZIF‐67) within the internal capillaries of an optical fiber, in doing so creating an all‐in‐one, plug‐in‐and‐play photoreactor. This system improves the reactivity of the photocatalyst, relative to the powdered form, for C-H activation leading to C-C bond formation, a significant process in pharmaceutical and organic synthesis. Performing this reaction using solar energy, and low temperature demonstrates the clear potential for these systems for large scale industrial applications.
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Dec 2020
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Abstract: Biophysical characterizations in the solution-state are not only critical to validating structural hypotheses derived from high-resolution structure determination methods but have provided key biological insights not accessible through high-resolution methods. Here we review the role of small angle X-ray scattering (SAXS), diffracted X-ray tracking (DXT) and X-ray footprinting mass spectrometry (XFMS) and their respective contributions to structural virology. SAXS, a low resolution X-ray scattering technique, is ideal for studying viruses as it readily captures structural information over many length-scales from monomers to the hierarchical capsid assembly in a single exposure. DXT and XFMS provide complimentary micro-to milli-second time-resolved measurements. DXT reveals how single protein molecules “wiggle” in solution whereas XFMS provides residue-specific, atomic-level information by mapping changes in solvent accessibility. Both DXT and XFMS can be performed in vivo allowing the testing of more challenging life sciences hypotheses.
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Dec 2020
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I02-Macromolecular Crystallography
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Hengmiao
Cheng
,
Suvi T. M.
Orr
,
Simon
Bailey
,
Alexei
Brooun
,
Ping
Chen
,
Judith G.
Deal
,
Yali L.
Deng
,
Martin P.
Edwards
,
Gary M.
Gallego
,
Neil
Grodsky
,
Buwen
Huang
,
Mehran
Jalaie
,
Stephen
Kaiser
,
Robert S.
Kania
,
Susan E.
Kephart
,
Jennifer
Lafontaine
,
Martha A.
Ornelas
,
Mason
Pairish
,
Simon
Planken
,
Hong
Shen
,
Scott
Sutton
,
Luke
Zehnder
,
Chau D.
Almaden
,
Shubha
Bagrodia
,
Matthew D.
Falk
,
Hovhannes J.
Gukasyan
,
Caroline
Ho
,
Xiaolin
Kang
,
Rachel E.
Kosa
,
Ling
Liu
,
Mary E.
Spilker
,
Sergei
Timofeevski
,
Ravi
Visswanathan
,
Zhenxiong
Wang
,
Fanxiu
Meng
,
Shijian
Ren
,
Li
Shao
,
Feng
Xu
,
John C.
Kath
Abstract: The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2′-amino-5-fluoro-2-(morpholin-4-yl)-4,5′-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.
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Dec 2020
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[21497]
Abstract: Here we describe the formation of an unexpected and unique family of hollow six-stranded helicates. The formation of these structures depends on the coordinative flexibility of silver and the 2-formyl-1,8-napthyridine subcomponent. Crystal structures show that these assemblies are held together by Ag4I, Ag4Br, or Ag6(SO4)2 clusters, where the templating anion plays an integral structure-defining role. Prior to the addition of the anionic template, no six-stranded helicate was observed to form, with the system instead consisting of a dynamic mixture of triple helicate and tetrahedron. Six-stranded helicate formation was highly sensitive to the structure of the ligand, with minor modifications inhibiting its formation. This work provides an unusual example of mutual stabilization between metal clusters and a self-assembled metal–organic cage. The selective preparation of this anisotropic host demonstrates new modes of guiding selective self-assembly using silver(I), whose many stable coordination geometries render design difficult.
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Dec 2020
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I19-Small Molecule Single Crystal Diffraction
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Abstract: Current strategies for the synthesis of molecular knots focus on twisting, folding and/or threading molecular building blocks. Here we report that Zn(II) or Fe(II) ions can be used to weave ligand strands to form a woven 3 × 3 molecular grid. We found that the process requires tetrafluoroborate anions to template the assembly of the interwoven grid by binding within the square cavities formed between the metal-coordinated criss-crossed ligands. The strand ends of the grid can subsequently be joined through within-grid alkene metathesis reactions to form a topologically trivial macrocycle (unknot), a doubly interlocked [2]catenane (Solomon link) and a knot with seven crossings in a 258-atom-long closed loop. This 74 knot topology corresponds to that of an endless knot, which is a basic motif of Celtic interlace, the smallest Chinese knot and one of the eight auspicious symbols of Buddhism and Hinduism. The weaving of molecular strands within a discrete layer by anion-template metal–ion coordination opens the way for the synthesis of other molecular knot topologies and to woven polymer materials.
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Dec 2020
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