E02-JEM ARM 300CF
|
Diamond Proposal Number(s):
[24245]
Open Access
Abstract: Shear-induced segregation, by particle size, is known in the flow of colloids and granular media, but is unexpected at the atomic level in the deformation of solid materials, especially at room temperature. In nanoscale wear tests of an Fe-based bulk metallic glass at room temperature, without significant surface heating, we find that intense shear localization under a scanned indenter tip can induce strong segregation of a dilute large-atom solute (Y) to planar regions that then crystallize as a Y-rich solid solution. There is stiffening of the material, and the underlying chemical and structural effects are characterized by transmission electron microscopy. The key influence of the soft Fe–Y interatomic interaction is investigated by ab-initio calculation. The driving force for the induced segregation, and its mechanisms, are considered by comparison with effects in other sheared media.
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Jul 2021
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I15-Extreme Conditions
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Diamond Proposal Number(s):
[21191]
Open Access
Abstract: In this work, the melting line of calcium has been characterized both experimentally, using synchrotron X-ray diffraction in laser-heated diamond-anvil cells, and theoretically, using first-principles calculations. In the investigated pressure and temperature range (pressure between 10 and 40 GPa and temperature between 300 and 3000 K) it was possible to observe the face-centred phase of calcium and to confirm (and characterize for the first time at these conditions) the presence of the body-centred cubic and the simple cubic phase of calcium. The melting points obtained with the two techniques are in excellent agreement. Furthermore, the present results agree with the only existing melting line of calcium obtained in laser-heated diamond anvil cells, using the speckle method as melting detection technique. They also confirm a flat slope of the melting line in the pressure range between 10 and 30 GPa. The flat melting curve is associated with the presence of the solid high-temperature body-centered cubic phase of calcium and to a small volume change between this phase and the liquid at melting. Reasons for the stabilization of the body-centered face at high-temperature conditions will be discussed.
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Jul 2021
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I13-2-Diamond Manchester Imaging
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Diamond Proposal Number(s):
[22588, 17241]
Open Access
Abstract: Colonic crypts are tubular glands that multiply through a symmetric branching process called crypt fission. During the early stages of colorectal cancer, the normal fission process is disturbed, leading to asymmetrical branching or budding. The challenging shapes of the budding crypts make it difficult to prepare paraffin sections for conventional histology, resulting in colonic cross sections with crypts that are only partially visible. To study crypt budding in situ and in three dimensions (3D), we employ X-ray micro-computed tomography to image intact colons, and a new method we developed (3D cyclorama) to digitally unroll them. Here, we present, verify and validate our ‘3D cyclorama’ method that digitally unrolls deformed tubes of non-uniform thickness. It employs principles from electrostatics to reform the tube into a series of onion-like surfaces, which are mapped onto planar panoramic views. This enables the study of features extending over several layers of the tube’s depth, demonstrated here by two case studies: (i) microvilli in the human placenta and (ii) 3D-printed adhesive films for drug delivery. Our 3D cyclorama method can provide novel insights into a wide spectrum of applications where digital unrolling or flattening is necessary, including long bones, teeth roots and ancient scrolls.
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Jul 2021
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I04-1-Macromolecular Crystallography (fixed wavelength)
I24-Microfocus Macromolecular Crystallography
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Martin A.
Redhead
,
C. David
Owen
,
Lennart
Brewitz
,
Amelia H.
Collette
,
Petra
Lukacik
,
Claire
Strain-Damerell
,
Sean W.
Robinson
,
Patrick M.
Collins
,
Philipp
Schäfer
,
Mark
Swindells
,
Chris J.
Radoux
,
Iva Navratilova
Hopkins
,
Daren
Fearon
,
Alice
Douangamath
,
Frank
Von Delft
,
Tika R.
Malla
,
Laura
Vangeel
,
Thomas
Vercruysse
,
Jan
Thibaut
,
Pieter
Leyssen
,
Tu-Trinh
Nguyen
,
Mitchell
Hull
,
Anthony
Tumber
,
David J.
Hallett
,
Christopher J.
Schofield
,
David I.
Stuart
,
Andrew L.
Hopkins
,
Martin A.
Walsh
Open Access
Abstract: Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.
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Jun 2021
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I18-Microfocus Spectroscopy
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Diamond Proposal Number(s):
[20533]
Open Access
Abstract: The high-energy release of plutonium (Pu) and uranium (U) during the Maralinga nuclear trials (1955–1963) in Australia, designed to simulate high temperature, non-critical nuclear accidents, resulted in wide dispersion µm-sized, radioactive, Pu–U-bearing ‘hot’ particles that persist in soils. By combining non-destructive, multi-technique synchrotron-based micro-characterization with the first nano-scale imagining of the composition and textures of six Maralinga particles, we find that all particles display intricate physical and chemical make-ups consistent with formation via condensation and cooling of polymetallic melts (immiscible Fe–Al–Pu–U; and Pb ± Pu–U) within the detonation plumes. Plutonium and U are present predominantly in micro- to nano-particulate forms, and most hot particles contain low valence Pu–U–C compounds; these chemically reactive phases are protected by their inclusion in metallic alloys. Plutonium reworking was observed within an oxidised rim in a Pb-rich particle; however overall Pu remained immobile in the studied particles, while small-scale oxidation and mobility of U is widespread. It is notoriously difficult to predict the long-term environmental behaviour of hot particles. Nano-scale characterization of the hot particles suggests that long-term, slow release of Pu from the hot particles may take place via a range of chemical and physical processes, likely contributing to on-going Pu uptake by wildlife at Maralinga.
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May 2021
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B21-High Throughput SAXS
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Ami
Miller
,
Adam
Leach
,
Jemima
Thomas
,
Craig
Mcandrew
,
Emma
Bentley
,
Giada
Mattiuzzo
,
Lijo
John
,
Ali
Mirazimi
,
Gemma
Harris
,
Nadisha
Gamage
,
Stephen
Carr
,
Hanif
Ali
,
Rob
Van Montfort
,
Terence
Rabbitts
Diamond Proposal Number(s):
[27159]
Open Access
Abstract: Approaches are needed for therapy of the severe acute respiratory syndrome from SARS-CoV-2 coronavirus (COVID-19). Interfering with the interaction of viral antigens with the angiotensin converting enzyme 2 (ACE-2) receptor is a promising strategy by blocking the infection of the coronaviruses into human cells. We have implemented a novel protein engineering technology to produce a super-potent tetravalent form of ACE2, coupled to the human immunoglobulin γ1 Fc region, using a self-assembling, tetramerization domain from p53 protein. This high molecular weight Quad protein (ACE2-Fc-TD) retains binding to the SARS-CoV-2 receptor binding spike protein and can form a complex with the spike protein plus anti-viral antibodies. The ACE2-Fc-TD acts as a powerful decoy protein that out-performs soluble monomeric and dimeric ACE2 proteins and blocks both SARS-CoV-2 pseudovirus and SARS-CoV-2 virus infection with greatly enhanced efficacy. The ACE2 tetrameric protein complex promise to be important for development as decoy therapeutic proteins against COVID-19. In contrast to monoclonal antibodies, ACE2 decoy is unlikely to be affected by mutations in SARS-CoV-2 that are beginning to appear in variant forms. In addition, ACE2 multimeric proteins will be available as therapeutic proteins should new coronaviruses appear in the future because these are likely to interact with ACE2 receptor.
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May 2021
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I07-Surface & interface diffraction
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Diamond Proposal Number(s):
[19763]
Open Access
Abstract: A novel neutron and X-ray reflectometry sample environment is presented for the study of surface-active molecules at solid–liquid interfaces under shear. Neutron reflectometry was successfully used to characterise the iron oxide–dodecane interface at a shear rate of 7.0×102
7.0
×
10
2
s−1
s
−
1
using a combination of conventional reflectometry theory coupled with the summation of reflected intensities to describe reflectivity from thicker films. Additionally, the structure adopted by glycerol monooleate (GMO), an Organic Friction Modifier, when adsorbed at the iron oxide–dodecane interface at a shear rate of 7.0×102
7.0
×
10
2
s−1
s
−
1
was studied. It was found that GMO forms a surface layer that appears unaltered by the effect of shear, where the thickness of the GMO layer was found to be 24.3+9.9−10.2
24.3
−
10.2
+
9.9
Å under direct shear at 7.0×102
7.0
×
10
2
s−1
s
−
1
and 25.8+4.4−5.2
25.8
−
5.2
+
4.4
Å when not directly under shear. Finally, a model to analyse X-ray reflectometry data collected with the sample environment is also described and applied to data collected at 3.0×103
3.0
×
10
3
s−1
s
−
1
.
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May 2021
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I13-2-Diamond Manchester Imaging
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Diamond Proposal Number(s):
[16144]
Open Access
Abstract: The number of the Asbestos Bodies (AB), i.e. asbestos that developed an iron-protein coating during its permanence in biological tissues, is one of the most accessible markers of asbestos exposure in individuals. The approaches developed to perform AB count in biological tissues are based on the manual examination of tissue digests or histological sections by means of light or electron microscopies. Although these approaches are well established and relatively accessible, manual examination is time-consuming and can be reader-dependent. Besides, approximations are applied because of the limitations of 2D readings and to speed up manual counts. In addition, sample preparation using tissue digests require an amount of tissue that can only be obtained by invasive surgery or post-mortem sampling. In this paper, we propose a new approach to AB counting based on non-destructive 3D imaging, which has the potential to overcome most of the limitations of conventional approaches. This method allows automating the AB count and determining their morphometry distribution in bulk tissue samples (ideally non-invasive needle biopsies), with minimal sample preparation and avoiding approximations. Although the results are promising, additional testing on a larger number of AB-containing biological samples would be required to fully validate the method.
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May 2021
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B21-High Throughput SAXS
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Lucia
Silvestrini
,
Norhan
Belhaj
,
Lucia
Comez
,
Yuri
Gerelli
,
Antonino
Lauria
,
Valeria
Libera
,
Paolo
Mariani
,
Paola
Marzullo
,
Maria Grazia
Ortore
,
Antonio
Palumbo Piccionello
,
Caterina
Petrillo
,
Lucrezia
Savini
,
Alessandro
Paciaroni
,
Francesco
Spinozzi
Diamond Proposal Number(s):
[27078]
Open Access
Abstract: The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.
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Apr 2021
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I18-Microfocus Spectroscopy
|
Diamond Proposal Number(s):
[17304]
Open Access
Abstract: Laser processing is a highly versatile technique for the post-synthesis treatment and modification of transition metal dichalcogenides (TMDCs). However, to date, TMDCs synthesis typically relies on large area CVD growth and lithographic post-processing for nanodevice fabrication, thus relying heavily on complex, capital intensive, vacuum-based processing environments and fabrication tools. This inflexibility necessarily restricts the development of facile, fast, very low-cost synthesis protocols. Here we show that direct, spatially selective synthesis of 2D-TMDCs devices that exhibit excellent electrical, Raman and photoluminescence properties can be realized using laser printing under ambient conditions with minimal lithographic or thermal overheads. Our simple, elegant process can be scaled via conventional laser printing approaches including spatial light modulation and digital light engines to enable mass production protocols such as roll-to-roll processing.
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Mar 2021
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