Use of interplay between A-site non-stoichiometry and hydroxide doping to deliver novel proton-conducting perovskite oxides

Funding: UK Engineering and Physical Sciences Research Council (Grant Number(s): EP/R023522, EP/R023751, EP/L017008, EP/P007821, EP/L000202, EP/R029431); Diamond Light Source (Grant Number(s): SP17198-8); Rutherford Appleton Laboratory (Grant Number(s): RB1920629).The magnitude of ionic conductivity is known to depend upon both mobility and number of available carriers. For proton conductors, hydration is a key factor in determining the charge–carrier concentration in ABO3 perovskite oxides. Despite the high reported proton mobility of calcium titanate (CaTiO3), this titanate perovskite has thus far been regarded as a poor proton conductor due to the low hydration capability. Here, the enhanced proton conductivity of the defective calcium titanate Ca0.92TiO2.84(OH)0.16 prepared by replacing lattice oxygens with hydroxyl groups via a solvothermal route is shown. Conductivity measurements in a humidified Ar atmosphere reveal that, remarkably, this material exhibits one order of magnitude higher bulk conductivity (10−4 Scm−1 at 200 °C) than hydrated stoichiometric CaTiO3 prepared by traditional solid-state synthesis due to the higher concentration of protonic defects and variation in the crystal structure. The replacement of Ca2+ by Ni2+ in the Ca1−xTi1O3−2x(OH)2x, which mostly exsolve metallic Ni nanoparticles along orthorhombic (100) planes upon reduction, is also demonstrated. These results suggest a new strategy by tailoring the defect chemistry via hydration or cation doping followed by exsolution for targeted energy applications.Publisher PDFPeer reviewe

Adaptive Manufacturing for Healthcare During the COVID-19 Emergency and Beyond

During the COVID-19 pandemic, global health services have faced unprecedented demands. Many key workers in health and social care have experienced crippling shortages of personal protective equipment, and clinical engineers in hospitals have been severely stretched due to insufficient supplies of medical devices and equipment. Many engineers who normally work in other sectors have been redeployed to address the crisis, and they have rapidly improvised solutions to some of the challenges that emerged, using a combination of low-tech and cutting-edge methods. Much publicity has been given to efforts to design new ventilator systems and the production of 3D-printed face shields, but many other devices and systems have been developed or explored. This paper presents a description of efforts to reverse engineer or redesign critical parts, specifically a manifold for an anaesthesia station, a leak port, plasticware for COVID-19 testing, and a syringe pump lock box. The insights obtained from these projects were used to develop a product lifecycle management system based on Aras Innovator, which could with further work be deployed to facilitate future rapid response manufacturing of bespoke hardware for healthcare. The lessons learned could inform plans to exploit distributed manufacturing to secure back-up supply chains for future emergency situations. If applied generally, the concept of distributed manufacturing could give rise to “21st century cottage industries” or “nanofactories,” where high-tech goods are produced locally in small batches

Measurement of Myofilament-Localised Calcium Dynamics in Adult Cardiomyocytes and the Effect of Hypertrophic Cardiomyopathy Mutations

Rationale: Subcellular Ca2+ indicators have yet to be developed for the myofilament where disease mutation, or small molecules may alter contractility through myofilament Ca2+ sensitivity. Here we develop and characterise genetically encoded Ca2+ indicators restricted to the myofilament to directly visualise Ca2 changes in the sarcomere. Objective: To produce and validate myofilament restricted Ca2+ imaging probes in an adenoviral transduction adult cardiomyocyte model using drugs that alter myofilament function (MYK-461, omecamtiv mecarbil and levosimendan) or following co-transduction of two established hypertrophic cardiomyopathy (HCM) disease causing mutants (cTnT R92Q and cTnI R145G) that alter myofilament Ca2+ handling. Methods and Results: When expressed in adult ventricular cardiomyocytes RGECO-TnT/TnI sensors localise correctly to the sarcomere without contractile impairment. Both sensors report cyclical changes in fluorescence in paced cardiomyocytes with reduced Ca2+ on and increased Ca2+ off rates compared with unconjugated RGECO. RGECO-TnT/TnI revealed changes to localised Ca2+ handling conferred by MYK-461 and levosimendan, including an increase in Ca2+ binding rates with both levosimendan and MYK-461 not detected by an unrestricted protein sensor. Co-adenoviral transduction of RGECO-TnT/TnI with HCM causing thin filament mutants showed that the mutations increase myofilament [Ca2+] in systole, lengthen time to peak systolic [Ca2+], and delay [Ca2+] release. This contrasts with the effect of the same mutations on cytoplasmic Ca2+, when measured using unrestricted RGECO where changes to peak systolic Ca2+ are inconsistent between the two mutations. These data contrast with previous findings using chemical dyes that show no alteration of [Ca2+] transient amplitude or time to peak Ca2+. Conclusions: RGECO-TnT/TnI are functionally equivalent. They visualise Ca2+ within the myofilament and reveal unrecognised aspects of small molecule and disease associated mutations in living cells

Melatonin reduces TNF-a induced expression of MAdCAM-1 via inhibition of NF-kB.

BACKGROUND: Endothelial MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression is associated with the oxidant-dependent induction and progress of inflammatory bowel disease (IBD). Melatonin, a relatively safe, potent antioxidant, has shown efficacy in several chronic injury models may limit MAdCAM-1 expression and therefore have a therapeutic use in IBD. METHODS: We examined how different doses of melatonin reduced endothelial MAdCAM-1 induced by TNF-a in an in vitro model of lymphatic endothelium. Endothelial monolayers were pretreated with melatonin prior to, and during an exposure, to TNF-a (1 ng/ml, 24 h), and MAdCAM-1 expression measured by immunoblotting. RESULTS: MAdCAM-1 was induced by TNF-a. Melatonin at concentrations over 100 μm (10(-4) M) significantly attenuated MAdCAM-1 expression and was maximal at 1 mM. CONCLUSIONS: Our data indicate that melatonin may exert therapeutic activity in IBD through its ability to inhibit NF-kB dependent induction of MAdCAM-1

A molecular and antigenic survey of H5N1 highly pathogenic avian influenza virus isolates from smallholder duck farms in Central Java, Indonesia during 2007-2008

Background: Indonesia is one of the countries most severely affected by H5N1 highly pathogenic avian influenza (HPAI) virus in terms of poultry and human health. However, there is little information on the diversity of H5N1 viruses circulating in backyard farms, where chickens and ducks often intermingle. In this study, H5N1 virus infection occurring in 96 smallholder duck farms in central Java, Indonesia from 2007-2008 was investigated and the molecular and antigenic characteristics of H5N1 viruses isolated from these farms were analysed

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

TOI-3984 A b and TOI-5293 A b: two temperate gas giants transiting mid-M dwarfs in wide binary systems

We confirm the planetary nature of two gas giants discovered by TESS to transit M dwarfs with stellar companions at wide separations. TOI-3984 A ($J=11.93$) is an M4 dwarf hosting a short-period ($4.353326 \pm 0.000005$ days) gas giant ($M_p=0.14\pm0.03~\mathrm{M_{J}}$ and $R_p=0.71\pm0.02~\mathrm{R_{J}}$) with a wide separation white dwarf companion. TOI-5293 A ($J=12.47$) is an M3 dwarf hosting a short-period ($2.930289 \pm 0.000004$ days) gas giant ($M_p=0.54\pm0.07~\mathrm{M_{J}}$ and $R_p=1.06\pm0.04~\mathrm{R_{J}}$) with a wide separation M dwarf companion. We characterize both systems using a combination of ground-based and space-based photometry, speckle imaging, and high-precision radial velocities from the Habitable-zone Planet Finder and NEID spectrographs. TOI-3984 A b ($T_{eq}=563\pm15$ K and $\mathrm{TSM}=138_{-27}^{+29}$) and TOI-5293 A b ($T_{eq}=675_{-30}^{+42}$ K and $\mathrm{TSM}=92\pm14$) are two of the coolest gas giants among the population of hot Jupiter-sized gas planets orbiting M dwarfs and are favorable targets for atmospheric characterization of temperate gas giants and three-dimensional obliquity measurements to probe system architecture and migration scenarios.Comment: Submitted to AJ, 42 pages, 14 figures. arXiv admin note: substantial text overlap with arXiv:2201.0996

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Facilitated Monocyte-Macrophage Uptake and Tissue Distribution of Superparmagnetic Iron-Oxide Nanoparticles

BACKGROUND: We posit that the same mononuclear phagocytes (MP) that serve as target cells and vehicles for a host of microbial infections can be used to improve diagnostics and drug delivery. We also theorize that physical and biological processes such as particle shape, size, coating and opsonization that affect MP clearance of debris and microbes can be harnessed to facilitate uptake of nanoparticles (NP) and tissue delivery. METHODS: Monocytes and monocyte-derived macrophages (MDM) were used as vehicles of superparamagnetic iron oxide (SPIO) NP and immunoglobulin (IgG) or albumin coated SPIO for studies of uptake and distribution. IgG coated SPIO was synthesized by covalent linkage and uptake into monocytes and MDM investigated related to size, time, temperature, concentration, and coatings. SPIO and IgG SPIO were infused intravenously into naïve mice. T(2) measures using magnetic resonance imaging (MRI) were used to monitor tissue distribution in animals. RESULTS: Oxidation of dextran on the SPIO surface generated reactive aldehyde groups and permitted covalent linkage to amino groups of murine and human IgG and F(ab')(2) fragments and for Alexa Fluor(R) 488 hydroxylamine to form a Schiff base. This labile intermediate was immediately reduced with sodium cyanoborohydride in order to stabilize the NP conjugate. Optical density measurements of the oxidized IgG, F(ab')(2), and/or Alexa Fluor(R) 488 SPIO demonstrated approximately 50% coupling yield. IgG-SPIO was found stable at 4 degrees C for a period of 1 month during which size and polydispersity index varied little from 175 nm and 200 nm, respectively. In vitro, NP accumulated readily within monocyte and MDM cytoplasm after IgG-SPIO exposure; whereas, the uptake of native SPIO in monocytes and MDM was 10-fold less. No changes in cell viability were noted for the SPIO-containing monocytes and MDM. Cell morphology was not changed as observed by transmission electron microscopy. Compared to unconjugated SPIO, intravenous injection of IgG-SPIO afforded enhanced and sustained lymphoid tissue distribution over 24 hours as demonstrated by MRI. CONCLUSIONS: Facilitated uptake of coated SPIO in monocytes and MDM was achieved. Uptake was linked to particle size and was time and concentration dependent. The ability of SPIO to be rapidly taken up and distributed into lymphoid tissues also demonstrates feasibility of macrophage-targeted nanoformulations for diagnostic and drug therapy