42 research outputs found

    Effects of Normative Aging on Eye Movements during Reading

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    Substantial progress has been made in understanding the mostly detrimental effects of normative aging on eye movements during reading. This article provides a review of research on aging effects on eye movements during reading for different writing systems (i.e., alphabetic systems like English compared to non-alphabetic systems like Chinese), focused on appraising the importance of visual and cognitive factors, considering key methodological issues, and identifying vital questions that need to be addressed and topics for further investigation

    Design and preparation of a novel colon-targeted tablet of hydrocortisone

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    ABSTRACT The objective of this research was to design a new colon-targeted drug delivery system based on chitosan. The properties of the films were studied to obtain useful information about the possible applications of composite films. The composite films were used in a bilayer system to investigate their feasibility as coating materials. Tensile strength, swelling degree, solubility, biodegradation degree, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Scanning Electron Microscope (SEM) investigations showed that the composite film was formed when chitosan and gelatin were reacted jointly. The results showed that a 6:4 blend ratio was the optimal chitosan/gelatin blend ratio. In vitro drug release results indicated that the Eudragit- and chitosan/gelatin-bilayer coating system prevented drug release in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF). However, the drug release from a bilayer-coated tablet in SCF increased over time, and the drug was almost completely released after 24h. Overall, colon-targeted drug delivery was achieved by using a chitosan/gelatin complex film and a multilayer coating system

    A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research

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    The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science

    In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2

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    Remdesivir (RDV), a broadly acting nucleoside analogue, is the only FDA approved small molecule antiviral for the treatment of COVID-19 patients. To date, there are no reports identifying SARS-CoV-2 RDV resistance in patients, animal models or in vitro. Here, we selected drug-resistant viral populations by serially passaging SARS-CoV-2 in vitro in the presence of RDV. Using high throughput sequencing, we identified a single mutation in RNA-dependent RNA polymerase (NSP12) at a residue conserved among all coronaviruses in two independently evolved populations displaying decreased RDV sensitivity. Introduction of the NSP12 E802D mutation into our SARS-CoV-2 reverse genetics backbone confirmed its role in decreasing RDV sensitivity in vitro. Substitution of E802 did not affect viral replication or activity of an alternate nucleoside analogue (EIDD2801) but did affect virus fitness in a competition assay. Analysis of the globally circulating SARS-CoV-2 variants (>800,000 sequences) showed no evidence of widespread transmission of RDV-resistant mutants. Surprisingly, we observed an excess of substitutions in spike at corresponding sites identified in the emerging SARS-CoV-2 variants of concern (i.e., H69, E484, N501, H655) indicating that they can arise in vitro in the absence of immune selection. The identification and characterisation of a drug resistant signature within the SARS-CoV-2 genome has implications for clinical management and virus surveillance

    Impact of glacial isostatic adjustment on the long-term stability of the Antarctic ice sheet

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    Projections of the contribution of the Antarctic ice sheet to future sea-level rise remain highly uncertain, especially on long timescales. One of the reasons for this uncertainty lies in the uncertainty in the intensity of the feedbacks of glacial isostatic adjustment (GIA; i.e. the combination of bedrock adjustment and gravitationally-consistent sea-surface changes due to ice mass changes) on ice-sheet evolution. Indeed, the Antarctic ice sheet lies on a solid Earth that displays large spatial variations in rheological properties, with a thin lithosphere and low-viscosity upper mantle beneath West Antarctica and an opposing structure beneath East Antarctica (Morelli & Danesi, 2004; Lloyd et al. 2020). In addition to this West-East dichotomy, strong viscoelastic heterogeneities (sometimes by several orders of magnitude across relatively short spatial scales) exist within the East and West Antarctic regions (An et al. 2015). These lateral variations are known to have a significant impact on the ice-sheet grounding-line stability (Gomez et al. 2015; Konrad et al. 2015). However, large uncertainties remain in determining these viscoelastic properties with precision.Here, we investigate the influence of GIA feedbacks on the uncertainty in assessing the long-term contribution of the Antarctic ice sheet to future sea-level rise (SLR). In this framework, we design an ensemble approach, taking advantage of the computational efficiency of the Elementary GIA model (Coulon et al. under review). The latter consists of a modified Elastic Lithosphere—Relaxing Asthenosphere model able to consider spatially-varying viscoelastic properties supplemented with an approximation of gravitationally-consistent geoid changes, allowing to approximate near-field relative sea-level changes. Using existing upper-mantle viscosity and lithosphere thickness maps, we produce a large range of plausible Antarctic viscoelastic properties by varying the level of lateral variability in the associated relaxation time and flexural rigidity. We thereby take into account (i) the important lateral variations in rheological properties observed beneath the Antarctic ice sheet as well as (ii) the strong uncertainty characterizing the estimation of Antarctic solid Earth properties. We investigate the potential stabilizing role of GIA effects as well as their influence on multi-centennial to multi-millenial SLR. In addition, we investigate whether GIA feedbacks are able to stabilize the Antarctic ice sheet on short or longer timescales for strong and intermediate mitigation climate scenarios. Preliminary results (Coulon et al. under review) show that the weak Earth structure observed beneath West Antarctica plays a significant role in promoting the stability of the West Antarctic ice sheet (WAIS). However, WAIS collapse cannot be prevented under high-emissions climate scenarios. The highest uncertainty arises from the East Antarctic ice sheet (EAIS) where ice retreat in the Aurora Basin is highly dependent on mantle viscosity.info:eu-repo/semantics/nonPublishe

    Contrasting Response of West and East Antarctic Ice Sheets to Glacial Isostatic Adjustment

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    The Antarctic ice sheet (AIS) lies on a solid Earth that displays large spatial variations in rheological properties, with a thin lithosphere and low-viscosity upper mantle (weak Earth structure) beneath West Antarctica and an opposing structure beneath East Antarctica. This contrast is known to have a significant impact on the ice-sheet grounding-line stability. Here, we embed within an ice-sheet model a modified glacial-isostatic Elastic Lithosphere-Relaxing Asthenosphere model that considers a dual pattern for the Earth structure beneath West and East Antarctica supplemented with an approximation of gravitationally consistent geoid changes, allowing to approximate near-field relative sea-level changes. We show that this elementary GIA model captures the essence of global Self-Gravitating Viscoelastic solid-Earth Models (SGVEMs) and compares well with both SGVEM outputs and geodetic observations, allowing to capture the essential features and processes influencing Antarctic grounding-line stability in a computationally efficient way. In this framework, we perform a probabilistic assessment of the impact of uncertainties in solid-Earth rheological properties on the response of the AIS to future warming. Results show that on multicentennial-to-millennial timescales, spatial variability in solid-Earth deformation plays a significant role in promoting the stability of the West Antarctic ice sheet (WAIS). However, WAIS collapse cannot be prevented under high-emissions climate scenarios. On longer timescales and for unmitigated climate scenarios, continent-wide mass loss projections may be underestimated because spatially uniform Earth models, as typically considered in numerical ice sheet models, will overestimate the stabilizing effect of GIA across East Antarctica, which is characterized by thick lithosphere and high upper-mantle viscosity
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