Structure-based analysis of CysZ-mediated cellular uptake of sulfate

Sulfur, most abundantly found in the environment as sulfate (SO42-), is an essential element in metabolites required by all living cells, including amino acids, co-factors and vitamins. However, current understanding of the cellular delivery of SO42- at the molecular level is limited. CysZ has been described as a SO42- permease, but its sequence family is without known structural precedent. Based on crystallographic structure information, SO42- binding and flux experiments, we provide insight into the molecular mechanism of CysZ-mediated translocation of SO42- across membranes. CysZ structures from three different bacterial species display a hitherto unknown fold and have subunits organized with inverted transmembrane topology. CysZ from Pseudomonas denitrificans assembles as a trimer of antiparallel dimers and the CysZ structures from two other species recapitulate dimers from this assembly. Mutational studies highlight the functional relevance of conserved CysZ residues

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

Comment on ‘‘\u3ci\u3eAn unconfined groundwater model of the Death Valley Regional Flow System and a comparison to its confined predecessor\u3c/i\u3e’’ by R.W.H. Carroll, G.M. Pohll and R.L. Hershey [\u3ci\u3eJournal of Hydrology\u3c/i\u3e 373/3–4, pp. 316–328]

Carroll et al. (2009) state that the United States Geological Survey (USGS) Death Valley Regional Flow System (DVRFS) model, which is based on MODFLOW, is ‘‘conceptually inaccurate in that it models an unconfined aquifer as a confined system and does not simulate unconfined drawdown in transient pumping simulations.’’ Carroll et al. (2009) claim that ‘‘more realistic estimates of water availability’’ can be produced by a SURFACT-based model of the DVRFS that simulates unconfined groundwater flow and limits withdrawals from wells to avoid excessive drawdown. Differences in results from the original MODFLOW- based model and the SURFACT-based model stem primarily from application by Carroll et al. (2009) of head limits that can also be applied using the existing MODLOW model and not from any substantial difference in the accuracy with which the unconfined aquifer is represented in the two models. In a hypothetical 50-year predictive simulation presented by Carroll et al. (2009), large differences between the models are shown when simulating pumping from the lower clastic confining unit, where the transmissivity is nearly two orders of magnitude less than in an alluvial aquifer. Yet even for this extreme example, drawdowns and pumping rates from the MODFLOW and SURFACT models are similar when the head-limit capabilities of the MODFLOW MNW Package are applied. These similarities persist despite possible discrepancies between assigned hydraulic properties. The resulting comparison between the MODFLOW and SURFACT models of the DVRFS suggests that approximating the unconfined system in the DVRFS as a constant-saturated-thickness system (called a ‘‘confined system’’ by Carroll et al., 2009) performs very well

Interbasin flow in the Great Basin with special reference to the southern Funeral Mountains and the source of Furnace Creek springs, Death Valley, California, U.S.

Interbasin flow in the Great Basin has been established by scientific studies during the past century. While not occurring uniformly between all basins, its occurrence is common and is a function of the hydraulic gradient between basins and hydraulic conductivity of the intervening rocks. The Furnace Creek springs in Death Valley, California are an example of large volume springs that are widely accepted as being the discharge points of regional interbasin flow. The flow path has been interpreted historically to be through consolidated Paleozoic carbonate rocks in the southern Funeral Mountains. This work reviews the preponderance of evidence supporting the concept of interbasin flow in the Death Valley region and the Great Basin and addresses the conceptual model of pluvial and recent recharge [Nelson, S.T., Anderson, K., Mayo, A.L., 2004. Testing the interbasin flow hypothesis at Death Valley, California. EOS 85, 349; Anderson, K., Nelson, S., Mayo, A., Tingey, D., 2006. Interbasin flow revisited: the contribution of local recharge to high-discharge springs, Death Valley, California. Journal of Hydrology 323, 276–302] as the source of the Furnace Creek springs. We find that there is insufficient modern recharge and insufficient storage potential and permeability within the basin-fill units in the Furnace Creek basin for these to serve as a local aquifer. Further, the lack of high sulfate content in the spring waters argues against significant flow through basin-fill sediments and instead suggests flow through underlying consolidated carbonate rocks. The maximum temperature of the spring discharge appears to require deep circulation through consolidated rocks; the Tertiary basin fill is of insufficient thickness to generate such temperatures as a result of local fluid circulation. Finally, the stable isotope data and chemical mass balance modeling actually support the interbasin flow conceptual model rather than the alternative presented in Nelson et al. [Nelson, S.T., Anderson, K., Mayo, A.L., 2004. Testing the interbasin flow hypothesis at Death Valley, California. EOS 85, 349] and Anderson et al. [Anderson, K., Nelson, S., Mayo, A., Tingey, D., 2006. Interbasin flow revisited: the contribution of local recharge to high-discharge springs, Death Valley, California. Journal of Hydrology 323, 276–302]. In light of these inconsistencies, interbasin flow is the only readily apparent explanation for the large spring discharges at Furnace Creek and, in our view, is the likely explanation for most large volume, low elevation springs in the Great Basin. An understanding of hydrogeologic processes that control the rate and direction of ground-water flow in eastern and central Nevada is necessary component of regional water-resource planning and management of alluvial and bedrock aquifers