473 research outputs found
Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection
Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues
General anesthesia does not have persistent effects on attention in rodents
Background: Studies in animals have shown that general anesthesia can cause persistent spatial memory impairment, but the influence of anesthetics on other cognitive functions is unclear. This study tested whether exposure to general anesthesia without surgery caused a persistent deficit in attention in rodents.Methods: To evaluate whether anesthesia has persistent effects on attention, rats were randomized to three groups. Group A was exposed for 2 h to isoflurane anesthesia, and tested the following seven days for attentional deficits. Group B was used as a control and received room air before attentional testing. Since there is some evidence that a subanesthetic dose of ketamine can improve cognition and reduce disorders of attention after surgery, rats in group C were exposed to isoflurane anesthesia in combination with a ketamine injection before cognitive assessment. Attention was measured in rats using the 5-Choice Serial Reaction Time Task, for which animals were trained to respond with a nose poke on a touchscreen to a brief, unpredictable visual stimulus in one of five possible grid locations to receive a food reward. Attention was analyzed as % accuracy, % omission, and premature responses.Results: Evaluating acute attention by comparing baseline values with data from the day after intervention did not reveal any differences in attentional measurements. No significant differences were seen in % accuracy, % omission, and premature responses for the three groups tested for 7 consecutive days.Conclusion: These data in healthy rodents suggest that general anesthesia without surgery has no persistent effect on attention and the addition of ketamine does not alter the outcome
Almost-Euclidean subspaces of via tensor products: a simple approach to randomness reduction
It has been known since 1970's that the N-dimensional -space contains
nearly Euclidean subspaces whose dimension is . However, proofs of
existence of such subspaces were probabilistic, hence non-constructive, which
made the results not-quite-suitable for subsequently discovered applications to
high-dimensional nearest neighbor search, error-correcting codes over the
reals, compressive sensing and other computational problems. In this paper we
present a "low-tech" scheme which, for any , allows to exhibit nearly
Euclidean -dimensional subspaces of while using only
random bits. Our results extend and complement (particularly) recent work
by Guruswami-Lee-Wigderson. Characteristic features of our approach include (1)
simplicity (we use only tensor products) and (2) yielding "almost Euclidean"
subspaces with arbitrarily small distortions.Comment: 11 pages; title change, abstract and references added, other minor
change
Experimental study of a fast gas-particle separator
A horizontal rapid gas-particle separator dedicated to the Fluid Catalytic Cracking process was tested on a small scale cold Circulating Fluidized Bed. Air (density 1.2 kg/m3, dynamic viscosity 1.8Ă10-5 Pa.s) and typical FCC particles (density 1400 kg/m3, mean diameter 70 mm) are used. The inlet gas velocity is kept constant at 7.3 m/s while the inlet solid loading and the separator dipleg back pressure range from 0 to 16 kg/kg and 100 to 500 Pa, respectively. Solid collection efficiency and pressure drop are studied. A model based on cyclone concepts is proposed. The solid collection efficiency increases with the inlet solid loading and reaches an asymptotic value close to 95 % when the inlet loading is above 5 kg/kg. Two flow regimes are observed in the separator dipleg through the range of inlet solid loadings, related to the available flow section modification and the interstitial gas entrainment. At constant gas collection efficiency, the separator pressure drop is maximum under single-phase flow conditions and reaches a minimum when the inlet solid loading is close to 2.5. The pressure drop increases again for higher inlet solid loading. The final modeling allows good prediction of the separator operation for all inlet solid loading conditions when the gas collection efficiency is at 100 %
The Glasgow Voice Memory Test: Assessing the ability to memorize and recognize unfamiliar voices
One thousand one hundred and twenty subjects as well as a developmental phonagnosic subject (KH) along with age-matched controls performed the Glasgow Voice Memory Test, which assesses the ability to encode and immediately recognize, through an old/new judgment, both unfamiliar voices (delivered as vowels, making language requirements minimal) and bell sounds. The inclusion of non-vocal stimuli
allows the detection of significant dissociations between the two categories (vocal vs. non-vocal stimuli). The distributions of accuracy and sensitivity scores (dâ) reflected a wide range of individual differences in voice recognition performance in the population. As expected, KH showed a dissociation between the recognition of voices and bell sounds, her performance being significantly poorer than matched controls for voices but not for bells. By providing normative data of a large sample and by testing a developmental phonagnosic subject, we demonstrated that the Glasgow Voice Memory Test, available online and accessible fromall over the world, can be a valid screening tool (~5 min) for a preliminary detection of potential cases of phonagnosia and of âsuper recognizersâ for voices
Estimation in high dimensions: a geometric perspective
This tutorial provides an exposition of a flexible geometric framework for
high dimensional estimation problems with constraints. The tutorial develops
geometric intuition about high dimensional sets, justifies it with some results
of asymptotic convex geometry, and demonstrates connections between geometric
results and estimation problems. The theory is illustrated with applications to
sparse recovery, matrix completion, quantization, linear and logistic
regression and generalized linear models.Comment: 56 pages, 9 figures. Multiple minor change
CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis
Humoral immunity develops in the spleen during blood-stage Plasmodium infection. This elicits parasite-specific IgM and IgG, which control parasites and protect against malaria. Studies in mice have elucidated cells and molecules driving humoral immunity to Plasmodium, including CD4(+) T cells, B cells, interleukin (IL)-21 and ICOS. IL-6, a cytokine readily detected in Plasmodium-infected mice and humans, is recognized in other systems as a driver of humoral immunity. Here, we examined the effect of infection-induced IL-6 on humoral immunity to Plasmodium. Using P.\ua0chabaudi chabaudi AS (PcAS) infection of wild-type and IL-6(-/-) mice, we found that IL-6 helped to control parasites during primary infection. IL-6 promoted early production of parasite-specific IgM but not IgG. Notably, splenic CD138(+) plasmablast development was more dependent on IL-6 than germinal centre (GC) B-cell differentiation. IL-6 also promoted ICOS expression by CD4(+) T cells, as well as their localization close to splenic B cells, but was\ua0not required for early Tfh-cell development. Finally, IL-6 promoted parasite control, IgM and IgG production, GC B-cell development and ICOS expression by Tfh cells in a second model, Py17XNL infection. IL-6 promotes CD4(+) T-cell activation and B-cell responses during blood-stage Plasmodium infection, which encourages parasite-specific antibody production
Old vaccines for new infections: Exploiting innate immunity to control COVID-19 and prevent future pandemics
The COVID-19 pandemic triggered an unparalleled pursuit of vaccines to induce specific adaptive immunity, based on virus-neutralizing antibodies and T cell responses. Although several vaccines have been developed just a year after SARS-CoV-2 emerged in late 2019, global deployment will take months or even years. Meanwhile, the virus continues to take a severe toll on human life and exact substantial economic costs. Innate immunity is fundamental to mammalian host defense capacity to combat infections. Innate immune responses, triggered by a family of pattern recognition receptors, induce interferons and other cytokines and activate both myeloid and lymphoid immune cells to provide protection against a wide range of pathogens. Epidemiological and biological evidence suggests that the live-attenuated vaccines (LAV) targeting tuberculosis, measles, and polio induce protective innate immunity by a newly described form of immunological memory termed âtrained immunity.â An LAV designed to induce adaptive immunity targeting a particular pathogen may also induce innate immunity that mitigates other infectious diseases, including COVID-19, as well as future pandemic threats. Deployment of existing LAVs early in pandemics could complement the development of specific vaccines, bridging the protection gap until specific vaccines arrive. The broad protection induced by LAVs would not be compromised by potential antigenic drift (immune escape) that can render viruses resistant to specific vaccines. LAVs might offer an essential tool to âbend the pandemic curve,â averting the exhaustion of public health resources and preventing needless deaths and may also have therapeutic benefits if used for postexposure prophylaxis of disease
One vaccine to counter many diseases? Modeling the economics of oral polio vaccine against child mortality and COVID-19
INTRODUCTION: Recent reviews summarize evidence that some vaccines have heterologous or non-specific effects (NSE), potentially offering protection against multiple pathogens. Numerous economic evaluations examine vaccines\u27 pathogen-specific effects, but less than a handful focus on NSE. This paper addresses that gap by reporting economic evaluations of the NSE of oral polio vaccine (OPV) against under-five mortality and COVID-19.
MATERIALS AND METHODS: We studied two settings: (1) reducing child mortality in a high-mortality setting (Guinea-Bissau) and (2) preventing COVID-19 in India. In the former, the intervention involves three annual campaigns in which children receive OPV incremental to routine immunization. In the latter, a susceptible-exposed-infectious-recovered model was developed to estimate the population benefits of two scenarios, in which OPV would be co-administered alongside COVID-19 vaccines. Incremental cost-effectiveness and benefit-cost ratios were modeled for ranges of intervention effectiveness estimates to supplement the headline numbers and account for heterogeneity and uncertainty.
RESULTS: For child mortality, headline cost-effectiveness was 23,000-65,000 if it were administered simultaneously with a COVID-19 vaccine \u3c200 days into a wave of the epidemic. If the COVID-19 vaccine availability were delayed, the cost per averted death would decrease to $2600-6100. Estimated benefit-to-cost ratios vary but are consistently high.
DISCUSSION: Economic evaluation suggests the potential of OPV to efficiently reduce child mortality in high mortality environments. Likewise, within a broad range of assumed effect sizes, OPV (or another vaccine with NSE) could play an economically attractive role against COVID-19 in countries facing COVID-19 vaccine delays.
FUNDING: The contribution by DTJ was supported through grants from Trond Mohn Foundation (BFS2019MT02) and Norad (RAF-18/0009) through the Bergen Center for Ethics and Priority Setting
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