A tweak to cellular machinery could hold promise for treatment Inosine could be a potential route to the first RNA and the origin of life on Earth RNA errors linked to ALS and dementia Viruses are masterful invaders. They cannibalize host cells by injecting their genetic material, often making thousands of copies of themselves in a single cell to ensure their replication and survival.Some RNA viruses — viruses whose RNA, not DNA, carries their genetic information — insert their genetic material into cells as a single piece, while others chop it up. The latter are aptly named segmented viruses.Such segmented RNA viruses, including several that cause human diseases like influenza, have long been an enigma to researchers: How do they accomplish the precise copying and insertion of each segment? How do they ensure that individual segments are all copied by the same enzyme and that each segment can make different amounts of RNA? Such exquisite regulation is critical to making the correct levels of the viral proteins necessary for successful replication.Now research by scientists at Harvard Medical School’s Blavatnik Institute yields a surprising answer: The viral machinery in charge of this survival-ensuring maneuver becomes activated by RNA from the tail end of the segment, opposite to where the copying starts.The findings, published May 9 in PNAS, identify new potential targets to inhibit the replication of segmented viruses. This group includes several emerging and highly fatal viruses such as Lassa fever virus, bunyaviruses like La Crosse and Rift Valley fever, as well as the better-known and more common influenza viruses.“Climate change has altered and intensified the spread of some serious and emerging viruses to new geographic regions, creating an acute challenge to global health. Our findings identify a critical mechanism that allows some of these pathogens to replicate and survive,” said Sean P.J. Whelan, professor of microbiology at HMS and director of the Harvard Program in Virology.Being infected with the Lassa fever virus, for example, is rarely fatal, but once the actual disease develops, it can cause hemorrhaging in multiple organs in one out of five people. The mortality rate can reach 50 percent during epidemics, according to the Centers for Disease Control and Prevention.In the study, Whelan and his co-author Jesse Pyle, a graduate student in his lab, worked with the Machupo virus, an arenavirus that, like Lassa virus, infects rodents, which transmit the virus to humans, in whom it can cause fatal hemorrhagic fevers.Unlike the flu virus, whose genome has eight segments, the Machupo virus has only two segments — called small and large segments — offering a much simpler way to understand how segments are copied in the correct amounts.Previous clues about this mechanism came from research on influenza and La Crosse viruses that showed the viral protein responsible for copying the key segment — RNA-dependent RNA-polymerase (RdRP) — interacted with the 5′ end of the segment, which is the exact opposite end to the location where the protein initiates copying. Yet, the importance of this interaction was not fully understood.The experiments revealed that mixing short 13-nucleotide RNAs from the 5′ end of the Machupo virus segments with the RdRP, the catalyst that initiates RNA replication, stimulated the ability of this enzyme to copy the viral segment. The two-segment Machupo virus contains four subtly different 5′ RNAs that each bind the RdRP enzyme. Remarkably, the scientists observed, those RNAs dictate which of four different start sites the enzyme actually uses.Whelan and Pyle say these results not only shed light on an important question in basic virology, but also identify a target that may illuminate how to develop of a new class of antiviral drugs directed at this essential 5′ RNA activation. Related Life, with another ingredient Most antiviral drugs currently on the market target viral enzymes involved in replicating genetic material or in the processing of viral proteins. None, however, interfere with the particular mechanism described in the current study.“Our work demonstrates that both the 5′ RNA and its binding site on the viral enzyme are potential new targets for inhibition of viral replication,” Whelan said. “An important next goal would be to hunt for molecules that interfere with this process and set the stage for new drug design.”This research was funded by National Institutes of Health.
Leicester City Manager, Bredan Rodgers, has confessed that he really missed the absence of Nigeria wonder-kid, Wilfred Ndidi, after their defeat against Southampton on Sunday. Ndidi makes 100 Premier league appearances Leicester slumped to their fifth defeat of the season against Southampton, putting in an underwhelming performance against a side that they had hammered 9-0 back in October. The Foxes’ performance was worrying and starkly exposed Brendan Rodgers’ reliance on the brilliant Wilfred Ndidi. Although Jamie Vardy has stolen most of the headlines, the real epicenter of Leicester’s success this season has been the ever-reliable Ndidi. Operating as a defensive midfielder in Brendan Rodgers’ devastating 4-1-4-1 formation, the 23-year-old has frequently acted as Leicester’s ‘get of jail free card’ for their expansive tactical style. His rangy, almost octopus-like legs, his telepathic reading of the game and his marathon runner levels of stamina, equipping with the attributes to sweep the entire width of the pitch in front of the Foxes defence. The Nigerian’s influence really cannot be overstated. His role is indispensable to the team, helping each one of his teammates perform more effectively. Ndidi’s stoic and energetic defensive performances have allowed full-backs Ben Chilwell and Ricardo Pereira to bomb forward, while also offering James Maddison and Youri Tielemans significant creative freedom in midfield. Thus, when the news broke that Leicester’s talisman would be out until February there was more than a few City fans who were worried. The Foxes’ performance against Aston Villa in midweek did little to arrest these fears. In response to Ndidi’s absence, Rodgers re-jigged the side – fielding a 3-5-2 formation which included a central midfield three of Dennis Praet, Youri Tielemans and Maddison. Both Belgians in this trio had underwhelming games with Tielemans in particular looking completely off the pace – suggesting that the huge amount of games he has been involved in this season are beginning to take their toll on his performances. He was eventually dragged off for Marc Albrighton but it would be Praet’s replacement that changed the game: the often forgotten Hamza Choudhury. Industrious, technical-sound and aggressive, the England Under 21 international helped Leicester take control of the midfield, sparking some muted calls for the player to receive a senior Three Lions call up. Choudhury was a passenger for the majority of the game, dropping far too deep and inviting pressure from the visitors. There were period were he retreated as far as Leicester’s defensive line with Jonny Evans having the urge to the youngster to push up on more than one occasion. Leicester also surrendered possession constantly in one of their least dominant displays of the campaign. Choudhury was partly to blame. The 22-year-old was not proactive enough in creating passing options for his teammates as Ndidi does so effectively and was guilty of overplaying – particularly in the second half. Choudhury’s usual combativeness was also curiously absent from his performance with both Praet and Pereira leading him in possession gained by some distance. The Saints’ performance revealed an issue that Leicester fans have been fearing for a long time. How does this thin squad keep up their Champions League challenge alive in the face of injuries to their star names? Ndidi’s surgery successful, says Rodgers Yes, Choudhury is only 22 and yes, he will improve as he gets more game time over the next several weeks, but he is clearly nowhere near disciplined or talented enough to play Ndidi’s highly specialised role in the 4-1-4-1 system. Rodgers may need to go back to the drawing board tactically because a few more performances like this and Leicester’s comfortable lead over fifth place is going to disappear at an alarming rate. FacebookTwitterWhatsAppEmail分享 Despite playing just 45 minutes, Hamza Choudhury won more tackles vs. Aston Villa (3/3) than any other Leicester City midfielder. Rodgers would admit after the game that he had made a mistake in not trusted the Foxes youth academy graduate to fulfill Ndidi’s role in the 4-1-4-1, an error that he responded to by starting him in Leicester’s 2-1 defeat to Southampton this afternoon. Loading… Promoted ContentMind-Bending Technology That Was Predicted Before It AppearedTop 10 Most Populated Cities In The WorldWhich Country Is The Most Romantic In The World?6 Interesting Ways To Make Money With A Drone9 Facts You Should Know Before Getting A TattooCan Playing Too Many Video Games Hurt Your Body?Best Car Manufacturers In The World7 Universities In The World Where Education Costs Too MuchBest & Worst Celebrity Endorsed Games Ever MadeWho Earns More Than Ronaldo?5 Of The World’s Most Unique Theme ParksSome Impressive And Almost Shocking Robots That Exist