Neuronal nicotinic receptors: the role of β3 and α5 subunits

Using a reporter mutation approach and the two-electrode voltage clamp technique, Groot-Komielink et al (1998) have shown that the 'orphan' α3 subunit can be incorporated into a functional 'triplet' α3β4α3 neuronal nicotinic acetylcholine receptor, when expressed in Xenopus oocytes. Based on the observation that in α3β4 receptors the EC50 value decreases with the number of 9'T mutations, we used the same reporter mutation approach to determine the stoichiometry of 'triplet' receptors. When either α3 or β4 carried the 9'T mutation in 'triplet' α3β4α3 or α3β4α5 receptors, the observed decreases in EC50 values were similar and larger than if only α3 or α5 were mutated. This suggests α3 and β4 are present in equal copy number, greater than that of α3 or α5, namely; 2 copies of β, 2 copies of β and 1 copy of α3 or α5. Potency ratio data for α3β4 and α3β4α3 receptors demonstrated that the incorporation of α3 reduced the potency of lobeline (relative to ACh) from 23.0 to 7.14 (p 0.01). However, the rank order of the seven nicotinic agonists tested was unchanged. Schild analysis showed that the Kd for the competitive antagonist trimetaphan was not affected by α3 incorporation (75.5 and 66.0 nM for α3β4 and α3β4α3, respectively), suggesting that α3 may not contribute to the properties of the agonist binding site. Calcium permeability data failed to detect differences in calcium permeability for α3β4 and α3β4α3 receptors, with mean shifts in reversal potential of 7.68 mV for α3β4 and 5.20 mV for α3β4α3 (for a 10 times increase in external calcium concentration)

Temperature Dependence of the Extrinsic Incubation Period of Orbiviruses in Culicoides Biting Midges

The rate at which viruses replicate and disseminate in competent arthropod vectors is limited by the temperature of their environment, and this can be an important determinant of geographical and seasonal limits to their transmission by arthropods in temperate regions.Here, we present a novel statistical methodology for estimating the relationship between temperature and the extrinsic incubation period (EIP) and apply it to both published and novel data on virus replication for three internationally important orbiviruses (African horse sickness virus (AHSV), bluetongue virus (BTV) and epizootic haemorrhagic disease virus (EHDV)) in their Culicoides vectors. Our analyses show that there can be differences in vector competence for different orbiviruses in the same vector species and for the same orbivirus in different vector species. Both the rate of virus replication (approximately 0.017-0.021 per degree-day) and the minimum temperature required for replication (11-13°C), however, were generally consistent for different orbiviruses and across different Culicoides vector species. The estimates obtained in the present study suggest that previous publications have underestimated the replication rate and threshold temperature because the statistical methods they used included an implicit assumption that all negative vectors were infected.Robust estimates of the temperature dependence of arbovirus replication are essential for building accurate models of transmission and for informing policy decisions about seasonal relaxations to movement restrictions. The methodology developed in this study provides the required robustness and is superior to methods used previously. Importantly, the methods are generic and can readily be applied to other arbovirus-vector systems, as long as the assumptions described in the text are valid

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Daily and sub-daily hydrometeorological and soil data (2013-2017) [COSMOS-UK]

This dataset contains daily and sub-daily hydrometeorological and soil observations from COSMOS-UK (cosmic-ray soil moisture) monitoring network from October 2013 to the end of 2017. These data are from 46 sites across the UK recording a range of hydrometeorological and soil variables. Each site in the network hosts a cosmic-ray sensing probe; a novel sensor technology which can be used, in combination with hydrometeorological data, to calculate the volumetric water content of soil over a field scale. The hydrometeorological and soil data are recorded at a 30 minute resolution and they include neutron counts from the Cosmic-ray sensing probe, humidity and atmospheric pressure data that are used to derive volumetric water content at two temporal resolutions (hourly and daily). Also included are soil heat flux, air temperature, wind speed and radiation data which are used to derive potential evapotranspiration at a daily resolution

Daily and sub-daily hydrometeorological and soil data (2013-2019) [COSMOS-UK]

This dataset contains daily and sub-daily hydrometeorological and soil observations from COSMOS-UK (cosmic-ray soil moisture) monitoring network from October 2013 to the end of 2019. These data are from 51 sites across the UK recording a range of hydrometeorological and soil variables

Daily and sub-daily hydrometeorological and soil data (2013-2018) [COSMOS-UK]

This dataset contains daily and sub-daily hydrometeorological and soil observations from COSMOS-UK (cosmic-ray soil moisture) monitoring network from October 2013 to the end of 2018. These data are from 50 sites across the UK recording a range of hydrometeorological and soil variables. Each site in the network records the following hydrometeorological and soil data at 30 minute resolution: Radiation (short wave, long wave and net), precipitation, atmospheric pressure, air temperature, wind speed and direction, humidity, soil heat flux, and soil temperature and volumetric water content (VWC), measured by point senors at various depths. Each site hosts a cosmic-ray sensing probe; a novel sensor technology which counts fast neutrons in the surrounding atmosphere. In combination with the recorded hydrometeorological data, neutron counts are used to derive VWC over a field scale (COSMOS VWC), at two temporal resolutions (hourly and daily). The presence of snow leads to erroneously high measurements of COSMOS VWC due to all the extra water in the surrounding area. Included in the daily data are indications of snow days, on which, the COSMOS VWC are adjusted and the snow water equivalent (SWE) is given. The potential evapotranspiration (PE), derived from recorded hydrometeorological and soil are also included at daily resolution. Two levels of quality control are carried out, firstly data is run through a series of automated checks, such as range tests and spike tests, and then all data is manually inspected each week where any other faults are picked up, including sensor faults or connection issues. Quality control flags are provided for all recorded (30 minute) data, indicating the reason for any missing data

COSMOS-UK: national soil moisture and hydrometeorology data for environmental science research

The COSMOS-UK observation network has been providing field-scale soil moisture and hydrometeorological measurements across the UK since 2013. At the time of publication a total of 51 COSMOS-UK sites have been established, each delivering high-temporal resolution data in near-real time. Each site utilizes a cosmic-ray neutron sensor, which counts epithermal neutrons at the land surface. These measurements are used to derive field-scale near-surface soil water content, which can provide unique insight for science, industry, and agriculture by filling a scale gap between localized point soil moisture and large-scale satellite soil moisture datasets. Additional soil physics and meteorological measurements are made by the COSMOS-UK network including precipitation, air temperature, relative humidity, barometric pressure, soil heat flux, wind speed and direction, and components of incoming and outgoing radiation. These near-real-time observational data can be used to improve the performance of hydrological models, validate remote sensing products, improve hydro-meteorological forecasting, and underpin applications across a range of other scientific fields. The most recent version of the COSMOS-UK dataset is publically available at https://doi.org/10.5285/b5c190e4-e35d-40ea-8fbe-598da03a1185 (Stanley et al., 2021)