Low-Level ionizing radiation induces selective killing of HIV-1-infected cells with reversal of cytokine induction using mtor inhibitors

HIV-1 infects 39.5 million people worldwide, and cART is effective in preventing viral spread by reducing HIV-1 plasma viral loads to undetectable levels. However, viral reservoirs persist by mechanisms, including the inhibition of autophagy by HIV-1 proteins (i.e., Nef and Tat). HIV-1 reservoirs can be targeted by the “shock and kill” strategy, which utilizes latency-reversing agents (LRAs) to activate latent proviruses and immunotarget the virus-producing cells. Yet, limitations include reduced LRA permeability across anatomical barriers and immune hyper-activation. Ionizing radiation (IR) induces effective viral activation across anatomical barriers. Like other LRAs, IR may cause inflammation and modulate the secretion of extracellular vesicles (EVs). We and others have shown that cells may secrete cytokines and viral proteins in EVs and, therefore, LRAs may contribute to inflammatory EVs. In the present study, we mitigated the effects of IR-induced inflammatory EVs (i.e., TNF-α), through the use of mTOR inhibitors (mTORi; Rapamycin and INK128). Further, mTORi were found to enhance the selective killing of HIV-1-infected myeloid and T-cell reservoirs at the exclusion of uninfected cells, potentially via inhibition of viral transcription/translation and induction of autophagy. Collectively, the proposed regimen using cART, IR, and mTORi presents a novel approach allowing for the targeting of viral reservoirs, prevention of immune hyper-activation, and selectively killing latently infected HIV-1 cells

Environmental disclosure in Spain: Corporate characteristics and media exposure

Social and environmental issues have become a major concern for accounting research over the past two decades. Social and Environmental Accounting has attracted the attention of a number of researchers attempting to understand, explain and predict the disclosure of information on the social and environmental implications of business activities. Empirical research has hypothesized that size, profitability and the potential environmental impact of the firm are the main factors explaining the amount of information disclosed. On the other hand, several studies have focused on the motivations for disclosing environmental information, hypothesizing that disclosures are aimed at building or sustaining corporate legitimacy. We test the main hypotheses developed to date by empirical research with regard to the disclosure of environmental information based on a sample of companies listed on the Madrid Stock Exchange. Results of a content analysis show that firms disclosing environmental information tend to be larger, have higher risk (measured by the beta coefficient) and operate in industries that have a high potential environmental impact. The environmental implications of the activities carried out by these companies also seem to receive more attention from print media. Our results also provide evidence that two factors directly associated with the amount of environmental information disclosed are the potential environmental impact of the industry and the extent of media coverage of the firms

In Situ Observations of the Deformation Behavior and Fracture Mechanisms of Ti-45Al-2Nb-2Mn+0.8 vol pct TiB₂

The deformation and fracture mechanisms of a nearly lamellar Ti-45Al-2Nb-2Mn (at. pct) + 0.8 vol pct TiB₂ intermetallic, processed into an actual low-pressure turbine blade, were examined by means of in situ tensile and tensile-creep experiments performed inside a scanning electron microscope (SEM). Low elongation-to-failure and brittle fracture were observed at room temperature, while the larger elongations-to-failure at high temperature facilitated the observation of the onset and propagation of damage. It was found that the dominant damage mechanisms at high temperature depended on the applied stress level. Interlamellar cracking was observed only above 390 MPa, which suggests that there is a threshold below which this mechanism is inhibited. Failure during creep tests at 250 MPa was controlled by intercolony cracking. The in situ observations demonstrated that the colony boundaries are damage nucleation and propagation sites during tensile creep, and they seem to be the weakest link in the microstructure for the tertiary creep stage. Therefore, it is proposed that interlamellar areas are critical zones for fracture at higher stresses, whereas lower stress, high-temperature creep conditions lead to intercolony cracking and fracture.The authors are grateful to Industria de Turbo Propulsores, S.A. for supplying the intermetallic blades. Funding from the Spanish Ministry of Science and Innovation through projects MAT2009-14547-C02-01 and MAT2009-14547-C02-02 is acknowledged. The Madrid Regional Government supported this project partially through the ESTRUMAT grant P2009/MAT-1585. C.J.B. acknowledges the support from Grant SAB2009-0045 from the Spanish Ministry of Education for his sabbatical stage in Madrid.Publicad

The Sudbury Neutrino Observatory

The Sudbury Neutrino Observatory is a second generation water Cherenkov detector designed to determine whether the currently observed solar neutrino deficit is a result of neutrino oscillations. The detector is unique in its use of D2O as a detection medium, permitting it to make a solar model-independent test of the neutrino oscillation hypothesis by comparison of the charged- and neutral-current interaction rates. In this paper the physical properties, construction, and preliminary operation of the Sudbury Neutrino Observatory are described. Data and predicted operating parameters are provided whenever possible.Comment: 58 pages, 12 figures, submitted to Nucl. Inst. Meth. Uses elsart and epsf style files. For additional information about SNO see http://www.sno.phy.queensu.ca . This version has some new reference

Opposing authigenic controls on the isotopic signature of dissolved iron in hydrothermal plumes

Iron is a scarce but essential micronutrient in the oceans that limits primary productivity in many regions of the surface ocean. The mechanisms and rates of Fe supply to the ocean interior are still poorly understood and quantified. Iron isotope ratios of different Fe pools can potentially be used to trace sources and sinks of the global Fe biogeochemical cycle if these boundary fluxes have distinct signatures. Seafloor hydrothermal vents emit metal rich fluids from mid-ocean ridges into the deep ocean. Iron isotope ratios have the potential to be used to trace the input of hydrothermal dissolved iron to the oceans if the local controls on the fractionation of Fe isotopes during plume dispersal in the deep ocean are understood. In this study we assess the behaviour of Fe isotopes in a Southern Ocean hydrothermal plume using a sampling program of Total Dissolvable Fe (TDFe), and dissolved Fe (dFe). We demonstrate that δ56Fe values of dFe (δ56dFe) within the hydrothermal plume change dramatically during early plume dispersal, ranging from −2.39 ± 0.05‰ to −0.13 ± 0.06‰ (2 SD). The isotopic composition of TDFe (δ56TDFe) was consistently heavier than dFe values, ranging from −0.31 ± 0.03‰ to 0.78 ± 0.05‰, consistent with Fe oxyhydroxide precipitation as the plume samples age. The dFe present in the hydrothermal plume includes stabilised dFe species with potential to be transported to the deep ocean. We estimate that stable dFe exported from the plume will have a δ56Fe of −0.28 ± 0.17‰. Further, we show that the proportion of authigenic iron-sulfide and iron-oxyhydroxide minerals precipitating in the buoyant plume exert opposing controls on the resultant isotope composition of dissolved Fe passed into the neutrally buoyant plume. We show that such controls yield variable dissolved Fe isotope signatures under the authigenic conditions reported from modern vent sites elsewhere, and so ought to be considered during iron isotope reconstructions of past hydrothermalism from ocean sediment records

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

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research