agent Albany real estate agents report tightening rental market By www.abc.net.au Published On :: Fri, 06 Dec 2013 14:30:00 +1100 Real estate agents say Albany's rental market has tightened significantly in recent times. Full Article ABC South Coast southcoast Business Economics and Finance:Industry:Housing Australia:WA:Albany 6330
agent Weekend Bookworm: Agent 6 By www.abc.net.au Published On :: Fri, 15 Jul 2011 13:59:00 +1000 Rob Minshull produces Weekends with Warren and is an avid reader. Full Article ABC Local brisbane Arts and Entertainment:All:All Arts and Entertainment:Books (Literature):All Arts and Entertainment:Books (Literature):Adventure Australia:All:All Australia:QLD:All Australia:QLD:Brisbane 4000
agent This real estate agent says she's never seen the market like this. Here's why By www.abc.net.au Published On :: Fri, 08 May 2020 06:05:21 +1000 Recently, there's been a surge in withdrawals, with people scared of selling in an unstable market as a recession looms and job losses hit. Agents like Rufina have never seen anything like it. Full Article Housing Industry Industry Business Economics and Finance Consumer Finance
agent Real estate agent Hayley Marley-Duncan fined and banned for abusing tenants and police By www.abc.net.au Published On :: Mon, 28 Oct 2019 19:06:00 +1100 A South Australian real estate agent made notorious by Today Tonight is banned from practising and fined $7,500 for labelling a tenant a "Centrelink dweller" and tribunal members "incompetent". Full Article ABC Radio Adelaide adelaide Business Economics and Finance:Consumer Protection:All Business Economics and Finance:Industry:Housing Government and Politics:States and Territories:All Information and Communication:Broadcasting:Television Law Crime and Justice:All:All Australia:All:All Australia:SA:Adelaide 5000 Australia:SA:All Australia:SA:Gawler 5118
agent Tenants' agents on the rise as would-be renters find it tough By www.abc.net.au Published On :: Sat, 01 Jun 2019 06:00:00 +1000 The barriers to finding a rental home have become so taxing that some tenants are forced to enlist outside help. Full Article 1233 ABC Newcastle newcastle sydney Business Economics and Finance:All:All Business Economics and Finance:Industry:All Business Economics and Finance:Industry:Housing Government and Politics:Housing:All Australia:All:All Australia:NSW:All Australia:NSW:Newcastle 2300 Australia:NSW:Sydney 2000 Australia:NT:All Australia:QLD:All Australia:SA:All Australia:TAS:All Australia:VIC:All Australia:WA:All
agent Pig stock agent Murray Reid By www.abc.net.au Published On :: Fri, 26 Jul 2019 06:20:00 +1000 Full Article ABC Central West NSW centralwest Disasters and Accidents:Drought:All Rural:All:All Rural:Livestock:All Rural:Livestock:Pig Production Australia:NSW:Forbes 2871
agent Agents lament 'grossly shortsighted' approach to 2020 MLB Draft By www.thescore.com Published On :: Sat, 09 May 2020 13:01:03 +0000 Full Article
agent Holloway v. Showcase Realty Agents, Inc. By feeds.findlaw.com Published On :: 2018-04-26T08:00:00+00:00 (California Court of Appeal) - Reversing the dismissal of a claim relating to the alleged conflict of interest in the acquisition of property by the San Lorenzo Valley Water District's acquisition of property where one of the District's directors had partial ownership of the agency facilitating the sale of the property and whose wife was its listing agent because the former owner had standing under the Government Code to bring the action and that the action was not subject to validation statutes because it was a conflict of interest rather than a contracts claim. Full Article Water Law Civil Procedure Property Law & Real Estate Public Utilities Contracts
agent Expert Suggests Alleged Mastermind of Venezuela's Failed Coup Is 'Double Agent' Working for Maduro By feedproxy.google.com Published On :: Fri, 08 May 2020 15:33:09 +0000 The Venezuelan military defector identified as the ringleader of the botched coup attempt in Venezuela was likely working as a "double agent" for the same man he allegedly attempted to overthrow, socialist narco-dictator Nicolás Maduro, Breitbart News has learned. Full Article Latin America National Security Center for a Secure Free Society (SFS) coup Joseph Humire Nicolas Maduro Venezuela
agent Secret Service Agent Talks About Protecting Michelle Obama By feeds.bet.com Published On :: Thu, 7 May 2020 15:44:00 EDT He gave a rare interview for “Becoming.” Full Article National News
agent Secret Service Agent Talks About Protecting Michelle Obama By feeds.bet.com Published On :: Thu, 7 May 2020 15:44:00 EDT He gave a rare interview for “Becoming.” Full Article National News
agent IBM lanza Watson Virtual Agent en español para ayudar a las empresas a construir su propio agente virtual By www.ibm.com Published On :: jue, 24 ago 2017 09:26:17 GMT IBM presenta Watson Virtual Agent en español, una solución que permite a las empresas construir un agente virtual para atención al cliente, flexible y fácil de configurar y adecuada a las necesidades de los negocios. Full Article IBM Watson
agent Critical Security Patches Released for Magento, Adobe Illustrator and Bridge By feedproxy.google.com Published On :: Tue, 28 Apr 2020 15:24:10 PDT It's not 'Patch Tuesday,' but software giant Adobe today released emergency updates for three of its widely used products that patch dozens of newly discovered critical vulnerabilities. The list of affected software includes Adobe Illustrator, Adobe Bridge, and Magento e-commerce platform, containing a total of 35 vulnerabilities where each one of them is affected with multiple critical Full Article
agent Shady Leasing Agent Learns About Lease From Tenant By feedproxy.google.com Published On :: Sat, 09 May 2020 10:00:00 -0700 Ah, yes, a fine example of a sketchy leasing agent getting bested by a truly, professional revenge. This tenant was well equipped to educate the leasing agent on the finer details of how the lease worked. Makes you wonder how many more unsuspecting tenants that leasing agent might've fooled. Well, not this one.Check out more juicy apartment drama with this story about a dude who was threatened by his landlord, and proceeded to go full Karen. Full Article satisfying revenge smart awesome Reddit win apartment
agent Scottish agents urge Government to relax furlough scheme By www.travelmole.com Published On :: Tue, 05 May 2020 13:50:01 -0400 Staff are 'being threatened' for not giving refunds Full Article
agent SEE IT: Video shows random attack on real estate agent in Los Angeles: ‘Seeing my legs in the air, it’s like a movie’ By www.nydailynews.com Published On :: Tue, 24 Sep 2019 18:31:16 +0000 A Los Angeles real estate agent was shoved backwards off a stairway and pinned to the ground by an unknown open house visitor who flashed a chilling smile at a security camera seconds earlier. Full Article
agent New York to probe claims of biased behavior by real estate agents By www.nydailynews.com Published On :: Wed, 20 Nov 2019 17:57:38 +0000 New York Attorney General Letitia James is investigating allegations of racially discriminatory tactics by Long Island real estate agents as described in a sweeping Newsday report. Full Article
agent Letters to the Editor: Packed flights, unmasked TSA agents: How is this still allowed? By www.latimes.com Published On :: Wed, 29 Apr 2020 06:00:38 -0400 If there are still crowded flights and TSA agents are not required to wear masks, how will we ever be able to return to normal? Full Article
agent Baseball agent Scott Boras inks deal for Newport Beach home By www.latimes.com Published On :: Wed, 15 Apr 2020 17:48:47 -0400 In Newport Beach, baseball super-agent Scott Boras has paid $3.925 million for a stylish home a few blocks from the ocean. Full Article
agent Tottenham tipped to sign Premier League free agent and convert the star into a wing-back By www.express.co.uk Published On :: Wed, 06 May 2020 06:31:00 +0100 Tottenham have been tipped to sign Ryan Fraser when his contract with Bournemouth ends. Full Article
agent Mike Tyson vs Danny Williams 2 in the pipeline as Brit's agent 'awaits answer' from legend By feedproxy.google.com Published On :: Wed, 06 May 2020 20:07:00 +0100 Mike Tyson has talked possibly coming out of retirement to fight in charity exhibition match-ups. Full Article
agent Undrafted free agents: Colts sign Georgia kicker Rodrigo Blankenship, Indy's Kendall Coleman By rssfeeds.indystar.com Published On :: Wed, 29 Apr 2020 15:41:50 +0000 Colts continue adding players after NFL Draft. Full Article
agent REPORT: Recent documents reveal number of Secret Service agents with COVID-19 By dennismichaellynch.com Published On :: Sat, 09 May 2020 15:57:28 +0000 The DML News App offers the best in news reporting. The post REPORT: Recent documents reveal number of Secret Service agents with COVID-19 appeared first on Dennis Michael Lynch. Full Article News Feed Powered by DMLNewsApp.com
agent Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents By feedproxy.google.com Published On :: 2004-12-01 Philip L. RossDec 1, 2004; 3:1154-1169Research Full Article
agent A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent By feedproxy.google.com Published On :: 1989-04-01 M el-SaadaniApr 1, 1989; 30:627-630Articles Full Article
agent CBD News: Rural women are integrally connected to all aspects of local biodiversity - as users, custodians and agents of change. By www.cbd.int Published On :: Thu, 15 Oct 2015 00:00:00 GMT Full Article
agent Raiders agree to deal with free agent RB Devontae Booker By www.upi.com Published On :: Thu, 07 May 2020 09:55:57 -0400 The Las Vegas Raiders have agreed to a deal with free agent running back Devontae Booker. Full Article
agent New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 2 Diabetes Using Oral Agents and Basal Insulin: Glucose Control and Hypoglycemia in a 6-Month Randomized Controlled Trial (EDITION 2) By care.diabetesjournals.org Published On :: 2014-12-01 Hannele Yki-JärvinenDec 1, 2014; 37:3235-3243Emerging Technologies and Therapeutics Full Article
agent John Marshall : shipowner, lloyd's reformer and emigration agent / Elizabeth Rushen. By www.catalog.slsa.sa.gov.au Published On :: Marshall, John, 1787-1861. Full Article
agent Die Prüfung der im Handel vorkommenden Gewebe durch das Mikroskop und durch chemische Reagentien / von Hermann Schacht. By feedproxy.google.com Published On :: Berlin : G.W.F. Muller, 1853. Full Article
agent Risk-Aware Energy Scheduling for Edge Computing with Microgrid: A Multi-Agent Deep Reinforcement Learning Approach. (arXiv:2003.02157v2 [physics.soc-ph] UPDATED) By arxiv.org Published On :: In recent years, multi-access edge computing (MEC) is a key enabler for handling the massive expansion of Internet of Things (IoT) applications and services. However, energy consumption of a MEC network depends on volatile tasks that induces risk for energy demand estimations. As an energy supplier, a microgrid can facilitate seamless energy supply. However, the risk associated with energy supply is also increased due to unpredictable energy generation from renewable and non-renewable sources. Especially, the risk of energy shortfall is involved with uncertainties in both energy consumption and generation. In this paper, we study a risk-aware energy scheduling problem for a microgrid-powered MEC network. First, we formulate an optimization problem considering the conditional value-at-risk (CVaR) measurement for both energy consumption and generation, where the objective is to minimize the loss of energy shortfall of the MEC networks and we show this problem is an NP-hard problem. Second, we analyze our formulated problem using a multi-agent stochastic game that ensures the joint policy Nash equilibrium, and show the convergence of the proposed model. Third, we derive the solution by applying a multi-agent deep reinforcement learning (MADRL)-based asynchronous advantage actor-critic (A3C) algorithm with shared neural networks. This method mitigates the curse of dimensionality of the state space and chooses the best policy among the agents for the proposed problem. Finally, the experimental results establish a significant performance gain by considering CVaR for high accuracy energy scheduling of the proposed model than both the single and random agent models. Full Article
agent CARL: Controllable Agent with Reinforcement Learning for Quadruped Locomotion. (arXiv:2005.03288v1 [cs.LG]) By arxiv.org Published On :: Motion synthesis in a dynamic environment has been a long-standing problem for character animation. Methods using motion capture data tend to scale poorly in complex environments because of their larger capturing and labeling requirement. Physics-based controllers are effective in this regard, albeit less controllable. In this paper, we present CARL, a quadruped agent that can be controlled with high-level directives and react naturally to dynamic environments. Starting with an agent that can imitate individual animation clips, we use Generative Adversarial Networks to adapt high-level controls, such as speed and heading, to action distributions that correspond to the original animations. Further fine-tuning through the deep reinforcement learning enables the agent to recover from unseen external perturbations while producing smooth transitions. It then becomes straightforward to create autonomous agents in dynamic environments by adding navigation modules over the entire process. We evaluate our approach by measuring the agent's ability to follow user control and provide a visual analysis of the generated motion to show its effectiveness. Full Article
agent Biologic and systemic agents in dermatology By dal.novanet.ca Published On :: Fri, 1 May 2020 19:44:43 -0300 Callnumber: OnlineISBN: 9783319668840 (electronic bk.) Full Article
agent Ex-FBI Agent Defends Flint Water Probe After Criticism By www.wkar.org Published On :: Tue, 02 Jul 2019 17:00:12 +0000 A former FBI agent who investigated the Flint water scandal says the team was moving toward new charges when new prosecutors took over. Full Article
agent Player agents, executives call for NBA to cancel season: report By www.cbc.ca Published On :: Thu, 30 Apr 2020 15:20:27 EDT National Basketball Association executives and player agents are calling on the league to cancel the remainder of the 2019-20 season due to health concerns over the novel coronavirus outbreak, CNBC reported on Thursday. Full Article Sports/Basketball/NBA
agent Bruins sign pending free agent Jaroslav Halak to 1-year deal By www.cbc.ca Published On :: Sat, 2 May 2020 11:56:31 EDT Boston Bruins goaltender Jaroslav Halak signed a one-year contract worth $2.25 million US, the team announced Friday. He was playing in the final season of a two-year contract. Full Article Sports/Hockey/NHL
agent Team Jennifer Jones adds free-agent all-star lead Lisa Weagle By www.cbc.ca Published On :: Wed, 18 Mar 2020 12:31:24 EDT Let go last week after a decade-long run with skip Rachel Homan's Ottawa-based rink, lead Lisa Weagle has joined Team Jennifer Jones, which will operate with five members. Full Article Sports/Olympics/Winter Sports/Curling
agent Jennifer Jones was ready to pounce when Lisa Weagle suddenly became star free agent By www.cbc.ca Published On :: Tue, 28 Apr 2020 23:26:11 EDT The time was right for Lisa Weagle to join forces with Olympic champion Jennifer Jones. Jones told CBC Sports' Anastasia Bucsis that the latest addition to her five-person rink "was like the clouds parted and the sun came out." Full Article Sports/Olympics/Winter Sports/Curling
agent The Effect of an Osmotic Contrast Agent on Complete Meconium Evacuation in Preterm Infants By pediatrics.aappublications.org Published On :: 2012-11-26T05:32:44-08:00 Delayed meconium passage impairs gastrointestinal function in premature infants. No intervention has been identified that accelerates meconium passage sufficiently. Gastrografin is an osmotic contrast agent used for radiologic examination of the bowel or for conservative treatment of uncomplicated meconium ileus.Gastrografin did not accelerate complete meconium evacuation but stimulated gastrointestinal motility in a randomized, placebo-controlled trial in premature infants. Application shortened the time to full enteral feedings and hospital stay but was associated with necrotizing enterocolitis as a possible adverse event. (Read the full article) Full Article
agent Assessment of drug resistance during phase 2b clinical trials of presatovir in adults naturally infected with respiratory syncytial virus [Antiviral Agents] By aac.asm.org Published On :: 2020-02-18T08:15:40-08:00 Background: This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults.Methods: Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported.Results: Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but similar clinical outcomes.Conclusions: Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with vs without genotypic resistance development had decreased virologic responses but comparable clinical outcomes. Full Article
agent MK-571, a cysteinyl leukotriene receptor-1 antagonist, inhibits hepatitis C virus (HCV) replication [Antiviral Agents] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct acting-antivirals (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with an EC50 of 9±0.3 μM and a maximum HCV RNA level reduction of approximatively 1 Log10. MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonists SR2640 increased HCV-SGR RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle. Full Article
agent Rapid-Release Griffithsin Fibers for the Dual Prevention of HSV-2 and HIV-1 Infections [Antiviral Agents] By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 The biologic Griffithsin (GRFT) has recently emerged as a candidate to safely prevent sexually transmitted infections (STIs) including human immunodeficiency virus (HIV-1) and herpes simplex virus 2 (HSV-2). However, to date, there are few delivery platforms that are available to effectively deliver biologics to the female reproductive tract (FRT). The goal of this work was to evaluate rapid-release polyethylene oxide (PEO), polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) fibers, that incorporate GRFT, in in vitro (HIV-1 and HSV-2) and in vivo (HSV-2) infection models. GRFT loading was determined via ELISA, and the bioactivity of GRFT fibers was assessed using in vitro HIV-1 pseudovirus and HSV-2 plaque assays. Afterwards, the efficacy of GRFT fibers was assessed in a murine model of lethal HSV-2 infection. Finally, murine reproductive tracts and vaginal lavages were evaluated for histology and cytokine expression, 24 and 72 hr after fiber administration, to determine safety. All rapid-release formulations achieved high levels of GRFT incorporation and were completely efficacious against in vitro HIV-1 and HSV-2 infections. Importantly, all rapid-release GRFT fibers provided potent protection in a murine model of HSV-2 infection. Moreover, histology and cytokine levels, evaluated from collected murine reproductive tissues and vaginal lavages treated with blank fibers, showed no increased cytokine production or histological aberrations, demonstrating the preliminary safety of rapid-release GRFT fibers in vaginal tissue. Full Article
agent Novel ionophores active against La Crosse virus identified through rapid antiviral screening [Antiviral Agents] By aac.asm.org Published On :: 2020-04-13T08:15:30-07:00 Bunyaviruses are significant human pathogens, causing diseases ranging from hemorrhagic fevers to encephalitis. Among these viruses, La Crosse virus (LACV), a member of the California serogroup, circulates in the eastern and midwestern United States. While LACV infection is often asymptomatic, dozens of cases of encephalitis are reported yearly. Unfortunately, no antivirals have been approved to treat LACV infection. Here, we developed a method to rapidly test potential antivirals against LACV infection. From this screen, we identified several potential antiviral molecules, including known antivirals. Additionally, we identified many novel antivirals that exhibited antiviral activity without affecting cellular viability. Valinomycin, a potassium ionophore, was among our top targets. We found that valinomycin exhibited potent anti-LACV activity in multiple cell types in a dose-dependent manner. Valinomycin did not affect particle stability or infectivity, suggesting that it may preclude virus replication by altering cellular potassium ions, a known determinant of LACV entry. We extended these results to other ionophores and found that the antiviral activity of valinomycin extended to other viral families including bunyaviruses (Rift Valley fever virus, Keystone virus), enteroviruses (Coxsackievirus, rhinovirus), flavirivuses (Zika), and coronaviruses (HCoV-229E and MERS-CoV). In all viral infections, we observed significant reductions in virus titer in valinomycin-treated cells. In sum, we demonstrate the importance of potassium ions to virus infection, suggesting a potential therapeutic target to disrupt virus replication.Importance No antivirals are approved for the treatment of bunyavirus infection. The ability to rapidly screen compounds and identify novel antivirals is one means to accelerate drug discovery for viruses with no approved treatments. We used this approach to screen hundreds of compounds against La Crosse virus, an emerging bunyavirus that causes significant disease, including encephalitis. We identified several known and previously unidentified antivirals. We focused on a potassium ionophore, valinomycin, due to its promising in vitro antiviral activity. We demonstrate that valinomycin, as well as a selection of other ionophores, exhibits activity against La Crosse virus as well as several other distantly related bunyaviruses. We finally observe that valinomycin has activity against a wide array of human viral pathogens, suggesting that disrupting potassium ion homeostasis with valinomycin may be a potent host pathway to target to quell virus infection. Full Article
agent Efficacy of neuraminidase inhibitors against H5N6 highly pathogenic avian influenza virus in a non-human primate model [Antiviral Agents] By aac.asm.org Published On :: 2020-04-13T08:15:30-07:00 Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used non-human primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. H5N6 HPAIV infection led to high fever in cynomolgus macaques. The lung injury caused by the virus was severe with diffuse alveolar damage and neutrophil infiltration. In addition, an increase in IFN-α showed an inverse correlation with virus titers during the infection process. Oseltamivir was effective for reducing H5N6 HPAIV propagation, and continuous treatment with peramivir reduced virus propagation and severity of symptoms in the early stage. This study also showed the pathologically severe lung injury states in the cynomolgus macaques infected with H5N6 HPAIV, even in those that received early antiviral drug treatments, indicating the need for close monitoring and the need for further studies on the virus pathogenicity and new antiviral therapies. Full Article
agent Development of Novel Anti-influenza Thiazolides with Relatively Broad-spectrum Antiviral Potentials [Antiviral Agents] By aac.asm.org Published On :: 2020-04-20T08:36:46-07:00 Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug-resistance to specific anti-influenza drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug nitazoxanide with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza potentials with 10-fold improvement, compared with nitazoxanide, and were effective against a variety of influenza subtypes including oseltamivir-resistant strains. Notably, the combination using of compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effect against oseltamivir-resistant strain. Mode of action analysis demonstrated that compounds 4a/4d acted at the late phase of viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of up-regulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, our study pointed the optimization direction of nitazoxanide as anti-influenza drug, and discovered two novel-structured candidates 4a/4d with relatively broad-spectrum antiviral potential. Full Article
agent A novel class of chikungunya virus small molecule inhibitors that targets the viral capping machinery [Antiviral Agents] By aac.asm.org Published On :: 2020-04-27T08:14:57-07:00 Despite the worldwide re-emergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. We here aim to identify the target of a novel class of CHIKV inhibitors i.e. CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low micromolar range. A CHVB-resistant variant (CHVBres) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2 and one mutation in nsP3. Reverse genetics studies demonstrated that both nsP1 mutations were necessary and sufficient to achieve ~18-fold resistance, suggesting that CHVB targets viral mRNA capping. Interestingly, CHVBres was cross-resistant to the previously described CHIKV capping inhibitors from the MADTP series, suggesting they share a similar mechanism of action. In enzymatic assays, CHVB inhibited the methyltransferase and guanylyltransferase activities of alphavirus nsP1 proteins. To conclude, we identified a class of CHIKV inhibitors that targets the viral capping machinery. The potent anti-CHIKV activity makes this chemical scaffold a potential candidate for CHIKV drug development. Full Article
agent Quercetin blocks Ebola Virus infection by counteracting the VP24 Interferon inhibitory function [Antiviral Agents] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Ebola Virus (EBOV) is among the most devastating pathogens causing fatal hemorrhagic fever in humans. The 2013–2016 epidemics resulted in over 11000 deaths, while another outbreak is currently ongoing. Since there is no FDA-approved drug so far to fight EBOV infection, there is an urgent need to focus on drug discovery. Considering the tight correlation between the high EBOV virulence and its ability to suppress the type-I Interferon (IFN-I) system, identifying molecules targeting viral protein VP24, one of the main virulence determinants blocking IFN response, is a promising novel anti-EBOV therapy approach. Hence, in the effort of finding novel EBOV inhibitors, a screening of a small set of flavonoids was performed, showing that Quercetin and Wogonin can suppress the VP24 effect on IFN-I signaling inhibition. The mechanism of action of the most active compound, Quercetin, showing an IC50 value of 7.4 μM, was characterized to significantly restore the IFN-I signaling cascade, blocked by VP24, by directly interfering with the VP24 binding to karyopherin-α and thus restoring P-STAT1 nuclear transport and IFN genes transcription. Quercetin significantly blocked viral infection, specifically targeting EBOV VP24 anti-IFN-I function. Overall, Quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps. Full Article
agent Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs [Antiviral Agents] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Drug repositioning is the only feasible option to address the COVID-19 global challenge immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and in particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects. Full Article
agent Inhibition of SARS-CoV-2 infection by the cyclophilin inhibitor Alisporivir (Debio 025) [Antiviral Agents] By aac.asm.org Published On :: 2020-05-06T08:16:52-07:00 Cyclophilins play a key role in the lifecycle of coronaviruses. Alisporivir (Debio 025) is a non-immunosuppressive analogue of cyclosporin A with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in VeroE6 cell line, with an EC50 of 0.46±0.04 μM. Alisporivir inhibited a post-entry step of the SARS-CoV-2 lifecycle. These results justify that a proof-of-concept Phase 2 trial be rapidly conducted with alisporivir in patients with SARS-CoV-2 infection. Full Article
agent Becoming certified agents on OM Riverboat By feedproxy.google.com Published On :: Mon, 12 Mar 2018 13:18:20 +0000 Disguised in different roles–from rebellious teenagers to homeless people to prostitutes and pimps–community members responsible for the onshore segment of The Agency experience act out the types of least reached people in society. Full Article