Nov 21, 2006 (CIDRAP News) – Researchers recently reported identifying two mutations in the H5N1 avian influenza virus that seem to improve its ability to attach to human cells, a finding that may help scientists spot H5N1 strains capable of infecting humans.An international team of scientists determined that in the laboratory, two mutations in the hemagglutinin (HA) molecule of H5N1 viruses gave them the ability to recognize and bind to human-type cell receptors, according to the report in the Nov 16 issue of Nature.”The amino acid changes that we identify might serve as molecular markers for assessing the pandemic potential of H5N1 field isolates,” says the report by Shinya Yamada of the University of Tokyo and other scientists from Japan, Vietnam, Indonesia, the United Kingdom, and the United States.H5N1 viruses have killed millions of birds since late 2003 but still infect humans relatively rarely, having caused 258 illness cases with 153 deaths so far. Previous studies have shown that avian and human influenza A viruses recognize different host-cell receptors. Avian flu viruses prefer a cell receptor molecule consisting of sialic acid with an alpha2,3 linkage to galactose (called SA-alpha2,3Gal), whereas human flu viruses prefer receptors consisting of sialic acid with an alpha2,6 linkage to galactose (called SA-alpha2,6Gal).Because of this, a change in preference from SA-alpha2,3Gal to SA-alpha2,6Gal is believed to be one of the steps that could enable the H5N1 virus to readily infect humans and possibly lead to a pandemic.Yamada and colleagues set out to determine which mutations in the HA protein enable it to recognize human type receptors. They used clones of three H5N1 isolates from Vietnam, and they also synthesized the HAs of eight other H5N1 viruses collected from humans in Thailand, Vietnam, and Cambodia by using data from a public sequence database. The team created hybrid viruses by combining these HAs with the neuraminidase from a 2004 Vietnam H5N1 isolate and six genes from a laboratory strain of H1N1 virus.The researchers then assessed the binding of these viruses to artificial surfaces made of sialylglycopolymers that featured either the avian or the human type of receptor. They found that none of the five avian strains attached to the human type receptors, whereas 3 of 21 viruses representing human isolates bound to both the avian and human receptors.In comparing the HAs of these three viruses with an avian type HA, the scientists found that two of them differed from the avian type HA at two amino acid positions each (a total of four mutations, at positions 192, 223, 139, and 182). To test the effects of these mutations, the team introduced the mutations into the virus with the avian form of HA. They found that introducing one of a pair of mutations improved the virus’s ability to bind to human type receptors, and introducing both mutations increased that ability further.The team also analyzed the crystal structure of one of the viruses and concluded that the locations of two of the mutations, at positions 182 and 192, suggest that an effect on receptor binding is plausible.Further, the scientists report that these same two changes (at 182 and 192) were present in H5N1 viruses isolated from two people in Azerbaijan and one person in Iraq, but not in any of more than 600 avian isolates that have been examined.The authors conclude that amino acid changes at positions 182 and 192 in the HA molecule “independently convert the HAs of H5N1 viruses known to recognize the avian receptor to ones that recognize the human receptor.”However, the mutations the scientists identified have not yet equipped H5N1 to spread easily from person to person, and the authors acknowledge that mutations in proteins other than HA may be necessary before that can happen. But the mutations they identified “might provide useful molecular markers in assessments of H5N1 field isolates for their capacity to replicate in humans—an essential indicator of pandemic potential,” they write.The senior author of the article isYoshihiro Kawaoka of the University of Wisconsin and the University of Tokyo. In a University of Wisconsin news release, he said it is not known how many mutations will be required for the virus to fully adapt to humans. But if scientists continue to monitor the virus in humans, they may be able to trace a “mutation trajectory” that will help them predict when the virus will reach that point, he said.Hamada S, Suzuki Y, Suzuki T, et al. Haemagglutinin mutations responsible for the binding of H5N1 influenza A virus to human-type receptors. Nature 2006 Nov 16;444(7117):378-82 [Abstract]See also:University of Wisconsin news release (Nov 15)http://www.news.wisc.edu/13198.html
The summary said the Chinese trial involved 237 patients, with 158 on the drug and 79 in a control group. Remdesivir was stopped early in 18 patients because of side effects.The authors said remdesivir was “not associated with a difference in time to clinical improvement” compared to the control.After a month, 13.9 percent of the patients on remdesivir had died compared to 12.8 percent of those in the control group. The difference is not statistically significant.The WHO told the Financial Times that the draft is undergoing peer review and was published early in error. Trials continue A spokesman for Gilead told AFP: “We believe the post included inappropriate characterizations of the study,” saying it was terminated early due to low enrollment and was therefore not statistically meaningful.”As such, the study results are inconclusive, though trends in the data suggest a potential benefit for remdesivir, particularly among patients treated early in disease,” the spokesman added.The study does not represent the final word on the matter, and there are several large-scale trials in advanced stages that should soon provide a clearer picture.Remdesivir, which is administered intravenously, was among the first drugs suggested as a treatment for the novel coronavirus and as such has great hopes riding on it. Stephen Evans, a professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, who was not involved in the research, said “the trial was too small in numbers recruited” to detect either benefit or risk.But he added: “If the drug only works well when given very early after infection, it may be much less useful in practice.”Last week, Stat reported it had shown significant efficacy at a Chicago hospital where patients who are part of one of the major trials are being treated.The US National Institutes for Health also reported it had proven effective in a small experiment on monkeys. Remdesivir, which previously failed in trials against Ebola, belongs to a class of drugs that act on the virus directly — as opposed to controlling the abnormal and often lethal autoimmune response it causes.It mimics one of the four building blocks of RNA and DNA and gets absorbed into the virus’s genome, which in turn stops the pathogen from replicating.The antimalarial drugs hydroxychloroquine and chloroquine are also being widely used on COVID-19 on a so-called “compassionate basis” pending results from large trials, with early studies decidedly mixed.Other therapies that are being studied include collecting antibodies from COVID-19 survivors and injecting them in patients, or harvesting antibodies from genetically-engineered mice that were deliberately infected. Topics : The experimental coronavirus treatment remdesivir has failed in its first randomized clinical trial, inadvertently released results showed Thursday, dampening expectations for the closely watched drug. A draft summary went online briefly on the website of the World Health Organization (WHO) and was first reported by the Financial Times and Stat, which posted a screenshot.But Gilead Sciences, the company behind the medicine, disputed how the now-deleted post had characterized the findings, saying the data showed a “potential benefit.”
Simmons has been criticized by those within and outside the Philadelphia organization for not evolving his game to include long-range shooting, which continues to be his singular but glaring weakness.He played well against the Thunder following Brown’s public message, scoring 17 points, grabbing 15 boards and dishing eight assists. The effort kept him on an All-Star trajectory.But Simmons did not attempt a 3-pointer in Monday night’s game. Before the contest, Brown shouldered blame for the lack of jumpers by Simmons but did not provide a plan to correct course.”Evidently I have failed, and it’s something that we’re all mindful of, and this is one of these things that is never gonna go away,” Brown told reporters. “The attention this has received is remarkable. But I guess I helped fuel it, and I own it. I’ve got to help him find this, and most importantly, he has to help himself.”#Sixers coach Brett Brown responds to Ben Simmons not shooting a three-pointer per game after Brown suggested in a post-game press conference last month that he do so: pic.twitter.com/1tI2uExTRI— Keith Pompey (@PompeyOnSixers) January 6, 2020MORE: Bleakest NBA franchises Brett Brown has said on multiple occasions he wants Ben Simmons to shoot regularly from behind the arc. Simmons has attempted five 3-pointers this season.The apparent disconnect between the 76ers coach and skilled ball handler looms over an otherwise successful team. Philadelphia improved to 24-14 with its 120-113 win over the Thunder on Monday night.
It’s not out until 29 September, so EA Sports are teasing us with this trailer for FIFA 17.Three options are available for those of you who want to order the game ahead of its release date: Super Deluxe, Deluxe and Standard editions.Real Madrid’s James Rodriguez, Man United’s Anthony Martial, Marco Reus of Borussia Dortmund and Chelsea playmaker Eden Hazard all feature in the ad as does the voice of Man United manager Jose Mourinho.It means there will be no Lionel Messi on the cover for the first time since 2012.Check out the FIFA gaming section on the talkSPORT YouTube channel here.