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Structure–property relationships in disodium anthracene dicarboxylate for sodium-ion storage via 3D electron diffraction
Get PDFFunding: A. V. D., R. E. M. and A. R. A. thank the Faraday Institution for funding (grants – FIRG018, FIRG064). The authors also acknowledge the support from EPSRC for the Light Element Facility Grant (EP/T019298/1), Strategic Equipment Resource Grant (EP/R023751/1), and EPSRC Core Equipment Grant (EP/V034138/1). H. S. S. thanks the Allan Handsel Postgraduate Research Scholarship for Chemistry for funding. D. N. R. and S. J. C. thank the EPSRC (EP/X014444/1) for funding.Organic materials are increasingly commanding attention as a sustainable choice for charge storage in rechargeable batteries. To fully realise their promise, significantly more understanding is needed in terms of structure–property correlations. Here we report a highly conjugated molecule, disodium anthracene-9,10-carboxylate (Na2ADC), synthesised using rapid microwave-assisted heating and evaluated as an anode material in sodium-ion batteries. Detailed material characterisation is reported, including the crystal structure determined from three-dimensional electron diffraction (3D ED) studies, demonstrating the suitability and advantage of this method for the structural characterisation of organic electrode materials. This study highlights the role of molecular design and structural properties in facilitating the delivery of high-performing organic electrode materials.Peer reviewe
Rethinking the history of microbiology : new actors, geographies, places of knowledge, and ecologies
Get PDFFunding: Wellcome Trust (217988/Z/19/Z); Domaine d’Intérêt Majeur Matériaux Anciens et Patrimoniaux.In this introduction, we first paint a panorama of the historiography of microbiology from the end of the nineteenth century until today, spanning from Pasteurian hagiographies, institutional histories, STS-informed analyses to critical research on the emergence of microbiology in an age of global empires. We then suggest three possibilities for historians and anthropologists to rethink the past and present of microbiology: 1) by centralizing the focus of their analyses on geographies and actors outside of the realm of the Pasteur Institute and of the Pasteurians; 2) by studying places of knowledge beyond the laboratory and their interactions with the laboratory; and 3) by researching the past and present of complex ecologies that go beyond sole interactions between humans and pathogenic microbes. These three ways of recentralizing the history of microbiology are not unprecedented nor were they firstly enacted in this collection. On the contrary, this collection builds on a growing stream of innovative research and widens current avenues of research, helping thus to rethink the history of microbiology in a more global and inclusive way.Peer reviewe
Investigating the possible contribution of helicity condensation to the ambient increase in solar open flux
Get PDFFunding: J.J.K. acknowledges financial support by the UK's Science and Technology Facilities Council (STFC) Doctoral Training Partnership Grant via ST/W507829/1. D.H.M. is supported by the STFC via ST/W001195/1.The Sun's Open Flux plays a vital role in heliospheric physics and for the origin of the solar wind. A key problem faced by global magnetic field models of the solar corona is that they consistently underestimate the amount of Open Flux compared to in situ measurements. The purpose of the present paper is to consider if statistically averaged helicity condensation (SAHC) can reduce this discrepancy by increasing the simulated Open Flux found in potential field source surface (PFSS) models. We consider each Carrington rotation from 1646–2149 (1976 September to 2014 April). For each rotation, we hold the photosphere fixed, construct a PFSS model, and inject nonpotentiality into the coronal field by applying SAHC at different angular rotation rates, ω. When ω exceeds 2.5 × 10−6 s−1, both ambient and sporadic enhancements of Open Flux are found within the Carrington rotation timescale. As ω increases, the amount of ambient Open Flux increases, along with the frequency of sporadic events. These enhancements are accompanied by increased footpoint area of open field lines, where the open field locations at each pole expand by up to 3°–6° of latitude. A solar cycle dependence is found with higher increases in ambient Open Flux at solar maximum compared to solar minimum. Comparing our results with 27 day averaged OMNI spacecraft measurements, our highest value of ω = 10 × 10−6 s−1 can resolve just under 50% of the discrepancy between in situ Open Flux measurements and PFSS models. Although helicity condensation cannot fully resolve the discrepancy, it can significantly contribute toward reducing it.Peer reviewe
High-throughput screening of potent drug-like molecules targeting 17β-HSD10 for the treatment of Alzheimer's disease and cancer
Get PDFFunding: This research was funded by the European Lead Factory. This research was also kindly supported by MRC-IAA, The Rosetrees Trust, The Alzheimer’s Society, and the RS MacDonald Charitable Trust.In this study, the first industrial-scale high-throughput screening of nearly 350,000 drug-like molecules targeting the enzyme 17β-HSD10, a promising therapeutic target for Alzheimer’s disease and cancers, is presented. Two novel series of potent 17β-HSD10 inhibitors that demonstrate low nanomolar potency against both the enzyme and in vivo cellular assays with minimal cytotoxicity were identified. These inhibitors were characterized further through a series of assays demonstrating ligand–protein interactions and co-crystallography, revealing un-/non-competitive inhibition with respect to the cofactor NADH, unlike previously published inhibitors. This work significantly advances the development of 17β-HSD10-targeting therapeutics, offering new potential leads for treating Alzheimer’s disease and cancers.Peer reviewe
Sequential normalization : embracing smaller sample sizes for normalization
Get PDFFunding information: Authors gratefully acknowledge the support of NVIDIA Corporation with the donation of the Quadro P6000 GPU used for this research. We are also grateful for the support from iCAIRD which is funded by Innovate UK on behalf of UK Research and Innovation (UKRI) (project number: 104690).Normalization as a layer within neural networks has over the years demonstrated its effectiveness in neural network optimization across a wide range of different tasks, with one of the most successful approaches being that of batch normalization. The consensus is that better estimates of the BatchNorm normalization statistics (μ and σ2) in each mini-batch result in better optimization. In this work, we challenge this belief and experiment with a new variant of BatchNorm known as GhostNorm that, despite independently normalizing batches within the mini-batches, i.e., μ and σ2 are independently computed and applied to groups of samples in each mini-batch, outperforms BatchNorm consistently. Next, we introduce sequential normalization (SeqNorm), the sequential application of the above type of normalization across two dimensions of the input, and find that models trained with SeqNorm consistently outperform models trained with BatchNorm or GhostNorm on multiple image classification data sets. Our contributions are as follows: (i) we uncover a source of regularization that is unique to GhostNorm, and not simply an extension from BatchNorm, and illustrate its effects on the loss landscape, (ii) we introduce sequential normalization (SeqNorm) a new normalization layer that improves the regularization effects of GhostNorm, (iii) we compare both GhostNorm and SeqNorm against BatchNorm alone as well as with other regularization techniques, (iv) for both GhostNorm and SeqNorm models, we train models whose performance is consistently better than our baselines, including ones with BatchNorm, on the standard image classification data sets of CIFAR–10, CIFAR-100, and ImageNet ((+0.2%, +0.7%, +0.4%), and (+0.3%, +1.7%, +1.1%) for GhostNorm and SeqNorm, respectively).Peer reviewe
Evaluating Diuretics in Normal Care (EVIDENCE) : a feasibility report of a pilot cluster randomised trial of prescribing policy in primary care to compare the effectiveness of thiazide-type diuretics in hypertension
Get PDFFunding: The pilot study referred to in this article is funded by a Catalyst Grant from CSO (Chief Scientist Office) Scotland.Background Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here, we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence. In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK. Methods Patients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating general practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalisation and death data in the NHS will be used to compare cardiovascular event rates between the two policies. Results This pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients) and 15 to bendroflumethiazide (3437 patients), a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch. Conclusion The pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study; currently, 102 GP practices (> 12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas.Peer reviewe
Anomalous δ15N values in the Neoarchean associated with an abundant supply of hydrothermal ammonium
Get PDFFunding: Funding for A.N.M. and S.W. (WE 2850/17-1), and M.M.G. (GE 2558/4-1) was provided by the German Research Foundation (DFG) priority programme SPP-1833 Building a Habitable Earth. A.N.M. was supported by additional funding from the DFG priority programme SPP-2238 Dynamics of Ore Metals Enrichment (MA 9571-3-1). E.E.S. acknowledges support from a UK Natural Environment Research Council (NERC) Frontiers grant (NE/V010824/1) and a Leverhulme Trust grant (RPG-2022-313). M.M. acknowledges funding from a Royal Society Award (URF\R1\231546). A.H. acknowledges logistical support from the Department of Geology, University of Zimbabwe.Unusually high δ15N values in the Neoarchean sedimentary record in the time period from 2.8 to 2.6 Ga, termed the Nitrogen Isotope Event (NIE), might be explained by aerobic N cycling prior to the Great Oxidation Event (GOE). Here we report strongly positive δ15N values up to +42.5 ‰ in ~2.75 – 2.73 Ga shallow-marine carbonates from Zimbabwe. As the corresponding deeper-marine shales exhibit negative δ15N values that are explained by partial biological uptake from a large ammonium reservoir, we interpret our data to have resulted from hydrothermal upwelling of 15N-rich ammonium into shallow, partially oxic waters, consistent with uranium isotope variations. This work shows that anomalous N isotope signatures at the onset of the NIE temporally correlate with extensive volcanic and hydrothermal activity both locally and globally, which may have stimulated primary production and spurred biological innovation in the lead-up to the GOE.Peer reviewe
Cloud formation in exoplanet atmospheres : nucleation of small molecular clusters
Get PDFIt has been inferred that many exoplanets host clouds in their atmospheres. Understanding the processes through which these clouds form, and being able to model them is essential for our understanding of their climate and to explain our observations. The first step of cloud formation in gaseous exoplanet atmospheres is the formation of cloud condensation nuclei (CCN). These CCN form from the gas phase through a process called nucleation. This work aims to investigate the nucleation process, analysing it through the nucleation species TiO₂ and its small molecular clusters. We present a method to find energetically favourable isomers for small (TiO₂)N nano clusters of size N “ 3´15. These isomers are analysed using high-level quantum chemical density functional theory (DFT) methods, to calculate their thermochemical properties. Two different nucleation descriptions are used to calculate the nucleation rate in an example exoplanet atmosphere. We find that using the updated, accurate cluster data changes the physical regime where nucleation is viable, possibly changing the lower boundaries of cloud formation in these atmospheres. We also analyse the harmonic vibrational spectra of the TiO₂ clusters. I find visible differences in the spectra for clusters of different sizes and for different isomers of clusters of the same size. I compute their total absorbance in two example hot Jupiter atmospheres and find significant differences in the abundances of different cluster sizes between morning and evening terminators of the same planet, between different types of planets and between different heights in the atmosphere. At some location the most abundant cluster is not the largest one in the dataset, hinting at possible limits to nucleation at those locations
Fermi surface origin of the low-temperature magnetoresistance anomaly
Get PDFFunding: Y.F. acknowledges support from the Okinawa Institute of Science and Technology Graduate University with subsidy funding from the Cabinet Office, Government of Japan. Y.W. acknowledges startup support from the University of Tennessee, Knoxville. T.F.R. acknowledges support from US Department of Energy Basic Energy Science award no. DE-SC0014866. P.B.L. is funded by the Gordon and Betty Moore Foundation (grant GBMF12763). H.C. acknowledges support from US NSF CAREER grant DMR-1945023.Magnetoresistance (MR) at a fixed field can demonstrate a non-monotonic temperature dependence—an anomaly—in many systems, including low-dimensional chalcogenides, spin- and charge-density-wave metals, and topological semimetals. These systems are often low-carrier-density compensated metals, and the physics are expected to be quasi-classical. Nevertheless, the MR anomaly also exists in the highly conductive metals Cr, Mo, and W for both linear and quadratic field dependence, with their non-saturation attributed to either open orbit or electron-hole compensation. We argue that quantum transport across sharp Fermi surface arcs, but not necessarily the full cyclotron orbit, governs this MR anomaly, thereby accounting for the profound effects of disorder. In Cr, an overlay exists between three temperature dependences: MR at a constant high field, linear MR at a low field, and Shubnikov-de Haas (SdH) oscillations of the smallest orbit. In Mo, the MR anomaly extends beyond the temperature of its SdH oscillations but disappears before Kohler’s scaling reemerges.Peer reviewe
Quantifying extracellular solute clearance from the murine hippocampus
No full textThe clearance of solutes from the brain plays a crucial role in maintaining its homeostasis. An imbalance between the production and elimination of toxic protein aggregates has been linked to several neurodegenerative pathologies, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), among others. Numerous studies have sought to characterize the mechanisms underlying the efflux of solutes and waste products from the brain to the cerebrospinal fluid (CSF), yet these efforts have yielded contrasting results. This has generated criticisms that undermine the validity of proposed models such as the glymphatic, intramural periarterial drainage (IPAD), and mixing models. In this thesis, I have applied a combination of advanced microscopy techniques, various fluorescent probes and in vivo surgical procedures on mice to create a platform aimed at clarifying these controversies. I used this platform to quantitatively analyse how factors—including solute size and structure, animal age, and extracellular space (ECS) complexity—influence the efficiency of solutes elimination from the brain to the CSF and dura mater. My results revealed strong size- and structure-dependent effects on the drainage of both fluorescent nanoparticles and fluorescent Aβ1-42 aggregates. Additionally, older animals showed a drastic decrease in their ability to eliminate solutes from the brain into the CSF compared to younger mice. I used fluorescent probes to create a detailed map of solute movement within the brain, which allowed me to clarify and confirm the differential roles of the periarterial spaces as entry routes and the perivenous spaces as exit routes for solutes in the glymphatic system. Finally, I have refined my study of solute clearance by characterizing the elimination of chronically produced toxic proteins in the 5xFAD animal model for AD, thereby establishing this model as a valuable platform for solute clearance studies. This work expands knowledge of the mechanisms behind solute clearance enabling for the first time a quantitative approach."This work was supported by Alzheimer’s Society [#AS-PhD-19a-016] and the ERC [#804581]."--Fundin
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