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As for me, I believe that the world as we know now wasn't created by some superhuman being, but it rather evolved by the processes well explained by modern science. I also believe that there is no overall "bad", nor "good" - there are things that you personally approve and disapprove deep down in your conscience. In the end it's just a matter of opinion, hence ie. some people consider killing for faith a good thing, others don't. And which side do you choose doesn't really matter after you die, it only matters if you care to leave you want to leave your mark as a success or a failure. There's no heaven nor hell, you just fade away. And maybe you wake up unplugged from something like the Matrix or (most probably) you just rot buried in the ground - we won't know 'till it gets proven. And it won't.I'm open-minded, so I'd believe in god if someone would scientifically explain his existence, cause right now people are killing each other in the name of something that exists with as much probability as an Invisible Pink Unicorn. The only real "religion" right now is ethics, which some people don't even care about and that makes them a kind of heretics, which we don't have the power to expel from the society as a sort of atheist excommunication. The law is not perfect and will never be.I think believing in something supernatural is pretty much pointless. Either you get your expectations about the meaning of life too high or too low. It's best to just live your life and do your best, and if there's nothing after - it's exactly as expected, but if there is something - you'd be pleasantly surprised. A win-win situation.
Person you = new Person(); if(you.AreHappy && you.KnowIt){ you.ClapHands(); }
...Then there is the point of view shared by Gaijin, that there is birth and death. That life is the only form of consciousness. And then it ends. Sometimes I wonder if we can make machines conscious and self-aware. Cleverbot already feels incredibly human-like, but in the end all it can do is talk. Generate replies, basing on the input and its database. That, however, is off-topic.
I'm on Gaijin's stance here, albeit a bit more to the agnostic side. I'm open to the existence of anything as long as I can see some convincing proof.However, I find the thought of submission to a nameless higher power quite repulsive. If a God or gods turned up to be actually real, and demanded the kind of submission most religions (in particular the biblical ones) demand, I'd probably be joining a resistance movement just as I would if the Russians invaded and tried to impose Russian laws.
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Applecore wrote:The original? Or did you mean Quentin Tarantino's new film, "Inglourious Basterds"?
If you meant the original, I've heard good things and am planning to find the DVD tomorrow (it's been re-released to coincide with Tarantino's new offering).
If you meant QT's film, then yes I have and it's FUCKING AMAZING. Now get off the internet and go see it.
The older film isn't the original, it's actually a totally different film. Tarantino just liked the name, which is why he took it for his film. So if you're looking for the old one, don't expect it to be the same story.
Inglorious Basterds is quite possibly my favourite film so far this year.


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Up and down the nation, rads begin their back to life after a summer season of hibernation. With power costs soaring in recent times, and also even more individuals aware of energy usage, several make it a point of concept that their home boiler replacement cost heating remains off up until the begin of October, which suggests any nippy late September mornings simply have to be endured.
However given just how moderate the fall has been so far, others might wait a pair much more weeks before the huge switch-on.
Far from being a modern-day development, there were kinds of central furnace in ancient Greece, and also later the Romans improved what were called hypocausts to heat public baths and also private houses.
In late Victorian Britain, well-to-do houses had a form of main heating. Yet it was a very long time prior to main home heating came to be prevalent and also cost effective, and also fired by a gas central heating boiler.
Old home building contractors maintained rooms small for warmth.
Central heating was just taking off after that as well as there was a sense of exhilaration. It resembled getting the initial colour tv.
Unless you were wealthy, you didn't have any kind of radiators. There was a dreadful great deal of solid fuel around after that, an open hearth fire in the living room generally, which heated the water as well. Other homes simply had a three-bar electric fire, so you required lots of coverings at night. I remember that a lot of wintertimes were horrendous. By the end of that decade, and also right into the very early 1980s, having main home heating was regarded as a standard requirement, he claims.
In 1974, central home heating was simply taking off. It was fairly costly after that due to the fact that it was a large task. We had to secure a lot of old-style coal fires with a back central heating boiler to warm the warm water and also an open grate at the front. However people liked it, after being chilly for all those years. There were obvious health and wellness benefits - warmer houses helped to address winter mortality prices - but the effect was broader than that.
People don't use clothes to maintain warm any more. One of the social standards is that people can walk around in t-shirt sleeves at home or in the office. So central home heating has altered the method individuals consider garments. Instead of put added garments on, they put the home heating on. It used to be that if it obtained cold, you put a jacket on and also if it obtained cozy you opened a window. People do not have an assumption that they will need to transform the way they act in cold weather.
In addition to a huge increase in power usage there were likewise layout effects. Insulation like double as well as triple-glazing has come to be a lot more common, as well as spaces are bigger. Everybody desires open-plan now, but you can just have open-plan with main heating. The standard style of little areas with an induction heat resource has gone.
The entire loft-living idea wouldn't have actually taken place without main heating individuals made use of to gather in tiny areas around a fire place, yet the tv has most likely taken over from the fire place. You used to require cozy rugs and also heavy curtains and drapes, whereas now people can live with laminate floors and floorboards. The normal Victorian home had extremely heavy materials and also a curtain over every door to stop the draughts.
Individuals are likewise able to stay up later, he states. Individuals utilized to need to go to bed when it obtained also cool,. Now individuals can sit up in a T-shirt and also go to sleep when they intend to.
The method the fireplace was no more the emphasis of the British living room is still being felt today. Central heating additionally indicated the rise of the room as a living - not just resting room - for kids, as opposed to everyone gathering together in the living-room or cooking area.
So the teenager's domain, a symbol today for youth intake as well as flexibility from parents, was birthed.
Have you ever before questioned what an enjoyment it would be to wake up in the early morning and have a home filled with warmth, not having to wait ages for your electric heating systems to produce warmth and discover simply obtaining warm as you have to overlook into the chilly morning? Look below to see exactly how Central Heating can assist you as well as your family in more than one means.
Modern main heating systems when utilized effectively can assure minimized bills all year around. Upgrading an existing main heating system could knock up to 30% off your annual gas expense. Modern A-rated condensing central heating boilers with heating controls are far more reliable than older central heating boilers. While there might be exceptions, such as in areas with no gas primary connections, gas central home heating is normally cheaper than electric or oil powered heating. For an oil main heater you will certainly need both a fancy home heating heater that would certainly shed the oil.
Central furnace are recognized to aid protect against numerous health issue such as hypothermia, Asthma, respiratory disease, cardiac arrest and also strokes. Central heating also shields your wellness, home & belongings by minimizing condensation and mould development which are usually a huge problem with storage space heating systems and so on
Not just does Central heating aid with the price of costs but it can likewise reduce carbon dioxide emissions and also as a result assist you to aid the setting. Compared to oil main home heating, gas main heating will certainly create substantially less discharges. For that reason it's not only a lot more green however also cleaner; gas central heating will only give off water as well as co2 and as necessary does not need routine upkeep such as cleaning up both the heating unit as well as the smokeshaft from burning residues.
Central furnace are completely controllable with the use of a timer, area thermostat, as well as thermostatic radiator valves so that you can set each area to a different temperature level or establish the timer to a particular time to make sure that you can awaken to a charming heat instead of waiting ages for storage space heaters to warm up. Gas home heating installment for a typical two-storey house will cost around ₤3100 consisting of the boiler and the radiators.
Central Heating Boilers Opinions
Apr 02, 2019


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CAN DO: Don Lane (left) was pastor of the Sebastopol, California, (U.S.A.), Seventh-day Adventist Church when "One Dollar Love Call" was launched. Lane, the author, and Larry Nakashima encouraged church members to donate US$1 a week for missions.Challenges and Opportunities
INTELLIGENT DESIGN: Rebecca Wong, a talented young church member, designed the label for the "One Dollar Love Call" can.As I contemplated these sobering facts it became clear that we could, and must, do more for missions. From this conviction was born the "One Dollar Love Call"—an invitation to give a single dollar a week to missions; using small change, as it were, to change the world. One hundred Adventists, giving at least one dollar a week for one year, could build a church and sponsor three full-time missionaries in many countries of the world.
SO MUCH FOR SO LITTLE: The believers in Banghan, Thailand, now have their own building in which to worship and from which to reach out to their community. It was the first "One Dollar Love Call" project.Now we send out a simple message from the offering cans and hearts of the Seventh-day Adventist Church in Sebastopol, California, with the prayer that congregations around the world will join us in fulfilling the holy purpose for which our movement was called into being. This is our commitment:


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Actors: Edward Ackroyd (actor), Chris Chittell (actor), Adrian Dunbar (actor), Lee Ingleby (actor), Tony Mooney (actor), Lucy Chalkley (actress), Isabella Hammill (actress), Iona Thonger (actress), Paul Ackroyd (producer), Mark Brooke (producer), Shane Hamill (producer), Jill Kemp (producer), Menzies Kennedy (producer), Dawn Makin (producer), Barry Reed (producer),
Plot: Charlie is a high flying businessman living in his perfect world. Feeling trapped, he gives in to temptation and is about to commit an adulterous affair with a work colleague. Charlie enters the lift of the prestigious Queens Hotel where all is not what it seems.Genres: Comedy, Drama, Short,
Actors: Heinie Conklin (actor), Dick Curtis (actor), Hugh Herbert (actor), Johnny Kascier (actor), Jack Norton (actor), John Tyrrell (actor), Christine McIntyre (actress), Isabel Withers (actress), Hugh McCollum (producer), Harry Edwards (writer), Harry Edwards (writer), Harry Edwards (director), Henry Batista (editor),
Plot: In this 1944 All-Star Comedy series, Hugh Herbert decides to help out a buddy who is having wife trouble. Before he is done, Hugh not only ends up fighting his friend, he also has a wife problem.Keywords: two-reeler
Actors: Lee Bennett (actor), Paul Bryar (actor), Ed Cassidy (actor), Laurence Criner (actor), Frankie Darro (actor), Pat Gleason (actor), Herman Hack (actor), Robert Homans (actor), Jack Ingram (actor), Jack Kenney (actor), Keye Luke (actor), Irving Mitchell (actor), Jackie Moran (actor), Mantan Moreland (actor), Marcia Mae Jones (actress),
Plot: Frankie O'Malley and Jefferson Smith are broke and looking for work. In the help-wanted section of the newspaper they see employment offered at the Overland Transport Company, a hauling firm owned by "Pop" Wallace. Unaware that a trucking war is going on and that Wallace's trucks are being wrecked and his men killed, Frankie and Jefferson apply for work and are hired by "Chick" Daly , mechanic at the garage, and by Patsy Wallace, the daughter of "Pop" Wallace. On their first haul---Frankie is the driver and Jefferson is the helper---they have a run-in with the hi-jackers, but escape after a race between the two five-ton trucks. But they aren't as lucky on their second trip as their truck is run off the road and the hi-jackers take them prisoner. Frankie recognizes the assailants as drivers for a rival trucking firm. Meanwhile, George Lee, Chinese undercover agent for the insurance company that is covering Wallace's claims, has learned that Wallace is working with Ray Saunders, division superintendent for the insurance company. Saunders has a hold over Wallace and his forcing him to participate against his will. Frankie and Jefferson, after a knock-down battle, escape for the hi-jacker's garage in a stolen truck and return to Wallace's garage to find him slugged and unconscious. Frankie and Jefferson decide to get the evidence that will clear Wallace before the police move in. Frankie, Jefferson, "Chick" and Patsy break into the hi-jacker's stronghold, but are captured by Norton's men. Norton has the foursome loaded into a truck and driven out into the country-side to be killed.Keywords: 1940s, african-american, ambush, apartment, archive-footage, art-deco, b-movie, big-city, black-american, california
Actors: Josef Dischner (actor), Rudolf Klein-Rogge (actor), Henki Kolstad (actor), Knut Langgaard (actor), Paul Rehkopf (actor), Paul Richter (actor), Ada Kramm (actress), Mona Mårtenson (actress), George Schnéevoigt (writer), George Schnéevoigt (director),Genres: ,
Actors: Guty Cárdenas (actor), Alfredo del Diestro (actor), Martin Garralaga (actor), Francisco Moreno (actor), Ramón Pereda (actor), Antonio Vidal (actor), Luana Alcañiz (actress), Ligia de Golconda (actress), Delia Magaña (actress), Henry Blanke (producer), Forrest Halsey (writer), Guillermo Prieto Yeme (writer), Kenneth J. Saunders (writer), Kathryn Scola (writer), William C. McGann (director),Genres: ,
Actors: Billy Gilbert (actor), Barney Hellum (actor), William McCall (actor), Roger Moore (actor), Danny O'Shea (actor), Alice Day (actress), Eugenia Gilbert (actress), Sunshine Hart (actress), Thelma Hill (actress), Marion McDonald (actress), Kathryn Stanley (actress), Ruth Taylor (actress), Mack Sennett (producer), Hampton Del Ruth (writer), Al Giebler (writer),Genres: Comedy, Short,
Actors: Robert Anderson (actor), Wade Boteler (actor), Sidney Bracey (actor), Percy Challenger (actor), Buck Connors (actor), Harry De Vere (actor), Tote Du Crow (actor), William T. Horne (actor), Tom London (actor), Jack Mulhall (actor), Scott Pembroke (actor), William Welsh (actor), Fontaine La Rue (actress), Margaret Livingston (actress), Lucille Ricksen (actress),
Plot: John "Jack" Norton ('Jack Mulhall' (qv)), before the war a society playboy and fop, returns from the trenches of World War One a two fisted American who finds his father, Raymond Norton ('William Welsh (I)' (qv)), in jail, charged with theft of funds from the bank in which he was the president. The money, placed there by the American authorities for the Kingdom of Thorwald, and Princess Elise ('Margaret Livingston (I)' (qv)), is on the way to collect it. John lets his father think he is still the playboy he was before the war, but secretly dons his old 'Doughboy" uniform and sets out after the gang that has framed his father.Keywords: 1910s, 1920s, bank, banker, cigarettes, cliffhanger, damsel-in-distress, episodic, father, fictional-country
Actors: Lon Chaney (actor), Joseph De Grasse (actor), William C. Dowlan (actor), Pauline Bush (actress), James Dayton (writer), Olga Printzlau (writer), Joseph De Grasse (director),
Plot: Rose is rescued by Jack, a ranger and he falls in love with the Girl.Paul, an artist sees her and induces her to pose for him.He takes her to his studio,but when she learns that he is married runs away.Paul follows her and is stopped by Jack.Silent Jordan, a old man living in the woods stop Jack from shooting Paul.He tells them a sad story and Jack, with tears in his eyes takes Rose in his arms.Keywords: artist
Actors: Jack Conway (actor), Francis Ford (actor), Robert Stanton (actor), Ann Little (actress), Thomas H. Ince (producer), Harry G. Stafford (writer), Francis Ford (director),Genres: Short, Western,
Actors: Rollo Balmain (actor), W. Maining (actor), Austin Milroy (actor), Bessie Armitage (actress), Antonia Reith (actress), Florence Winter (actress), H.O. Martinek (director),Genres: Drama, Short,


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Skip to comments.Robert De Niro's lawyer says coronavirus has caused the actor financial strain.
Posted on 07/10/2020 7:22:06 AM PDT by carriage_hill
click here to read article
He got woke. He's going broke. Pity.
He really played himself in the movie Cape Fear!!!!!
Play another gangster in a movie, Bobby. You'll get it back.
He sure did.
He'll be in diapers soon, and on a walker, and no more movies for him. His days are long over.
De Niro has $500 million while his business partner has $200 million. They did not need the $28 million they received from the taxpayer. He is just greedy.
De Niro has a compound? geez....
68ac compound in upstate NY:
Welcome to the party pal.
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.


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The Silence of Lorna
Lorna, an Albanian working in a Belgian laundry, needs money to open a snack bar. The first step is citizenship, so she marries a very sick heroin addict who no-one expects to live very long. Then she plans to marry again, for money.
It all goes awry when Lorna can't be as mercenary as the gangster who's arranging her second marriage expects.
Rooted in time, place and social class, as all the Dardennes' films are, this is an unsentimental, low-key and gripping drama that doesn't let go.
This article is from
the December 2008 issue
of New Internationalist.
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-As the world marks Father's Day, a 21-year-old woman from Omutwe-Wondjaba has reunited with her father, whom she last saw while only four years old.
-The Namibian Police at Okakarara has arrested a 27-year-old woman on suspicion of her father's murder.
-Founding President Sam Nujoma has registered his satisfaction with the operation of the clinic at Etunda, noting that it has helped close the health gap in the area.
-A father accused of killing his six-year-old daughter has been denied bail.
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Nicole claims: I took alongside withme a big provide of tampons, however womanly care items are literally easy to find in Argentina. We won't declare that there are not any gold-diggers among Argentines in any respect, however amongst Argentinian mail purchase brides which might girl from argentina be significantly desirous about engaged and getting married such have grow to be unusual.
Severely talking, though, like most of Latin American girls, Argentinian ladies seem to gravitate in direction of their variety. First (and only to date) woman to function Governor of Buenos Aires. Signal as much as fulfill engaging argentinian girls and likewise develop a charming partnership with out leaving your residence. While Argentina is definitely geographically positioned in SouthThe United States- as well as therefore Latin America- Argentina is muchmore International than kind of every other nation in bothSouthor even The United States And Canada.
Torie mentions: There are actually no areas in Buenos Aires which might be particularly dangerous for women. As a household is actually a terrific top priority to girls coming from Argentina, they put together to give up their careers and numerous different points to see to it that the loved ones receives all they're worthy of. Household is important to them, however Argentine brides aren't often keen to be easy, submissive wives, and maybe that's part of why the country just isn't a prime international dating vacation spot.
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Given that Argentina is definitely a creating nation and supplies a danger-free as well as high quality lifestyle, quite a lot of Western males placed on' t also thoughts to maneuver listed beneath and cultivate a severe connection withlocal space women. Margaret Atwood, creator of The Handmaid's Tale," wrote a tweet that went viral by which she asked the Vice President of Argentina to vote in favor of the bill: Do not look away from the hundreds of deaths yearly from illegal abortions.
The leading Latin relationship techniques withcountless profile pages of actual ladies coming from throughout SouthAmerica. In case your favored one is short-fused, loves displaying issues, forgives quickly or even neglects her dramatization, if she' s very meaningful and passionate & hellip; at that time for sure, she' s an Argentinian girl. The unmarried females from international locations like Argentina might be the aspiration girl meant for solo males from Europe.
The officers had detained the two, 15- and 18-years-previous on the time, while they walked in a low-income group in Buenos Aires. Courting an Argentinian woman is a dream for single males from Europe. You may positively fall in love with the gorgeous great thing about Argentina and luxuriate in your time within the country. In case you look for a associate who will encourage you, create the relationship and constantly maintain you fascinated, it ought to be actually a mail-order bride coming from Argentina.
Precisely the same report that reported in practice habits additionally pointed out that Argentine women are inclined to smoke the drink less than completely different Latina ladies. BUENOS AIRES, Argentina (AP) — Dozens of trophies, balls and cups sit on two worn, picket shelves within the small residence in a Buenos Aires suburb of Mara Gómez, who's poised to turn out to be the primary transgender woman to play professional soccer in Argentina.
Throughout my journey to the nation I visited Buenos Aires, Cordoba, Rosario and Mendoza. You'll hardly observe the ladies getting XL. Very hot argentinian girls deal with on their own, embrace sports activities and in addition lead an lively lifestyle. Meet Argentinian women at these dependable dating internet sites that supply excessive-grade hunt as well as communications assets to make your on-line courting experiences undoubtedly helpful.
Before attempting on-line courting, you may need to discover out what to anticipate from an Argentina mail order bride. You can start dating an Argentinian girl online. It wouldn' t be so toughbecause attractive Argentinian new brides have the most superb Britishabilities in SouthThe United States and in addition essentially the most ideally suited communicative capabilities all around the planet.
It can save you interval and cash and this moreover permits getting together with so much extra females than when ever venturing out upon a Sat evening time. Some trustworthy online relationship websites the place you might uncover Argentinian females are as follows. It stays within the practices of Argentinian ladies to worth loved ones prior to every factor else.


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Pegs bounce back to move level with Loreto; Bann vs Town the men's highlight
Pegasus moved back into a share of top spot of the women's EY Hockey League – albeit with a game extra played – with a midweek 2-1 win over Belfast Harlequins courtesy of Alex Speers goal three minutes from time.
Lizzie Colvin put Quins ahead and in the mood for a first win of the campaign but Pegs equalised through Niamh McIvor in her second game of the day having helped BRA reach the Ulster girls Senior Cup final.
And Speers then grabbed the winner to lift Pegasus back to a share of first place with Loreto on 22 points heading into this weekend's fixtures.
Next on their list is their second meeting of the season with Railway Union at home, hoping to repeat their success from opening day.
Loreto's only loss of the campaign came at Pembroke, a 3-2 loss at Serpentine Avenue, and so they will be gunning for revenge when they lock horns on Saturday at Beaufort.
Old Alex are on the road to Belfast for the second week in succession, this time going to Harlequins, aiming to continue their perfect record in 2020 to date.
UCD take on Cork Harlequins in Belfield; Yvonne O'Byrne was in ubiquitous form in Quins' performance last weekend against Loreto when they probably should have nabbed a draw but for a late aberration. The two sides drew on opening day.
Draw-masters Muckross are the other home club this weekend with the showdown of Anna O'Flanagan and Roisin Upton the key one when Catholic Institute come visiting, their third straight trip to Dublin.
EYHL2 has a big day ahead; Pool B's top two showdown at the Mardyke with Ards the visitors to UCC. Their first meeting was UCC's toughest of their season to date and they know they will need to keep tabs on sharp-shooter Zara Malseed who has been scoring at a goal a game.
But a victory could see them top of the group and right in the frame for a playoff place. Monkstown will hope for no slip-up at Greenfields to progress their claims.
Pool A has been dominated by Corinthian so far and they will be favourites to continue their perfect record in all leagues this term when they host currently bottom side NUIG.
At least one of their nearest will lose ground as Lurgan and Trinity – both eight points back on 12 points – look for a big win in their playoff pursuit.
It leaves three Leinster Division One games on the card – North Kildare look to continue their winning streak when they meet Genesis; Rathgar take on Naas and Avoca play Glenanne. Avoca were 3-0 winners over Genesis in midweek to move up to fifth place with Zoe Watterson, Moirin O'Neill and Anna Richardson scoring the goals.
Trinity's title hopes took a blow, meanwhile, drew with Glenanne 2-2 which puts them seven points off the pace with an extra game played.
In the men's EYHL, the big game is on Sunday when in-form Banbridge face Monkstown at Havelock Park off the back of five wins in the last six outings.
Lisnagarvey have continued their unbeaten run into the new year but the big wins have been narrowed of late with two single-goal wins in the last couple of weeks. As such, Pembroke will hope they can keep things tight and that Alan Sothern – with eight goals in three games – can do the business.
Glenanne and YMCA have a big game on their hands with the loser of the tie set to be in the relegation playoff place. The Glens hit the Y with a sucker-punch in their first meeting of the season after a big comeback to win 3-2.
Corinthian are unbeaten since November and will be ambitious to use their game at Annadale to close the gap on the top five. Dale, though, have only one point this season but it did come against the reds and if they are to escape their predicament, this is the kind of tie they will need points from.
It is crunch time in EYHL Division 2. Cork C of I and Harlequins both currently top their groups in the men's competition; should the former beat Railway Union at Park Avenue, they would be assured of a semi-final berth with a couple of games to spare.
Instonians can put the pressure on when they meet Avoca who need a win to avoid elimination.
Harlequins, meanwhile, go to in-form Clontarf who can leap-frog them with a win in Pool B. Cookstown and Kilkeel reprise their cracking 5-4 contest from the Ulster Premier League last week in the other tie.
Three games in Leinster Division One – Dublin University and Dublin North meet in a well-matched tie between seventh and eighth. Third placed Portrane are on the road to Kilkenny while Weston face Rathgar.
Three Rock Rovers face effectively three relegation pool games following two defeats on day one of the EuroHockey Indoor Club Trophy in Alanya, Turkey.
Despite a second half comeback, the Rathfarnham club fell 6-3 to England's East Grinstead early in the morning with Ross Canning getting a double. They subsequently were picked apart by a patient HK Zelina from Croatia 6-1.
It condemns Ireland to the relegation pool with a game to spare but Saturday morning's opponents SCHC – from the Netherlands – are in the same boat.
That means that result will carry through to the four-team relegation pool where they will be joined by Switzerland's Rotweiss Wettingen and Portugal's AD Lousada.
EuroHockey Indoor Club Trophy (all in Alanya, Turkey – all times Irish): Three Rock Rovers 3 (R Canning 2, J Walker) East Grinstead (ENG) 6; Three Rock Rovers 1 (H Morris) HK Zelina (CRO) 6
Saturday 15th February 2020
EuroHockey Indoor Club Trophy (all in Alanya, Turkey – all times Irish): Three Rock Rovers v SCHC (NED), 6am
EYHL Division 1: Annadale v Corinthian, Strathearn, 4pm; Glenanne v YMCA, St Andrews, 1.45pm; Pembroke v Lisnagarvey, Serpentine Avenue, 2.30pm
EYHL Division 2 – Pool A: Instonians v Avoca, Shaw's Bridge, 2.30pm; Railway Union v Cork C of I, Park Avenue, 1pm
Pool B: Clontarf v Cork Harlequins, Mount Temple, 2pm; Kilkeel v Cookstown, Kilkeel HS, 2.30pm
Leinster Division 1: Dublin University v Dublin North, Santry Avenue, 11am; Kilkenny v Portrane, Kilkenny College, 1.45pm; Weston v Rathgar, Griffeen Valley Park, 12pm
Munster Charity Cup: Waterford v Bandon, Newtown, 3.30pm; Ashton v UCC, Ashton School, 4pm
EYHL Division 1: Belfast Harlequins v Old Alexandra, Deramore Park, 2.30pm Loreto v Pembroke, Beaufort, 2.45pm; Muckross v Catholic Institute, Muckross Park, 1pm; Pegasus v Railway Union, Queens University, 4pm; UCD v Cork Harlequins, Belfield, 1pm
EYHL Division 2 – Pool A: Corinthian v NUIG, Whitehchurch Park, 3.15pm; Lurgan v Trinity, Lurgan JHS, 2.30pm
Pool B: Greenfields v Monkstown, Dangan, 2.30pm; UCC v Ards, Mardyke, 12pm
Leinster Division 1: Avoca v Glenanne, Sion Hill, 2.30pm; North Kildare v Genesis, The Maws, 3.15pm; Rathgar v Naas, The High School, 3pm
Munster Division 1: Ashton v Bandon, Ashton School, 12.30pm; Cork C of I v Limerick, Garryduff, 2pm; Waterford v Belvedere, Newtown, 12.30pm
Sunday 16th February 2020
EuroHockey Indoor Club Trophy (all in Alanya, Turkey – all times Irish): classification matches
EYHL Division 1: Banbridge v Monkstown, Havelock Park, 2.30pm
Jacqui Potter Cup semi-final: Loreto v UCD, Beaufort, 2pm


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About A+ Weddings
A+ Weddings is a Nanaimo, British Columbia-based, one-stop wedding studio specializing in event planning and floral design. Owner Michelle Whitehead opened A+ Weddings with the sole purpose of assisting couples to plan their day and bring it to successful completion. A team of skilled and trained experts is always at your disposal and will work tirelessly with you to craft experiences that aptly do your wedding vision justice. Michelle and her team of floral specialists are known to create beautiful arrangements that are sure to add many elements of elegance and chic to your wedding.
Products offered
The creative team at A+ Weddings is passionate about helping brides bring their wedding dream to fruition by offering discerning services which begin with a complimentary consultation. The team examines and understands every detail of each wedding, including the venue, colour palette, style, preferences, and more. Clients are encouraged to bring magazines and photos of blooms they like so that the floral experts can get a fair idea as to what flowers and textures will best portray their personality. Apart from this, A+ Weddings also handles cleanup, setup, and delivery. The company offers many floral wedding packages, including All Gerberas, All Roses, and White Elegance. The following items are included in these packages:
A-la-carte options are available for all packages. Centerpieces, altar or buffet arrangements, and cake toppers are also available. A standalone Centerpieces and Decor package, including hair flowers, rose petals, pillars and stands, aisle runners, table arrangements, napkin detailing, and more, is also offered.
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Mesenchymal–epithelial interactions involving epiregulin in tuberous sclerosis complex hamartomas
Communicated by Martha Vaughan, National Institutes of Health, Bethesda, MD, December 31, 2007 (received for review November 30, 2007)
Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the existence or location of cells with biallelic mutations ("two-hit" cells) was unclear. We compared TSC skin hamartomas (angiofibromas and periungual fibromas) with normal-appearing skin of the same patient, and we observed more proliferation and mTOR activation in hamartoma epidermis. Two-hit cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal–epithelial interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed with real-time PCR, and increased amounts of epiregulin protein were demonstrated with immunoprecipitation. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by two-hit cells in the dermis and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin.
Hamartomas are benign growths composed of cells normally found in an organ or tissue but in abnormal mixture or organization. Clues to the pathogenesis of hamartomas have come from studies of inherited syndromes in which these lesions are characteristic (1). Patients with tuberous sclerosis complex (TSC), an autosomal dominant tumor syndrome affecting ≈1 in 10,000 individuals, develop hamartomas in multiple organs because of a mutation that inactivates one allele of a tumor suppressor gene, either TSC1 or TSC2 (2). The protein products of these genes, hamartin and tuberin, respectively, form a complex that inhibits the mammalian target of rapamycin (mTOR) pathway, which regulates cell growth (3). TSC hamartomas typically show a "second-hit" somatic mutation that inactivates the wild-type allele. Loss of functional hamartin/tuberin in TSC tumors leads to hyperactivation of mTOR signaling and increased cell number and cell size.
Approximately 90% of TSC patients develop skin hamartomas such as facial angiofibromas (AFs) and periungual fibromas (PFs) (4). These tumors are benign but can be disfiguring or cause bleeding and pain. Current treatments are surgical and have the potential to leave scarring (5).
Like other hamartomas, those in TSC skin contain abnormal numbers of several types of cells. In the dermis, there are increased numbers of large stellate fibroblasts, capillaries, and dermal dendritic cells (6–9). The epidermis is acanthotic (i.e., thickened from increased numbers of keratinocytes in the spinous layer). Acanthosis is pronounced in PFs and variable in AFs (7, 8). The epidermis of treated AFs, several months after argon or CO2 laser surgery, no longer appears acanthotic (10, 11).
We sought to determine whether the overgrowth of epidermal and dermal cells in TSC skin hamartomas was caused by second-hit mutations in the epidermis and dermis or by a "two-hit" cell population that induced proliferation of neighboring cells. Second-hit mutations in more than one cell population have been observed in TSC renal angiomyolipomas. These tumors contain blood vessels, smooth muscle cells, and fat cells; loss of heterozygosity (LOH) at the TSC1 or TSC2 locus in all of these cell lineages has been reported (12, 13). However, it plausible that one cell population could influence neighboring cells, especially in light of the many important mesenchymal–epithelial interactions involved in skin development (14), wound healing (15), and skin tumorigenesis (16). Disruptions in these interactions could contribute to the formation of hamartomas in TSC skin and other organs.
Here, we report that fibroblast-like cells in TSC skin tumors, but not epidermal cells, showed allelic deletion of TSC2. Epiregulin, an epidermal growth factor (EGF)-related growth factor, is overexpressed in fibroblast-like cells grown from TSC skin tumors and may induce epidermal changes.
Keratinocyte Proliferation and mTOR Activation in TSC Skin Tumors.
Tissue sections were stained for nuclear antigen Ki-67 as a marker of cell proliferation and phospho-S6 as a marker of mTOR activation. The number of Ki-67-positive cells in the epidermis of TSC AFs and PFs was clearly larger than that in the same patient's normal-appearing skin (Fig. 1). Cells that were positive for Ki-67 were seen mainly in the basal layer of the epidermis, with few apparent in the dermis.
Few cells in the patient's normal-appearing skin were positive for phospho-S6. These cells were restricted almost entirely to a thin layer of cells comprising the granular layer of the epidermis; almost no cells in the dermis were positive for phospho-S6 (Fig. 2 A). In contrast, the acanthotic epidermis of TSC skin tumors was strongly positive for phospho-S6 (Fig. 2 C). The dermis also contained spindle- and stellate-shaped cells positive for phospho-S6 scattered between collagen bundles, with greater numbers located adjacent to the epidermis. Acanthosis in TSC skin tumors was accompanied by both increased keratinocyte proliferation and mTOR activation.
Two-Hit Cells Are Present in the Dermis, but Not the Epidermis, of TSC Skin Tumors.
The pattern of staining for phospho-S6 in TSC skin tumors appeared consistent with the possibility that keratinocytes and/or scattered fibroblast-like cells in the dermis represented two-hit neoplastic cells. To identify these two-hit cells, samples were analyzed for LOH at the TSC1 and TSC2 loci. LOH was not detected in DNA extracted from microdissected epidermis or dermis of three different AFs (data not shown). Because LOH in two-hit cells could be masked by cellular heterogeneity, we turned to interphase fluorescence in situ hybridization (I-FISH), which allows individual nuclei to be scored for allelic deletion of TSC1 or TSC2, based on the presence of only one signal per nucleus rather than the expected two signals per nucleus for each gene. Keratinocytes derived from three AFs did not show allelic deletion of TSC1 or TSC2 (Table 1); almost all nuclei showed two signals each for TSC1 and TSC2, with 0–4% showing only one signal. (In normal tissues, one signal is often observed in a small percentage of cells because of insufficient hybridization or overlapping signals.) Touch preparations of the dermal side of normal-appearing skin and cultured fibroblasts derived from normal-appearing skin from TSC patients showed similar patterns, with 0–8% showing one signal for TSC1 and 2–12% showing a single signal for TSC2. Among touch preparations or cells cultured from AFs and PFs only 0–8% showed one signal for TSC1, but 11–51% of nuclei had one signal for TSC2. These results are consistent with allelic deletion of TSC2 in a fraction of cells located in the dermis of AFs and PFs, but not in the keratinocytes associated with these tumors, which suggested that the epidermal changes in the tumor originated from effects of tumor mesenchymal cells.
Epiregulin mRNA Content of Fibroblast-Like Cells Derived from TSC Skin Tumors Is Greater Than That of the Patient's Fibroblasts from Normal-Appearing Skin.
RNA from fibroblast-like cells grown from four AFs, three PFs, and normal fibroblasts from four patients were analyzed by using Affymetrix GeneChips. In total, amounts of 22 probe sets representing 20 genes were increased, and 33 probe sets representing 28 genes were decreased by 3-fold or more (tumor vs. normal) in both AFs and PFs [supporting information (SI) Table 3]. The mRNA with the greatest mean elevation in AFs and PFs was epiregulin, which was 11.8-fold that of the patient's normal fibroblasts in AFs and 22.5-fold in PFs. Another mRNA that was highly overexpressed was MCP-1, which was 9.5-fold the control level in AFs and 3.9-fold in PFs, consistent with our earlier experiments using filter-based arrays (17). Epiregulin, an EGF family member, was investigated further because it appeared relevant to the observed epidermal changes. Amounts of epiregulin mRNA measured in samples from 17 patients using real-time PCR were 3.7- to 690-fold the paired controls in AF cells (n = 13, P = 0.001) and 4.5- to 5,660-fold in PF cells (n = 9, P = 0.008; Table 2). The addition of 100 nM rapamycin for 24 h did not significantly change epiregulin mRNA levels (P = 0.84; SI Table 4).
Release of Epiregulin Protein by Fibroblast-Like Cells from TSC Skin Tumors.
After incubation of cells in medium containing [35S]methionine for 24 h, samples of medium were subjected to immunoprecipitation with antibodies against epiregulin, which yielded immunoreactive proteins of ≈5 kDa by using medium from fibroblast-like cells of TSC skin tumors but not from patients' normal-appearing skin (Fig. 3 and SI Fig. 6). The addition of unlabeled recombinant epiregulin protein before immunoprecipitation eliminated this band but not other, apparently nonspecific bands. Incubation of cells with EGF did not measurably alter epiregulin release by TSC tumor cells or normal skin fibroblasts (Fig. 3). Searchlight Protein Array analysis showed that the levels of epiregulin in conditioned medium from PF cells of two patients were 12.8 and 43.6 pg/ml, respectively, whereas the protein in conditioned medium from their normal TSC fibroblasts was undetectable. Changes in levels of other EGF family members (EGF, TGF-α, heparin-binding EGF-like growth factor, and amphiregulin) and keratinocyte growth factor, if seen, were inconsistent (data not shown).
Keratinocyte Proliferation and Phosphorylation of Ribosomal Protein S6 Enhanced by Epiregulin.
Recombinant epiregulin added in vitro to normal human keratinocytes stimulated cell proliferation in a concentration-dependent manner (Fig. 4), with a maximum 1.9-fold increase in the rate of BrdU incorporation with 20 ng/ml. Treatment of keratinocytes with epiregulin increased phosphorylation of ribosomal protein S6 within 10 min, which persisted at 1 h and decreased to basal levels after 24 h (Fig. 5 A and C). The epiregulin effect was concentration-dependent and maximal at 100 ng/ml (Fig. 5 B and D). Epiregulin increased phosphorylation of p70S6K similar to ribosomal protein S6 (data not shown). The data indicate that epiregulin enhanced keratinocyte proliferation and mTOR activation.
Increased epidermal thickness of AFs and PFs was associated with increased proliferation of keratinocytes and mTOR activation. Although mTOR activation is characteristic of two-hit populations in other TSC-related tumors (18–21), we found no evidence of second-hit mutations in the epidermal keratinocytes. Instead, allelic deletion of TSC2 was observed in fibroblast-like cells from the AFs and PFs. These results are consistent with immunohistochemical studies of AFs and PFs that showed loss of hamartin or tuberin expression in fibroblastic interstitial but not epidermal cells (22, 23). Therefore, changes in epidermal cells overlying the tumor appear to the result of the influence of associated mesenchymal cells. Consistent with this view, we found that the release of epiregulin by fibroblast-like cells from TSC skin tumors was significantly greater than that by fibroblasts grown from normal skin of the same patients.
Epiregulin is a member of the EGF family that includes EGF, TGF-α, heparin-binding EGF-like growth factor, amphiregulin, and betacellulin. Epiregulin was first purified from conditioned medium of the NIH 3T3/T7 mouse fibroblast-derived cell line (24). Epiregulin is not produced by normal human fibroblasts, but it is expressed by human fibroblasts immortalized by telomerase reverse transcriptase (25), fibroblastic cells in malignant fibrous histiocytomas (26), and, as we show here, fibroblast-like cells from TSC skin tumors. Epiregulin is an autocrine or paracrine factor that is produced by many human cancers (27, 28).
We propose that epiregulin released by fibroblast-like cells in TSC skin tumors stimulates epidermal cell proliferation and acanthosis. This hypothesis is supported by in vitro studies presented here and others showing that epiregulin is mitogenic for keratinocytes (29–31) and stimulates phosphorylation of EGF receptor in keratinocytes (30) and by the in vivo demonstration that application of recombinant epiregulin to murine excisional wounds increased epidermal proliferation and thickness (32). Epiregulin has also been implicated as a contributing factor to the epidermal changes in psoriasis because it is overexpressed by acanthotic psoriatic epidermis (33). Other paracrine factors may also participate in epidermal acanthosis in TSC skin tumors, but we found that other EGF family members and keratinocyte growth factor were inconsistently, if at all, elevated in tumor-derived cells.
The cause of increased epiregulin expression by fibroblast-like cells derived from TSC skin tumors is unclear. It may not be related to mTOR activation resulting from TSC2 loss because rapamycin treatment did not decrease epiregulin mRNA levels. Furthermore, treatment of normal fibroblasts with TSC2 siRNA dramatically decreased tuberin levels, but epiregulin mRNA levels were only 1.5-fold that in cells treated with control siRNA (S.L., Q.F., and T.N.D., unpublished observations). Recombinant EGF (100 ng/ml) increased the levels of epiregulin mRNA ≈50% in TSC skin tumor cells and normal fibroblasts (S.L. and T.N.D., unpublished observations), consistent with the work of others showing stimulation of epiregulin production through the EGFR pathway (30, 34, 35). This finding appears not to account for elevated levels of basal expression in tumors, however, because treatment of TSC skin tumor cells with AG1478, an EGFR inhibitor, or U0126, a MEK inhibitor, did not change epiregulin mRNA levels (S.L., J.-a.W., and T.N.D., unpublished observations). We note that epiregulin expression is directly regulated by the aryl-hydrocarbon receptor (36), one of the genes identified by using the arrays as overexpressed 2.1-fold in TSC tumor cells.
The disorganized overgrowth of hamartomas is suggestive of abnormal continued expression of factors that stimulate growth early in development. Epiregulin is a plausible candidate for a "hamartic" factor in TSC because it is normally expressed early in development and exists in only a few adult cell lineages (24, 37). Persistent expression of epiregulin by fibroblast-like cells in TSC skin tumors would be consistent with a less than normally differentiated fibroblast phenotype. In this regard, it is of interest that expression of epiregulin in the adult mouse cornea is restricted to a stem cell population in the limbal epithelium (38).
Hamartic factors may be expected to play other roles in tissue morphogenesis. Investigation of the functions of epiregulin in organ formation is at an early stage, but it has been reported to be important in nephron morphogenesis (39). Epiregulin and its receptors or downstream effectors, which appear to be involved in the formation of hamartomas in skin and possibly other organs affected by TSC, could be a therapeutic target for treatment of this disease.
Materials and Methods
Tumor Sample and Cell Culture.
Patients meeting clinical criteria for diagnosis of TSC (40) were enrolled in protocol 00-H-0051 approved by the National Heart, Lung, and Blood Institute/National Institutes of Health (NIH) Institutional Review Board. Samples of AFs, PFs, and normal-appearing skin were obtained and bisected, with one portion used for routine pathology and the other used for frozen sections or cell culture. Fibroblasts from normal-appearing skin or fibroblast-like cells from AFs and PFs were isolated from explants as described in ref. 41 and then cultured in DMEM supplemented with 10% FBS, 100 units/ml penicillin, and 100 μg/ml streptomycin. Keratinocytes from TSC skin samples were obtained by using standard methods (42). Keratinocytes were cultured in serum-free medium (keratinocyte-SFM; Invitrogen), supplemented with EGF and bovine pituitary extract. For studies of the effects of epiregulin on proliferation and cell signaling, keratinocytes from foreskins of unidentified normal neonates were used (provided by Jonathan Vogel, National Cancer Institute, NIH).
Immunohistochemical Staining.
Sections were incubated with mouse anti-human Ki-67 monoclonal antibody (1 μg/ml, clone MIB-1; DakoCytomation), rabbit anti-phospho-S6 (1:200; Cell Signaling Technology), or source- and subtype-matched control IgG (DakoCytomation). Sections were stained with a Vectastain Elite ABC kit and 3,3′-diaminobenzidine peroxidase substrate kit or Vectastain ABC-alkaline phosphatase with Vector red substrate (Vector Laboratories) and counterstained with Mayer's hematoxylin solution (Sigma–Aldrich).
Cells obtained from touch preparations or culture of TSC normal-appearing skin and skin tumors were analyzed for allelic deletion of TSC1 and TSC2 by using I-FISH as was described in ref. 43. At least 50 nuclei were scored for each sample.
Gene Expression Array.
Early passage cells (passages 3–5) were grown until 70–80% confluent. Total RNA was extracted by using an RNeasy minicolumn (Qiagen), and gene expression analysis was performed as described in the Affymetrix expression analysis technical manual by using 10 μg of total RNA. Fragmented, biotinylated cRNA was hybridized to human genome U133A GeneChips (Affymetrix). Fluorescent probes were added, and intensities were quantified with a GeneArray scanner. Arrays that passed initial quality control requirements were analyzed with Affymetrix MAS 5.1. A total of 11 arrays from four patients were analyzed. Each PF and AF were first compared with the respective patient's control cells from behind the ear or the back. Analysis of the intensities showed that differences between the back and ear locations were small compared with differences between controls and tumor tissue. Also, a comparison of results using normalization methods based on individual controls vs. grouped controls showed little effect (with 994 of 1,180 possible probe sets in common). Probe sets that were identified as "present or marginal" by MAS 5.1 were used for subsequent analysis. Lists of probe sets were constructed for evaluation including those with threefold change and/or statistically significant with a false discovery rate <1% by using a Benjamini–Hochberg multiple testing correction.
Real-Time PCR.
Tumor cells or normal fibroblasts grown from AFs, PFs, or normal skin were incubated in 1% FBS/DMEM with or without 100 nM rapamycin for 24 h before isolation of total RNA from the cells by RNeasy mini kit (Qiagen). Epiregulin mRNA levels were quantified by real-time PCR using the TaqMan universal master mix with assay-on-demand epiregulin primers (Applied Biosystems, Hs 00154995_AI), and values were expressed relative to levels in the same cells of 18S rRNA by using assay-on-demand primers Hs 99999901_S1. Real-time PCR was performed by using the GeneAmp 5700 sequence detection system (Applied Biosystems).
Immunoprecipitation and Multiplex Assay.
Epiregulin protein in conditioned medium of TSC skin tumor cells was detected by using metabolic labeling and immunoprecipitation as reported in ref. 30. Briefly, patient normal fibroblasts or skin tumor cells (1 × 106 cells per 10-cm dish) were labeled in 5 ml of methionine-free DMEM containing 10% dialyzed FBS (Invitrogen) and 1 mCi of [35S]methionine (Amersham Pharmacia Biotech). To some, 100 ng/ml EGF was added at the beginning of the labeling. After 24 h, conditioned media were collected, and an aliquot (1.25 ml) of each medium was used for immunoprecipitation with rabbit anti-epiregulin IgG. The immunoprecipitants were subjected to electrophoresis in 18% Tris-glycine gels (Invitrogen) and analyzed by using the FLA-5100 Bio-Imaging System (Fujifilm Medical System, Inc.). Epiregulin protein released by TSC skin tumor cells was quantified by Thermo Scientific SearchLight multiplex assay (Pierce) according to the manufacturer's procedures.
Cell Proliferation.
Keratinocytes from neonatal human foreskins were added to 96-well Costar Black plates with clear bottoms (1 × 104 cells per well). The next day, wells were washed with keratinocyte-SFM without bovine pituitary extract and human recombinant EGF, and cells were incubated for 24 h followed by incubation for 24 h more in the same medium containing the indicated concentrations of recombinant epiregulin. Cells were labeled with 10 μM BrdU for 3 h, and incorporated BrdU was quantified by using a chemiluminescent ELISA kit (Roche), with chemiluminescence measured with a Fluoroskan Ascent FL (Thermo Labsystems).
Western Blot Analysis.
Neonatal human foreskin keratinocytes were plated on 60-mm dishes at 6 × 105 cells in keratinocyte-SFM. The next day, medium was changed to keratinocyte-SFM without EGF and bovine pituitary extract and incubated for 24 h. Cells were treated with epiregulin as indicated and lysed in protein extraction buffer [20 mM Tris (pH 7.5), 150 mM NaCl, 1% Nonidet P-40, 20 mM NaF, 2.5 mM Na2P4O7, 1 mM β-glycerophosphate, 1 mM benzamidine, 10 mM p-nitrophenyl phosphate, 1 mM phenylmethylsulfonyl fluoride]. Equivalent samples of total proteins were separated in 10% (wt/vol) polyacrylamide gels and transferred to 0.45-μm Invitrolon PVDF membranes (Invitrogen) before immunoblotting with 5 μg of anti-phospho-S6 ribosomal protein (Ser-235/236) or anti-S6 ribosomal protein antibodies (Cell Signaling), horseradish peroxidase-conjugated anti-rabbit antibodies (GE Healthcare), and a SuperSignal West Pico chemiluminescence detection kit (Pierce). Band intensity was measured by using a Kodak Capture DC 290 imaging system (Eastman Kodak).
Statistical Analysis.
Epiregulin mRNA data were evaluated by using Wilcoxon signed-rank test. Proliferation (chemiluminescence values) and S6 phosphorylation (ratio of phospho- to total S6 on a log scale) were assessed by using two-way ANOVA with the primary variable epiregulin or time adjusted for differences in baseline level among experiments, followed by Dunnett t test to compare each treatment group with control. Significance was defined as P < 0.05.
We thank the Tuberous Sclerosis Alliance and The LAM Foundation for patient referral. We also thank Catherine Jozwik for the radiolabeling labeling of the cells. This work was supported by a Clinical Scientist Development Award from the Doris Duke Charitable Foundation and National Institutes of Health (NIH) Grant 1 R01 CA100907 (to T.N.D.). G.P.-R. and J.M. were supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, NIH.
- §To whom correspondence should be addressed. E-mail: tdarling{at}usuhs.mil
Author contributions: S.L. and T.N.D. designed research; S.L., F.T., J.-a.W., Q.F., G.P.-R., and T.N.D. performed research; T.K. contributed new reagents/analytic tools; S.L., F.T., J.-a.W., Q.F., E.M.B., G.P.-R., J.M., and T.N.D. analyzed data; and S.L., J.M., and T.N.D. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE9715).
This article contains supporting information online at www.pnas.org/cgi/content/full/0712397105/DC1.
- © 2008 by The National Academy of Sciences of the USA
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22 January 2019, Apia Samoa. A 20 year old man appeared in the Supreme Court before Justice Leiataualesa Darryl Clarke this morning charged with the kidnapping and indecent assault of a 3-year-old girl.
Manusamoa Sialafua, unrepresented, entered a not guilty plea to both charges.
Justice Leiataualesa asked the accused if he wanted to liaise with a lawyer for representation, reminding him of the seriousness of the charges against him.
However, the defendant confidently told the Court that he did not need a lawyer, and entered a not guilty plea.
Justice Leiataualesa issued a suppression order to protect the victim and instructed the media to not reveal her name as well as her village or any information that could easily identify her.
The incident occurred in November last year where the defendant allegedly kidnapped the 3 year old victim.
He then allegedly tried to force his hands into the victim's undergarments.
Ms. Sio-Ofoia of the Attorney General's office did not oppose bail. The Court granted bail for the defendant on condition that he surrender all travel documents, sign at the Faleata Police Station every Monday and Thursday before 12 noon and reside with his aunty at Tulaele. He was ordered not to make any contact with prosecution witnesses.
- Pregnant Mother Charged for the Death of her One-Year Old Fails to Appear in Court - August 13, 2019
- Short Stop-Over Visit for NZ Prime Minister on route to Tokelau - July 27, 2019
- Man Found Guilty of Murder Sentenced to Life in Prison - July 27, 2019


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22-y-old charged for selling Instagram account
ST ANN, Jamaica— Twenty-two-year-old Ivany Wright is set to appear in the St Ann's Bay Parish Court today to answer to charges of fraudulent conversion.
According to the police, Wright, who is of a St Andrew address, was charged by detectives in St Ann on Sunday in relation to allegations that she conned money from a woman by pretending to sell an Instagram account.
The police said the woman reportedly paid Wright $65,000 for the Instagram account.
However, after handing over the money, Wright allegedly blocked her access to the account and stopped taking the complainant's phone calls.
Lawmen said that during investigations, it was revealed that Wright is also a suspect in at least one other case that is being investigated by detectives in the St Andrew Central Division.
The investigation centres on alleged breaches of the Cybercrimes Act, the police said.
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Thank Bmann for the Lil Big Hauler lines
Am considering one of the Piko Moguls... Can anyone add anything to the pervious comments, running experience and the sound quality?
Thanks in advance
We have a member that has a newer version and it runs great. While i'm not a Piko guy this has encouraged me to what to order the Camel back as a pusher engine to retrieve all the dead Aristo loco's around the layout. The 0 6 0 runs well.
Nick S. said:engine to retrieve all the dead Aristo loco's around the layout. The 0 6 0 runs well.
Shannon car Shops
Home of the infamous leg lamp
I.A.R.R.R. Member #12
and King Butt Modeler
In all fairness - I've only had trouble with one Aristocraft engine- An early version Pacific -I liked it enough that I replaced it with another (newer version). Never had any trouble with any of my Hartland or LGB engines - I have only had one USA train engine, which after less the six months would only run in one direction, and which they would not repair the one-year warranty- They wanted over $100. to fix for an engine that retailed at the time for $169.00 I'll never give em another chance even though I loved the quality of the graphics ... Really unfortunate, as I live about three miles from Charles Ro Supply. Anyway should know about the Piko soon enough as Fed-ex is supposed to deliver it today.
Thanks for your input-
I find your accounting of Charles Ro, Inc., not honoring their one-year warranty strange at best.
My interpretation is you personally went to the company, presented evidence of date of purchase, after your problem description, they tested it, and then refused to either fix it or replace it -- unless a $100 repair fee.
Is this sequence of events accurate?
I am very surprised -- in particular since you were in the store personally and this was not a e-mailed impersonal transaction.
What reason was given for not honoring the warranty?
Did either of the Ro family interact with you?
In fairness to Charles Ro...
I purchased the engine at a Dealer on Cape Cod which is about 60 miles or so from Malden, Mass.When I started having trouble with it, I called, explained the situation, the unit, when I purchased it,Etc. I was told that they would only repair it for the $100.00, I found out later that that employee was let go (hearsay)
In hindsight, I should of taken it over to the store, with the receipt, however the drive is miserable from here (even as close as I'm located... just 3 miles or so). I just find the "new" store employees rude, and don't want to deal with them-it's easier to punch a few buttons on-line and watch for the "Wells Fargo Wagon coming down the Street" To paraphrase a saying from my days in the service "i voted with my wallet (feet) I personally like Charlie, and yes I know it can be absolutely miserable dealing with the public... I recall I also had trouble with two Aristocraft eggliners, one they mailed me a new engine motor no questions asked, the other was a wire not connected at the factory
In addition I love the quality graphics on USA products, I see that a huge number of fellow G scalers think highly of his products, To me good service is paramount - I have received that from Aristocraft and Hartland when needed so that's who I have supported. I can only relay my own experiences - Feel free to disagree


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To our Family Pet family:
During this unprecedented period of social distancing due to the Coronavirus, we are now offering telemedicine consultations with our doctors. Please know that we continue to offer in-hospital exams for patients that need our care.
Telemedicine is the use of telecommunications technology to help diagnose and treat patients. Given the current circumstances, this is a necessary and valuable service we want to offer to our clients. However, please understand that telemedicine has many limitations. We want to provide guidance on when a telemedicine consultation may be a useful option versus an in-person exam.
Is telemedicine a good option for my pet?
Telemedicine may be used when wishing to speak face-to-face, virtually, with your veterinarian for a more personal experience. Using FaceTime, for example, you can discuss your concerns and have the ability to show an ailment to your doctor including, but not limited to:
- Coughing or sneezing
- Lameness or a change of your pet's mobility
- Skin changes including visualization of your pet licking, scooting, biting himself/herself
- Ocular changes (i.e. redness, discharge)
- External ear changes
Telemedicine will NOT be helpful if:
- A pet is vomiting and/or has diarrhea
- Inappetence (not eating)
- Abnormal breathing
- Lethargy (excessively sleeping or drowsiness)
- A vague concern that "something may be wrong"
Unfortunately, nothing replaces a comprehensive in-person examination. A virtual exam does not allow further investigation via palpation of the abdomen, evaluation of dehydration and pain, evaluation of heart and lung sounds, etc. Veterinarians also rely heavily on diagnostics since our patients cannot speak and often instinctually hide their illnesses. A virtual exam would not allow for testing (i.e. radiographs, blood work, cytology and biopsies for skin masses, infections, parasites, etc.) and, most importantly, telemedicine does not offer in-hospital supportive care. A telemedicine consult may, ultimately, result in the recommendation for an in-person exam.
The cost for a telemedicine consultation is $77.50. In the event that your telemedicine consultation results in the recommendation to schedule an in-person examination, a reduced fee of $44.50 will apply.
If food or medication is prescribed, do I have to come to the hospital?
For consultations that prompt the dispensing of prescription medications or food, you may come to the hospital for curbside service. Please call us when you arrive.
Alternatively, if you would like to have the food or medication delivered to you, please contact We're There Pet Care (WTPC), our pet-sitting service partner, at (773) 935-9983. Please note that coordination, fee inquiries, requests for availability, and payments for delivery must be handled directly through We're There Pet Care.
* Controlled substances cannot be delivered and must be picked up curbside at Family Pet. *
What apps are you using for telemedicine consults?
We are using FaceTime (Apple/iPhone users) or Zoom Cloud Meetings (Android users – please download the app in advance and we will text you a meeting invitation at the start of the appointment). If you are interested in a telemedicine consultation with one of our doctors, please call (773) 935-2311 or email us to schedule an appointment.
Hopefully, this statement will help you navigate when a telemedicine consultation may be a useful option for your beloved pet. We deeply appreciate your continued support, patience, and understanding as we navigate these unprecedented circumstances.
Stay safe and healthy,
The doctors and staff at Family Pet Animal Hospital


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Contact Info
Devnet Inc
2254 Oakland Dr
Tel: 815-758-2071
Website: http://www.devnetinc.com
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About Devnet Inc
Offering Computer Software, the Sycamore based company Devnet Inc can be contacted on 815-758-2071 or visited at 2254 Oakland Dr, Sycamore, Illinois.
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DEVNET can simplify your tax bill and notice printing and mailing needs. DEVNET is celebrating 15 years of providing integrated Appraisal, Assessment, Collection and e-government solutions designed to empower the public sector user. Since our beginning, we have dedicated ourselves to taking a unique, personalized approach with every client.
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This week was a slightly short week with us having Friday off as part of our February break. Although I did have reports due, a PT meeting on Wednesday morning, a staff meeting after work on Wednesday and study club after school on Thursday so I was kept busy and it felt like I had worked a full week.
Here's what my classes were doing this week.
S2 – this week we were focussing on expanding single brackets. As a review from last week I set this as the starter.
I was interested to see what answers the class came up with for Q5. Most came up with 4(5x – 3) which bodes well for when we look at factorising although I was hoping that someone might come up with a total unexpected answer. We then explored how to expand brackets and simplify. As I thought, most understood the concept but did make errors with negative numbers. Some completed this settler task from www.mathsbox.org.uk
whilst others worked on these problems from Don Steward.
These problems from Don Steward provided a great level of challenge for those who were confident with the basic problems.
S3 – we completed our work with substitution with this lovely challenge from CIMT.
It did take a while for most of the class to buy into the activity and to have the confidence that they could actually produce solutions. We then moved onto expanding single brackets. The pupils would have done this in S2 but they struggle to recall most previous work so we are having a recap. The focus for the rest of the week was simply expanding single brackets and this was probably their favourite task of the week.
They had to match the question to the answer at the bottom. I deliberately left some blank for the class to fill in themselves. A copy of the sheet can be found here.
N5 – we were solving trigonometric equations this week. We started by looking at the graphs and exploring why there was more than one answer when solving something like sinx = 0.5. The class then practiced solving equations with positive and negative values before moving on to solving equations that required rearranging first. I know it can be controversial but I did use the CAST diagram as a method for finding the required angles. Hopefully though the class understood how it relates to the graphs of the trig functions. One activity we used was my Red Amber Green task cards. A copy can be found here.
This task allowed all pupils to work on an appropriate level of question with some completing more green questions whilst others completed only red questions.
Higher – we started looking at the equation of a circle. The first task the pupils completed was this sheet from www.mapmathshell.org
This provided a perfect introduction using the equation of a circle. We also looked at the general form for the equation of a circle and spent a few periods solving exam style questions. I did make a bad mistake though. After going through an example of intersecting lines and circles I set the class a few questions from the textbook without really checking the questions first. The first problem ended up being far trickier than the example I had done and meant that those weaker pupils really struggled and lost all confidence with the work they were doing. I usually check the questions first but had completely forgotten in this instance.
S1 Numeracy – this was a lovely little task this week. We explored digital roots.
The pupils engaged well with it and were very keen to share any patterns they found. It also provided great discussion with the circle diagrams as to why some had the same design.


text:
He's back!!
This is a forum dedicated to Hermit Crab Association members posting pictures of their crabs and crabitats.
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Re: He's back!!
I'm soo glad he picked that one!
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- Joined: Tue Dec 11, 2018 12:20 pm
Re: He's back!!
Me too! He looks gorgeous in it!! Have to share some more y'all. Hope you don't mind some more crabby pics..... hahaha Yes I am a comedian, thank you.
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