The type III secretion system (T3SS) is a large, transmembrane protein machinery used by various pathogenic gram‐negative bacteria to transport virulence factors into the host cell during infection. ...Understanding the structure of T3SSs is crucial for future developments of therapeutics that could target this system. However, much of the knowledge about the structure of T3SS is available only for Salmonella, and it is unclear how this large assembly is conserved across species. Here, we combined cryo‐electron microscopy, cross‐linking mass spectrometry, and integrative modeling to determine the structure of the T3SS needle complex from Shigella flexneri. We show that the Shigella T3SS exhibits unique features distinguishing it from other structurally characterized T3SSs. The secretin pore complex adopts a new fold of its C‐terminal S domain and the pilotin MxiMSctG locates around the outer surface of the pore. The export apparatus structure exhibits a conserved pseudohelical arrangement but includes the N‐terminal domain of the SpaSSctU subunit, which was not present in any of the previously published virulence‐related T3SS structures. Similar to other T3SSs, however, the apparatus is anchored within the needle complex by a network of flexible linkers that either adjust conformation to connect to equivalent patches on the secretin oligomer or bind distinct surface patches at the same height of the export apparatus. The conserved and unique features delineated by our analysis highlight the necessity to analyze T3SS in a species‐specific manner, in order to fully understand the underlying molecular mechanisms of these systems. The structure of the type III secretion system from Shigella flexneri delineates conserved and unique features, which could be used for the development of broad‐range therapeutics.
PDB Code(s): 8AXK, 8AXN and 8AXL;
Two computable general equilibrium models, one global and the other providing U.S. regional detail, are applied to analysis of the future of U.S. natural gas. The focus is on uncertainties including ...the scale and cost of gas resources, the costs of competing technologies, the pattern of greenhouse gas mitigation, and the evolution of global natural gas markets. Results show that the outlook for gas over the next several decades is very favorable. In electric generation, given the unproven and relatively high cost of other low-carbon generation alternatives, gas is likely the preferred alternative to coal. A broad GHG pricing policy would increase gas use in generation but reduce use in other sectors, on balance increasing its role from present levels. The shale gas resource is a major contributor to this optimistic view of the future of gas. Gas can be an effective bridge to a lower emissions future, but investment in the development of still lower CO2 technologies remains an important priority. International gas resources may well prove to be less costly than those in the U.S., except for the lowest-cost domestic shale resources, and the emergence of an integrated global gas market could result in significant U.S. gas imports.
► The shale gas resource is a major contributor to an optimistic view of the future of natural gas. ► A broad carbon policy would increase natural gas use in power generation. ► Natural gas can be an effective bridge to a lower emissions future. ► In the next decade there is a potential for small U.S. gas exports. ► An integrated global gas market could result in significant U.S. gas imports by 2030–2050.
Tixagevimab-cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab-cilgavimab versus ...placebo, in patients receiving remdesivir and other standard care.
In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg-cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab-cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing.
From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab-cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab-cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio RRR 1·08 95% CI 0·97-1·20; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 0·97-1·34; p=0·13). Mortality was lower in the tixagevimab-cilgavimab group (61 9%) versus placebo group (86 12%; hazard ratio HR 0·70 95% CI 0·50-0·97; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab-cilgavimab and 212 (30%) placebo group participants (HR 0·83 0·68-1·01; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab-cilgavimab group and 38 (5%) in the placebo group.
Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab-cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.
US National Institutes of Health (NIH) and Operation Warp Speed.
To evaluate the prevalence and correlates of human immunodeficiency virus (HIV)-infected cells in urethral secretions, samples were collected from 106 HIV-seropositive men with and without ...urethritis. HIV DNA was detected by polymerase chain reaction in 27% of 184 urethral specimens and was associated with CD4 cell depletion (P for trend, .03) and with urethritis (odds ratio OR, 2.4; 95% confidence interval CI, 1.2–4.6) or gonorrhea (OR, 2.9; 95% CI, 1.5–5.8). Two multivariate models were constructed that included age, CD4 cell count <200/mm3, and either urethritis or gonococcal infection. Detection of HIV-infected cells in urethral secretions was independently associated with <200 CD4 cells/mm3 (OR, 2.2; 95% CI, 0.9–5.2; P = .05) and urethritis (OR, 2.7; 95% CI, 1.3–5.3; P = .003) in the first model and with gonococcal infection (OR, 3.2; 95% CI, 1.6–6.4; P < .001) in the second model. Successful treatment of gonococcal urethritis was associated with a 2-fold reduction in urethral HIV DNA (44% vs. 21%; P = .02). Thus, treatment of gonococcal urethritis may be an effective strategy for reducing HIV transmission.
To identify risk factors involved in heterosexual transmission of human immunodeficiency virus (HIV), a cross-sectional study of HIV-seropositive men and their spouses was conducted in Nairobi, ...Kenya. Of 70 spouses, 40 (57%) were seropositive and 30 (43%) were seronegative for HIV. In univariate analysis, the presence of cervical ectopy (odds ratio, 4.7; P = .006) was the only statistically significant variable associated with HIV infection in women. After controlling for possible confounding variables using multivariate logistic regression analysis, the presence of cervical ectopy (odds ratio, 5.0; P = .007) remained the only independent predictor of HIV seropositivity. These findings suggest that cervical ectopy may be a newly identified risk factor for heterosexual transmission of HIV.
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