text:
->"Do not let my calm demeanor fool you, '''''RANGER!'''''"
-->-- '''Marshal Pentecost''', ''Film/PacificRim''
Two characters are carrying on a conversation. Alice says something. Bob responds in his regular voice, but then '''SUDDENLY HE'S SHOUTING!'''
Typically happens for one of three reasons:
* '''Anger''': Something Alice said just really infuriates Bob, or perhaps simply made an already bad mood worse. Often this is preceded by other visual cues of anger, such as a twitching eye, giving the impression that despite his feelings Bob is still trying to maintain some sense of composure before finally [[RageBreakingPoint giving in and letting loose with an impassioned tirade]].
* '''Surprise / Fear''': Bob is carrying on as normal, when suddenly [[GhostlyChill a cold, dead hand]] settles on his shoulder, or someone sets off an explosive in his presence, or something else happens that he just didn't or couldn't expect. Often accompanied by an [[ScreamsLikeALittleGirl upward shift in pitch]].
* '''Drama''': Bob is naturally a LargeHam and wants you to know that what he is revealing is quite important, [[MundaneMadeAwesome no matter how mundane it may actually be]]. This is a technique actually used by army trainers when scolding trainees, to keep them on their toes and to vary the tempo of the berating.
Compare CarefulWithThatAxe and LastNoteNightmare, which apply a similar sort of logic to music. Sometimes overlaps with PunctuatedForEmphasis or HaHaHaNo.
* Lampshaded in a Creator/DaveBarry column on ads he and the rest of the world hates:
--> "[...] ads where the announcer SHOUTS AT YOU AS THOUGH YOU ARE AN IDIOT and then reads, in very muted tones, [[RattlingOffLegal what sounds like the entire US tax code]]."
* In ''Manga/DragonBall'', Bulma uses type A for snark value when complaining about how recklessly endangering her companions are.
** A [[MemeticMutation much more well-known example]] is found in '''Anime/DragonBallZ:'''
-->'''Vegeta:''' [[ReadingsAreOffTheScale It's over NINE THOUSAND!!!]][[note]]Or in the original Japanese, "Hassen IJOU DA (lit. 'It's over '''Eight''' Thousand')!!!"[[/note]]
** Gohan gets a truly epic example of this trope in ''[[Anime/DragonBallZBojackUnbound Bojack Unbound]]'' after turning Super Saiyan 2.
-->'''Gohan:''' I know your kind, you think you can just walk in and take our planet. But you forgot one thing, I'm my father's '''''SOOOOOOOOOOOOOOOOOOOOOOOOON!!!'''''
* ''Manga/FullmetalAlchemist'':
-->'''Colonel Mustang:''' When I'm Führer, there will be changes. That day, all female officers will be required to wear...TINY MINISKIRTS!
** About half of Major Armstrong's lines are like this, particularly when they have to do with things being passed down the Armstrong line FOR GENERATIONS!
* ''Anime/CowboyBebop'':
-->'''Vicious''': The same blood runs through both of us. The blood of a ravenous beast hungry for the blood of others.
--> '''Spike''': I've bled all that blood away.
-->'''Vicious''': ''THEN WHY ARE YOU STILL ALIVE?!''
* In the ''LightNovel/HaruhiSuzumiya'' episode "[[NonIndicativeFirstEpisode The Adventures of Mikuru Asahina]]", when Itsuki attempts to kiss a drunk Mikuru:
-->'''Kyon:''' Okay, how is this happening right now? If your mouth gets any closer to her, someone standing off camera is gonna step into frame and KICK YOUR ASS, DAMMIT!
* In Chapter 36 of the manga for ''Anime/NeonGenesisEvangelion'', [[SmittenTeenageGirl 14 year-old Asuka]] tells Kaji to stop treating her like a child and starts taking off her clothes. [[ChivalrousPervert When Kaji refuses her]], Asuka replies, "It's Misato, isn't it? [[{{tsundere}} YOU STILL LOVE MISATO, DON'T YOU?! SO YOU'RE SAYING THERE'S NO ROOM FOR ME?!]]" causing an alarmed Kaji to think that she really ''is'' like a child after all.
* ''LightNovel/SwordArtOnline'': During the climax of the Fairy Dance arc, Kirito dips into this after performing his HeroicSecondWind and turning the tables on Sugou, particularly after he gives Sugou a small cut on the cheek, and [[MinorInjuryOverreaction Sugou flips out and whines about the pain]]:
-->'''Kirito''': Hurts, doesn't it? But it's ''nothing'' like [[AttemptedRape the pain you made Asuna feel]]. ''NOT EVEN '''CLOSE!!'''''\\
[''cue him [[AnArmAndALeg lopping Sugou's right arm clean off]]'']
* In the Anime/YuGiOh Doma ark, Seto Kaiba does not take Yugi's loss to Rafael very well.
-->'''Kaiba:''' YUGI LOST?!
* In an early ''ComicStrip/{{Garfield}}'' strip:
--> '''Jon''': Be careful there, Garfield. Hanging on the drapes can be very painful. 'CAUSE I'M GONNA BREAK YOUR LEGS IF YOU DON'T GET OFF THEM THIS INSTANT!
** He also does it again later:
---> '''Jon''': Some dirty, rotten, low-down, slimy, filthy, disgusting, gluttonous, hog STOLE MY SUPPER!
** And in another, Garfield is watching "The Loud Channel":
--> We're loud... We're proud... -Garfield gets closer to the TV to hear what they're saying- AND WE'RE MEAN TOO!
[[folder:Fan WORKS!]]
* In ''FanFic/{{Retribution}}'', Spock [[NotSoStoic raises his voice in frustration]] when Kirk contradicts his statement that the captain "[has] no idea of the gravity of offenses that can be committed between us."
* In ''[[https://www.fanfiction.net/s/5178251/22/30-Minutes-That-Changed-Everything 30 Minutes That Changed Everything]]'' a recently-freed Sirius is talking to Remus about what happened during his illegal imprisonment.
-->'''Sirius:''' Dumbledore seems to have sent MY GODSON to live with Lily's vile sister!
* In ''FanFic/ThisBites'', while calmly summing up Cross, Luffy, and Ace's antics in Nanohana, Vivi suddenly starts yelling demanding to know why the town is on fire.
[[folder:Film - ANIMATED!]]
* A couple of examples from the ''WesternAnimation/ToyStory'' series:
** From [[WesternAnimation/ToyStory the first movie]]: "He's not a space ranGER!"
*** Also: "I hate to break up the staff meeting, but...THEY'RE HERE! BIRTHDAY GUESTS AT THREE O'CLOCK!"
*** Additionally: [[PunctuatedForEmphasis "YOU. ARE. A. TOOOOOY!"]]
** From [[WesternAnimation/ToyStory3 the third movie]]: "He was putting you IN THE ATTIC!"
* ''WesternAnimation/TheIronGiant'':
** "There are two kinds of metal in this yard: scrap and art. If ya gotta eat one of 'em, eat the scrap. What you currently have IN YOUR '''MOUTH''' IS '''ART!'''"
** "Biggest thing around here is probably the prom queenOH MY GOD!!!"
** "Oh my God....uh...Ohhh my God, we uh ''thank you'' for the food that mom has put in front of us and '''STOP!!!''' -th..the Devil! From doing bad things...and uh '''GET OUT OF HERE!!!''' ...Satan? '''GO! GO!''' ...so that we may live in peace. Amen."
* ''WesternAnimation/{{Ratatouille}}'': When Skinner questions his sous chef how Linguini could have changed the recipe if he had tasted it.
--> "Because he changed it AS IT WAS GOING OUT THE DOOR!"
** This also happens when Colette lectures Linguini on cooking:
---> '''Colette:''' ''(sweetly)'' Keep your station clear, ''(not so sweetly)'' or I WILL KILL YOU!
* A few instances in ''Disney/PeterPan'', and all directed at Mr. Smee:
** "Good form, Mr. Smee? ''BLAST'' GOOD FORM! DID PAN SHOW GOOD FORM WHEN HE DID ''(holds up hook)'' ''THIS'' TO ME?!?"
** "For the last time, Mr. Smee, take the princess back to her people! UNDERSTAND?!?!?"
** "You will go ashore, pick up Tinker Bell, and bring her to me. UNDERSTAND?!"
** And in the sequel, ''Return to Neverland'': "Mr. Smee? Be a good fellow and fix the plank SO I CAN MAKE YOU WALK IT!"
* [[FinalGirl Jenny]] from ''Famine'' talks like this all the time. And yes, her classmates and teachers think there is something terribly wrong with her because of it.
* ''WesternAnimation/MonstersInc'' Mike does this at least 3 times
** First when he pretends to be a TV Host while Sulley is sleeping in bed (''Meta note:'' The producers had wanted something to lead up to the morning workout montage, so they let Billy Crystal cook up something. He delivered this gem):
-->'''Mike:''' Hey! Good morning, Monstropolis. It's now five after the hour of 6:00 A.M. in the big monster city. Temperature's a balmy 65 degrees - which is good news for you reptiles - and it looks like it's gonna be a perfect day to maybe, hey, just lie in bed, sleep in, or simply... WORK OUT THAT FLAB THAT'S HANGIN' OVER THE BED!! GET UP, SULLEY!!!" ''(cue air horn)
** Later as Boo is getting sleepy
-->'''Sulley''': Mike? I think she's getting tired.\\
'''Mike:''' Well, then why don't you find someplace for it to sleep...''WHILE I THINK OF A PLAN!''
** Then as Sulley doesn't think Boo's dangerous, Mike's not so convinced
-->'''Sulley''': Hey, Mike, this might sound crazy, but I don't think that kid's dangerous.\\
'''Mike:''' [[SarcasmMode Really? Let's keep it. I always wanted a pet]] ''[[SarcasmMode THAT COULD KILL ME!]]''
** Randall also frequently does this.
-->'''Randall''' (''to Fungus''): If I don't see a new door in my station in 5 seconds, I will personally put you '''''THROUGH THE SHREDDER!!!'''''
* In ''Disney/AliceInWonderland'':
-->'''Alice:''' Three inches is such a wretched height...\\
'''Caterpillar:''' ''I'' am ''exac-tically'' three inches ''high'', and it is a very good height INDEED!\\
'''Alice:''' But I'm ''not'' used to it! And you needn't... SHOUT!
** This is also a character trait of the Queen of Hearts.
* Georgette in ''Disney/OliverAndCompany'', when she catches Oliver eating from her bowl.
-->Well, it may be Jenny's house, but everything from the doorknobs down IS MINE!
* In ''Disney/TheHunchbackOfNotreDame'', when Frollo notices one of Quasi's wooden figures shaped like Esmerelda
--> '''Frollo''': Isn't this one new? It's awfully good. Looks very much like the...Gypsy Girl. I know... YOU HELPED HER ''ESCAPE!!!!''
* In ''WesternAnimation/KungFuPanda2'' The wicked peacock Shen does this to his wolves to get his fleet ready. He even whispers to them before screaming it out.
-->'''Shen''': [''whispering''] Get the wolves ready. We're loading the ships now.. [''yells''] '''NOW!''' NOW! NOW! NOW! NOW!
* Disney's ''{{Disney/Hercules}}'': Done by Hades too many times to count. Let's just say that James Woods has a ''fun habit'' of playing characters who have a tendency to suddenly yell.
* ''WesternAnimation/RecessSchoolsOut'': Dr. Phillium Benedict, also by James Woods. One time when he's done yelling at his goons, Benedict then whines "Aww, man! I got spittle on my lapel!"
* Gogo in ''Disney/BigHero6'', when Yokai pursues the heroes:
-->'''Gogo''': Why are we stopped?\\
'''Wasabi''': The light's red!\\
'''Gogo''': ''[[NotSoStoic THERE ARE NO RED LIGHTS]]'' '''''[[NotSoStoic IN A CAR CHASE!]]'''''
* Sebastian in ''Disney/TheLittleMermaid''
-->'''Sebastian:''' What is all this!?
-->'''Ariel:''' It, err...It's just my...collection.
-->'''Sebastian:''' [''chuckling''] Oh, I see. Your collection. Hmm... '''IF YOUR FATHER KNEW ABOUT THIS PLACE, HE'D--''' ''(Flounder cuts him off)''
* It happens to be the first line of dialogue in the first ''WesternAnimation/IceAge'' movie.
-->'''Freaky Mammal 1''': Why not call it "the Big Chill", or the "Nippy Era." I'm just sayin', [[AskAStupidQuestion how do we know it's an ice age?]]
-->'''Freaky Mammal 2''': Because...of all...''[[CaptainObvious THE ICE!!]]''
-->'''Freaky Mammal 1''': Well, things just got a little chillier.
* [[BigBad Silver]] from ''WesternAnimation/TreasurePlanet''.
-->'''Silver''': (Talking to his pirate crew) Now, if ya' pardon my plain speakin', gentlemen, are ya' all (Draws out a cutlass) '''STARK-RAVIN' TOTALLY BLINKIN' DAFT?!!!'''
** Later, on Treasure Planet with Jim and Morph
-->'''Silver''': Morph, hop to it. (Morph refuses) '''NOW!!'''
* Madame Medusa in ''Disney/TheRescuers'' when coercing Penny go down into the cave to retrieve the diamond by taking her teddy bear hostage.
-->"You get down there and find the big diamond OR YOU WILL ''NEVER SEE THAT TEDDY AGAIN!!!''"
** Happens in the sequel, ''Disney/TheRescuersDownUnder'' as well.
-->'''Cody''': ''[pounding on the cage]'' Let me outta here!! Let me go!! You can't do this!! Help! Help! Help!\\
'''[=McCleach=]''': Breaker, breaker, little mate. I forgot to tell ya around here, you need to be '''QUIET!!!''' ...or the rangers might hear you.
* ''WesternAnimation/{{Shrek 2}}'': Shrek does this to Donkey during the carriage ride to Far Far Away.
-->'''Shrek:''' For five minutes, could you not be yourself? FOR '''FIVE MINUTES!!!'''
* In ''Disney/{{Aladdin}}'', Genie's famous advice to Aladdin on how to win Jasmine's heart combines this with PunctuatedForEmphasis.
-->'''Genie''': Alright, Sparky, here's the deal. If you wanna court the little lady, you gotta be a straight shooter. Ya got it?
-->'''Aladdin''': What?
-->'''Genie''': Tell. her. the... '''''TRUTH!'''''
[[folder:Film - LIVE-ACTION!]]
* ''Film/TheLadykillers'':
--> '''Professor Marcus:''' Major, Major, Major... CALM DOWN!
* ''Film/{{The Big Lebowski}}'': Multiple instances throughout, for example:
-->'''The Dude:''' Hey man, nothing is fucked here...
-->'''The Big Lebowski:''' Nothing is [[AtomicFBomb FUCKED?]]
-->'''The Dude:''' No...
-->'''The Big Lebowski:''' THE GODDAMN PLANE HAS CRASHED INTO THE MOUNTAIN!
** And this one:
-->'''Walter:''' (''drawing a pistol'') Mark it zero, Smokey or you're in a world of pain.
-->'''Smokey:''' ''(starts stammering)''
-->'''Walter:''' A world of pain.
-->'''Smokey:''' Dude; - h-he's your partner -
-->'''Walter:''' (''stands up brandishing the pistol threateningly'') Has the whole world gone CRAZY? AM I THE ONLY ONE AROUND HERE WHO GIVES A SHIT ABOUT THE RULES? MARK IT ZERO!
** and...
-->'''Walter:''' Saturday is Shabbos, the Jewish day of rest. Means I don't work, I don't drive a car, I don't fucking ride in a car, I don't handle money, I don't turn on the oven, and I sure as shit DON'T FUCKING ROLL! SHOMER SHABBOS!
** In other words, it's pretty much Walter's defining trait.
* ''Film/{{The Avengers|2012}}'': Earlier in the film, Bruce Banner in his {{Troll}}-ish moment to pretend he's gonna start HulkingOut:
-->'''Bruce:''' (''in low deadpan tone'') [Fury] needs me in a cage?\\
'''Natasha:''' No-one's gonna put you in...\\
'''Bruce: [[JumpScare STOP LYING TO ME!]]'''\\
'''Natasha:''' (''[[JumpScare freaks out and draws her gun]]'')\\
'''Bruce:''' (''chuckles, looks'' '''obviously''' ''amused and satisfied'') I'm sorry, that was mean, I just wanted to see what you'd do.
* In ''Film/GuardiansOfTheGalaxy'', we get an example of this from Rocket, tired of people criticizing his escape plan (as he'd escaped from 22 prisons before). He then goes back to speaking normally.
-->'''Rocket:''' I got one plan and that plan requires a frickin' Quarnex battery so FIGURE IT OUT!... Can I get back to it?
* ''Film/TheThing1982''. Garry (the station commander) was tied down in case he was one of the Things. He has just been proved to be human and not a Thing, but he's still annoyed.
-->'''Garry:''' I know you gentlemen have been through a lot, but when you find the time, I'd rather not spend the rest of this winter TIED TO THIS [[PrecisionFStrike FUCKING]] COUCH!
* In the first ''Film/AustinPowers'' film, when Powers gets thawed out:
-->'''Austin Powers:''' WHO ARE THESE PEOPLE?
-->'''Basil Exposition:''' The shouting is a temporary side effect of the unfreezing.
-->'''Austin Powers:''' Yes... I'm having difficulty controlling THE VOLUME OF MY VOICE.
** A RunningGag with Frau Farbissina is her inability to give an order without shouting the last part.
-->"Bring in the fem-'''BOTS!'''
* ''Film/TheWeddingSinger'':
-->"Again, something that could have been brought to my attention YESTERDAY!"
* In ''Apollo13'', after being told that Ken Mattingly is scrubbed from the mission because he has been exposed to measles and might get ill during the flight, Jim Lovell doesn't react well.
-->"This...is...'''FLIGHT SURGEON [[PrecisionFStrike HORSESHIT]], DEKE!'''"
* ''[[Film/NationalTreasure National Treasure: Book of Secrets]]'', on the heels of Patrick Gates meeting his ex-wife and it not going well:
-->'''Ben Gates:''' At least we know where the rest of the plank is.
-->'''Patrick Gates:''' What? You know where it is? Why didn't you tell me?
-->'''Ben Gates:''' Because, obviously, you have a tendency to '''OVERREACT!'''
* ''Film/PathsOfGlory''. Colonel Dax's epic TheReasonYouSuckSpeech to his commanding officer.
-->"I apologize for not being entirely honest with you. I apologize for not revealing my true feelings. I apologize, sir, for not telling you sooner that you're a degenerate, sadistic old man. ''AND YOU CAN GO TO HELL BEFORE I APOLOGIZE TO YOU NOW OR EVER AGAIN!''"
* ''Film/CastAway'': This bit of dialog happens when Chuck tells [[CompanionCube Wilson the volleyball]] that he's making ready to leave the island for good:
-->'''Chuck:''' We might just make it. Did that thought ever cross your brain? Well, regardless, I would rather take my chance out there on the ocean, than to stay here and die on this shithole island, spending the rest of my life talking TO A GODDAMN ''VOLLEYBALL!!!''
* ''Film/KillBill'': O-Ren Ishii gets like this after cutting off Tanaka's head:
-->'''O-Ren:''' The price you pay for bringing up either my Chinese or American heritage as a negative is... I collect your fucking head. JUST like this fucker here. Now, if ''any'' of you sons of bitches GOT ''ANYTHING ELSE'' TO SAY, NOW'S THE FUCKING TIME!!!!
* ''Film/TheLionTheWitchAndTheWardrobe'':
-->'''Jadis:''' Tell me, Edmund. Are your sisters deaf?
-->'''Edmund:''' No.
-->'''Jadis:''' And your brother, is he unintelligent?
-->'''Edmund:''' Well, I think so. But Mum says...
-->'''Jadis:''' '''THEN HOW DARE YOU COME ALONE?!'''
* Bruce Wayne goes ballistic in the apartment scene in ''{{Film/Batman}}'' when the Joker comes calling.
-->'''Bruce Wayne:''' You want to know what happened to this guy, Jack? Well...he made mistakes...and then he had his...[''smashes a vase before exploding'']...AND THEN HE HAD HIS LIGHTS OUT! NOW YOU WANT TO GET NUTS?! COME ON! Let's get nuts!
* In ''Film/TheDarkKnight'', Harvey Dent/Two-Face is nearly always doing this.
** During Joker's handheld video threat to Batman with a captured Brian Douglas, he continues to address Brian in his usual low-volume mock-playful Joker voice until he gets really loud for the first time in the film, and it is unnerving, especially since he's off-screen so there's no warning it's coming.
-->''So you think Batman has made Gotham a better place? Look at me....'''LOOK AT ME!!!'''''
* ''Film/MoulinRouge''
** "It's not that I'm a jealous man... I just DON'T LIKE OTHER PEOPLE TOUCHING MY THINGS!!!!
** "Never fall in love with a woman who sells herself. It always ends '''BAD!!!'''"
* ''Film/{{Gettysburg}}''. The mild-mannered Confederate general Lee is giving a DisappointedInYou speech to his cavalry commander Jeb Stuart, who went off on a raid instead of scouting for the enemy, leading to near disaster when the Federal army came on them unexpectedly. Stuart wants to duel those officers who've criticized him. Lee replies quietly, "We have no time for that, sir." When Stuart persists, Lee erupts: "I HAVE TOLD YOU THERE IS NO TIME FOR THAT -- THERE IS NO TIME!"
* ''Film/TheBoondockSaints''. Agent Smecker's epic flipout when he discovers that the blood evidence found at the scene of the Saint's latest shootout is useless to Forensics:
--> '''Smecker:''' ''They used ammonia! You know what this means? None of this is any good--'''FUCK!!''' WHO THE FUCK ARE THEY?!''
* ''Film/MasterAndCommander''. Dr Maturin gets annoyed when his friend Captain Aubrey has to sail off after the French privateer, breaking his promise to let Maturin have a few days exploring the Galapagos Islands. Their conversation gets more and more heated until the captain cuts it off by shouting, "WE DO NOT HAVE TIME FOR YOUR DAMNED HOBBIES, SIR!"
* ''Film/KissKissBangBang''. Harmony, still pissed off at Harry, ignores his revelation on the case and slams her door (unknowingly) onto his fingers; cut to him leaving the hospital:
-->'''Harmony''': She sent you to that exact spot!\\
'''Harry''': That whole thing is wild. You know what else is nuts? '''''THAT YOU CUT OFF MY FINGER!'''''
* In ''Film/ThorTheDarkWorld'' when Thor accused Loki of not having been much help in his cell:
-->'''Loki''': Who put me there? WHO PUT ME THERE?!
** Also, earlier:
--->'''Frigga''': Your father-\\
'''Loki''': HE'S NOT MY FATHER!
* And in the first ''Film/{{Thor}}'':
-->'''Loki''': No, you took me for a purpose. What was it? [pause] ...TELL ME!!!
** Earlier in the movie, this is Odin's way to silence Loki:
-->'''Loki:''' Father...\\
'''Odin:''' ''HEEEAAAYYRGHHH!''
* In ''Film/{{Clue}}'' when Mr. Boddy is found dead in the hallway:
-->'''Wadsworth''': That's what we're trying to find out! We're trying to find out WHO killed him, and WHERE, and with WHAT!
-->'''Professor Plum''': There's no need to shout!
-->'''Wadsworth''': '''''I'M NOT SHOUTING!'''''
-->[Guests stare at him pointedly]
-->'''Wadsworth''': All right, I am! I'm shouting, I'm shouting, I'm shout...
-->[candlestick falls from above and hits him on the head]
* ''Film/PacificRim'', when Raleigh makes the mistake of trying to argue with his superior officer:
-->'''Marshal Pentecost:''' Do not let my calm demeanour fool you, '''''RANGER!!''''' '''NOW''' is not a good moment for your insubordination!
* Happens in ''Film/AceVentura'', when Ace exposed Lois Einhorn as Ray Finkle in disguise.
-->'''Ace:''' If the lieutenant is a definitely woman as she claims to be, then she is suffering from the worst case of hemorrhoids ''I HAVE EVER SEEN!!!''
* A memorable one from ''Film/{{Fear}}'', when David goes crazy and tries to get into the Walker's house.
-->'''David:''' "It all could have been different Mr. Walker, you should have allowed nature to take it's course. In the end it will anyway...SO LET ME IN THE FUCKING HOUSE!"
* ''Film/InTheLineOfFire'':
-->'''Mitch Leary:''' Do you know how easily I could kill you, Frank? Do you know how many times I watched you go in and out of that apartment? You are still alive because I have allowed you to live so you show me some GODDAMN RESPECT!
* ''Film/HarryPotterAndTheOrderOfThePhoenix'': Bellatrix voices her displeasure with Harry's lack of fear of Voldemort rather loudly.
-->'''Bellatrix:''' ''You dare speak his name...'' YOU FILTHY HALF BLOOD!
* In ''Film/{{Waterworld}}'', Helen is trapped on a boat with Kevin Costner's character, The Mariner, and starts getting crabby because she wants "some '''FOOD!'''"
* In ''Film/JupiterAscending'', when Balem Abrasax isn't whispering, he's shouting. Transcends into VillainousBreakdown by the end.
-->'''Balem:''' Bring her to me '''''NOW!'''''
* ''Film/TheProducers'': Both Bialystock and Bloom are prone to this.
-->'''Max''': Bloom, I'm drowning. Other men sail through life, Bialystock has struck a reef. Bloom, I'm going under. I'm condemned by a society that demands success when all I can offer is failure. Bloom, I'm reaching out to you. Don't send me to prison... '''HEEELLP!'''
* ''{{Prometheus}}'': The otherwise taciturn and soft-spoken Fifield [[ScrewThisImOuttaHere gets annoyed and starts to leave]] the cave when the crew stumbles across some decapitated alien corpses:
-->Look, [[ImADoctorNotAPlaceholder I'm just a geologist]]. I like rocks, I ''love'' rocks. It's clear you two don't give a shit about rocks, but what you do seem to care about is gigantic dead bodies, and I don't really have anything to contribute in the '''''gigantic dead body arena!''''' I'm gonna go back to the ship, if you don't mind.
* [[EveryoneCallsHimBarkeep The Graverobber]] from ''Film/RepoTheGeneticOpera'' has a hell of a time with this during "21st Century Cure".
-->It's quick!... It's ''clean''... And it's pure. It could change your ''life'', rest assured. It's the 21st Century... ''Cure!'' And it's my job... To steal and rob... ''GRAAAAAAAAAAAAAAAAAAAAAAAAAAAAVES!!!!''
* General Zod in ''Film/ManOfSteel'' promises in his trial that he '''WILL FIND HIM!''' Him being Superman.
* ''Film/TheMuppetChristmasCarol'' has Scrooge SuddenlyShouting at bookkeeper rats.
-->'''Scrooge''': And how does one spend one's Christmas ON THE UNEMPLOYMENT LINE?
* ''Film/TheJungleBook2016'' has Shere Khan's response to Akela's announcement that Mowgli has left the pack for the man-village, which doubles as a PreMortemOneLiner.
-->'''Shere Kahn:''' Well, I guess it's done then. ''Unless I can draw him'' '''''BACK OUT!'''''
* ''Film/WarCraft2016'' has Lothar failing at convincing the guard that he has calmed down:
-->'''Lothar''': (''calmly'') I've calmed down now. So, please let me out so that I can protect the King.\\
'''Guard''': *shakes his head*\\
'''Lothar''': ''LET ME OUT!''
* Happens in ''Film/{{UHF}}''.
-->'''George Newman''': Okay. Right now I'd like to show you one of my favorite cartoons. It's a sad, depressing story about [[WileECoyoteAndTheRoadRunner a pathetic coyote who spends every waking moment of his life in the futile pursuit of a sadistic roadrunner]], who '''MOCKS''' him and '''LAUGHS''' at him as he's repeatedly '''CRUSHED AND MAIMED'''! Hope you '''''[[RageBreakingPoint ENJOY IT]]!!!'''''
* In ''Literature/AnimalFarm'', after the first windmill is destroyed by a strong wind, Napoleon begins a speech for the animals:
-->Comrades, he said quietly, do you know who is responsible for this? Do you know the enemy who has come in the night and overthrown our windmill? [[TheScapegoat SNOWBALL!]] he suddenly roared in a voice of thunder.
* ''Literature/HarryPotterAndTheGobletOfFire'': [[spoiler: Fake]] Moody does this whenever he says [[CatchPhrase "CONSTANT VIGILANCE!"]]
* In the ''Literature/RevengeOfTheSith'' novelization, Palpatine is normally quite calm. It's a part of his manipulation of Anakin Skywalker that he seems to be breaking down over what he claims is a conspiracy against him.
--> "Here" The Chancellor rummaged around within his desk for a moment, then brought forth a document reader. "Do you know what this is?"\\
Anakin recognized the seal Padmé had placed on it. "Yes, sirthat's the Petition of the Two Thousand"\\
"''No,'' Anakin! No!" Palpatine slammed the document reader on his desktop hard enough to make Anakin jump. "It is a roll of ''traitors''."
* ''Literature/JourneyToChaos'': One moment Retis soft-spoken and polite, and then the next "OPEN THE DOOR YOU OLD MUMMY!"
[[folder:Live-ACTION TV!]]
* ''Series/{{Sharpe}}'': In the aftermath of a disastrous skirmish, in which an incompetent Colonel managed to lose the King's Colours (the Royal standard of the King of England), he tries to pass off the blame to a heroic Major he sent into the fray unaided, resulting in said Major's death in his report to Ser Arthur Wellesley, his commander and the later Duke Of Wellington. The exchange ''has'' to be read:
-->'''Wellesley (Calmly)''':...[[TheChessmaster Major Hogan]] reports a number of losses, Sir Henry. [[GeneralFailure He says you first lost your head, and, instead of destroying the bridge, you marched over it.]] [[DirtyCoward He says you then lost your nerve and ran from a small French patrol.]] [[SenselessSacrifice He says you lost ten men, a major and two sergeants.]] He says you lost your sense of honour and destroyed the bridge, cutting off a rescue party led by Lieutenant Sharpe. Major Hogan leaves the worst to the last: [[CurbStompBattle He says you lost the King's Colours.]]
-->'''[[ModernMajorGeneral Simmerson]]''': The fault was not mine sir. [[NeverSpeakIllOfTheDead Major Lennox must answer-]]
-->'''Wellesley (roaring)''': Major Lennox answered with his '''''LIFE''''' sir! As you ''should'' have done if you had any sense of honor! You ''shamed'' us sir! You ''disgraced us sir!'' ''You'' will answer. [[BadassBoast By God you will answer]]! The South Essex is stood down in name. If I wipe the name I may wipe the shame. I am making you a battalion of detachments, you will fetch and carry. The Light Company put up a fight, so I will let it stand under a new captain.
-->'''Simmerson''': To be commanded by the newly gazetted Captain Gibbons, sir?
-->'''Wellesley''': To be commanded by the newly gazetted Captain ''Sharpe'', sir.
-->'''Simmerson''': [[ScrewTheRulesIHaveConnections I have a cousin at Horse Guards...and friends at court.]]
-->'''Wellesley [[{{TranquilFury}} (deathly quiet)]]''': [[ShutUpHannibal A man who loses the King's Colours loses the King's friendship.]]
* ''Series/SaturdayNightLive'': Chris Farley would do this on several occasions, particularly with his Matt Foley character. He has gone on record to say that's it's based on a quirk his father used to embody.
--> '''Chris Farley:''' It's a little bit of my dad, you know? He used to start out slow and then build to a rage. He'd go like, uh... "I thought I told you boys to SHOVEL THE WALK!!! GET OUT THERE!!!"
* ''Series/TheFreshPrinceOfBelAir'': Phil did this several times with both Carlton and Will, usually after one of their schemes went badly awry. One classic example is the Season 2 episode "Striptease For Two" (where Will and Carlton sell Vivian's heirloom bracelet to buy stock ... for a company that, later that day, goes bankrupt). Made to confess, Phil at first collapses into uncontrollable laughter, and so do Will and Carlton ... only Phil has gotten them to lower their guard, fulfilling the trope's Surprise/Fear category when, without warning, he screams at the top of his lungs, "'''''[[RageBreakingPoint DO I LOOK LIKE]] [[Series/LeaveItToBeaver A WHITE GUY NAMED WARD]]???!!!???'''''" When Will and Carlton try to apologize, an outraged Phil snaps back, "''Now you get that bracelet back, and for the next six weeks, I don't want to hear you breathe ... '''OR I'M CALLING THE FEDS MYSELF!!!'''''"
* In an episode of ''{{Series/Workaholics}}'', Ders dips into this trope while he's high on "Mexican steroids" (which are actually PCP).
--> '''Ders:''' Adam had a heart attack. And the doctor said its your fault, [[BlatantLies and not all the Mexican steroids.]] So if its cool with you, I'M GONNA WARM UP NOW, MAN!
* From ''Series/DoctorWho'', New Series 1 finale (paraphrased):
-->'''The Doctor:''' I'm the Doctor, and if there's one thing I can do, it's talk. I've got five billion languages and you haven't got one way of stopping me. So if anybody's going to shut up, ''(spins round)'' [[BigShutUp IT'S YOU!]] ''(two Daleks jerk back in fear)'' [[DissonantSerenity Okeydoke. Where were we?]]
** The Eleventh Doctor does it when he gets particularly emotional.
--> '''The Doctor:''' I want you to tell your men to run away. I want people to call you 'Colonel Run-away'. I want children, laughing, because they've found the home of Colonel Run-away, and then if ''ever'' anyone asks you whether it's a good idea to get to me through the PEOPLE '''I LOVE'''... I want you to tell them your name.
** The Sixth Doctor pretty much embodies this trope.
** Inverted by the Fourth Doctor, who tends to generally shout a lot and suddenly drop into a weird, creepy whisper.
* Mike Myers used this in the same manner as the ''Film/AustinPowers'' example when he was on ''Series/SaturdayNightLive''.
-->'''Kenneth Rhys-Evans:''' That reminds me of a story that's in no way related. I was working with John Gielgud in a production of ''Theatre/TroilusAndCressida'', when I discovered I had no control OVER THE VOLUME OF MY VOICE!
* An iconic moment for Sylar in ''Series/{{Heroes}}'' happens this way.
-->'''Noah''': [[YoureInsane I think you're insane]]. I think the infusion of so many alterations to your D.N.A. has corrupted your mind. All this power is degrading you.\\
'''Sylar''': And yet, here I am, alive and well and as soon as I get out, I'm gonna collect one more ability from your daughter. Sweet, innocent...\\
'''Noah''': That's enough.\\
'''Sylar''': ...Ripe, indestructible-\\
'''Noah''': I said that's enough, [[spoiler:Gabriel]]!\\
'''Sylar''': '''MY NAME IS SYLAR!!!'''
* ''Series/JudgeJudy'' plays this card quite often when someone tries to talk over her, and she [[BigShutUp loudly reminds them she's talking]].
* ''Series/{{Supernatural}}'':
** Crowley does this a lot.
-->"Am I the only game piece on the board who '''''doesn't underestimate those denim-wrapped nightmares'''''?!"
** So did Pestilence. "If Satan wants them so bad he can '''GLUE THEM BACK TOGETHER!'''"
** Even angels get into the act.
-->'''Zachariah:''' "I'd walk these halls and people would ''AVERT THEIR EYES -- I HAD RESPECT!''"
* In ''Series/{{Merlin|2008}}'' Season 4, where Arthur is [[spoiler:confronting Gwen about kissing Lancelot]] he goes from almost zen-like monotone to completely losing it in less than a second. Considering who it's coming from, it's genuinely scary.
-->'''Arthur:''' Then forgive me, because I must be really stupid. WHAT! WERE YOU DOING?!
* On ''Series/{{Frasier}}'', Frasier Crane is the ''master'' of this trope:
--> '''Frasier''': [[BluffTheImpostor This morning you said you two met on a double date.]]
--> '''Roz''': Oh that's right, we did meet on a double date!
--> '''Frasier''': '''''[[LargeHam THIS MORNING YOU SAID NOTHING!!!]]'''''
* ''Series/{{Firefly}}'' Mal has a particularly good unexpected one during a stand off with his "wife" in the episode "Trash".
--> '''Mal''': "While this is touching, Yosaffbridge, I really- '''DROP IT, NOW!'''"
** And earlier in the same episode, Wash's reaction to hearing Saffron's [[ThePlan plan]]:
--> '''Wash''': I'm confused.
--> '''Saffron''': You're asking yourself, if I've got the security codes, why don't I go in, grab it for myself.
--> '''Wash''': No, actually, I was wondering... '''WHAT'S SHE DOING ON THE SHIP?!''' We're in space! How did she get here?
* [[Literature/TheLangoliers "Scaring the little gIRL?!]] [[LargeHam LADY!!]]"
* In ''Series/{{Seinfeld}}'', George has one in the episode "The Voice" after crawling his way through an air duct to get back into his boarded-up office.
-->'''George:''' Hello Margery, George Costanza. How are you, sweetheart? Listen, can you give Mr. Thomassoulo a message for me? Yes. If he needs me, tell him '''IM IN MY OFFICE!!!''' Thanks.
* In ''Series/{{Sherlock}}'', [[BigBad Moriarty]] does this more than once in "[[Recap/SherlockS01E03TheGreatGame The Great Game]]".
--> '''Sherlock:''' People have died.\\
'''Moriarty:''' That's what people '''DO!!!'''
** And Sherlock, while under quite a bit of stress in the "[[Recap/SherlockS02E03TheReichenbachFall The Reichenbach Fall]]" episode:
-->'''Sherlock:''' Moriarty is playing with your mind, too. Can't you SEE WHAT'S GOING ON?
* On ''Series/TheNewsroom'', after Mackenzie accidently [[spoiler:lets slip the details of her and Will's breakup in an email to the whole staff (after he specifically told her not to tell anyone about it)]], he confronts her in front of everyone in the newsroom. After talking to her in a calm, but simmering tone for a minute or two he finally lets loose:
-->'''Will:''' You know how sometimes something happens in an instant that's so astonishing you just shut down?
-->'''Mackenzie:''' Of course, that's understa-
-->'''Will:''' [[PunctuatedForEmphasis THAT DOESN'T! FUCKING! HAPPEN! TO ME!]]
* On ''Series/TheOfficeUS'', Gabe tries to embarrass Andy during his branch manager interview by asking him difficult, irrelevant questions. It backfires:
-->'''Gabe:''' How far away is the sun?
-->'''Andy:''' Uh, 93 million miles.
-->'''Jim:''' Is it?
-->'''Andy:''' Yeah. And the diameter of the sun is 870,000 miles, which makes it 109 times wider than the Earth, and 333,000 times heavier than the Earth-
-->'''Gabe:''' Shut up about the sun! SHUT UP ABOUT THE SUN!
-->(awkward silence)
* ''Series/HowIMetYourMother'' During Barney's CannotSpitItOut stage with Robin, Ted and Robin start a FriendsWithBenefits deal and explain that he's the one who gave them the idea.
-->'''Barney''': So I'm responsible for... [[TwitchyEye Excellent. Excellent. Excellent.]] ''[gets up]'' Next round's ON ME!
** On the flip side, Ted earlier claims to be totally okay with [[spoiler:Barney and Robin]] hooking up.
---> '''Ted''': Seriously, I'm fine with this.
---> '''Barney''': I'm so relieved to hear you say that.
---> '''Ted''': Yeah, yeah... Oh hey, I just remembered, my mom is coming into town next month. Maybe YOU'D LIKE TO NAIL HER TOO!
* In an installment of Season 8 of ''Series/HellsKitchen'', Creator/GordonRamsay does this to Boris when delivering a GetOut, in his ear. "(''whispering'') Get out. Get out. ... '''''Get out!!!!!'''''"
* In ''Series/{{Spaced}}'', this happens to Tyres as a side effect of his constant clubbing and ecstasy usage.
-->'''Tyres:''' I just wish I could control these '''FUCKING MOOD SWINGS!!'''
* ''Series/DropTheDeadDonkey''. Henry Davenport gets drunk at his award ceremony and has an InVinoVeritas moment.
-->"I remember the days when the television industry was run by giants. Whereas now it is run...BY PYGMIES! ''(pointing)'' LIKE HIM! AND HIM!"
* ''Series/BuffyTheVampireSlayer''
** Spike does this when [[TheDitz Harmony]] asks one too many stupid questions.
-->"Harm, I've been wondering, just for my own curiosity, what's it take to get you to SHUT THE HELL UP?"
** Willow's [[WolfMan werewolf]] boyfriend [[TheStoic Oz]] has only a singular display of anger throughout the three eventful seasons we see him. It wasn't when everyone else was freaking out at Buffy for skipping town at the end of Season 2, or even after witnessing Willow and Xander ''making out'' in the warehouse basement Spike locked them in. In the Season 4 episode "Wild at Heart", Willow is in tears over seeing Oz with another woman, fellow werewolf Veruca, in his cage after one of the nights where he transforms. [[NotWhatItLooksLike Totally naked]]. While Oz explains that he needed to find a way to cage her up, given that she doesn't care about who she kills while in beast form, it doesn't really help his case much, especially given that Veruca did, in a way, succeed in tempting the beast in him. When Oz tells her to leave so he can explain the situation, Veruca feels the need to keep talking, prompting one incredibly loud "NOW" from Oz the likes of which have never been seen (or heard, rather). Even given her dangerously high snark levels, she apparently leaves so quickly that they didn't even need another shot of her to show it.
** Played seriously in "The Gift". Giles is trying to get Buffy to acknowledge that killing her little sister [[BarrierMaiden Dawn]] may be necessary to save not only the world, but all of reality.
-->'''Buffy:''' I don't wanna hear it. ''(turns away)''\\
'''Giles:''' ''(gently)'' I understand that--\\
'''Buffy:''' ''(whirls back)'' No! No, you don't understand. We are not talking about this.\\
'''Giles:''' ''(jumping up from the table)'' YES, WE BLOODY WELL ARE!
* ''Jimmy Kimmel Live''. Creator/GaryOldman would like to speak on behalf of [[https://www.youtube.com/watch?v=CIaWo-BlBjs Actors Against Acting Athletes]].
-->"And just as I, Gary Oldman, would never join an NBA team just because I'm famous, I Gary Oldman would very much appreciate it if professional basketball players would ''STAY THE [[SoundEffectBleep BLEEP]] OUT OF MOVIES!''"
* ''Series/{{Cracker}}''. A different take on this trope appears in "Men Should Weep". Fitz is complaining about his son's layabout ways.
-->"You know Mark, you appear to be a symbol of the Lost Generation. Yes, that could well be the case. The crisis of Western capitalism has deprived you of work, motivation and the will to succeed but personally Mark, personally ''(cuts to someone listening outside the house to the faint voice of Fitz shouting inside)'' I think you're a bone-idle git!
* ''Series/{{Luther}}''. SmugSnake Lucien Burgess having his VillainousBreakdown when he realises Luther has outwitted him.
-->'''Burgess:''' Well, DCI ''Luther''. First you umm...you assault me. YOU [[PunctuatedForEmphasis PUBLICLY-ASSAULT-]]'''[[PunctuatedForEmphasis ME!]]''' WHY CAN'T YOU SHOW ME SOME RESPECT?!
* ''Series/GameOfThrones''. The closest we ever see TheStoic [[DragonInChief Lord Tywin Lannister]] get to a VillainousBreakdown is after he gets the news that his favorite son Jaime Lannister has been captured and his army defeated. Tywin remains silent as his bannermen argue over what to do next, then he shuts everyone up by shouting, "THEY HAVE MY SON!"
* In ''Series/BattlestarGalactica2003'' episode arc introducing the Battlestar Pegasus, Colonel Fisk scolds some fighter bay pit crewmembers and some marines that were abusing Tyrol and Helo in the brig. He's mostly exercising TranquilFury to intimidate them, but when one of them speaks out of line, he suddenly lets loose with "'''''SHUT YOUR FRAKKING MOUTH!'''''", and then returns to silent anger when dressing them down.
* From ''Series/HerculesTheLegendaryJourneys'', "Wait a minute... This isn't my world... [[http://www.youtube.com/watch?v=_O1hM-k3aUY DISAPPOINTED!]]"
* ''Franchise/StarTrek:''
** A very drunk Scotty in the ''[[Series/StarTrekTheOriginalSeries TOS]]'' episode "By Any Other Name" combines this and MoodWhiplash during a drinking contest with an alien. After having made their way through Mr. Scott's entire supply of booze, the engineer has no choice but to break out a special bottle of scotch he had been saving for a special occasion. He speaks of it fondly, before briefly becoming inexplicably angry:
-->'''Scotty''': All I have is a bottle of very, very, very old scotch. ''WHISKY!''
** ''Series/StarTrekVoyager''. A TeleporterAccident turns Tuvok and Neelix into [[TwoBeingsOneBody a joined being known as Tuvix]]. When Voyager's crew figure out how to reverse the effect, Tuvix pleads with them to live as the person he is.
-->"Commander [Chakotay], are you going to stand by and do nothing while [Captain Janeway] commits murder? Mister Ayala. Yes, Lieutenant Paris, you... ''(no-one responds)'' [[WhatTheHellHero DOESN'T ANYONE SEE THAT THIS IS WRONG?]]"
* During ''Series/LawAndOrder'''s final episode "Rubber Room":
-->'''Jack [=McCoy=]''': You get no argument from me there. But if your obstruction allows a massacre to happen, I will crucify you, Mr. Kralik. I will charge you with negligent homicide and after I convict you I will resign my job and represent the families of the victims in a wrongful death suit against you and the union. By the time I'm done, you'll be finished. So my advice to you is '''''GET OUTTA MY WAY!'''''
* ''Series/TheFlash2014'': Dr Harrison Wells, the TeamDad of S.T.A.R. Labs, is usually quite soft-spoken, but has a tendency to suddenly switch straight to shouting when angry at people (usually [[TheHero Barry]]).
* ''Series/MagnificentCentury'' has Pargalı İbrahim Pasha, who is '''very''' prone to this. It's a little scary.
* On ''Series/{{Cram}}'', after sixty seconds of listening to facts recited by Miss Pickwick in a soothing setting, the contestants were rudely shouted into getting up by Graham Elwood.
--->'''Graham''': '''''Get up, get up! Clock's ticking, clock's ticking!'''''
* This was a criticism of Patrick Wayne's hosting on the 1990 version of ''Series/TicTacDough'', as he would explain the game and read the questions in a dry monotone, but suddenly scream "YOU BLOOOOCK!" if a contestant placed an X or O to block their opponent, or "[[MemeticMutation YOU WIIIIIIIIN!!!!]]" if they won.
* ''Series/LazyTown'':
-->'''Robbie Rotten:''' Have you ever heard the sound of a rubber ball breaking a window?\\
'''Trixie:''' Uh-uh.\\
'''Robbie Rotten:''' [[MemeticMutation WOULD YOU LIKE TO?]]
[[folder:Musical COMPOSITIONS!]]
* Music/{{Bjork}} does this with her version of [[https://www.youtube.com/watch?v=TEC4nZ-yga8 "It's Oh So Quiet"]]; she starts singing in a whispery voice, even making "Shh" sounds, and then belts out "You fall in love!"
[[folder:Professional WRESTLING!]]
* Truth Martini and Wrestling/JayLethal's promo on ACH for the 2014 ''[[Wrestling/RingOfHonor All-Star Extravaganza]]''. Lethal started by telling Martini to keep calm and that they were not going to yell but neither of them could keep their cool.[[/folder]]
* Hancock in ''Theatre/SeventeenSeventySix'' after New York has abstained (courteously) from [[RunningGag one too many votes]].
--> "Mr. Morris, ''WHAT IN HELL GOES ON IN NEW YORK?!''"
* In the musical adaptation of ''Theatre/LegallyBlonde'', [[SadClown Paulette]] has a tendency to do this.
-->'''Paulette:''' (''after putting on an Enya CD for Elle'') Isn't that relaxing? It's called "CELTIC MOODS"!\\
'''Emmet:''' Anyone who bakes their dog a birthday cake deserves nothing less.\\
'''Paulette:''' And it's shaped '''LIKE A BONE!'''
[[folder:Stand-Up COMEDY!]]
* Creator/BillEngvall does this in one skit when he and his son go to a drugstore to find maxi-pads for his daughter. He can't find the pads, but his son does and yells "HERE'S THE LITTLE GIRL NARROW PADS, DADDYYYYY!!!" To which Bill responds, "...Thank you, son. Listen, I don't think they heard you in SCOTLAND!!!"
* Creator/SamKinison's whole act centered around this trope. He'd go from soft tones to full tilt screaming in the blink of an eye.
** Same with Creator/LewisBlack.
* How can we ''possibly'' forget ''Creator/GilbertGottfried''?
* ''VideoGame/CastlevaniaDawnOfSorrow'': The final boss of the bonus mode, [[spoiler:Julius Mode]], does this when you fight him with the titular character.
-->'''[[spoiler:Soma]]:''' Kuru ga ii...Yuriusu...BERUMONDOOOOOO!
* This [[MemeticMutation legendary]] line from ''VideoGame/DawnOfWar Soulstorm'':
--> [[http://www.youtube.com/watch?v=cO3MttgvHUY Look! Rhinos, RHINOS! Our enemies hide in]] '''[[AwesomePersonnelCarrier METAL BOXES]]'''! The cowards, the FOOLS! We... We should take away... their metal '''boxes'''.
* [[MagnificentBastard Kane]], of all people, pulls one in [[VideoGame/CommandAndConquerTiberianSeries Tiberium Wars]]
--> But of course, I could not have planned for an ambush BY MY OWN FORCES!
* ''VideoGame/{{Halo 4}}'' gives us this happening increasingly frequently as Cortana's Rampancy progresses. Also, we have Captain Andrew Del-Rio after the Chief refuses to give Cortana up for deletion in response to her condition:
-->'''Del Rio''': I... am ordering you... to SURRENDER THAT AI!!
-->'''Master Chief''': ...[[TranquilFury No]], [[GoThroughMe sir]].
* Shortly before the release of ''VideoGame/SuperSmashBros For [=WiiU=]'', a [[http://www.nintendo.com/nintendo-direct/10-23-2014/#/video-ndirect half-hour video]] detailing the game's new features, voiced by the game's LargeHamAnnouncer. For the most part, his voice is relatively calm, but every time he mentions the name of a character or lists a new feature, he reverts back to his BOOMING ANNOUNCER VOICE.
* In ''VideoGame/MassEffect1'', an InternalAffairs agent is working undercover to bring down a corrupt administrator. Shepard can find evidence and choose to give it to her...or s/he can give it to said administrator instead, resulting in this response:
-->'''Parisini:''' Spectre, have you given any more consideration to my offer?\\
'''Shepard:''' Anoleis paid me for it. Tough luck.\\
'''Parisini:''' You're kidding. Do you have any I...WHAT THE HELL WERE YOU THINKING?!\\
'''Shepard:''' Language, miss.
* In ''VideoGame/DmCDevilMayCry'', Vergil does this twice. [[spoiler: Interestingly, the two times that this happens are related to Kat, in missions 12 and 20.]]
-->'''Dante''': We don't have time for this!
-->'''Vergil''': '''THEN MAKE TIME, DANTE!'''
** And
-->'''Kat''': Vergil please...
-->'''Vergil''': '''Stay out of this!'''
* ''Webcomic/EightBitTheater'': Black Mage usually invokes this trope when he needs to sarcastically tell the rest of the party that what they have decided to do is a stupid idea... for him.
* This is [[spoiler:Sober!Gamzee]]'s trademark speech quirk in ''Webcomic/{{Homestuck}}''. The other characters even [[LampshadeHanging complain about his volume fluctuations]].
* To be really evil, [[http://www.missmab.com/Comics/Vol_618.php pretend you're telling a secret]] as Abel does here in ''Webcomic/DanAndMabsFurryAdventures''.
* WebVideo/GameGrumps does this quite a bit, but one more memorable instance came from the episode where they played "Mary Kate and Ashley - Sweet 16: License to Drive", where they play out a scene where Mary Kate and Ashley reminisce about making a manmade river in California, just so they can '''KAYAK DOWN IT!!!'''
--> '''Arin''': '''OH MAH GAWD!!!''' So... you know...
--> '''Jon''': Ha, yeah, it's just like, "'''KAYAK DOWN IT, OH MAH GAWD!!!''' And you know, that's really all one can ask for".
* Website/ThatGuyWithTheGlasses does this when something really pisses him off, or when a character in a movie does it.
--> ''[[Film/WarriorsOfVirtue Komodo]]'': And I'll enjoy your lifespring FOR DESSERT!
--> ''Yun'': [[BigNo NOOOOOO!]]
--> ''Komodo'': [[HamToHamCombat YEEEES!]]
--> ''Nostalgia Critic'': Now allow me to continue '''''[[VoiceOfTheLegion SHOUTING AT RANDOM!]]'''''
* A large part of {{WebVideo/Caddicarus}}' style of NonSequitur humour often results in this, particularly when reviewing a game he's about to slaughter, as opposed to salvage.
* {{WebVideo/JonTron}} tends to do this when he encounters something particularly ridiculous.
--> '''[=JonTron=]''': Also I'd just like to point out that THERE IS A ''[[VideoGame/TakeshisChallenge LICENSED NINTENDO GAME]]'' '''''WITH DOMESTIC VIOLENCE IN IT!'''''
* Episode 40 of ''WebVideo/TheMusicVideoShow'': "First of all, and I can't stress this enough, ROCK MUSIC DOES NOT HAVE AUTOTUNE!"
* Lt. Hammer does this in ''Machinima/SpriggsAHalo3Machinima''.
--> '''Hammer''': I don't care about the mongooses. Not even my warthog. I'm a little bit curious about the rest of the warthogs, and I'd love to know where our power supply went to, but what I really wanna know is WHERE ARE MY GODDAMN TANKS?
* [=SammyClassicSonicFan=] uses this a lot, to unintentionally hilarious effect.
--> '''Sammy:''' ''[calmly]'' This system [the Nintendo 2DS] was meant for those kinds of people who like non hinged, non folding systems, all right guys? So '''''SHUT THE FRICK UP!!!'''''
* Kirito indulges in this in ''WebVideo/SwordArtOnlineAbridged'':
-->'''Kirito''': I'm sorry, am I the only one in this damn game that understands HOW AGGRO WORKS!?
* Although it was done with text, the ''Literature/{{Animorphs}}'' review blog Blog/CinnamonBunzuh does this with Ifi's response to the ending of "The Beginning".
--> '''Ifi:''' Oh
--> '''Ifi:''' It
--> '''Ifi:''' it appears
--> '''Ifi:''' it appears that
--> '''Ifi:''' the author
--> '''Ifi:''' [[LeftHanging FORGOT TO FINISH WRITING THE BOOK]]
* Agent Washington does this in ''Machinima/RedVsBlue'', while failing to keep his patience with Donut's less than stellar attempt to help the Blood Gulch Crew while they are shipwrecked on an unknown planet.
-->'''Wash:''' [[LetMeGetThisStraight So you heard our distress signal]] took Doc hopped on a ship AND THEN TOLD THE SHIP TO LEAVE?! AND ''THAT'S'' YOUR IDEA OF SENDING HELP!?
* In ''WebAnimation/TheMostPopularGirlsInSchool'', Mackenzie is rather prone to this in general. In Episode 42, Brittnay and Saison do this to each other:
-->'''Brittnay:''' Saison, don't talk to me. From now until the end of time, I don't want to hear any more of your stupid fucking words coming out of that tiny little mouth, on that tiny little head, underneath THAT RIDICULOUSLY LARGE HAT!\\
'''Saison:''' Oh Brittnay, you are [[spoiler:going to make such a wonderful godmother to my child!]]\\
'''Brittnay:''' [[BigWhat WHAT?!]]\\
'''Saison:''' [[OnceMoreWithVolume I said,]] [[spoiler:YOU ARE GOING TO MAKE A WONDERFUL GODMOTHER TO MY CHILD!]]
* ''WesternAnimation/AdventuresOfSonicTheHedgehog'':
-->'''Professor Caninestein:''' I can't go through with zis! My theories of time und space were developed for peace, not for your evil schemes!
-->'''Robotnik:''' Oh, that's all right, Professor. You don't have to do anything you don't want to... '''''[[LargeHam AS LONG AS YOU DON'T MIND]] [[ThrownDownAWell BEING THROWN INTO A DUNGEON]] [[SnakePit FULL OF SNAKES]] [[ReducedToRatburgers AND EATING DEAD SPIDERS]] FOR THE [[TrrrillingRrrs RRRREST]] OF YOUR LIFE!!!'''''
* ''WesternAnimation/TheFoxbusters'':
--> '''King Voracious''': That baby...Daddy was telling SUCH A NICE STORY!
* On ''WesternAnimation/GoofTroop'', this was one of Peg and Pete's character traits.
* ''WesternAnimation/{{Arthur}}'':
-->'''D.W.''': What did you draw?
-->'''Arthur''': (holds up drawing of a dog) A dog, and he's bored. What did you draw?
-->'''D.W.''': (holds up drawing of a straight line) A stick.
-->'''Arthur''': (incredulous) A ''stick''?!
-->'''D.W.''': [''sudden outburst''] A stick from the park where you PROMISED TO TAKE ME TODAY!!!
* A few WesternAnimation/LooneyTunes examples:
** Some early WesternAnimation/BugsBunny cartoons use this gag, notably in ''WesternAnimation/AWildHare'';
-->'''Elmer''': Pardon me, but y'know, you wook just wike a wabbit.
-->'''Bugs''': C'mere. (Elmer leans in closer) Listen, Doc, now don't spread this around... but, confidentially...(yells in his ear) I ''AM'' A WABBIT!
** Dan Backslide from ''WesternAnimation/TheDoverBoys'' of Pimento University [[http://www.youtube.com/watch?v=fMtTHFEXLvU loves]] this trope.
--> '''Dan''': A runabout! '''I'LL STEAL IT! ''NO ONE WILL EVER KNOW!'''''
** In "Bugsy and Mugsy", where Bugs Bunny plays psychological warfare on Rocky and Mugsy, leading the former to believe the latter is plotting to kill him. Even after Rocky has beaten Mugsy near-unconscious and left him hog-tied ''outside of the room'', Bugs still manages to make him think Mugsy is to blame, leading to the memorable line:
--> '''Rocky:''' I don't know how ya's done it, BUT I KNOW YA'S DONE IT!!!
* ''WesternAnimation/MyLittlePonyFriendshipIsMagic'':
** In "Mare in the Moon", when Twilight Sparkle is annoyed by the overly-friendly reception she's been getting from the citizens of Ponyville.
--->'''Twilight Sparkle:''' All the ponies in this town are '''''crazy!'''''
** In "The Ticket Master", during Rarity's imagine spot of meeting her PrinceCharming at the Grand Galloping Gala:
--->'''Rarity:''' He would ask for my hoof in marriage, and of course I would say... ''[[BigYes YES!]]''
** In "Keep Calm and Flutter On", when Twilight Sparkle sees that Celestia has brought along the petrified form of [[MadGod Discord]], villain of the season 2 premiere...
--->'''Twilight Sparkle:''' [[WithDueRespect With all due respect]], Princess Celestia... ''how could you bring Discord '''here?!''''' (''ahem'') Your majesty.
** In "Every Little Thing She Does", after Starlight Glimmer tries using ''mind control'' on Twilight's friends to hang out with them in a more efficient manner:
--->'''Rainbow Dash:''' Here's a friendship lesson for ya... ''don't cast spells on your friends!''
* ''WesternAnimation/SpongeBobSquarePants'':
** From the episode "Clams":
--->'''Squidward:''' Um, [=SpongeBob=], haven't you noticed that Mr. Krabs has gone COMPLETELY INSANE?!
** From "Sandy, [=SpongeBob=], and The Worm":
--->'''Squidward:''' That idea...may just be crazy enough...TO GET US ALL KILLED!
** From "Skill Crane"
--->'''Squidward:''' ''Because I'm all out of'' '''''MONEY!'''''
** From "Graveyard Shift"
--->'''Squidward:''' Spongebob, how could I be out there when I'm standing RIGHT HERE?!
** From "Wormy"
---> '''Spongebob:''' "We did it, Patrick! Sandy's gonna be so proud of us. We got that horrible monster out of her house and best of all her pets are safe, 'cause that horrible creature is now '''''HEADING STRAIGHT FOR THE KRUSTY KRAB!'''''"
* The Red Guy from ''WesternAnimation/CowAndChicken'' did this all the time, no matter what. He was crazy like that.
* ''WesternAnimation/CodenameKidsNextDoor'': [[BigBad Father]] does this a lot. Take the episode "Operation: T.R.A.I.N.I.N.G.", for example:
-->'''Henchman:''' ''(as he tries to open the door containing the KND code module)'' Uh... I think it's locked.\\
'''Father:''' Oh, really? Well, I guess we'll just have to pack up and go--'''''OF COURSE IT'S LOCKED!!!'''''
** In the same episode, Father makes it clear to the KND-in-training that he plans to destroy their base and them along with it.
--->'''Lee:''' [[DramaticallyMissingThePoint Cool!]]\\
'''Father:''' Yes, you say "Cool", but it's about to get very '''HOT!!!'''
* Happens surprisingly often in ''WesternAnimation/InvaderZim'', most by the titular character, but other characters are prone to it.
-->'''Tallest Red''': ''(After hearing Zim MotorMouth for three hours)'' I was curious to see if you'd shut up on your own, but it's been '''three''' hours now, Zim. '''THREE HOURS!'''
* One of Ren Hoek's traits from ''WesternAnimation/TheRenAndStimpyShow'':
** In "The Big Shot", Ren tries to take his mind off Stimpy having left to become a big Hollywood star:
--->'''Ren:''' I'll watch some TV... it'll help me to RELAX! (''grins maniacally, creepy BGM plays'')
** In "The Big House!", after another inmate at the pound is taken away for "the big sleep":
--->'''Stimpy:''' "What's the "big sleep" Ren?\\
'''Ren:''' Come closer... It's DEATH!, DEATH YOU IDIOT! YOU KNOW WHAT DEAD IS?! IT'S WHAT WE'LL BE IF WE DON'T GET OUT OF HERE!
* Denzel Crocker from ''WesternAnimation/TheFairlyOddParents'' does this all the time.
-->'''Crocker:''' If they survive, THEY'RE FAIRIES! If they don't, I HAVE TENURE!!!
* From the ''WesternAnimation/SouthPark'' "Mysterion Trilogy"
-->'''Cartman:''' You can't kick me out of Coon & Friends. I'm the FUCKING COON!!!
* In ''WesternAnimation/CloneHigh'' a JFK clone opens door to Joan, who's standing in the rain.
-->'''JFK:''' You're wet. Allow me to dry you off... WITH MY PANTS!
* ''WesternAnimation/TheAdventuresOfJimmyNeutronBoyGenius'': Cindy would often do this to Jimmy whenever his inventions, discoveries etc started wreaking havoc on Retroville.
-->'''Cindy''': Uh, excuse me, Neutron. Now that you're done talking to yourself...''WE HAVE A SITUATION HERE!''
* Edd from ''WesternAnimation/EdEddNEddy'' has a knack for doing this when exasperated.
-->"No one would ever suspect Mother Nature to harbor a spring loaded circus cannon and ''BLOW INNOCENT BYSTANDERS TO KINGDOM COME!''
** Eddy tends to do this a lot, too, more or less as a side-effect of his [[NoIndoorVoice lack of an indoor voice]].
-->"Hey, Jonny. People really like it when you say ''WHY ALL THE TIME!''
* ''WesternAnimation/KingOfTheHill'' has a hilarious example when Peggy is struggling in a Boggle Tournament she's in. Hank attempts to comfort and motivate her. But since he's doing it in the fashion of his high school football coach, it comes across as [[ReasonYouSuckSpeech something completely different]].
-->'''Hank''': Hey, you know, Coach used to say something that would fire us up when we were behind.\\
'''Peggy''': Yeah? What?\\
'''Hank''': '''LOSER! YOU'RE A LOSER!''' Are you feeling sorry for yourself?! Well you should be, 'cause you are '''DIRT!''' You make me '''SICK''' you big baby! Baby want a bottle?! A big '''DIRT BOTTLE?!'''\\
'''Peggy''': ''[crying]'' Why are you yelling at me?!\\
'''Hank''': Uh, I'm trying to be your Coach. Uh, it's, it's inspiring.
* ''WesternAnimation/ThePowerpuffGirls'', "Down 'N Dirty":
-->'''Mayor:''' Buttercup! Thank goodness we found you. As Mayor of Townsville, I feel it is my sworn duty to tell you that YOU STINK! YOU SMELL! YOU REEK! Youre stinking up the whole town! So either take a bath or take a hike!
* King K.Rool of ''WesternAnimation/DonkeyKongCountry'', like all [[EvilIsHammy Large Ham villains]], is prone to this;
-->'''King K.Rool:''' So judging from your in-depth, precise report on your spy mission, one thing is perfectly clear; YOU HAVE ABSOLUTELY NO IDEA WHAT THOSE APES ARE UP TO, DO YOU?!


text:
|The New York Observer (USA)
|10 January 2005, Vol. 19, Iss. 1, pg. 3, by: Marcus Baram, "The Transom: Remembering Jerry"
|Entertainment Weekly (USA)
|11 June 2004, Iss. 769, pg. 14, 16, by: Allison Hope Weiner, "Making the Brand"
|The New York Times (USA)
|20 March 2008, Vol. 157, Iss. 54,255, pg. B5, by: Sewell Chan, "Judge Rules That Suit Against 'Law & Order' Creator May Continue"
|The New York Times (USA)
|30 January 2008, Vol. 157, Iss. 54,205, pg. E2, by: Bill Carter, "NBC Sues Dick Wolf"
|The New York Times (USA)
|16 July 2006, pg. 2-1+2-30, by: Jacques Steinberg, "This Season, It's Law & Reorder: In the TV spinoff system, the brand most in need of a shake-up is represented by Dick Wolf. This is his story."
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Browse biographies section by name

subset: commoncrawl


text:
FRIDAY FINDS showcases the books you 'found' and added to your To Be Read (TBR) list… whether you found them online, or in a bookstore, or in the library — wherever! (they aren't necessarily books you purchased).
So, come on — share with us your FRIDAY FINDS!
My Finds:
"Notes From a Blue Bike" by Tsh Oxenreider
"Finding Me" by S K Hartley
"Fall" by Rachel Van Dyken
"Aha" by Kyle Idleman
"The Swiss Affair" by Emylia Hall
"Switched" by Cassie Mae
PLEASE LEAVE A COMMENT with either the link to your own Friday Finds post, or share your 'finds' in a comment here (if you don't have a blog). Thanks! 😀


text:
Current methods that assay hemoglobin β-globin chain variants can have limited clinical sensitivity when applied techniques identify only a predefined panel of mutations. Even sequence-based assays may be limited depending on which gene regions are investigated. We sought to develop a clinically practical yet inclusive molecular assay to identify β-globin mutations in multicultural populations. We highlight the β-globin mutation detection assay (β-GMDA), an extensive gene sequencing assay. The polymerase chain reaction (PCR) primers are located to encompass virtually all hemoglobin β locus (HBB) mutations. In addition, this assay is able to detect, by gap PCR, a common large deletion (Δ619 base pair), which would be missed by sequencing alone. We describe our 5-year experience with the β-GMDA and indicate its capability for detecting homozygous, heterozygous, and compound heterozygous sequence changes, including previously unknown HBB variants. The β-GMDA offers superior sensitivity and ease of use with comprehensive detection of HBB mutations that result in β-globin chain variants.
Numerous disorders of the β-globin chain of hemoglobin lead to different disease phenotypes.1,2 Of these, β-thalassemia is a subset of the β-hemoglobinopathies characterized by a hereditary anemia with a wide phenotypic spectrum that can have significant morbidity and mortality.2,3 This autosomal recessive condition afflicts thousands of people of many ethnicities worldwide.4 In India, the carrier frequency of β-thalassemia spans 0.3% to 15%, depending on the ethnic subgroup.5 On the African continent, the β-thalassemia carrier frequency varies from 1% to 13%.5 In Europe, the percentage of the population carrying a significant variant associated with β-thalassemia ranges from 0.12% in Finland to 15% in Cyprus.6 In the United States, screening in California identified 1 newborn with β-thalassemia for every 55,000 births.7 Exact carrier frequencies for the multiethnic population of the United States overall have, to our knowledge, not been reported. During the next 20 years, it is predicted that more than 900,000 children will be born with clinically significant β-thalassemia or hemoglobin E-β-thalassemia.8
The β-thalassemias exhibit a range of severities, each corresponding to an absence or reduction of β-globin protein synthesis. These β-thalassemia phenotypes are related to the myriad mutations that affect the β-globin gene (HBB) on chromosome 11p15.5 (OMIM number +141900), and different populations have their own mutation spectrum.9 More than 730 variants of the β-globin chain have been characterized, and more than 200 of these account for mutations causing β-thalassemia.10 The sequence variants range from point mutations to large deletions and affect HBB gene transcription, messenger RNA processing, translation, or gene product structure.2 While the majority of the variants are rare, 21 mutations account for more than 80% of all β-thalassemia determinants Table 1.2,11
A variety of assays have been developed to detect β-thalassemia. To screen for mutations, methods include denaturing gradient gel electrophoresis,12,13 temporal temperature gel electrophoresis,14 mismatch analysis,15,16 single-strand conformation polymorphism electrophoresis,17,18 and heteroduplex analysis with denaturing high-performance liquid chromatography.19–23 In addition, specific detection strategies can be used for known mutations, such as techniques that incorporate allele-specific oligonucleotide probes,24–26 the amplification refractory mutation system,27–30 allele-specific polymerase chain reaction (PCR),31 reverse dot blot,32,33 restriction fragment length polymorphisms,34 single base extension,35,36 PCR–enzyme-linked immunosorbent assay,37 real-time PCR,38 and array-based technologies.39–44 Mass spectrometry has also been used to identify hemoglobin variations on the nucleic acid and protein levels.45,46
Despite these numerous methods to assay for β-thalassemia, mutations can still go undetected, especially when using detection strategies that identify only a specific subset of the various β-globin variants. Direct DNA sequencing enables more comprehensive detection of known and unknown β-globin gene mutations.47–51 Sequencing allows the identification of most β-hemoglobinopathies, but the location of the primers is critical because mutations in the HBB gene are not limited to the exons and their direct splice sites. Sequence analysis cannot identify mutations caused by large deletions (or insertions) of 1 or more exons because primers would not be able to bind to a deleted sequence. Thus, the resulting sequence tracing would show only the (hemizygous) sequence from the present allele. This can be remedied by using a technique such as multiplex ligation-dependent probe amplification as a follow-up test, if so desired.52,53
Although heritable large duplications or deletions in the β-globin gene are typically rare, the 619-base-pair (bp) deletion mutation (Δ619 bp), which encompasses exon 3, is an exception that has greater prevalence.54–56 This deletion, associated primarily with certain Indian and Pakistani subpopulations,57 comprises up to 7.5% of the β-thalassemia subtypes found in the Indian population.58,59 To screen β-thalassemia mutations in the Southeast Asian and Indian populations, Wang et al60 designed a limited sequencing assay that also could detect the Δ619 bp allele. These investigators combined gap PCR (an amplification reaction for which primers flank the deletion site) to recognize this deletion mutation with multiplex minisequencing, which used primers to recognize 15 additional common mutations in their targeted population. Their combined strategy allowed the detection of this large deletion mutation and, in conjunction with minisequencing, enabled detection of more than 90% of β-thalassemia alleles in Southeast Asia and India. In the United States, however, the ethnic diversity is considerable. We hypothesized that a more inclusive mutation detection approach could be beneficial.
In the present article, we describe a combined gap PCR and broad sequencing method that combines the high sensitivity of sequencing with the ability to detect the Δ619 bp allele. As a result, this assay is able to identify all of the most prevalent β-thalassemia mutations mentioned earlier,2,11 in addition to detecting almost all other β-globin variants. We report our 5-year experience with this method.
Materials and Methods
Blood Specimens and Genomic DNA Extraction
Patient blood samples were submitted in EDTA, acid-citrate-dextrose, or sodium citrate. To extract DNA, the specimens were processed by using Qiagen minicolumns or the Qiagen EZ1 extraction procedure (Qiagen, Valencia, CA).
Multiplex Minisequencing Screen
The strategy to detect 15 β-thalassemia mutations with a multiplex minisequencing assay was described by Wang et al.60 This protocol was slightly modified, where the thermocycling conditions consisted of 1 denaturing cycle at 95°C for 10 minutes followed by 35 cycles of denaturing at 95°C for 30 seconds, annealing at 58.5°C for 1 minute, and extension at 72°C for 2 minutes. Final extension was at 72°C for 10 minutes.
Genomic DNA Amplification and Full Sequencing
To amplify and sequence the β-globin gene via PCR, primers Table 2 were designed and subsequently synthesized at Operon (Huntsville, AL). First, genomic DNA was amplified in 2 different PCR master mixes (PCR I and II), each containing a total volume of 50 μL per reaction. PCR I contained ddH2O (Teknova, Hollister, CA), 5 U of TaqGold (Applied Biosystems, Foster City, CA), PCR amplification buffer (Applied Biosystems), a final concentration of 1 mmol/L magnesium chloride (Applied Biosystems), 150 μmol/L 4dNTP mix (Pharmacia, Piscataway, NJ), 20 pmol of primer A, 20 pmol of primer B, 20 pmol of primer D, and 100 to 200 ng of DNA. PCR II contained the same reagents except for the primers, which were 20 pmol of primer C and 20 pmol of primer D. The thermocycling conditions were 1 denaturing cycle at 95°C for 10 minutes followed by 35 cycles of denaturing at 95°C for 30 seconds, annealing at 58.5°C for 1 minute, and extension at 72°C for 2 minutes. Final extension was at 72°C for 10 minutes. The amplification products were then electrophoresed in a 1% agarose gel to assess PCR efficacy and product size. The presence of the 619-bp deletion is assessed on this gel.
Before sequencing, the amplicons were purified with the QIAquick PCR Purification Kit (Qiagen) or with ExoSAP-IT (USB, Cleveland, OH). After purification, 5 μL of the amplicons served as templates for sequencing using the ABI PRISM BigDye Terminator version 3.1 Cycle Sequencing Kit (Applied Biosystems). The primers used for sequencing (PCR I, A and E; PCR II, C and F) were used at a final concentration of 1 μmol/L. The thermocycling conditions consisted of 25 cycles of denaturing at 96°C for 10 seconds, annealing at 50°C for 5 seconds, and extension at 60°C for 4 minutes. The resultant sequencing amplicons were purified with a 2.2% sodium dodecyl sulfate solution in Centri-Sep spin columns (Princeton Separations, Adelphia, NJ) and electrophoresed in an ABI PRISM 3130xl Genetic Analyzer (Applied Biosystems). The sequencing data were analyzed with Sequencing Analysis Software, version 5.2 (Applied Biosystems) or Mutation Surveyor (Softgenetics, State College, PA).
β-Globin Mutation Detection Assay
Figure 1 depicts the human β-globin gene with corresponding β-thalassemia mutations. To detect these mutations, gap PCR and direct sequencing were combined into a 2-phase assay. The primers used in the assay are listed in Table 2 and also graphically illustrated in Figure 1. As the first phase, the gap PCR, characterized by Wang et al,60 was conducted to detect the Δ619 bp mutation. Two PCR reactions (PCR I and II) were performed on genomic DNA. An unaffected wild-type patient would yield a 1,457-bp product from PCR I (primer pair A and B) and a 1,212-bp product from PCR II (primer pair C and D). In an affected person with a homozygous Δ619 bp allele, PCR I would yield a longer 1,671-bp product from the A and D primer pair (due to the deletion of the B primer binding site), and PCR II would yield a truncated product of 593 bp from the C and D primer pair. Heterozygous persons would have a combination of the 1,457- and 1,671-bp products from PCR I and the 1,212- and 593-bp products from PCR II.
The second phase in our assay used dye termination sequencing of the resultant PCR I and II amplicons. The sequencing primers (PCR I, A and E; PCR II, C and F) are listed in Table 2 and graphically depicted in Figure 1. The reverse sequencing product from PCR I is 696 bp and spans exon 1, intervening sequence (IVS) I, and exon 2. PCR II's reverse sequencing product is 719 bp long and covers a portion of IVS II and all of exon 3. Combined together, the forward and reverse sequencing data from PCR I and PCR II encompass virtually all of the known point mutations and small deletions of β-thalassemia (Figure 1).
Summary of β-Hemoglobinopathies
The β-globin mutation detection assay (β-GMDA) was implemented in our laboratory in March 2004 and continues to be performed to the present. The multiplex minisequencing assay described by Wang et al60 was used in our laboratory from December 2003 to February 2006. During the period when both techniques were offered for diagnosis, physicians were given the option to order either assay or to order the sequencing assay following the multiplex minisequencing assay if the latter was not definitive, such as would be the case when only 1 mutation was identified in an affected patient.
In Table 3, we summarize the β-hemoglobin variant data from 201 patients during a 5-year period (December 2003 to December 2008). Although RBC indices and ethnicity are requested by our laboratory, for most of our patients, this information is not provided and, unfortunately, could not be included in this study. The various mutations detected by the 2 assay systems were compiled with their respective frequencies and percentages of total identified alleles (n = 61). A total of 28 different β-globin alleles were identified. Of these, 19 were β-thalassemia mutations and 8 were β-hemoglobin variants associated with other conditions, such as hemoglobin C and hemoglobin S. The β-GMDA also identified just 1, to our knowledge, previously unreported variant, HBB:c.246C>A (Leu82Leu), which was thought to be most likely clinically insignificant because it was a silent mutation.
β-Globin Mutation Detection Assay
The β-GMDA is not limited to the identification of specific mutations; rather, known and unknown changes in the HBB gene can be detected by this sequencing-based method. With this assay, the HBB:c.316-90A>G variant in IVS II was discovered by our laboratory, and it was reported subsequently to the HbVar database on the globin gene server (IVS-II-761 A>G; http://globin.bx.psu.edu/hbvar). Of the 201 patients, 58 (28.9%) had detectable mutations. Three of these patients were compound heterozygous. Two patients were identified by the assay as being homozygous for HBB:c.47G>A (Trp16Stop) and HBB:c.79G>A (hemoglobin E), respectively. Two other patients in our tested population were compound heterozygous (patient 1: HBB:c.93-21G>A [IVS I] and HBB:c.114G>A [Trp38Stop]; and patient 2: HBB:c.79G>A [hemoglobin E] and HBB:c.441_442insAC [hemoglobin Tak]). Thus, in addition to heterozygous changes, the β-GMDA is capable of detecting homozygous and compound heterozygous gene alterations.
Elucidationofthepathophysiologyofthalassemiaspanned several decades. The imbalance of α or β globin chains was realized in the 1960s as globin synthesis was measured.61,62 During the 1970s and 1980s, investigators began to identify the molecular origins of the thalassemia conditions.56,63–65 With the advancement of molecular genetic techniques, most of the globin chain gene variants were understood and definitively characterized by the late 1990s.66,67
β-thalassemia mutations are composed primarily of mis-sense mutations or other small sequence changes.2 In contrast to α-thalassemia, a very small subset of the mutations is composed of large deletions. Only the Δ619 bp mutation, which is most prominently observed in some subpopulations from India and Pakistan,57–59,68 has increased prevalence. While sequencing strategies do not typically detect large deletions,49,50 the β-GMDA was designed to detect the Δ619 bp allele in the β-globin gene by combining the sequencing approach with a preceding gap PCR step.60 Fourteen other large deletions that range from 290 bp to greater than 60 kb2 would not be detected by the β-GMDA. Of the large β-globin deletions, however, only Δ619 bp is relatively common, and the remaining are extremely rare.2 If a large deletion mutation other than Δ619 bp is present in homozygous form, the primer binding sites will be absent, and no PCR product will be generated using the β-GMDA. Therefore, a negative amplification phase would suggest a technical amplification failure or the presence of homozygous, large, non–619-bp deletion mutations, which are exceedingly rare.
Panel testing for β-thalassemia typically recognizes only a limited number of mutations and is designed to find selected mutations among specific ethnic groups.24,27,37,60,69 A more comprehensive technique that identifies mutations from multiple ethnicities is expected to have greater sensitivity and, thus, greater usefulness in today's multicultural US society. Our laboratory used the multiplex minisequencing screen (MMS) described by Wang et al60 for almost 2 years concurrently with the β-GMDA. Both methods were characterized by excellent performance. The MMS has primer pairs that recognize 15 β-globin mutations. Table 3 lists the total cumulative alleles and their frequencies identified by the 2 methods during a 5-year period. As indicated in Table 3, 28 different β-globin variants were detected.
Compared with the β-GMDA, the MMS, not surprisingly, has limited sensitivity because it can only identify 15 β-globin variants in addition to the Δ619 bp mutation. As shown in Table 3, the MMS primer panel enables the detection of only 12 of these 28 variants. In addition, samples from 4 persons of the 201 patient sample population were assayed by the MMS and by the β-GMDA. These 4 people were initially screened as negative by the MMS. However, the β-GMDA subsequently revealed β-globin mutations (Trp16Stop, Trp38Stop, HBB:c.93-21G>A, and His118Arg) not detectable by the MMS primer panel. Together, these findings supported the need, for our patient population, to offer a comprehensive assay not limited by a specific mutation panel.
Our detection strategy was designed to be comprehensive in identification of numerous short-sequence alterations that dominate the expansive list of β-thalassemia mutations. In addition, the gap PCR component of our assay detects the Δ619 bp allele.60 This is a component that further increases the mutation detection capability.49,50 Because the majority of β-hemoglobin gene variants not associated with β-thalassemia (eg, hemoglobin S and hemoglobin C) also lie within the areas bounded by the sequencing primers used in the β-GMDA, our assay can be used for identification or confirmation of other HBB-associated diseases or the carrier status of such, as well. Although the assay does not cover the complete IVSs, it encompasses all exonic and intronic regions in which clinically significant changes have been reported (Figure 1). Thus, our detection system recognizes almost all β-thalassemia mutations and other β-hemoglobin variants (Table 3).
High-performance liquid chromatography and protein electrophoresis are routine methods often used to screen for β-hemoglobinopathies and may be sufficient for most clinical situations. However, there are circumstances when the β-GMDA would provide valuable diagnostic information not gleaned by conventional assays. For example, the molecular analysis of the β-GMDA can assess the β-hemoglobinopathy carrier state of a patient. This has important clinical implications, especially for couples planning to have children. In addition, the β-GMDA is amenable to prenatal diagnosis through the analysis of fetal DNA samples. Other clinical applications include providing prognostic data for patients affected with β-hemoglobinopathies. Especially for β-thalassemia with its numerous variants and variable severities,67 the β-GMDA identifies a patient's specific β-globin mutation and, in turn, enables a physician to provide the appropriate treatment and counseling. Therefore, the β-GMDA provides better discriminatory power over routine screening methods and could be used as clinically needed.
In our patient population during a 5-year span (Table 3), 46% (13/28) of the β-thalassemia variants detected were among the 21 most prevalent β-thalassemia determinants worldwide (Table 1). The remaining 54% (15/28) of the variants, comprising 43% (26/61) of the identified alleles in our sample population, indicated that a significant subset of our ethnically diverse patients carried rarer β-thalassemia mutations. Also, as indicated in Table 3, the mutation panel–based MMS would not detect 57% (16/28) of the total detected β-globin variants. Therefore, this finding reaffirms the need to have an inclusive, comprehensive, non–mutation panel–based assay to detect the less prevalent mutations in our geographic region.
Automated DNA sequencing is a reliable, sensitive, and specific method that has become a routine tool in many laboratories and is in use for HBB testing in several clinical laboratories (http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests). The β-GMDA capitalizes on the advantages that DNA sequencing offers over nonsequencing methods. In addition, it provides sequences that are not limited to exons and their exonintron boundaries, but rather includes virtually all areas of the gene where mutations have been described. The technology is advancing, leading to decreased processing times and increased ease of use.70 As the sequencing techniques mature, it is expected that the β-GMDA could be adapted to the various platforms that emerge.
The β-GMDA is a comprehensive and robust method for the detection of known and novel β-globin variants. The assay's ability to detect virtually all of the small β-globin variations through inclusive sequencing and detection of the Δ619 bp via gap PCR confers high sensitivity to the technique and will be highly valuable for β-hemoglobinopathy detection in multicultural populations.
We thank Linda Gojenola for help and technical expertise.


text:
- I have discovered that if you take up the piano, start night classes at music school, and move your computer up to your bedroom all in the same week, you end up going online roughly once every two weeks. Also, you will lose "followers," because people don't like it when you don't pay attention to them. Which I get, because I, too, am an attention whore. (Love me, please!)
- Marie, to Jack's friend: Look at this cup! It's full of my pee!
- It turns out that commercial house concerts are rather good fun, as long as you have a few drinks beforehand.
- I may need to move my computer back downstairs. I have been folding laundry and practising the piano during nap time, which cannot really be healthy. I can play a pretty little waltz now, though. And everyone has clean clothes.
- With my new night class/social schedule, I am at home only on Saturday nights. I'm not sure I can keep this pace going. I must now go and collapse into my bed.
Tuesday, 27 September 2011
There's life out there, and it's exhausting
30 comments:
There must be some kind of compromise/balance?ReplyDelete
If I moved my computer upstairs (hypothetically, obviously) I would lose so much weight just from running up and down them those stairs 50 million times a day!ReplyDelete
Welcome back!
Wow - well, just ... keep sleeping :)ReplyDelete
Good for you.
I have recently realised (to my dismay) that I can work and have a relationship, work and have leisure, or have a relationship and leisure, but not all three at once. There simply isn't enough time in the day or energy in this particular body. And sadly, not working is not an option. Sigh.ReplyDelete
Just a tab busy arn't you...I would be collapsing too. As long as you are happy and we hear from you now and then, all will be forgiven.ReplyDelete
x Sandi
Blimey - no wonder you're tired...ReplyDelete
Perhaps time to start using your fancy phone to get online? Or am I getting confused now
Oh my. How does she do it?ReplyDelete
I have the computer upstairs in the new house, having had it in the dining room before, and I have to say it has been healthy - I am not tempted to check emails when cooking supper or helping the boys with their homework. Well done for learning the piano - I gave up aged 18 and now that the kid are learning, am regretting it.ReplyDelete
I stopped blogging and facebooking for a couple of days and achieved so much.... started me thinking about all the other stuff I could have done if I hadn't been in love with my MacBook!!!ReplyDelete
you can't do it all! Stop trying, I suggest you give up all forms of housework and child care and concentrate on filling up that Saturday night ;0)ReplyDelete
You've got enough love, right? I'd move my own laptop into the bedroom for the sake of improved writing productivity but it would kind of kill off my own chances of that sort of thing for ever.ReplyDelete
My site was hacked in August/Sept and so I didn't blog much at all (or when I did I moaned about the hacking) for about a month. I achieved loads! I simply can't juggle more than two things no matter how many times I have tried. Although I lost about 5 followers I think I greatly benefited from the break.ReplyDelete
And just so you know, I wouldn't stop following someone unless they hadn't blogged for six months or so, and maybe not even then. I'm patient (and realistic) and I like your blogging. That's why I'm still here!
What are you doing to yourself? We love you please love yourself, occasionally take a break and come back.ReplyDelete
We'll still be here MWA, it's good to get on with other things you enjoy and to have a break from online when the rest of life calls.ReplyDelete
Clean clothes are massively overrated.ReplyDelete
never fear for I am here!ReplyDelete
Seriously lacking in blog motivation at the moment as far too busy in work!
Wow you sure sound busy... maybe you should take a couple days break to catch up on much needed sleep? :)ReplyDelete
Maybe sleep on the piano? Or the ironing board? Turn the iron off first, though.ReplyDelete
oh girl, I can relate. Not to the piano playing perhaps, but to the falling off the grid and the exhaustion... and the neverending laundry.ReplyDelete
look at all these lovely comments! - see...no need to worryReplyDelete
We stick around, us faithful followers. Although some of us are also only onthe computer about once a week, so it takes a while to get to your posts.ReplyDelete
Enjoy the break (as if looking after 3 children is ever a break, probably better to say enjoy time away from teh internet.) x
You sound so full!ReplyDelete
I haven't fallen off the side of the earth either. Just super busy. Can't imagine how you keep it all together!ReplyDelete
Hello, where are you?????ReplyDelete
I miss you! Come back soon?ReplyDelete
It doesn't look like you're losing followers to me! I get three comments on good days, these days :oReplyDelete
Cup full o pee, eh? A timeless classic.
Oh wait! This is an old post! I already commented on it! Baha! How the hell did I miss the pee bit before?ReplyDelete
Last time I was here, it wouldn't allow me to leave a comment. Seems to be a bit happier now. It makes me feel a little better to know that you're a bit hard pressed too. I'm not around on blog front much these days either. xReplyDelete
All I can say is that you are awesome!ReplyDelete
HAHAHA! Funny that I read this almost 6 months later! I've been "off" on the blogging and the reading myself. As evidenced by this comment being almost 6 months late! Enjoy life! We can type later. When we're old.ReplyDelete


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Seagate Technologies (NASDAQ:STX) and Western Digital (NASDAQ:WDC) are undoubtedly the two largest manufacturers and sellers of hard disk drives, or HDDs. On the surface, the two companies look nearly identical, creating storage devices that are used in everything from PCs, laptops, DVRs, home entertainment centers, hyperscale data centers, and the cloud. However, despite the combined leaders controlling 85% of the HDD space, one specific metric will identify the best investment opportunity.
1 metric says it all
Five years ago, both Seagate and Western Digital created nearly all of their revenue from PC-related applications. But, with falling PC and laptop sales, both companies have evolved, selling storage devices for smartphones and tablets, and benefiting from the enormous amounts of storage needed in cloud computing.
Nonetheless, the bulk of both companies' revenue still comes from HDDs, as solid state drives are growing fast, but are less than 5% of total revenue. Hence, the combined revenue of nearly $29 billion over the last 12 months created by Western Digital and Seagate is a near-perfect illustration of the HDD market, or at least 85% of it.
With that said, there is a constant debate surrounding which company is best, and while analysts look at P/E ratios, dividends, and operating margins, the best indicator of value lies in the HDD market itself, and the market share of each respected company, as seen below.
Western Digital
Seagate Technologies
January 2013
July 2013
January 2014
July 2014
Above, you can see the HDD market share for both Seagate Technologies and Western Digital over an 18-month span. One thing is clearly evident -- Western Digital has consistently stolen market share from its peer.
While Western Digital's market share is unknown as of July 2014, due to the company not yet announcing second-quarter earnings, Seagate's admission of a 39% share almost guarantees that Western Digital's share has increased, yet again. Therefore, at hand is a 600-basis-point loss in market share for Seagate Technologies, which begs the question of how any investor could find it more attractive than Western Digital?
The Western Digital difference
Why has Western Digital been able to steal the HDD market right out from under Seagate's feet? The answer lies in the product itself. According to online backup provider Blackblaze, Western Digital's drives have a 94.8% survival rate at 36 months. Meanwhile, Seagate's drives have just a 73.5% survival rate over the same duration.
Thus, Western Digital's success may be tied to reliability, or disgruntled Seagate customers who switch to Western Digital products after experiencing a high rate of failure. Regardless, Western Digital has emerged as the undisputed leader, and the clear investment favorite.
What about those metrics?
While Western Digital has shown itself to be the better company over a period of 16 months, you might still consider investing in Seagate if there is a large disconnect in the valuations of both companies. However, Western Digital and Seagate trade at 12 and 10 times forward earnings, respectively, both of which are cheap.
Furthermore, Seagate's operating margin of 13.1% is 30 basis points better than Western Digital at 12.8%. However, in fiscal 2013, which ends in June for both companies, Seagate and Western Digital had operating margins of 14.5% and 8.2%, respectively. Hence, Western Digital has seen major improvements, while Seagate's profitability has fallen at nearly the same rate as its market share.
Foolish thoughts
With all things considered, investors should like Western Digital's opportunity to see both continued operating efficiencies and further market share gains. Meanwhile, there doesn't seem to be an end in sight for Seagate's fall in either category.
As a result, 12 times forward earnings looks like a bargain, and while the debate over which stock is better will continue, a closer look at both businesses will reveal that this question is not too difficult to answer.
Brian Nichols owns shares of Apple. The Motley Fool recommends Apple. The Motley Fool owns shares of Apple and Western Digital.. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.


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Guerrero | Justene Jaro & Dawn Jaro by Danny Steezy for Benny Gold Summer 2013
This is pretty much the perfect way to market male street wear. You don't get other men to market your clothing, you get women. There's an adage that sex sells and Benny Gold in the midst of all of that. Danny Steezy gets to shoot the beautiful Justene Jaro and Dawn Jaro as they market some of the clothing, as well as article of clothing men shouldn't be caught dead in. The Jaro sisters must be really comfortable modeling together. I can't see any normal sisters so intimately together. Check out Justene Jaro and Dawn Jaro in the images above.


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