503 research outputs found
Virology
No full textArenaviruses are highly pathogenic viruses that pose a serious public health threat. Chapare virus (CHAV) and Machupo virus (MACV), two New World arenaviruses, cause hemorrhagic fevers with case fatality rates of up to 45%. Research on therapeutic drug targets and vaccines for these viruses is limited because biosafety level 4 containment is required for handling them. In this study, we developed reverse genetics systems, including minigenomes and recombinant viruses, that will facilitate the study of these pathogens. The minigenome system is based on the S segment of CHAV or MACV genomes expressing the fluorescent reporter gene ZsGreen (ZsG). We also generated recombinant CHAV and MACV with and without the ZsG reporter gene. As a proof-of-concept study, we used both minigenomes and recombinant viruses to test the inhibitory effects of previously reported antiviral compounds. The new reverse genetics system described here will facilitate future therapeutic studies for these two life-threatening arenaviruses.CC999999/ImCDC/Intramural CDC HHSUnited States
Investment protection a must in India-UK FTA
No full textThe India-UK investment relationship is no more a one-way street. In 2020, the stock of foreign direct investment from India in the UK was £10.6 billion as against £14.9 billion from the UK in India
A priori and a posteriori analysis of the hybrid two-level large-eddy simulation method for high Reynolds number complex flows
No full textWe present a priori and a posteriori analysis of the assumptions and predictions of the hybrid two-level large-eddy simulation (TLS-LES) method for high Reynolds number complex flows. The TLS-LES methodology is a multi-scale framework for simulation of turbulent flows in complex configurations at practically relevant Reynolds number. It additively combines the two-level simulation (TLS) model with a conventional large-eddy simulation (LES) approach by employing a static or dynamic blending function. In the present study, first we analyze the model assumptions employed by the TLS model to obtain the small-scale solution necessary for closure of the large-scale equations. Afterward, we analyze the large-scale and small-scale solutions to assess the predictive ability of the multi-scale framework for specific turbulence physics such as role of forward and backscatter of energy and presence of co- and counter-gradient diffusion. To perform these investigations, we consider cases with increasing degree of geometrical complexity, namely, flow in a periodic channel, flow past a bump placed on the lower surface of the channel and flow past a finite-span NACA0015 airfoil
mBio
No full textEbola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013-2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection | Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.| Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.2018K08 AI119448/AI/NIAID NIH HHS/United States29717011PMC5930306949
Front Cell Infect Microbiol
No full textAndes virus (ANDV) and Sin Nombre virus (SNV), highly pathogenic hantaviruses, cause hantavirus pulmonary syndrome in the Americas. Currently no therapeutics are approved for use against these infections. Griffithsin (GRFT) is a high-mannose oligosaccharide-binding lectin currently being evaluated in phase I clinical trials as a topical microbicide for the prevention of human immunodeficiency virus (HIV-1) infection (ClinicalTrials.gov Identifiers: NCT04032717, NCT02875119) and has shown broad-spectrum | activity against other viruses, including severe acute respiratory syndrome coronavirus, hepatitis C virus, Japanese encephalitis virus, and Nipah virus. In this study, we evaluated the | antiviral activity of GRFT and its synthetic trimeric tandemer 3mGRFT against ANDV and SNV. Our results demonstrate that GRFT is a potent inhibitor of ANDV infection. GRFT inhibited entry of pseudo-particles typed with ANDV envelope glycoprotein into host cells, suggesting that it inhibits viral envelope protein function during entry. 3mGRFT is more potent than GRFT against ANDV and SNV infection. Our results warrant the testing of GRFT and 3mGRFT against ANDV infection in animal models.33251157PMC7671970898
mBio
No full textLassa virus (LASV) infection is a major public health concern due to high fatality rates and limited effective treatment. The interferon-stimulated gene cholesterol 25-hydroxylase (CH25H) encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC). 25HC is involved in regulating cholesterol biosynthesis and has recently been identified as a potent antiviral targeting enveloped virus entry. Here, we show a previously unrecognized role of CH25H in inhibiting LASV glycoprotein glycosylation and the production of infectious virus. Overexpression of CH25H or treatment with 25HC decreased LASV G1 glycoprotein N-glycan maturation and reduced the production of infectious LASV. Depletion of endogenous CH25H using small interfering RNA (siRNA) enhanced the levels of fully glycosylated G1 and increased infectious LASV production. Finally, LASV particles produced from 25HC-treated cells were found to be less infectious, to incorporate aberrantly glycosylated GP1 species, and to be defective in binding alpha-dystroglycan, an attachment and entry receptor. Our findings identify a novel role for CH25H in controlling LASV propagation and indicate that manipulation of the expression of CH25H or the administration of 25HC may be a useful anti-LASV therapy.|Lassa fever is an acute viral hemorrhagic fever in humans caused by Lassa virus (LASV). No vaccine for LASV is currently available. Treatment is limited to the administration of ribavirin, which is only effective when given early in the course of illness. Cholesterol 25-hydroxylase (CH25H) is a recently identified interferon-stimulated gene (ISG); it encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC), which inhibits several viruses. Here, we identify a novel antiviral mechanism of 25HC that is dependent on inhibiting the glycosylation of Lassa virus (LASV) glycoprotein and reducing the infectivity of LASV as a means of suppressing viral replication. Since N-linked glycosylation is a critical feature of other enveloped-virus glycoproteins, 25HC may be a broad inhibitor of virus infectivity
International Outsourcing Hurdles in Value-added Services
No full textPurpose: International Outsourcing has been traditionally looked upon as a low end cost effective servicing option to take advantage of the cost arbitrage that exists across countries. Of late, many outsourcing vendors have realized that the advantages of cost differentials that spurred a lot of the global outsourcing business in the past 20 years will disappear in the medium term. This paper provides a perspective about how much value addition, besides cost, traditional outsourcing vendors can provide and what may be the facilitator/ inhibitors of such activities. Approach: To substantiate the claim, a brief case describing the setting up of an offshore analytics operation is presented which gives a back drop to the challenges faced in relatively high end value creation processes in a remote outsourced environment. Findings/Claim: The author uses the case to develop a conceptual model of off shoring value –added services. The key dimensions that will determine the extent to which international outsourcing of high end services will take place are: 1) Expertise of the vendor, 2) Environmental Stability of the Outsourcing Domain, 3) Physical Barriers to outsourcing complex business processes such as, Communication Problems and Proximity issues, 4) Possibility of Knowledge Leakage from Outsourcing Domain and, 5) Cost Benefits of Outsourcing. Practical Implications: The author contends that conventional outsourcing vendors may find it difficult to acquire “Expert Power” and, set aside negative perceptions of “Environmental Stability” of their domain, in the pursuit to climb up the value chain in their client organizations. The validation of the proposed model is an opportunity for future research. Originality: This paper is one of the first to present a model that will govern the growth of international outsourcing opportunities in high end value-added processes.
Andes Virus Disrupts the Endothelial Cell Barrier by Induction of Vascular Endothelial Growth Factor and Downregulation of VE-Cadherin
No full textABSTRACT
Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) are severe diseases associated with hantavirus infection. High levels of virus replication occur in microvascular endothelial cells but without a virus-induced cytopathic effect. However, virus infection results in microvascular leakage, which is the hallmark of these diseases. VE-cadherin is a major component of adherens junctions, and its interaction with the vascular endothelial growth factor (VEGF) receptor, VEGF-R2, is important for maintaining the integrity of the endothelial barrier. Here we report that increased secreted VEGF and concomitant decreased VE-cadherin are seen at early times postinfection of human primary lung endothelial cells with an HPS-associated hantavirus, Andes virus. Furthermore, active virus replication results in increased permeability and loss of the integrity of the endothelial cell barrier. VEGF binding to VEGF-R2 is known to result in dissociation of VEGF-R2 from VE-cadherin and in VE-cadherin activation, internalization, and degradation. Consistent with this, we showed that an antibody which blocks VEGF-R2 activation resulted in inhibition of the Andes virus-induced VE-cadherin reduction. These data implicate virus induction of VEGF and reduction in VE-cadherin in the endothelial cell permeability seen in HPS and suggest potential immunotherapeutic targets for the treatment of the disease.</jats:p
Regulation of nitrate uptake and calcium signaling in arabidopsis
No full textNitrogen (N) is one of the key nutrients required by plants, and its most abundant form, nitrate (NO3-), has been extensively used in fertilizers to improve crop yield. However, this has also led to increased environmental pollution due to leaching and volatilization. Improving nitrogen use efficiency (NUE) is one of the ways to reduce this environmental impact. Nitrogen uptake efficiency (NUpE) is a key component of NUE. The first step in NO3- uptake is the sensing of NO3- signal which was captured through the use of fluorescence imaging. The calcium responses to NO3- as a signal were captured for the two uptake kinetic systems, high-affinity transporter system (HATS) and low-affinity transporter system (LATS). A unique calcium signature was identified in root epidermal cells and root hair cell-specific responses were captured in response to low NO3-. Two potential transcriptional regulators (TFs) were identified through gene regulatory network analysis of NO3--responsive time-series datasets, DIV1 and MYB28, which play an antagonistic role in regulating the expression of the NO3- transporters, NPF6.3 and NRT2.1, and few NO3- assimilation genes. Further characterization revealed the role of DIV1 and MYB28 in altering the functional NO3- transporter activity, highlighting their role as potential candidates for improving NUpE. The regulation of the transporters occurs at the levels of transcription and post-translation. These regulatory processes were captured through individual models, which were combined into an integrated multiscale model describing the NO3- uptake dynamics for NPF6.3. The integrated model confirmed the switch between the uptake kinetic systems, HATS and LATS, to occur at NO3- concentrations above 1 mM and the threshold without incorporating the regulatory aspects was much lower, close to 0.4 mM. Further, at lower external NO3- concentrations, < 0.5 mM, the total assimilated N was more than 50% of the total predicted internal cellular N when using HATS kinetics, compared to only 30% to 40% assimilation when employing LATS mode for NPF6.3. These findings validate the existing knowledge about the NO3- uptake dynamics and open up avenues to study the impact of perturbations in the regulatory mechanisms on NO3- uptake, leading to novel possibilities of improving NUpE.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2023-05-01The student, Stuti Shrivastava, accepted the attached license on 2021-04-07 at 11:25.The student, Stuti Shrivastava, submitted this Dissertation for approval on 2021-04-07 at 11:50.This Dissertation was approved for publication on 2021-04-08 at 16:42.DSpace SAF Submission Ingestion Package generated from Vireo submission #16245 on 2021-09-16 at 17:02:36Made available in DSpace on 2021-09-17T02:34:20Z (GMT). No. of bitstreams: 3
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Computational analysis of planar wings designed for optimum span-load
No full textA computational analysis of three span-optimized wings was conducted using an open-source CFD tool. Simulations were carried out at Rec = 450; 000 in a semi-spherical domain consisting of unstructured tetrahedra close to the wing surface and pyramids in the farfield region. Simulations were carried out in both steady state and semi-transient states to predict ow transition. A comparative study of different turbulence models revealed k-omega-SST and k - kL-omega to be the most suitable turbulence models for this study. The model accuracy was determined using validations with experimental data from a previous study. The required accuracy was achieved using the most appropriate mesh resolution for all three wing designs and second order discretization schemes. Computational results indicated different drag characteristics between the three span-load optimized wings at the design CL. The Viscous Optimized Wing produced the minimum drag while the Elliptic Wing produced the largest drag at design CL. The Inviscid Optimized Wing had the largest aspect ratio but still produced lesser drag when compared to the Elliptical Wing. Surface ow visualization indicated different ow transition characteristics for the three wings. These differences were attributed to the twist distributions specific to each wing. The Inviscid Optimized wing was observed to have largest laminar boundary-layer region at design angle of attack. Qualitative wake analysis indicated different wake characteristics for each wing, attributed to the different span-loads. The Elliptic Wing had the most aggressive wake roll-up. Much lesser wake roll-up was observed for the Inviscid and Viscous Optimized Wings. The largest wake cross-section was observed for the Elliptic Wing, while the smallest wake cross-section was observed for the Inviscid Optimized Wing.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2018-08-01The student, Prateek Ranjan, accepted the attached license on 2016-07-22 at 11:12.The student, Prateek Ranjan, submitted this Thesis for approval on 2016-07-22 at 11:25.This Thesis was approved for publication on 2016-07-22 at 16:28.DSpace SAF Submission Ingestion Package generated from Vireo submission #10076 on 2016-11-10 at 12:27:41Made available in DSpace on 2016-11-10T18:35:38Z (GMT). No. of bitstreams: 2
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