Austria strike forces 2hour halt to train services
VIENNA — Austria’s national railway has suspended all services for two hours because of a walkout by a union in a pay dispute.Railway operator OeBB said trains on its network were being halted from noon to 2 p.m. local time (1100 to 1300 GMT) Monday. Replacement buses were operating in some areas.The warning strike by the Vida union went ahead after the two sides met Monday morning for another round of negotiations.Employers are offering what they say is a 3 per cent pay increase, but employee representatives argue that the offer actually amounts to considerably less, according to public broadcaster ORF.The Associated Press
Simon CoveneyRichard BrutonMicheál MartinDenis NaughtenSean ConlanMartin HaydonAnthony LawlorDerek KeatingMary Mitchell O’ConnorEoghan MurphyTom BarryArthur SpringHeather HumphreysTimmy DooleyBilly KelleherÁine CollinsSandra McLellenMichelle MulherinDeirdre CluneEamon CoghlanImelda HenryFidelma Healy EamesCait KeaneCatherine NooneSusan O’KeeffeHildegarde NaughtonJohn CrownMark DalyAveril PowerTrevor Ó ClochartaighJimmy Deenihan.This year politicians will have some professional models to contend with as models Rosanna Davison and Roz Purcell will be joining them on the catwalk.Special guests from the world of sport and TV including GAA All Star Paul Galvin, this year’s All-Ireland Final’s Man of the Match Bernard Brogan, rugby pundit Brent Pope, Robert Hall of RTÉ Racing, weather presenter Nuala Carey, will also be there on the night.Here are some images of last year’s events: A CHARITY FASHION show will see dozens of TDs and Senators take to the catwalk next week.Organised by the Arts Minister Jimmy Deenihan, the event will raise money for the Irish Motor Neurone Disease Association.This is the second annual Oireachtas Charity Show and is taking place in the Shelbourne Hotel on Tuesday 12 November at 7pm.Motor Neurone DiseaseThe idea for the event came about last year when Deputy Nicky McFadden was diagnosed with Motor Neurone Disease. Jimmy Deenihan, who is described as a close friend and colleague to McFadden, asked stylist Marietta Doran to organise a fashion show to generate funds for Irish Motor Neurone Disease Association and the MND Research Foundation.Last year, politicians such as Sinn Fein’s Pearse Doherty, Labour’s John Lyons and Fianna Fáil’s Averil Power all took part in the catwalk challenge. The event was a great success and raised more than €20,000 for charity.This year politicians that have signed up for the cause include:
19,518 Views 30 Comments Source: Wicklow Uplands CouncilA local sheep farmer, who has suffered a number of losses recently said that farmers in the area would be forced to withdraw access to established walks in Wicklow.“It is not something that we would want to do, people have been walking these routes for centuries and the Wicklow Way is an important part of tourism in the area.“But we also have our own livelihood, myself and a number of nearby farmers have had sheep killed over the years but it has gotten worse lately.“It has gotten to the stage that even dogs on leads are causing trouble as they are frightening the sheep.”Another farmer said that it would get to the stage that loose dogs that stray onto farms in the area would be shot.“I personally wouldn’t have a problem with dogs on leads, and most owners are responsible and understand that there are working farms in the area.“Recently though more dogs have been left to roam free without a lead and that it were the problems start.”Similar calls were made in rural Kerry last August after 40 sheep were killed in on a West Kerry farm.Read: First-home grants and looser mortgage lending rules will fuel house price rises this year Blood on the grass. Image: Wicklow Uplands Council By William O’Toole Tweet thisShare on FacebookEmail this article *WARNING: THIS PIECE CONTAINS A GRAPHIC IMAGE*WICKLOW UPLANDS COUNCIL are pleading with dog owners to stop walking their dogs in the Wicklow Mountains following a number of sheep killings over the past few weeks.The call comes after the latest incident on Saturday when a ewe was found butchered at White Road, near the Sally Gap.A spokesperson for the council said that the incident was not the first one reported in the last few weeks.“Footprints in the snow show that somebody, presumably the owner, caught the dog and took it away without reporting the incident.”“If anyone has any information please contact your local garda station, the attack happened between 1pm and 3pm.”Over the Christmas period, farmers near the Lugnaquilla area stopped a number of walkers with dogs from entering the area after a number of sheep were killed. Blood on the grass. Image: Wicklow Uplands Council Monday 16 Jan 2017, 4:34 PM http://jrnl.ie/3189659 Jan 16th 2017, 4:34 PM Dog walkers asked to stop using Wicklow Mountains after sheep killed Similar calls were made in rural Kerry last August after 40 sheep were killed in on a West Kerry farm. Short URL Share100 Tweet Email2 
Facebook Twitter: @NeosKosmos Instagram University of Sydney professor Manos Stamatakis has linked the benefits of dog ownership to positive impacts on human health.Research being undertaken at the university’s Faculty of Health Sciences considers aspects of ownership and its effects on physical activity, disease prevention, behavioural changes and interaction between humans and canines.“We know that dogs can be not only a catalyst for physical activity, which is a major health issue in our society, but dog ownership can also address social isolation; the lack of connection between humans,” said Professor Stamatakis.“What we want to understand is why these benefits occur. Is it because of the ownership itself, or because there is another mechanism that mediates this, like walking or companionship?” Approximately 39 per cent of Australian households own a dog, which, according to Stamatakis, have encouraging physical and psychological outcomes on humans, especially amongst the elderly. “We know that with older age comes increasing isolation, and with that comes loneliness. It’s a major cardiovascular disease risk factor, it’s a major cancer risk factor, and it’s a major risk factor for depression,” he said.“One aspect of human isolation can be addressed simply by owning a dog, because of their companionship, unconditional acceptance and love that humans often do not get from other people.”
Stay on target Catholic School Bans ‘Harry Potter’ Books Because SpellsToy Tuesday: The Best Animal Toys Many of us are still waiting for our Hogwarts acceptance letter (my owl got lost for 15 years), but during a Google announcement event on Tuesday, the company revealed that there will be another way to get that wizarding experience.An app based around Fantastic Beasts and Where to Find Them is headed to Google’s VR headset, Google Daydream. Announced during the Made in Google event, the app will allow users to swing the controller like a wand. And that’s about all we know.One of the most common responses to the release of the AR app Pokémon Go was the need for a similar experience for Harry Potter fans. The Daydream app is similar, allowing you to go into VR and use the Daydream controller like a wand. It works like a Wii controller, allowing the user to wave it around for three-dimensional movement.There are few other details available in regards to the app, but you will have a wand, and isn’t that the most important thing?Google revealed a long list of software and features for Daydream, including the announcement of a Star Chart app that’ll allow users to explore the stars, and the ability to watch Netflix, Hulu, and other media inside VR.Google Daydream is set to ship in November. There is no word on a release date for the Harry Potter app, but don’t be surprised if it comes out around the same time as the film. Daydream headsets will cost around $80. Customers can use them with Daydream-ready Pixel phones, which can be pre-ordered starting at around $650.
Hell Yeah, Put Tom Holland’s Spider-Man in ‘Venom’ and Rui…Watch: Here’s the First Close-Up Video of Ants Delivering Venom Stay on target It’s crazy to think about, but Venom was first announced as going into production in 2008 – a full decade ago. In the modern Marvel Cinematic Universe era, the concept of one of these flicks getting delayed at all is crazy. Studios have a schedule to keep, and superhero movies are basically a license to print money. That’s not always the case, though. Let’s dive into the studio longboxes to find eleven superhero films that are still stuck in development hell.LoboDC’s space-faring bounty hunter with a soft spot for dolphins seems like a lock in a post-Deadpool world, but somehow this big bastich just hasn’t been able to pull the trigger. We first heard rumors of a Lobo picture all the way back in 2009, with British director Guy Ritchie attached to direct. Ritchie was a great pick – he made his bones on foul-mouthed violent men – but he soon left the project to lens Sherlock Holmes: A Game Of Shadows and it fizzled. A few years later Dwayne Johnson was being talked about to play the Main Man (presumably with full-body white makeup), and most recently rumors are circulating that Warner Brothers is trying to lock down Michael Bay to direct.Black WidowIt’s more than a little strange that all of the original MCU Avengers got (multiple) solo films while Scarlett Johansson’s Black Widow… just didn’t. The character has an incredibly compelling backstory that’s barely touched on in the Avengers movies, and ScarJo is dependable cash at the box office. Marvel first started exploring a Widow solo film in 2004, with David Hayter penning a script for Lionsgate. After the launch of the MCU, talk of a Black Widow movie was in the air in 2010, with Johannson even talking to the press about how cool it would be to get deeper into her character. Sadly for her, it looks like Captain Marvel is going to be the first MCU heroine to anchor her own film.The Metal MenIf there’s one thing we love about DC, it’s that the company has an incredibly deep bench of memorable characters. Take the Metal Men, a quintet of humanoid robots, each composed of a different material, created by super-scientist Dr. Will Magnus to help humanity. Due to faulty responsometers, they attain sentience and personalities. The big draw of the Metal Men was their essential immortality – if they got smashed up in battle, Magnus was all too happy to repair them. Superstar director Barry Sonnenfeld was attached to a Metal Men movie back in 2012, but when the DCEU failed to launch the project was backburnered.GambitMarvel’s Cajun mutant was slated to hit the big screen multiple times, first with a cancelled appearance in X2 and then with Channing Tatum attached to the role. He was eventually played by Taylor Kitsch in X-Men Origins: Wolverine. Tatum has always expressed interest in the role, though, and in 2014 Fox announced they were returning to the actor for a standalone movie. Since then, though, things haven’t been great for the project, going through multiple directors including Doug Liman and Gore Verbinski. It’s currently on Fox’s release calendar for 2020, but let’s be honest here: it’s been bumped so many times that it might never see the light of day.NemesisWith Mark Millar signing a deal with Netflix, we wouldn’t be surprised to see this project resurrected. Millar and Steve McNiven’s 2010 Icon Comics series can best be described as “what if Batman, but bad?” The titular character wore an all-white costume and used his massive intellect and resources to completely destroy the life of a police Chief Inspector. It’s rife with all of Millar’s quirks and dark humor and Joe Carnahan was pegged to write a film with Tony Scott directing. After Scott passed away, Carnahan was given the director’s chair as well but since then it’s been stalled. The success of the Millar-based Kingsman movies might give it a jumpstart in the future though.CyborgDC’s somewhat unconventional strategy of introducing a bunch of heroes in the Justice League team-up flick before spinning them out into their own series doesn’t seem to have worked all that well, and one notable casualty is the Cyborg solo flick. Victor Stone is far and away DC’s most high-profile Black hero, and there are tons of stories that can be told with the character. Ray Fisher did fine work with the little he was given in League, and his solo flick was announced in 2014 with a reported 2020 release date. As we near that year, though, we’ve heard nothing about the project, and in Hollywood no news is bad news.Namor The Sub-MarinerMarvel’s aquatic ruler has been both hero and villain in the comics, clashing with the Fantastic Four and serving as an Avenger. Hollywood has been working on a film adaptation since 1997, because water-based movies were hip back then. 21 years later, we’re still no closer to seeing the ankle-winged mutant on the screen. Universal bought the movie in 2001 and eventually attached Chris Columbus to direct, but no shooting script was ever completed and the project stalled. Marvel’s rights issues have been complicated for some time, with different properties at different studios, and even though reports of a Subby movie started percolating again in 2017 – two decades after it began – we may never see it.TaskmasterThe idea of a villain-centric film isn’t a new one, and Suicide Squad showed there’s money to be made exploring the dark side of comics. But one Marvel flick that was way ahead of its time was Joe Carnahan’s Taskmaster solo movie, which was first announced to the press in 2008. The skull-faced foe with photographic reflexes is a solid supporting player, and Carnahan wanted to give him center stage with an origin narrative that would start with him getting the living hell kicked out of him by Moon Knight and move forward from there. We haven’t heard anything about the project in a decade, though, so hopes aren’t high.The CrowJames O’Barr’s gothic revenge comic was already made into a movie in 1994, probably best known for the on-set death of star Brandon Lee. Plans for a remake have been in the offing for decades, though, as director Stephen Norrington (best known for Blade) announced he’d be helming it in 2008 with Relativity Media backing the project. Things quickly went south from there, though, as Norrington left the movie and kicked off a revolving door of cast and crew turnover that saw actors as varied as Mark Wahlberg, Bradley Cooper and Jason Momoa as Eric Draven. As I write this, it doesn’t have a director or a star so who knows if it’ll ever make it out of development hell.Plastic ManDC’s stretchy hero was first rumored to be starring in his own film all the way back in the late 1990s with a screenplay penned by the pre-Matrix Wachowski siblings and Power Rangers director Bryan Spicer behind the camera. It never went into production, but after the flop of the brain-melting Speed Racer a decade and a half later the Wachowskis pulled the script out of mothballs to try and get it made. Bruce Campbell was at one point attached to play Eel O’Brian, which would have been absolutely brilliant. Keanu Reeves was also in consideration, but filming never started. Rumors that David Tennant would play the character in Justice League also didn’t come true, and as of press time there’s no new news on Plas’s solo outing.We3Grant Morrison’s tale of cybernetically enhanced animals on the run from their creators isn’t a superhero story per se, but it’s one of the Scottish writer’s best works and it was optioned very quickly by New Line Cinema after its publication in 2005. Sadly for fans of cute dogs and ultraviolence, the proposed adaptation hasn’t been able to get off the ground. Morrison completed a script a few years later and the rights went over to Relativity Media, but the selection of director John Stevenson – best known for Kung Fu Panda – didn’t have fans too excited. The project has remained in limbo ever since, with studio gossip hinting that the level of violence in the source material is a big roadblock.For more on Venom, here’s why we think Venom should ruin the MCU and our Geek Pick on an adult Venom costume.Let us know what you like about Geek by taking our survey.
Antoine Griezmann’s year just keeps on getting better and his joyful mood has seen him splash out on special gifts for all his Atletico Madrid team-matesThe Frenchman joined Los Rojiblancos in 2014 from Real Sociedad after Diego Simeone’s side famously beat both Real Madrid and Barcelona to the La Liga crown.But Griezmann would have to wait another four years before he could claim his first ever piece of major silverware.And what a year it has been for the 27-year-old.In just the past three months, Griezmann helped Atletico win the Europa League and later played a key role in securing France the 2018 World Cup.But the French striker isn’t done yet after helping Atletico claim the UEFA Super Cup over city rivals Real Madrid on Wednesday night.
La Liga Betting: Match-day 4 Stuart Heath – September 14, 2019 Despite it being very early into La Liga season, both Barcelona and Real Madrid have had unprecedented starts to their campaigns. With this in…While the trophy itself is hardly as significant as the Champions League, Griezmann was keen to mark the occasion nevertheless.Taking inspiration from US sports like the NBA and the Super Bowl, Griezmann presented his teammates specially designed champion rings to commemorate their achievements.Below is a picture of the gold and diamond rings that show the Atletico badge on the front.Antoine Griezmann has provided a ring with a club badge for all of his teammates after the victory in the Europa League, following NBA habits.. pic.twitter.com/fIWKNaQvLQ— It’s Me (@itsme77777) August 16, 2018
Watford boss Javier Gracia has been named the Premier League Manager of the Month for AugustThe Spaniard guided Watford to three successive victories in August to mark the club’s strongest start to a league campaign.The Hornets are currently one of just four teams to boast a 100% record after winning all four of their opening games.And Gracia intends to savour the moment.“I am very pleased,” said Gracia on the league website.“We are enjoying [it]. You never know what will happen.“Don’t look only at the end of the road. Try to enjoy day by day.“Try to enjoy the very good atmosphere, the workers who are helping us, the supporters in all the games are amazing.
Vidic: “Ronaldo is the most professional footballer I’ve seen” Andrew Smyth – September 14, 2019 Nemanja Vidic opened up on how a 21-year-old Cristiano Ronaldo’s professionalism left him stunned at Manchester United.“I think altogether we can achieve very good things.”Quique Sanchez Flores was the last Watford manager to win the accolade in December 2015.Liverpool’s Jurgen Klopp, Mauricio Pochettino of Spurs and Chelsea coach Maurizio Sarri had all been nominees for the award.? | Congratulations to Javi Gracia, who has been awarded the @BarclaysFooty’s @PremierLeague Manger of the Month for August!Cue the water, lads! ?#watfordfc pic.twitter.com/SY6vo6INmW— Watford Football Club (@WatfordFC) September 7, 2018
STANFORD, Calif. — Stepfan Taylor, Tyler Gaffney and Anthony Wilkerson powered seventh-ranked Stanford to a school-record 446 yards rushing to blow past No. 22 Washington 65-21 on Saturday night.The running backs gave Heisman Trophy hopeful Andrew Luck some rest as the Cardinal (7-0, 5-0 Pac-12) extended the nation’s longest winning streak to 15 games. Taylor ran for 138 yards, Gaffney 117 yards and Wilkerson 93 yards to break the previous team mark of 439 in a victory over Oregon State in 1981.Facing the first ranked opponent of the season, Stanford pounded the Huskies (5-2, 4-1) in a critical Pac-12 North matchup.Chris Polk ran for scores from 46 and 61 yards in the first half to keep Washington close early. He finished with 144 yards rushing as the Cardinal’s defense clamped down.Luck threw for 169 yards and two touchdowns and completed 16 of 21 passes but was overshadowed — for once — by a running game that has quietly been among the nation’s best the last few years. No matter what happens next week at Southern California, the victory also almost guarantees that Nov. 12 matchup against Oregon at Stanford Stadium will decide the North’s representative in the inaugural Pac-12 championship game.Taylor and Gaffney each ran for a touchdown and Wilkerson had two. Wilkerson’s 38-yard scamper late in the fourth quarter gave Stanford the most yards rushing in a single game, eclipsing a 439-yard mark set in a victory at Oregon State in 1981.
Active-duty members of the Army stationed at Joint Base Elmendorf-Richardson prepare to march in a Veterans parade in Downtown Anchorage on November 4th, 2017, a week ahead of Veterans Day (Photo: Zachariah Hughes – Alaska Public Media)Flying beside the American Flag this Veterans Day you’re likely to spot another national icon: the stark black symbol for prisoners of war and those missing in action.Listen nowDesigned in the early 70s, the POW/MIA flag was part of a national movement by families during the Vietnam War to resolve the fates of missing service members. In many parts of the country, the symbol is ubiquitous, even though the last decades of American conflicts have seen practically no POWs.To a younger generation of veterans for whom prisoners and the missing dead are no longer a part of combat, the POW/MIA flag’s symbolism is shifting away from the literal and toward a feeling of having dropped out of the national consciousness.It was 26 degrees on a recent Saturday morning in downtown Anchorage as members of the Service High School band shifted from foot to foot trying to stay warm as they clutched their instruments. Clad in green jackets, the teens were bringing up the tail of a parade for veterans, followed a stilt-walking clown, a reindeer on a leash and a cadre of older bikers.A man walks his reindeer toward the Park Strip as part of a parade for veterans in downtown Anchorage (Photo: Zachariah Hughes – Alaska PublicFlying from the back of their motorcycles is the black POW/MIA flag, with a white silhouette of a young man trapped behind wire and a menacing guard-tower. The text underneath read ‘You are not forgotten.’ The image is everywhere: Patches, flag-poles — there’s even a Dodge Charger with a paint job of the somber emblem covering the entire side.The license plate: POWMIA.According to Woody Quackenbush, the vehicle belongs to someone from nearby American Legion Post #1, where he is a member.A Dodge Charger painted with the POW/MIA flag drove behind a group of bikers in the veterans parade (Photo: Zachariah Hughes – Alaska Public Media)“During the Vietnam War and stuff they’d send people out on patrol, they didn’t know where they were,” Quackenbush said, his long gray beard hanging down toward his beige three-wheeled hog.In 1962, at age 17, Quackenbush enlisted in the Army. In his view, during and after the Vietnam War, the POW flag was a way to draw attention to soldiers the government didn’t work hard enough recover.“We’re still trying to find a lot of people that didn’t come back,” Quackenbush said. “They don’t really have any records of where they are or what to look for. Once in a great while they find somebody. It’s a shame.”Woody Quackenbush, center, rides a three-wheeled motorcycle as part of a group of veteran bikers from an American Legion Post in Anchorage (Photo: Zachariah Hughes – Alaska Public Media)Officially, as of September of 2017 there are still 1,602 Americans unaccounted for from the Vietnam War. That’s a lot, but it pales in comparison to past conflicts where neither the science nor the will was in place to recover the dead. From World War II alone, there are 72,977 service members still listed as missing.But this accounting of warfare is becoming extinct: since 1986 through the wars in Iraq and Afghanistan, the total number of service-members left un-recovered by the military is six.Roger Sparks recently retired from the military after more than two decades serving as a Marine infantryman and later a pararescue jumper, having deployed to some of the most rugged parts of Afghanistan. Now, he works as a tattoo artist at a studio in Eagle River.“The conflicts that we’re fighting now, it’s not an atmosphere that you’re being held captive,” Sparks explained, sitting in the garage he’s converted into a home studio, filled with art, movie posters and the large, curling horns of a doll sheep skull.Roger Sparks shows off a tattoo gun at his home studio in Eagle River (Photo: Zachariah Hughes – Alaska Public Media)Sparks is a highly decorated vet who did a total of ten combat tours. And according to him, for many younger veterans the POW flag no longer stands for the literal absence of comrades held behind enemy lines or lost in the battlefield.“I almost view that as, ‘Well that’s their era of symbolism,’” Sparks explained.“I can really identify with the severity of their experiences, but I don’t feel I have ownership of that,” Sparks added, referring to older sentiments toward the POW flag.Sparks grew up in Texas surrounded by Vietnam vets, men who tended to have been drafted and generally went on one combat deployment. Today’s volunteer military is made up of people more similar to Sparks, with multiple combat deployments accrued during military careers.Compared to the Vietnam era, Sparks sees the country’s relationship with its recent wars as marked less by fervent support or opposition than general indifference. Part of why he thinks the POW flag resonates today with so many veterans, service-members and families is less for the silhouetted young man behind barbed wire, than the words below about not being forgotten.“I think that when you look at the (American) flag you can say ‘Well that’s patriotism.’ But when you look at that POW/MIA flag it’s more of combat loss, the reaping, just horror of what has been paid for this country to go on,” Sparks said. “I think that’s why people feel so strongly about it.”When Sparks started tattooing guys in Afghanistan, they’d sometimes sit down to do sessions right after returning to base from pararescue operations. Sparks described it as almost like a ceremony to process what they’d experienced. There, and in the time since, no one’s asked for the POW insignia.
The rail communications between Sylhet and the rest of the country were restored after five and a half hours of disruption following derailment of a boggy of a freight train at Maizgaon in Fenchuganj upazila in Sylhet early Saturday, reports UNB.Abul Malek, officer-in-charge of Kulaura police station, said that the bogy of the Sylhet train veered off Sylhet-Akhaura rail track around 10:00pm on Friday.Passengers of ‘Upaban Express’ suffered a lot as the train remained stranded at Mogla Bazar station following the disruption.Later, the body of the freight train was salvaged around 3:30am, said Shafiqul Islam, station manager of Maizgaon railway station.
Explore further ATP-induced conformational changes. a) Superposition of the RecA-like subdomains of the NBDs (Nucleotide binding domains) of the ABCG2EQ–E1S (green) and ABCG2EQ–ATP (blue) structures. A roughly 35-degree inward rotation of the helical subdomain is observed upon ATP binding. b) Superposition of one ABCG2 monomer of the ABCG2EQ–E1S and ABCG2EQ–ATP structures, with the NBDs shown as a grey surface and the TMDs (transmembrane domains) as ribbons. The interface helices—CpH and CnH—are labelled. c) Superposition of the ABCG2EQ–E1S and ABCG2EQ–ATP structures along the two-fold symmetry axis (dotted line), showing a 7 Å inward movement of the CpH helices of each ABCG2 monomer. d) Comparison of a single ABCG2 monomer of the ABCG2EQ–E1S and ABCG2EQ–ATP structures. The NBDs have been superimposed, revealing a 20-degree rotation of the CnH and CpH helices (shown as ribbons) as well as a 40-degree rotation of the TMDs relative to one another. Credit: Nature, doi: https://doi.org/10.1038/s41586-018-0680-3. , Nature Structural & Molecular Biology Analyzing the substrate binding cavity and the mutant. a) C2-symmetrized electron microscopy density of ABCG2EQ-EIS; bound EIS molecule (pink or turquoise sticks) shown in two possible orientations rotated by 180 degrees along the y-axis. b) Similar to (a) but rotated 90 degrees and showing one EIS molecule and surrounding residues as labelled. c) Overlay of EIS (pink sticks) and inhibitors M229 (green sticks) and MB136 (yellow sticks) bound in the substrate-binding cavity after superposition of the three structures. d) Substrate-binding cavity viewed from within the membrane, showing side-chains (sticks) of residues interacting with EIS (pink sticks). e) ATPase activities of liposome-reconstituted wild type and mutant ABCG2 in the presence and absence of EIS (50 µM). f) The initial EIS-transport activities. Credit: Nature, doi: https://doi.org/10.1038/s41586-018-0680-3. Substrate translocation pathway. a) Cα trace of the translocation pathway region of ABCG2EQ–E1S. Residues lining the substrate-binding cavity are shown as sticks; bound E1S omitted for clarity. The dashed line shows the distance between the two F439 residues that stack against bound E1S. b) Vertical slice through a surface representation of ABCG2EQ–E1S, with bound E1S shown as pink spheres and the two cavities and plug region labelled. In the right-hand panel, a 90° rotation of the structure reveals the fit of E1S in the substrate-binding cavity, as viewed from the cytoplasm. The NBDs have been removed for clarity. c) and (d), As for a, b, but with the ABCG2EQ–ATP structure. In the right-hand panel of (d) the molecular surface of the external cavity is viewed from the extracellular space and color-coded by electrostatic potential ranging from blue (most positive) to red (most negative), shown with the extracellular loop EL3 removed for clarity. Credit: Nature, doi: 10.1038/s41586-018-0680-3. The transporter protein ABCG2 belongs to the ATP-binding-cassette (ABC) family. The protein is expressed in the plasma membranes of cells within a variety of tissues and tissue barriers, including the blood-brain, blood-testes and maternal-fetal barrier. The protein can be powered by ATP to translocate endogenous substrates, affect the pharmacokinetics of many drugs and protect against a variety of xenobiotics including anticancer drugs, notably in breast cancer. ABCG2 is often referred to as the breast cancer resistance protein, where previous studies have revealed the ABCG2 architecture and structural basis of ABCG2 inhibition with small molecules and antibodies. The mechanism of substrate recognition by ABCG2 alongside its ATP-driven transport capability remains yet to be determined. Protein dynamics: Molecular machines at work Structure and transport cycle of ABCG2. a) Cartoon representation of ABCG2EQ- E1S (left) and ABCG2EQ-ATP (right). ABCG2 monomers colored blue and orange. Bound E1S, ATP and Mg2 were shown as spheres. In ABCG2EQ the bound 5D3-Fab was omitted for clarity. b) structure of NBD dimer from the ATP-band state viewed from the cytoplasm with bound ATP (sticks) and Mg2+ ions (spheres). Inset rotated ~ 150 degrees to the right, viewed from membrane: electron microscopy density around bound ATP with Walker A and Walker B motif, E190 of the signature motif and the ‘switch’ histidine (H243) labelled and shown as sticks. The Mg2+ is shown as a purple sphere. Credit: Nature, doi: https://doi.org/10.1038/s41586-018-0680-3 One caveat in the study was that the E211Q mutation may have influenced the energetics of the conformational changes involved. The findings suggested that ATP binding may be sufficient for the substrate-extrusion step and the transporter could be reset to an inward-facing conformation by ATP hydrolysis. Unlike other transporters, the ABCG2 did not appear to form a stable, occluded conformation upon substrate binding, but demonstrated a transient conformation with peristalsis-like mechanisms akin to the bacterial BtuCD-F transporter. A key question that had remained unanswered with polyspecific multidrug transporters such as ABCG2 was why some compounds acted as substrates, while others acted as potent inhibitors. When the authors compared the binding modes of ABCG2 substrate with those of two potent inhibitors, all three molecules bound to the same cavity of the transporter. The study further showed that when the substrate EIS and ATP bound together to ABCG2, an opening of the plug allowed the substrate to be pushed into the external cavity. In contrast, inhibitors acted as wedges to immobilize the transporters by locking the structure in an inward-facing conformation. The study suggested that the size and binding affinity of the compounds were important for translocation in the transporters, thereby allowing to distinguish substrates from inhibitors. The work provides new insight to further understand dynamics of the transporter protein ABCG2. In a new report now published in Nature, Ioannis Manolaridis and colleagues presented high-resolution cryoelectron microscopy structures of human ABCG2 in its substrate-bound state of pre-translocation and in the ATP-bound post-translocation state. The scientists used a mutant protein containing a glutamine in place of the catalytic glutamate (ABCG2EQ) to observe both states. The mutant ABCG2EQ showed reduced ATPase and transport rates to enable conformational trapping suited for the structural studies. In the substrate-bound state of the study, about halfway across the membrane in a cytoplasm-facing cavity, a single molecule of estrone-3-sulfate (E1S) was integrated for functional studies. Rigid-body shifts of the transmembrane domain were observed as a result of ATP-induced conformational changes, pivoting the nucleotide-binding domains (NBDs) and changes in the relative NBD subdomain orientation. In its mechanism of action, ABCG2 harnessed the energy of ATP binding to extrude E1S and other endogenous substrates. Based on the size and binding affinity of compounds it was therefore possible to distinguish substrates from inhibitors in the study. Journal information: Nature , Cell More information: Ioannis Manolaridis et al. Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states, Nature (2018). DOI: 10.1038/s41586-018-0680-3 Scott M. Jackson et al. Structural basis of small-molecule inhibition of human multidrug transporter ABCG2, Nature Structural & Molecular Biology (2018). DOI: 10.1038/s41594-018-0049-1 Zachary Lee Johnson et al. ATP Binding Enables Substrate Release from Multidrug Resistance Protein 1, Cell (2017). DOI: 10.1016/j.cell.2017.12.005 Structurally in the ATP-bound state of ABCG2EQ-EIS, phenyl rings stacked against each other, collapsing the substrate-bending cavity without space for the bound substrate. For transportation across the membrane, the substrates had to move through the translocation pathway at the center of the transporter to reach the external cavity before the pathway closed completely. For this process, transient conformational changes resembling peristaltic motion had to occur to generate space for the substrate. The authors assumed that the substrate may bind via the cytoplasm or via the “membrane entrance” within the lipid bilayer. Once bound, the NBD dimer could only close when the substrate moved out of the substrate-binding cavity. In a productive transport cycle, the substrate was assumed to move through a translocation pathway at the center of the transporter via a “leucine plug.” Once a substrate cleared the plug area, the structure of ATP-bound ABCG2EQ suggested that the plug region closed, and substrate was released to the outside. The authors observed a density feature formed by the transmembrane (TM) helices TM2 and TM5a in the substrate-binding cavity of ABCG2 monomers. The density feature could bind one E1S substrate in two orientations, although two E1S molecules could not be bound simultaneously due to steric clashing of the polycyclic ring systems. The substrate binding cavity could also accommodate inhibitors, demonstrating its dual role in substrate and multidrug binding. In the study, the scientists generated single point mutations for ABCG2EQ- E1S to determine ATPase activity and E1S transport of the resulting mutant variants. The stability of all tested mutants showed similarity to the native, wild-type protein allowing direct comparison. The V546F mutant for instance, had impaired transport activity but a 12-fold increase in ATPase activity, although that was inhibited by E1S in a concentration-dependent manner. This result suggested that the introduction of two phenyl rings into the substrate cavity enabled substrate-binding mimicry for ATPase activity stimulation, but further inclusion of E1S ‘clogged’ the transporter. Results for other mutant variants varied in comparison to the wild-type protein in the study, emphasizing the sensitivity of the binding cavity to modifications. Additional functional studies with cryo-EM microscopy showed that ATP binding caused a 35 degree rotation of the α-helical domains of NBD (nucleotide-binding domains) for dimerization—to enable the ‘power stroke’ in the transport cycle. In each ABCG2 monomer, individual transmembrane nucleotide binding domain interfaces remained largely unchanged between the nucleotide-free and ATP-bound states. However, ATP-induced conformational changes triggered shifts in NBD causing cytoplasmic components of the transmembrane domain (TMD) to push towards each other. Such ATP-induced conformational changes have important roles in the substrate-translocation pathway. Citation: Cryogenic-electron microscopy (Cryo-EM) structures of a human ABCG2 mutant transporter protein (2018, November 21) retrieved 18 August 2019 from https://phys.org/news/2018-11-cryogenic-electron-microscopy-cryo-em-human-abcg2.html © 2018 Science X Network The authors first established that replacing the catalytic glutamate E211 with a glutamine in the Walker B motif (phosphate binding sequence) would result in mutants with greatly diminished (although not abolished), ATP hydrolysis and E1S transport activity. To determine the E1S bound structure, an antigen-binding fragment of monoclonal antibody 5D3 (5D3-Fab) was added to the sample – which bound to the external surface of ABCG2, to facilitate high-resolution structure determination. The ATP hydrolysis was slowed down and transport activity of liposome-reconstituted ABCG2 inhibited by the addition of 5D3-Fab, without impacting the interaction between ABCG2 and E1S substrate. The ABCG2EQ complex revealed an inward-open conformation with an overall resolution of 3.6 Å to clearly visualize the transmembrane domain and the substrate binding cavity. This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
Get the biggest Daily stories by emailSubscribeSee our privacy noticeThank you for subscribingSee our privacy noticeCould not subscribe, try again laterInvalid EmailThree people have been left injured and a Staffordshire Moorlands crossroad has been closed for more than four hours following a two-vehicle collision. The area around Malthouse Lane and Winterfield Lane, in Hulme near Werrington, has been closed since 4.40pm today (December 6) because of the accident. Police officers tonight confirmed two people sustained minor injuries while a third has been taken to hospital for scans on their neck and back. The road remains closed as a precautionary measure. Read MoreThree more arrests after Potteries derby trouble A Staffordshire Police spokesman said: “We were called to a two-vehicle road traffic collision at Winterfield Lane at the junction of Malthouse Lane. “We’re still at the scene and there are three people injured. One is still being treated at the hospital and the road remains closed as a precaution. “We are waiting for the all-clear to reopen the road and were called at 4.40pm.” Traffic monitoring company INRIX reports the road is expected to be closed ‘well into the evening’ but traffic in the area is coping well. Want to keep up to date with the latest traffic and travel news?Each day Stoke-on-Trent Live journalists bring you the latest news on the roads and railways across Stoke-on-Trent, North Staffordshire, South Cheshire and further afield to help keep you on the move. For the very latest updates on roads including the M6, A500, A50 and more, visit our dedicated traffic and travel news channel here. We also run a live news feed each weekday, which you can access on our website’s homepage from 7am to 9pm from Monday to Friday. And for more as-we-get-it updates on the roads across the region and beyond, join The Sentinel’s traffic and travel Facebook group here. Want to tell us about something going on where you live? Let us know – Tweet us @SOTLive or message us on our Facebook page . And if you have pictures to share, tag us on Instagram at StokeonTrentLive .
Catalyst PT image courtesy of C-RAD October 25, 2018 — iCAD Inc. announced new clinical research demonstrating positive outcomes supporting the use of the Xoft Axxent Electronic Brachytherapy (eBx) System for the treatment of early-stage breast cancer. Preliminary results demonstrated that intraoperative radiation therapy (IORT) using the Xoft System is safe, with excellent local control and cosmesis, and low morbidity. The analysis of the international, multi-center trial was unveiled during an oral presentation at the 60th American Society for Radiation Oncology (ASTRO) annual meeting, Oct. 21-24 in San Antonio, Texas.In the presentation, A.M. Nisar Syed, M.D., principle study investigator, and medical director, radiation oncology and endocurietherapy, MemorialCare Cancer Institute, Long Beach Memorial Medical Center, and professor of radiation oncology, UCI Medical Center and Harbor-UCLA School of Medicine, detailed clinical techniques and outcomes of IORT using the Xoft System at the time of breast conserving surgery with findings based upon ASTRO suitability criteria. The trial enrolled 1,201 patients between May 2012 and July 2018 at 28 international and U.S.-based institutions. With a median follow up of two years, less than 1 percent of patients had cancer regrowth (ipsilateral recurrence) or developed new primary cancers in the other breast. Treatment was well tolerated, with grade 3, 4 and 5 adverse events occurring in only 37 patients. Mean treatment time was 10.5 minutes.“Our research continues to demonstrate significant promise in the treatment of early-stage breast cancer with IORT using the Xoft System. Preliminary outcomes show that a single fraction of radiation with the Xoft System yields excellent results in patients meeting specific selection criteria,” said Syed. “By greatly reducing the number of treatment patients receive as compared to traditional radiation therapy, IORT provides valuable advantages to patients including shorter treatment times, fewer side effects, reduced costs and improved quality of life.”In addition to the new data release at the annual meeting, iCAD hosted a series of in-booth expert presentations and peer-to-peer learning opportunities led by Syed and other global experts, including:Paulo Costa, M.D., radiation oncologist, Instituto CUF Porto, Breast Surgery Unit Senhora da Hora, Matosinhos, Portugal;Charles Wesley Hodge, M.D., radiation oncologist, Florida Hospital Celebration Health, Celebration, Fla.; andChun-Shu Lin, M.D., chief, Department of Radiation Oncology, Tri-Service General Hospital, Taipei City, Taiwan.IORT with the Xoft System uses a miniaturized X-ray source to deliver one precise, concentrated dose of radiation to a tumor site at the time of breast-conserving surgery (lumpectomy). The treatment can be completed in as little as eight minutes, making it possible for appropriately selected patients to replace six to eight weeks of post-operative external beam radiation therapy (EBRT) with a single treatment.The Xoft System is cleared by the U.S. Food and Drug Administration, CE marked and licensed in a growing number of countries for the treatment of cancer anywhere in the body, including early-stage breast cancer, non-melanoma skin cancer, and gynecological cancers.For more information: www.xoftinc.com FacebookTwitterLinkedInPrint分享 News | Artificial Intelligence | August 13, 2019 Artificial Intelligence Could Yield More Accurate Breast Cancer Diagnoses University of California Los Angeles (UCLA) researchers have developed an artificial intelligence (AI) system that… read more Images of regions of interest (colored lines) in the white matter skeleton representation. Data from left and right anterior thalamic radiation (ATR) were averaged. Image courtesy of C. Bouziane et al. News | Brachytherapy Systems | August 14, 2019 Efficacy of Isoray’s Cesium Blu Showcased in Recent Studies August 14, 2019 — Isoray announced a trio of studies recently reported at scientific meetings and published in medica read more News | Brachytherapy Systems, Women’s Healthcare | October 25, 2018 Xoft Electronic Brachytherapy System Effective in Early-Stage Breast Cancer Multi-center research presented at ASTRO 2018 shows intraoperative radiation therapy with the Xoft System is safe with low recurrence and low morbidity in the treatment of breast cancer Related Content News | Patient Positioning Radiation Therapy | August 15, 2019 Mevion and C-RAD Release Integration for Improved Proton Therapy Treatment Quality Mevion Medical Systems and C-RAD announced the integration between the C-RAD Catalyst PT and the Mevion S250i proton… read more News | Radiation Therapy | August 15, 2019 First Patient Enrolled in World’s Largest Brain Cancer Clinical Trial Henry Ford Cancer Institute is first-in-the-world to enroll a glioblastoma patient in the GBM AGILE Trial (Adaptive… read more News | Radiation Therapy | August 16, 2019 Drug Accelerates Blood System’s Recovery After Radiation, Chemotherapy A drug developed by UCLA physician-scientists and chemists speeds up the regeneration of mouse and human blood stem… read more 
News | PACS | August 09, 2019 Lake Medical Imaging Selects Infinitt for Multi-site RIS/PACS Infinitt North America will be implementing Infinitt RIS (radiology information system)/PACS (picture archiving and… read more The MD Anderson Proton Therapy Center expansion is expected to be completed in 2023. Rendering courtesy of Stantec. Following radiation, the bone marrow shows nearly complete loss of blood cells in mice (left). Mice treated with the PTP-sigma inhibitor displayed rapid recovery of blood cells (purple, right). Credit: UCLA Broad Stem Cell Research Center/Nature Communications News | Mammography | August 14, 2019 Imago Systems Announces Collaboration With Mayo Clinic for Breast Imaging Image visualization company Imago Systems announced it has signed a know-how license with Mayo Clinic. The multi-year… read more News | Neuro Imaging | August 16, 2019 ADHD Medication May Affect Brain Development in Children A drug used to treat attention-deficit/hyperactivity disorder (ADHD) appears to affect development of the brain’s… read more Image courtesy of Imago Systems News | Pediatric Imaging | August 14, 2019 Ultrasound Guidance Improves First-attempt Success in IV Access in Children August 14, 2019 – Children’s veins read more News | Proton Therapy | August 08, 2019 MD Anderson to Expand Proton Therapy Center The University of Texas MD Anderson Cancer Center unveiled plans to expand its Proton Therapy Center during a… read more
At the recent Meetings & Events Australia (MEA) awards nights the Staging Connections’ teams in VIC, NSW and QLD were declared state winners for the Technical & Creative Production award for branch turnover greater than $5 million.The MEA Awards celebrate and recognise excellence in the meetings and events space. The Awards program acknowledges individuals and teams that demonstrate the highest standards the event industry has to offer in Australia. The category identifies members that provide superior staging, production, technical and creative design for meetings and special events. The Staging Connections’ teams were presented their awards at their respective state ceremonies over the past week in-front of industry peers. The team in Queensland can be particularly congratulated in retaining the national award from 2010 and now the state winners in this category two years running. Tony Chamberlain, Managing Director of the Staging Connections Group is thrilled that the teams have been acknowledged for their achievements.‘It is a great tribute indeed for not only the individuals involved but the broader team, for consistently producing amazing events for our clients. The type of commitment shown by our entire team when producing spectacular and dynamic events is unprecedented. I am proud to be part of such a talented and passionate team with such expertise,’ said Mr Chamberlain.Staging Connections can now look forward to the MEA National Awards to be announced in April at the MEA Conference Awards Night. The state branches will compete against each other and other state industry winners in the crown for National Technical & Creative Production award winners for branch turnover greater than $5 million. As finalists in the MEA National Awards the QLD branch will also contest the new ‘Education Award’ for companies whose events have demonstrated outstanding educational elements. This announcement will be made at the MEA Conference Awards Night in April.The declaration of the MEA state winners follows the recent announcement that Staging Connections had won the national mice.net Readers’ Choice award for Best AV and Production Services Company. Source = MEA
Freddie,Freddie Mac’s Mortgage Portfolio Shrinks at Fastest Rate This Year Agents & Brokers Attorneys & Title Companies Delinquency Freddie Mac Investors Lenders & Servicers Loan Modification Mortgage-Backed Securities Profits Refinance RMBS Service Providers 2013-12-06 Krista Franks Brock in Secondary Market December 6, 2013 435 Views 
Share “”Freddie Mac’s””:http://www.freddiemac.com/ mortgage book of business declined at an annualized rate of 6.4 percent in October, marking the fourth consecutive month of declines. The book has registered declines in seven of the first 10 months of this year, according to “”Freddie Mac’s monthly volume summary.””:http://www.freddiemac.com/investors/volsum/pdf/1013mvs.pdf [IMAGE]October’s pace of decline was the highest rate so far this year and is up from a 4.3 percent annualized rate reported for September. Freddie Mac’s total mortgage portfolio is valued at about $1.9 trillion. [COLUMN_BREAK]New business at the GSE is also down over the month, marking the fourth consecutive month of declining new business at the GSE. Freddie Mac’s purchases and issuances in October totaled about $22 billion. New business added in September was about $28 billion. Totaling $12 billion, single-family refinance-loan purchases and guarantees made up 58 percent of the GSE’s total single-family portfolio purchases or issuances in October. Forty-two percent of that comprised relief refinance mortgages (based on unpaid principal balance). While “”Fannie Mae””:https://themreport.com/articles/fannie-maes-book-of-business-increases-in-october-2013-12-05 reported a declining serious delinquency rate among both single-family and multifamily mortgages in October, Freddie Mac recorded a decrease for single-family mortgages but a slight increase for its multifamily business. The delinquency rate for single-family mortgages at Freddie Mac in October was 2.48 percent, down from 2.58 percent in September. The serious delinquency rate for multifamily loans increased from 0.05 percent to 0.06 percent. Freddie Mac completed 7,902 loan modifications in October, bringing the year-to-date total to 68,333.