Experimental depletion of CD8+ cells in acutely SIVagm-Infected African Green Monkeys results in increased viral replication

<p>Abstract</p> <p>Background</p> <p><it>In vivo </it>CD8⁺cell depletions in pathogenic SIV infections identified a key role for cellular immunity in controlling viral load (VL) and disease progression. However, similar studies gave discordant results in chronically-infected SMs, leading some authors to propose that in natural hosts, SIV replication is independent of cellular immunity. To assess the role of cellular immune responses in the control of SIV replication in natural hosts, we investigated the impact of CD8⁺cell depletion during acute SIV infection in AGMs.</p> <p>Results</p> <p>Nine AGMs were infected with SIVagm.sab and were followed up to day 225 p.i. Four were intravenously infused with the cM-T807 antibody on days 0 (50 mg/kg), 6, and 13 (10 mg/kg, respectively) post infection (p.i.). CD8⁺cells were depleted for up to 28 days p.i. in peripheral blood and LNs in all treated AGMs. Partial CD8⁺T cell depletion occurred in the intestine. SIVagm VLs peaked at similar levels in both groups (10⁷-10⁸RNA copies/ml). However, while VLs were controlled in undepleted AGMs, reaching set-point levels (10⁴-10⁵RNA copies/ml) by day 28 p.i., high VLs (>10⁶RNA copies/ml) were maintained by day 21 p.i. in CD8-depleted AGMs. By day 42 p.i., VLs were comparable between the two groups. The levels of immune activation and proliferation remained elevated up to day 72 p.i. in CD8-depleted AGMs and returned to preinfection levels in controls by day 28 p.i. None of the CD8-depleted animals progressed to AIDS.</p> <p>Conclusion</p> <p>CD8⁺cells are responsible for a partial control of postacute viral replication in SIVagm.sab-infected AGMs. In contrast to macaques, the SIVagm-infected AGMs are able to control viral replication after recovery of the CD8⁺T cells and avoid disease progression.</p

Visualization of Transepithelial Passage of the Immunogenic 33-Residue Peptide from α-2 Gliadin in Gluten-Sensitive Macaques

BACKGROUND: Based on clinical, histopathological and serological similarities to human celiac disease (CD), we recently established the rhesus macaque model of gluten sensitivity. In this study, we further characterized this condition based on presence of anti-tissue transglutaminase 2 (TG2) antibodies, increased intestinal permeability and transepithelial transport of a proteolytically resistant, immunotoxic, 33-residue peptide from alpha(2)-gliadin in the distal duodenum of gluten-sensitive macaques. METHODOLOGY/PRINCIPAL FINDINGS: Six rhesus macaques were selected for study from a pool of 500, including two healthy controls and four gluten-sensitive animals with elevated anti-gliadin or anti-TG2 antibodies as well as history of non-infectious chronic diarrhea. Pediatric endoscope-guided pinch biopsies were collected from each animal's distal duodenum following administration of a gluten-containing diet (GD) and again after remission by gluten-free diet (GFD). Control biopsies always showed normal villous architecture, whereas gluten-sensitive animals on GD exhibited histopathology ranging from mild lymphocytic infiltration to villous atrophy, typical of human CD. Immunofluorescent microscopic analysis of biopsies revealed IgG+ and IgA+ plasma-like cells producing antibodies that colocalized with TG2 in gluten-sensitive macaques only. Following instillation in vivo, the Cy-3-labeled 33-residue gluten peptide colocalized with the brush border protein villin in all animals. In a substantially enteropathic macaque with "leaky" duodenum, the peptide penetrated beneath the epithelium into the lamina propria. CONCLUSIONS/SIGNIFICANCE: The rhesus macaque model of gluten sensitivity not only resembles the histopathology of CD but it also may provide a model for studying intestinal permeability in states of epithelial integrity and disrepair

The Atomic to Molecular Transition in Galaxies. II: HI and H_2 Column Densities

Gas in galactic disks is collected by gravitational instabilities into giant atomic-molecular complexes, but only the inner, molecular parts of these structures are able to collapse to form stars. Determining what controls the ratio of atomic to molecular hydrogen in complexes is therefore a significant problem in star formation and galactic evolution. In this paper we use the model of H_2 formation, dissociation, and shielding developed in the previous paper in this series to make theoretical predictions for atomic to molecular ratios as a function of galactic properties. We find that the molecular fraction in a galaxy is determined primarily by its column density and secondarily by its metallicity, and is to good approximation independent of the strength of the interstellar radiation field. We show that the column of atomic hydrogen required to shield a molecular region against dissociation is ~10 Msun pc^-2 at solar metallicity. We compare our model to data from recent surveys of the Milky Way and of nearby galaxies, and show that the both the primary dependence of molecular fraction on column density and the secondary dependence on metallicity that we predict are in good agreement with observed galaxy properties.Comment: Accepted to ApJ. 22 pages, 13 figures, emulateapj format. This version corrects a minor error in the binning procedure in section 4.1.2. The remainder of the paper is unchange

Use of stable CHO pools and CHO TGE to accelerate SARS-CoV-2 vaccine development

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Fingerprints of the COVID-19 economic downturn and recovery on ozone anomalies at high-elevation sites in North America and western Europe

With a few exceptions, most studies on tropospheric ozone (O3) variability during and following the COrona VIrus Disease (COVID-19) economic downturn focused on high-emission regions or urban environments. In this work, we investigated the impact of the societal restriction measures during the COVID-19 pandemic on surface O3 at several high-elevation sites across North America and western Europe. Monthly O3 anomalies were calculated for 2020 and 2021, with respect to the baseline period 2000–2019, to explore the impact of the economic downturn initiated in 2020 and its recovery in 2021. In total, 41 high-elevation sites were analyzed: 5 rural or mountaintop stations in western Europe, 19 rural sites in the western US, 4 sites in the western US downwind of highly polluted source regions, and 4 rural sites in the eastern US, plus 9 mountaintop or high-elevation sites outside Europe and the United States to provide a “global” reference. In 2020, the European high-elevation sites showed persistent negative surface O3 anomalies during spring (March–May, i.e., MAM) and summer (June–August, i.e., JJA), except for April. The pattern was similar in 2021, except for June. The rural sites in the western US showed similar behavior, with negative anomalies in MAM and JJA 2020 (except for August) and MAM 2021.The research leading to these results has received funding from the European Union's Horizon 2020 research and innovation program (grant agreement no. 654109). Surface O3 measurements at Summit are made possible via the US National Science Foundation Office of Polar Programs and their contract with Battelle Arctic Research Operations (contract no. 49100420C0001). Owen R. Cooper, Kai-Lan Chang, Irina Petropavlovskikh, and Peter Effertz were supported by a NOAA cooperative agreement (grant no. NA22OAR4320151). The publication costs of this research have been partially supported by the European Commission under the Horizon 2020 research and innovation framework program through ACTMO-ACCESS Integrating Activity (grant agreement no. 101008004)

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al

Population pharmacokinetics of fluconazole in critically ill patients receiving continuous venovenous hemodiafiltration - using Monte Carlo Simulations to predict doses for specified pharmacodynamic targets

Fluconazole is a widely used antifungal agent that is extensively reabsorbed in patients with normal renal function. However, its reabsorption can be compromised in patients with acute kidney injury, thereby leading to altered fluconazole clearance and total systemic exposure. Here, we explore the pharmacokinetics of fluconazole in 10 critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF). We performed Monte Carlo simulations to optimize dosing to appropriate pharmacodynamic endpoints for this population. Pharmacokinetic profiles of initial and steady-state doses of 200 mg intravenous fluconazole twice daily were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis and to perform Monte Carlo simulations. For each dosing regimen, the free drug area under the concentration-time curve (fAUC)/MIC ratio was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values. A two-compartment model adequately described the disposition of fluconazole in plasma. The estimate for total fluconazole clearance was 2.67 liters/h and was notably 2.3 times faster than previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CL(CVVHDF)) represented 62% of its total systemic clearance. Furthermore, the predicted efficiency of CL(CVVHDF) decreased to 36.8% when filters were in use >48 h. Monte Carlo simulations demonstrated that a dose of 400 mg twice daily maximizes empirical treatment against fungal organisms with MIC up to 16 mg/liter. This is the first study we are aware of that uses Monte Carlo simulations to inform dosing requirements in patients where tubular reabsorption of fluconazole is probably nonexistent

A Disintegrating Minor Planet Transiting a White Dwarf

White dwarfs are the end state of most stars, including the Sun, after they exhaust their nuclear fuel. Between 1/4 and 1/2 of white dwarfs have elements heavier than helium in their atmospheres1,2, even though these elements should rapidly settle into the stellar interiors unless they are occasionally replenished3–5. The abundance ratios of heavy elements in white dwarf atmospheres are similar to rocky bodies in the Solar system6,7. This and the existence of warm dusty debris disks8–13 around about 4% of white dwarfs14–16 suggest that rocky debris from white dwarf progenitors’ planetary systems occasionally pollute the stars’ atmospheres17. The total accreted mass can be comparable to that of large asteroids in the solar system1. However, the process of disrupting planetary material has not yet been observed. Here, we report observations of a white dwarf being transited by at least one and likely multiple disintegrating planetesimals with periods ranging from 4.5 hours to 4.9 hours. The strongest transit signals occur every 4.5 hours and exhibit varying depths up to 40% and asymmetric profiles, indicative of a small object with a cometary tail of dusty effluent material. The star hosts a dusty debris disk and the star’s spectrum shows prominent lines from heavy elements like magnesium, aluminium, silicon, calcium, iron, and nickel. This system provides evidence that heavy element pollution of white dwarfs can originate from disrupted rocky bodies such as asteroids and minor planets.Astronom

Prevailing theories of consciousness are challenged by novel cross-modal associations acquired between subliminal stimuli

While theories of consciousness differ substantially, the ‘conscious access hypothesis’, which aligns consciousness with the global accessibility of information across cortical regions, is present in many of the prevailing frameworks. This account holds that consciousness is necessary to integrate information arising from independent functions such as the specialist processing required by different senses. We directly tested this account by evaluating the potential for associative learning between novel pairs of subliminal stimuli presented in different sensory modalities. First, pairs of subliminal stimuli were presented and then their association assessed by examining the ability of the first stimulus to prime classification of the second. In Experiments 1-4 the stimuli were word-pairs consisting of a male name preceding either a creative or uncreative profession. Participants were subliminally exposed to two name-profession pairs where one name was paired with a creative profession and the other an uncreative profession. A supraliminal task followed requiring the timed classification of one of those two professions. The target profession was preceded by either the name with which it had been subliminally paired (concordant) or the alternate name (discordant). Experiment 1 presented stimuli auditorily, Experiment 2 visually, and Experiment 3 presented names auditorily and professions visually. All three experiments revealed the same inverse priming effect with concordant test pairs associated with significantly slower classification judgements. Experiment 4 sought to establish if learning would be more efficient with supraliminal stimuli and found evidence that a different strategy is adopted when stimuli are consciously perceived. Finally, Experiment 5 replicated the unconscious cross-modal association achieved in Experiment 3 utilising non-linguistic stimuli. The results demonstrate the acquisition of novel cross-modal associations between stimuli which are not consciously perceived and thus challenge the global access hypothesis and those theories embracing it