I03-Macromolecular Crystallography
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William
Mccoull
,
Scott
Boyd
,
Martin R.
Brown
,
Muireann
Coen
,
Olga
Collingwood
,
Nichola L.
Davies
,
Ann
Doherty
,
Gary
Fairley
,
Kristin
Goldberg
,
Elizabeth
Hardaker
,
Guang
He
,
Edward J.
Hennessy
,
Philip
Hopcroft
,
George
Hodgson
,
Anne
Jackson
,
Xiefeng
Jiang
,
Ankur
Karmokar
,
Anne-Laure
Lainé
,
Nicola
Lindsay
,
Yumeng
Mao
,
Roshini
Markandu
,
Lindsay
Mcmurray
,
Neville
Mclean
,
Lorraine
Mooney
,
Helen
Musgrove
,
J. Willem M.
Nissink
,
Alexander
Pflug
,
Venkatesh Pilla
Reddy
,
Philip B.
Rawlins
,
Emma
Rivers
,
Marianne
Schimpl
,
Graham F.
Smith
,
Sharon
Tentarelli
,
Jon
Travers
,
Robert I.
Troup
,
Josephine
Walton
,
Cheng
Wang
,
Stephen
Wilkinson
,
Beth
Williamson
,
Jon
Winter-Holt
,
Dejian
Yang
,
Yuting
Zheng
,
Qianxiu
Zhu
,
Paul D.
Smith
Diamond Proposal Number(s):
[17180]
Abstract: Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.
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Sep 2021
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B18-Core EXAFS
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Abstract: The recent report of P2–Na2/3Mg0.28Mn0.72O2 (P2-NMM) demonstrated the possibility of utilizing the oxygen redox couple in a layered oxide cathode without the need for alkali ions or vacancies in the transition metal layer. In this work, we report the synthesis of a new P2-type compound, Na2/3Mg1/4Mn7/12Co1/6O2 (P2-NMMC), which exhibits reversible specific capacities as high as 173 mAh g−1 and an improvement of the first cycle voltage hysteresis over P2-NMM. The material was characterised using a combination of ex-situ and operando techniques including X-ray diffraction (XRD), differential electrochemical mass spectrometry (DEMS) and X-ray spectroscopy (XAS) to identify potential sources for this improvement.
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Sep 2021
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Muhamamd
Faheem
,
Napoleao
Fonseca Valadares
,
Jose
Brandao-Neto
,
Domenico
Bellini
,
Patrick
Collins
,
Nicholas M.
Pearce
,
Louise
Bird
,
Juliana
Torini De Souza
,
Raymond
Owens
,
Humberto
Pereira
,
Frank
Von Delft
,
João Alexandre Ribeiro Gonçalves
Barbosa
Diamond Proposal Number(s):
[11175]
Open Access
Abstract: Several Schistosoma species cause Schistosomiasis, an endemic disease in 78 countries that is ranked second amongst the parasitic diseases in terms of its socioeconomic impact and human health importance. The drug recommended for treatment by the WHO is praziquantel (PZQ), but there are concerns associated with PZQ, such as the lack of information about its exact mechanism of action, its high price, its effectiveness – which is limited to the parasite’s adult form – and reports of resistance. The parasites lack the de novo purine pathway, rendering them dependent on the purine salvage pathway or host purine bases for nucleotide synthesis. Thus, the Schistosoma purine salvage pathway is an attractive target for the development of necessary and selective new drugs. In this study, the purine nucleotide phosphorylase II (PNP2), a new isoform of PNP1, was submitted to a high-throughput fragment-based hit discovery using a crystallographic screening strategy. PNP2 was crystallized and crystals were soaked with 827 fragments, a subset of the Maybridge 1000 library. X-ray diffraction data was collected and structures were solved. Out of 827-screened fragments we have obtained a total of 19 fragments that show binding to PNP2. 14 of these fragments bind to the active site of PNP2, while five were observed in three other sites. Here we present the first fragment screening against PNP2.
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Sep 2021
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I09-Surface and Interface Structural Analysis
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Diamond Proposal Number(s):
[18787]
Abstract: One of the most important functionalities of the atomically thin insulator hexagonal boron nitride (hBN) is its ability to chemically and electronically decouple functional materials from highly reactive surfaces. It is therefore of utmost importance to uncover its structural properties on surfaces on an atomic and mesoscopic length scale. In this paper, we quantify the relative coverages of structurally different domains of a hBN layer on the Ni(111) surface using low-energy electron microscopy and the normal incidence x-ray standing wave technique. We find that hBN nucleates on defect sites of the Ni(111) surface and predominantly grows in two epitaxial domains that are rotated by
60
∘
with respect to each other. The two domains reveal identical adsorption heights, indicating a similar chemical interaction strength with the Ni(111) surface. The different azimuthal orientations of these domains originate from different adsorption sites of N and B. We demonstrate that the majority (
≈
70
%
) of hBN domains exhibit a
(
N
,
B
)
=
(
top
,
fcc
)
adsorption site configuration while the minority (
≈
30
%
) show a
(
N
,
B
)
=
(
top
,
hcp
)
configuration. Our study hence underlines the crucial role of the atomic adsorption configuration in the mesoscopic domain structures of in situ fabricated two-dimensional materials on highly reactive surfaces.
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Sep 2021
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Krios III-Titan Krios III at Diamond
Krios IV-Titan Krios IV at Diamond
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Diamond Proposal Number(s):
[20287]
Open Access
Abstract: RNA polymerase inhibition plays an important role in the regulation of transcription in response to environmental changes and in the virus-host relationship. Here we present the high-resolution structures of two such RNAP-inhibitor complexes that provide the structural bases underlying RNAP inhibition in archaea. The Acidianus two-tailed virus encodes the RIP factor that binds inside the DNA-binding channel of RNAP, inhibiting transcription by occlusion of binding sites for nucleic acid and the transcription initiation factor TFB. Infection with the Sulfolobus Turreted Icosahedral Virus induces the expression of the host factor TFS4, which binds in the RNAP funnel similarly to eukaryotic transcript cleavage factors. However, TFS4 allosterically induces a widening of the DNA-binding channel which disrupts trigger loop and bridge helix motifs. Importantly, the conformational changes induced by TFS4 are closely related to inactivated states of RNAP in other domains of life indicating a deep evolutionary conservation of allosteric RNAP inhibition.
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Sep 2021
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I08-Scanning X-ray Microscopy beamline (SXM)
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Diamond Proposal Number(s):
[24782]
Abstract: Synchrotron-based small-angle X-ray scattering and near-edge X-ray absorption fine structure spectromicroscopy have been used to study the phase separation of thermoplastic polyurethane in a confined thin-film geometry. The functional nanomaterials were introduced in a polymer matrix, where the shape and nature of the functional surface were varied to gain insight into the mechanism of aggregation of polyurethane segments enriched with functional moieties. Using soft X-ray scattering it has been established that the two-dimensional flat functional surface displayed higher phase-segregated geometries with a wider distribution of interdomain spacing in comparison to the one-dimensional contour shaped nanofillers. A strong chemical environment dependence has been observed for π–π or electrostatic interactions during the nanoscale phase separation of the polyurethane matrix by X-ray absorption spectromicroscopy. Our results support the fact that soft X-ray-based spectromicroscopy can be exclusively used as a powerful noninvasive technique for the structure–property analysis of polymer nanocomposites.
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Sep 2021
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I15-1-X-ray Pair Distribution Function (XPDF)
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Diamond Proposal Number(s):
[23125]
Open Access
Abstract: In modern Li-based batteries, alloying anode materials have the potential to drastically improve the volumetric and specific energy storage capacity. For the past decade silicon has been viewed as a “Holy Grail” among these materials; however, severe stability issues limit its potential. Herein, we present amorphous substoichiometric silicon nitride (SiNx) as a convertible anode material, which allows overcoming the stability challenges associated with common alloying materials. Such material can be synthesized in a form of nanoparticles with seamlessly tunable chemical composition and particle size and, therefore, be used for the preparation of anodes for Li-based batteries directly through conventional slurry processing. Such SiNx materials were found to be capable of delivering high capacity that is controlled by the initial chemical composition of the nanoparticles. They exhibit an exceptional cycling stability, largely maintaining structural integrity of the nanoparticles and the complete electrodes, thus delivering stable electrochemical performance over the course of 1000 charge/discharge cycles. Such stability is achieved through the in situ conversion reaction, which was herein unambiguously confirmed by pair distribution function analysis of cycled SiNx nanoparticles revealing that active silicon domains and a stabilizing Li2SiN2 phase are formed in situ during the initial lithiation.
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Sep 2021
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Jonathan
Youngs
,
Nicholas M.
Provine
,
Nicholas
Lim
,
Hannah R.
Sharpe
,
Ali
Amini
,
Yi-Ling
Chen
,
Jian
Luo
,
Matthew D.
Edmans
,
Panagiota
Zacharopoulou
,
Wentao
Chen
,
Oliver
Sampson
,
Robert
Paton
,
William J.
Hurt
,
David A.
Duncan
,
Anna L.
Mcnaughton
,
Vincent N.
Miao
,
Susannah
Leaver
,
Duncan L. A.
Wyncoll
,
Jonathan
Ball
,
Philip
Hopkins
,
Donal T.
Skelly
,
Eleanor
Barnes
,
Susanna
Dunachie
,
Graham
Ogg
,
Teresa
Lambe
,
Ian
Pavord
,
Alex K.
Shalek
,
Craig P.
Thompson
,
Luzheng
Xue
,
Derek C.
Macallan
,
Philip
Goulder
,
Paul
Klenerman
,
Tihana
Bicanic
Open Access
Abstract: Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49–14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08–18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 –a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.
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Sep 2021
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I03-Macromolecular Crystallography
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Diamond Proposal Number(s):
[10071]
Open Access
Abstract: Aspergillus fumigatus is a human opportunistic pathogen showing emerging resistance against a limited repertoire of antifungal agents available. The GTPase Rho1 has been identified as an important regulator of the cell wall integrity signaling pathway that regulates the composition of the cell wall, a structure that is unique to fungi and serves as a target for antifungal compounds. Rom2, the guanine nucleotide exchange factor to Rho1, contains a C-terminal citron homology (CNH) domain of unknown function that is found in many other eukaryotic genes. Here, we show that the Rom2 CNH domain interacts directly with Rho1 to modulate β-glucan and chitin synthesis. We report the structure of the Rom2 CNH domain, revealing that it adopts a seven-bladed β-propeller fold containing three unusual loops. A model of the Rho1–Rom2 CNH complex suggests that the Rom2 CNH domain interacts with the Rho1 Switch II motif. This work uncovers the role of the Rom2 CNH domain as a scaffold for Rho1 signaling in fungal cell wall biosynthesis.
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Sep 2021
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I13-2-Diamond Manchester Imaging
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Diamond Proposal Number(s):
[20155]
Abstract: Objective: Dental erosion is a common oral condition caused by chronic exposure to acids from intrinsic/extrinsic sources. Repeated acid exposure can lead to the irreversible loss of dental hard tissues (enamel, dentine, cementum). Dentine can become exposed to acid following severe enamel erosion, crown fracture, or gingival recession. Causing hypersensitivity, poor aesthetics, and potential pulp involvement. Improving treatments that can restore the structural integrity and aesthetics are therefore highly desirable. Such developments require a good understanding of how acid demineralisation progresses where relatively little is known in terms of intertubular dentine (ITD) and peritubular dentine (PTD) microstructure. To obtain further insight, this study proposes a new in vitro method for performing demineralisation studies of dentine. Methods: Advanced high-speed synchrotron X-ray microtomography (SXM), with high spatial (0.325 μm) and temporal (15 min) resolution, was used to conduct the first in vitro, time-resolved 3D (4D) study of the microstructural changes in the ITD and PTD phases of human dentine samples (∼0.8 × 0.8 × 5 mm) during 6 h of continuous acid exposure. Results: Different demineralisation rates of ITD (1.79 μm/min) and PTD (1.94 μm/min) and their progressive width-depth profiles were quantified, which provide insight for understanding the mechanisms of dentine demineralisation. Significance: Insights obtained from morphological characterisations and the demineralisation process of ITD and PTD during acid demineralisation would help understand the demineralisation process and potentially aid in developing new therapeutic dentine treatments. This method enables continuous examination of relatively large volumes of dentine during demineralisation and also demonstrates the potential for studying the remineralisation process of proposed therapeutic dentine treatments.
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Sep 2021
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