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ABSTRACT This is a proposal to develop a highly selective and potent antiviral benzodiazepine compound against yellow fever virus YFV as a therapeutic agent for treatment of yellow fever and understand its antiviral mechanism. Yellow fever is an acute viral hemorrhagic disease which threatens approximately one billion people living in tropical areas of Africa, Central and South America.
Although a highly effective yellow fever vaccine has been available for more than seven decades, the low vaccination rate fails to prevent outbreaks in at-risk regions. It has been estimated that up to 1. Thus far, there is no specific antiviral treatment for yellow fever. To cope with this medical challenge, we discovered an acetic acid benzodiazepine BDAA compound that potently inhibited YFV replication in both mammalian and insect cells by targeting the viral non-structural 4B NS4B protein.
We have already demonstrated in YFV-infected hamsters that oral administration of BDAA significantly protected the animals from death, reduced viral load by greater than 2 logs and attenuated viral infection-induced liver injury and body weight loss. Building on these encouraging preclinical studies, we propose in this project to optimize the lead compound to obtain benzodiazepine derivatives with improved solubility and reduced plasma protein binding ability to achieve improved in vivo antiviral efficacy and safety profile.
Meanwhile, we will continue our efforts toward understanding the molecular mechanism by which BDAA and its derivatives inhibit YFV replication. Specifically, impacts of the compound on NS4B protein metabolism, integrity and function of viral RNA replication complex as well as YFV interaction with host cellular innate immune response will be investigated. In addition to knowing how the compound inhibits YFV replication, our studies proposed in this project should also enrich our knowledge on the function of NS4B protein in YFV replication and evasion of host innate immunity.
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Updated: August 24, am. The body of water to the right, normally a farm field, has been dubbed Lake Watson. Floodwaters came to this area in the middle of March. Those Northwest Missouri residents who suffered from historic flooding in know all too well about the unstoppable force of water, how it will go where it wants, when it wants. Unfortunately, many of these farmers and property owners are learning that government bureaucracy sometimes proves to be an equally determined and unmovable foe.
A federal disaster declaration establishes April 29 as the starting date for covering flood damage impacting individuals this spring. That comes as news to some who had cleared out of their property more than a month before that date, when waters started going through and over levees protecting farms and small towns across Northwest Missouri. Recall that Gov. Mike Parson declared a state of emergency on March 21, as the the swollen Missouri River began to devastate communities and infrastructure in its path.
The river gauge in Rulo, Nebraska, — just across from Atchison County — showed a record crest reached one day earlier, on March
Cambridge HOTmaths is a comprehensive mathematics learning system — an interactive online maths learning, teaching and assessment resource for students and teachers, for individuals or whole classes, for school and at home. A suite of flexible resources printable and online is provided for all types of classrooms ranging from those with no technology to full laptop access, and includes projectable material in all lessons for interactive and non-interactive whiteboards.
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Please log in, or sign up for a new account and purchase a subscription to continue reading. Please log in, or sign up for a new account to continue reading. Sixty-four avalanches hit state Highway 21 between Stanley and Lowman this winter, up from an average of per season; 34 of those were large enough to destroy a car or a wood frame house. Nearly 40 professionals, including ski guides, highway forecasters, ski area snow-safety workers, search and rescue personnel, meteorologists and U.
Forest Service staff, attended the event. According to a press release from the center, there was plenty to discuss after a year of snow and avalanches that set records across the West. The event featured talks about historic avalanche cycles and remote sensing of snow, professional decision-making, cloud seeding and workplace accident reporting.
Contents: Bank of Ireland Cheques Register Now Customers bouncing cheques now face jail – dating Post-dated cheque Ten things you can no longer do at the bank. The study, which was the first major analysis of cheque usage in this country, found more than 84 million cheques were issued in one year, making Ireland second only to France when it comes to cheque usage.
The majority of these cheques were made out to businesses. Businesses issued 44 per cent of all cheques, equating to around 37 million in total.
BAARERSTRASSE 2. Issuer Name and Ticker or Trading Symbol. CRISPR Therapeutics AG [ CRSP ]. 3. Date of Earliest Transaction (Month/Day/Year).
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Besides face mask, reusable water bottles are the coolest and most responsible accessory you can own. By shedding the habit, you’ll not only cut out a dubious practice, you’ll also have the chance to to pick out a sharp accessory to bring with you anywhere. The market for reusable water bottles has never been better, with countless companies trying to make the perfect insulated containers and fashion brands seeking to turn them into a statement piece. You know the game was changed when Virgil Abloh partnered with Evian and Prada made a bottle last year that couldn’t stay stocked.
Who knows, maybe the right water bottle is the key to you finally getting enough fluids on a daily basis. Nalgene is a tried-and-true staple with the outdoor crowd, and the classic bottle gets a punk spin courtesy of Los Angeles’ Pleasures. Real ones will recognize Gogo’s bleeding eyes from Kill Bill , and anyone who doesn’t can give you all the strange looks they want. Another take on Nalgene comes from And Wander, the stylish outdoor brand from Tokyo.
This mountainscape and accompanying poem comes in a range of colors, but it’s the yellow version that sticks out to us most. Personally, I don’t want anything to do with a water bottle that isn’t insulated. I’m a stickler for ideal beverage temperatures, no matter what the science says on ice-cold water. This vacuum-sealed, double-walled bottle from Snow Peak, the Patagonia of Japan , is as good as it gets.
Fossilised ‘ocean lizard’ found inside ‘sea monster’ reveals rare behaviour
Your web browser is no longer supported. To improve your experience update it here. News World. Fossilised ‘ocean lizard’ found inside ‘sea monster’ reveals rare behaviour. Reconstruction of the Shonisaurus, a giant ichthyosaur.
The triangle below Canal, AKA Tribeca, is one of New York City’s original residential neighborhoods dating back to the s. Bounded by Canal Street, West.
On 30 July, we were targeted by a sophisticated cyber-attack. As a precaution, we took some of our systems offline, including our website. In recent discussions with RQIA regarding the resumption of on-site inspections, we stressed the need for a sensible and light-touch approach at this difficult time. We’re pleased to see the Scottish Government take note of the concerns we raised on behalf of Vocational Dental Practitioners VDPs , and welcome their decision to provide additional financial support for VDPs moving to associate position, and for vocational trainers.
We met with the RQIA this week to outline our objections to their plan for the renewal of site inspections in September. We made clear that extra disruption caused by an RQIA inspection is the very last thing practitioners need in the current circumstances. We are concerned about the funding package available to Vocational Dental Practitioners VDPs in Scotland and the consequences they face financially should they move to an associate position at the end of their VDP year in August After pushing for answers on various issues relating to associates pay and abatement, we are pleased to see NHS England provide clarity on a number of issues.
We are pushing for the Welsh Government to provide more funding for AGPs and to match the abatement figure announced in England this week. Dentistry in Scotland moved to phase 3 of reopening this week. At this time, we have urged the Scottish Government and NHS Boards to manage patients’ expectations and to look again at the financial support available to dentists.