document_title: Feist (singer)

question_text: who sings the counting to 4 song on sesame street

text: Feist (singer)

text: Early life[edit]

text: Leslie Feist was born on 13 February 1976 in Amherst, Nova Scotia, Canada. Her parents are both artists. Her father, Harold Feist, is an American-Canadian abstract expressionist painter who taught at both the Alberta College of Art and Design and Mount Allison University in Sackville, New Brunswick.[citation needed] Her mother, Lyn Feist, was a student of ceramics from Saskatchewan. After their first child, Ben, was born, the family moved to Sackville.[citation needed]

text: Feist's parents divorced soon after she was born and Ben, Feist and their mother moved to Regina, Saskatchewan, where they lived with her grandparents. They later moved to Calgary, Alberta, where she attended Bishop Carroll High School as well as Alternative High School. She aspired to be a writer, and spent much of her youth singing in choirs.[7] At the age of twelve, Feist performed as one of 1,000 dancers in the opening ceremonies of the Calgary Winter Olympics, which she cites as inspiration for the video "1234."

text: Because her father is American, Feist has dual Canadian-U.S. citizenship,[8] joking later that she was given U.S. citizenship as part of a deal with Apple.[9][10]

text: Music career[edit]

text: In 1991, at age 15, Feist got her start in music when she founded and was the lead vocalist for a Calgary punk band called Placebo (not to be confused with the English band Placebo).[7][11] She and her bandmates won a local Battle of the Bands competition and were awarded the opening slot at the festival Infest 1993, featuring the Ramones. At this concert she met Brendan Canning, whose band hHead performed immediately before hers, and with whom she joined in Broken Social Scene ten years later.[12]

text: In 1995, Feist was forced to take time off from music to recover from vocal cord damage. She moved from Calgary to Toronto in 1996. That year she was asked by Noah Mintz of hHead to play bass in his solo project Noah's Arkweld. She played the bass guitar in Noah's Arkweld for a year despite never having played bass before. In 1998, she became the rhythm guitarist for the band By Divine Right and toured with them throughout 1998, 1999, and 2000. She also played guitar for some live performances by Bodega, but was never an official member of the band.[13]

text: In 1999, Feist moved into a Queen West apartment above Come As You Are with a friend of a friend, Merrill Nisker, who then began to perform as electro-punk musician Peaches.[14][15] Feist worked the back of the stage at Peaches' shows, using a sock puppet and calling herself "Bitch Lap Lap".[16] The two also toured together in England from 2000–2001, staying with Justine Frischmann of Elastica and MIA[17] Feist appeared as a guest vocalist on The Teaches of Peaches. Feist appears in Peaches' video for the song "Lovertits", suggestively rubbing and licking a bike. Later, Feist covered this song with Gonzales (whom she met while touring with Peaches) on her album Open Season. In 2006, Feist contributed backup vocals on a track entitled "Give 'Er", which appeared on Peaches' album Impeach My Bush.

text: Monarch (Lay Your Jewelled Head Down) (1999-2001)[edit]

text: Feist's solo debut album, Monarch, was released in 1999. It is composed of ten songs, including "Monarch" and "That's What I Say, It's Not What I Mean." The album was produced by Dan Kurtz, who would later form Dragonette.

text: Let It Die (2001-2006)[edit]

text: In the summer of 2001, Feist self-produced seven songs at home which she called The Red Demos, which have never been released commercially. She spent more than two years touring throughout Europe with Gonzales. In that same year she joined a group of old friends in forming a new version of Toronto indie rock group Broken Social Scene, adding vocals to many tracks after being forbidden to play guitar by de facto bandleader Kevin Drew.[18] She subsequently recorded You Forgot It in People with the band. While on tour in Europe with Gonzales, they began recording new versions of her home recorded Red Demos, which would later become her major label debut Let It Die. Let It Die featured both original compositions and covers, and Feist has been noted both as a songwriter and as an innovative interpreter of other artists' songs.

text: After the recording of Let It Die, Feist moved to Paris. While in Europe, she collaborated with Norwegian duo Kings of Convenience as co-writer and guest vocalist on their album Riot on an Empty Street, singing on "Know How," and "The Build Up." She also co-wrote and sang "The Simple Story" as a duet with Jane Birkin on her album Rendezvous.

text: Feist toured during 2004, 2005 and 2006 through North America, Europe, Asia, and Australia supporting Let It Die. She won two Canadian Juno Awards for "Best New Artist" and "Best Alternative Rock Album" in 2004. Sales of Let It Die totaled 500,000 internationally, and she was awarded a platinum record in Canada, as well as a gold album in France. Fellow Canadian Buck 65 appeared in the Feist-directed music video for "One Evening," which was also nominated for Video of the Year at the 2004 Juno Awards.

text: In 2005, Feist contributed to the UNICEF benefit song "Do They Know It's Hallowe'en?" The track "Mushaboom" was used in an advert for a Lacoste men's fragrance, as well as in the film 500 Days of Summer.

text: An album of remixes and collaborations, Open Season, was released on 18 April 2006.

text: Feist also lent her voice to the two tracks "La Même Histoire" and "We're All in the Dance" for the soundtrack to the 2006 film Paris, je t'aime.

text: The Reminder (2006-2007)[edit]

text: In early 2006, Feist moved to Paris,[15] where she recorded a followup to Let It Die at LaFrette Studios with Gonzales, Mocky, Jamie Lidell, and Renaud Letang, as well as her touring band Bryden Baird, Jesse Baird, Julian Brown of Apostle of Hustle, and Afie Jurvanen of Paso Mino.

text: Feist's third solo album, The Reminder, was released on 23 April 2007 in Europe, and on 1 May 2007 in Canada, the USA, and the rest of the world. She toured worldwide to promote the album.[19] The album features "1234," a song co-written by New Buffalo's Sally Seltmann, that became a surprise hit after being featured in a commercial for the iPod nano, hitting No. 8 in the US, a rare feat for indie rock musicians and even more notable since it hit the Top Ten on the strength of downloads alone. She has been lauded in the press and was featured on the cover of the New York Times arts section in June 2007. The Reminder had sold worldwide over 1,000,000 copies and is certified gold in the U.S.[20] The album also won a 2008 Juno Award for "Album of the Year" on 6 April 2008 in Calgary, Alberta.

text: Videos for many of the singles were directed by Patrick Daughters, who previously directed the video for "Mushaboom" and went on to direct "1234," "My Moon, My Man," and "I Feel It All." "1234" and "My Moon, My Man" were choreographed by the acclaimed choreographer & dancer Noemie Lafrance. The video for Honey, Honey features the work of avant-garde puppet troupe, The Old Trout Puppet Workshop.

text: "I Feel It All" was featured in the UK teen comedy The Inbetweeners and was used in the film The Accidental Husband. "Honey Honey" was featured in The L Word (episode 5.06, "Lights! Camera! Action!"). "I Feel It All" was featured in the 2008 film The Women. Popular German DJ Boys Noize remixed "My Moon, My Man," which appears on his 2007 debut album Oi Oi Oi. The DJ has also been known to close sets with the remix. In January 2009, Bon Iver played a cover of Feist's "The Park" from The Reminder on Australian radio's Triple J. The song "Limit to Your Love" was featured in season 2, episode 1 of British teen drama Skins, and was used in the film The Accidental Husband. A cover version of the song was released by UK singer-producer James Blake as a single from his 2011 self-titled album.

text: Prior to the airing of an Apple iPod nano commercial featuring this song, The Reminder was selling at approximately 6,000 copies per week, and "1234" at 2,000 downloads per week. Following the commercial, the song passed 73,000 total downloads and reached No. 7 on Hot Digital Songs and No. 8 on the Billboard Hot 100; The Reminder jumped from No. 36 to No. 28 on the Billboard 200, with sales of 19,000.[21] Following the television advertisement for the iPod nano in the UK, the single beat its original chart position of 102 to become number 8 in the UK charts. Time magazine named "1234" one of The 10 Best Songs of 2007, ranking it at No. 2. Writer Josh Tyrangiel called the song a "masterpiece," praising Feist for singing it "with a mixture of wisdom and exuberance that's all her own".[22][23] On 6 April 2008, Feist won a Juno Award for the single as "Single of the Year".

text: Feist performed an alternate version of "1234" on Sesame Street during its 39th season (2008), teaching children to count to the number four.[24] She said working with the Muppets was a career highlight.[25]

text: "The Water"[edit]

text: In 2009, Feist appeared in a short film directed by Broken Social Scene bandmate Kevin Drew that focused on her song "The Water." Feist appears alongside Cillian Murphy and David Fox in the silent role of "Mother." This film was streamed from Pitchfork.com for a week starting on 2 March 2009. In an interview with the site, Feist described the experience of being in this movie as "watching a movie while being in a movie."[26]

text: Metals (2007-2013)[edit]

text: In 2007, Feist was placed No. 9 on Spinner.com's 2007 Women Who Rock Right Now.[27] and named both Spin's and Blender's Breakout Artist of the Year.[28][29] After taking Bob Wiseman on the road as her opening act in Europe she acted in his video Who Am I and joined him on drums for You Don't Love Me, both of which are visible on YouTube.

text: Feist was photographed by Annie Leibovitz for the November 2007 issue of Vanity Fair as part of a photo essay on folk music.[30] On 3 November that year, she performed "1234" and "I Feel It All" on Saturday Night Live.[31]

text: Feist was on the cover of the Spring 2008 edition of Naked Eye. On 28 April, Feist was interviewed by Stephen Colbert. At the end of the show she performed "I Feel It All," while Colbert donned Feist's blue, sequined, strapless jumpsuit from the "1234" video. Feist joined Colbert again on his first-ever Christmas special, A Colbert Christmas: The Greatest Gift of All!, which first aired on 23 November 2008. She played an angel working for Heaven's overloaded phone (prayer) service. She also accompanied the Disko Bay Expedition of Cape Farewell.[32] On 20 October 2008, she told The Canadian Press that, following the success of her last album, The Reminder, she felt she needed to step away from the pressures of the music industry to consider her next career move and "rest for a minute".[33]

text: In March 2009, it was announced that she would make a guest appearance on the track "You and I" on Wilco's seventh album.[34]

text: In 2009, Feist was featured in the CTV television film "My Musical Brain" with neuroscientist and writer Daniel Levitin, based on Levitin's bestselling book This Is Your Brain on Music.

text: Feist collaborated with Brooklyn band Grizzly Bear on the song "Service Bell" for the AIDS charity the Red Hot Organization. This song appears on Red Hot's album Dark Was the Night, and she joined the band in June 2009 during their Toronto show to sing this song and contribute backing vocals to the song "Two Weeks." She also collaborated with Ben Gibbard on a cover of Vashti Bunyan's "Train Song" for the same Dark Was the Night album.

text: In June 2009, she re-joined Broken Social Scene at a North by Northeast performance celebrating the launch of the band's biography entitled This Book Is Broken, in which she is prominently featured. This contradicted various rumors saying that it was unlikely Feist would ever play with the band again; this was the first of several appearances with BSS. She performed with Broken Social Scene during their concert of 11 July 2009 at Toronto's Harbourfront Centre, singing and playing guitar through most of the concert,[35] as well as performing a medley of her solo songs with Kevin Drew and his solo songs. The concert was filmed by director Bruce Macdonald and released as This Movie Is Broken. She sings on Broken Social Scene's most recent album Forgiveness Rock Record. She performed with the band again in June 2010 on Olympic Island, and at the Sound Academy in Toronto on 9 and 10 December 2010.

text: Feist joined Beck, Wilco, Jamie Lidell and James Gadson in a Los Angeles studio covering Skip Spence's Oar as part of Beck's Record Club series, with videos appearing on Beck's website beginning November 2009.[36]

text: She also contributed vocals on Constant Companion the second album from Canadian songwriter Doug Paisley. Feist sings on the tracks "What I Saw" and the duet "Don't Make Me Wait". The album was released 12 October 2010.

text: Her song "Limit to Your Love" was covered by British post-dubstep artist James Blake and later remixed as a dubstep track by Benny Benassi and played to high acclaim at the 2011 Ultra Music Festival.

text: On 7 July 2011, Feist with Radiohead's Colin Greenwood, Air's Nicolas Godin, The Hotrats and Soap&Skin performed The Velvet Underground and Nico's "Femme Fatale" at an all-star gig "The Velvet Underground Revisited" which took place in Cité de la Musique, Paris.[37][38]

text: Her album Metals was released on 30 September 2011. Collaborators include Valgeir Sigurðsson, Chilly Gonzales, and Mocky.[39] The album received widespread acclaim from music critics. It achieved an overall rating of 7.6/10 at[40] AnyDecentMusic? based on 32 reviews.

text: In 2012, Feist plans to cover a song from the progressive metal band Mastodon, with Mastodon also covering Feist, and release both songs on a split 7" on Record Store Day.[41] They also released a crossfading interactive video for the song 'A Commotion'.[5]

text: Feist also has a cameo in the 2011 movie The Muppets.

text: In 2012, she wrote the song "Fire in the Water" exclusively for the film The Twilight Saga: Breaking Dawn - Part 2. The song was played when Edward and Bella are intimate in their cottage, and has been well received by critics.

text: Her song "The Water" was covered on American jazz violinist Zach Brock's 2012 album Almost Never Was.

text: On 14 January 2013, it was announced Feist would headline, along with labelmate Broken Social Scene, the Arts & Crafts Field Trip Music Festival to commemorate the tenth anniversary of Arts & Crafts.[42]

text: Look at What the Light Did Now (2013-present)[edit]

text: In September 2010, Feist announced through her website the release of a documentary film about the creative process of making of The Reminder, called Look at What the Light Did Now.[43] It was directed by Canadian film director Anthony Seck and was shot on Super 8 mm film. The film was released on DVD in December 2010, and a limited series of screenings were conducted including a Toronto screening at the Royal Ontario Museum, which featured a post-film interview of Feist by George Stroumboulopoulos.

text: The film focuses on the recording of The Reminder as well as the development of the tour through puppetry and projection. The film includes interviews with band member Afie Jurvanen; producer Chilly Gonzales; Broken Social Scene bandmates Kevin Drew and Andrew Whiteman; and video director Patrick Daughters.

text: Bonus materials on the DVD include "This One Jam", an early performance of Feist with Gonzales at Trash Club; live performances from the Reminder tour; and two short films: "The Water" starring Feist and "Departures" starring Kevin Drew and based on an idea by Feist. A CD is also included that contains the documentary soundtrack (tracks from The Reminder re-interpreted and performed by Gonzales), live performances by Feist, as well as two versions of the title track, "Look at What the Light Did Now", one of which was recorded as a duet with the song's writer, American musician Kyle Field.

text: In April 2017, Feist released Pleasure, preceding it with the release of the title track "Pleasure" as a single in March 2017.[44] On April 27, 2017 she introduced the album (a day ahead of its release) at Trinity St. Paul, Toronto, before an adoring crowd. She performed the entire content of the album (in reverse order) as well as some of her earlier work including, "I Feel It All".

text: Discography[edit]

text:
Monarch (1999)
Let It Die (2004)
The Reminder (2007)
Metals (2011)
Pleasure (2017)

text: Filmography[edit]

text:
List of television and films credits

Year
Title
Role
Notes

2007
Departures
Herself
Is in the process of filming the video for "My Moon My Man"; does not speak

2007
Saturday Night Live
Herself
"Brian Williams/Feist" (Season 33, Episode 4)

2008
Sesame Street
Herself
"The Golden Triangle of Destiny" (Season 39, Episode 1)

2008
A Colbert Christmas: The Greatest Gift of All!
Angel/Herself

2009
The Musical Brain
Herself
Documentary

2009
In the Corner.
Herself
Documentary

2009
Burning Ice
Herself
Documentary

2009
Love Shines
Herself
Documentary

2009
The Water
The Mother

2010
Ivory Tower[45]
Unknown

2010
Look at What The Light Did Now[46]
Herself

2011
The Muppets
Smalltown Resident
Performs "Life's A Happy Song" with Jason Segel, Amy Adams, "Walter" (Peter Linz), and Mickey Rooney

2017
Legion
Soundtrack
"The Undiscovered First" (Season 1, Episode 4)

text: Awards[edit]


document_title: Puppy Dog Pals

question_text: who does the voice of frank on puppy dog pals

root

text: Puppy Dog Pals

text: Plot[edit]

text: Puppy Dog Pals is about brothers[1] Bingo and Rolly, two pug puppies who have fun traveling around their neighborhood and the world when their owner Bob leaves home. They also have a cat sister named Hissy, and a robot dog named Automatic Doggy Robotic Friend or ARF.

tag: p

text: Characters[edit]

text: Main[edit]

text:
Bingo (voiced by Issac Ryan Brown) is a black pug with a blue collar. He is the leader of the two and is Rolly's older brother.
Rolly (voiced by Sam Lavagnino) is a fawn pug with a red collar. He isn't as smart as Bingo, and is very silly. He is Bingo's younger brother. In "Bob Loves Mona", he starts a bad habit of chewing everything he can find.
Bob (voiced by Harland Williams) is the owner of Bingo, Rolly, Hissy, and A.R.F. He works as an inventor.
Hissy (voiced by Jessica DiCicco) is a sarcastic purple cat. In some episodes, she ends up going along with Bingo and Rolly on their missions. These episodes are: "A Pyramid Scheme", "Hissy's Big Day", "Bob Loves Mona", "Puzzling Pugs", "A Seat at the Theatre", and "Return to the Pumpkin Patch", She is the first and currently only female character to sing.
A.R.F. (fully known as Auto-Doggy Robotic Friend; voiced by Tom Kenny) is a robotic dog that Bob invented. He first appears in the episode "A.R.F.". Later in the series, he is updated by Bob in "Go, Dog, Go!"

tag: ul

text: Recurring[edit]

text:
Cupcake (voiced by Jill Talley) is a pink puppy who does not like Bingo and Rolly. She is the main antagonist of the series.
Rufus (voiced by Leslie David Baker) is the bulldog with a black collar who is always with Cupcake. He cannot speak much except growl and mutter. He has been known to chase Bingo and Rolly multiple times, but in "Haunted Howl-O-Ween", he helped them instead.
Captain Dog (voiced by Patrick Warburton) is the star of the pups' favorite television show.
Frank Exposition (voiced by Leslie David Baker) is a man who is usually seen vacationing with his wife during Bingo and Rolly's missions. In "A Pyramid Scheme" he gets tangled in ribbons, which leads to Bingo and Rolly mistaking him for a mummy.
Esther Exposition (voiced by Cheri Oteri) is Frank's wife. In "Hissy's Big Day", she is shown to have a pet iguana named Iggy who didn’t appear again until "The Great Pug-scape".
Daisy (voiced by Yvette Nicole Brown) is a kind German Shepherd. She first appeared in "History Mystery". She appeared again in "A Very Pug Christmas".
Bulworth (voiced by Huey Lewis) is the junkyard dog.
Hedgie the Hedgehog (voiced by Jack McBrayer) is a hedgehog who first appeared in “Winter Wonder Pug”.
The Go-Long Retriever (voiced by Harland Williams) is the toy stick and one of Bob's inventions that Bingo and Rolly tried to get rid of. It doesn't say anything other than "Play fetch with me!"
Johnathan (voiced by Jeff Bennett) is Bingo and Rolly's wisecracking seagull friend.
Cagey (voiced by Jeff Bennett) is Bingo and Rolly's guinea pig friend who used to live at the Pet Store, but is now Chloe’s pet.
Crumpet (voiced by Jeff Bennett) is the royal Corgi dog.
Whaley (voiced by Jessica DiCicco) is the whale that Bingo and Rolly helped jump over the other side of the wall.
Dallie (voiced by Tom Kenny) is a dalmatian.
Jackie (voiced by Jill Talley) is an orange collie with a magenta bandanna.
Nelly (voiced by Grey DeLisle) is a bluebird who appears in "Polly Wants A Pug". She appears again in "Winter Wonder-Pug".
Miss Mudge (voiced by Alanna Ubach) is Snowflake's owner.
Guard Dog (voiced by Kevin Michael Richardson) is a Doberman who is friends with Bulworth.
Chloe (voiced by Emma Shannon) is a little girl who is Bob's neighbor.
Chloe's Mom (voiced by Tara Strong) is Chloe's mom.
Bob's Mom (voiced by Tress MacNeille) is an old lady who appears in three episodes: "Special Delivery" , "Your Royal Pug-Ness", and “A Pug-Tastic Day with Grandma”.
Bizzy the Beaver (voiced by Kevin Michael Richardson) is a beaver who lives in the forest.
Strider the Sheepdog (voiced by Mo Collins) is a fast-talking sheep herder who appears in the episodes, "Counting Sheep" and "Rhapsody in Pug".
Shockero (voiced by Kevin Michael Richardson) is a lavender Scotty dog.
Bark Knight (voiced by Gary Anthony Williams) is Captain Dog's sidekick.
Titus (voiced by Jeff Bennett) is a leopard who now owns Hissy's squeaky toy.
Harriet (voiced by Mo Collins) is a smart African elephant.
Barry (voiced by Jeff Bennett) is a giraffe who let Bingo, Rolly, and Hissy ride on his head.
Quinty Mcsquinty (voiced by Jeff Bennett) is an old basset hound who told Bingo and Rolly the legend of Ol' Snapper.
Ol' Snapper (voiced by Tom Kenny) is a turtle mistaken as a monster.
Baby (barks provided by Jessica DiCicco) is a huge Great Dane puppy.
Queen Kazoo (voiced by Alanna Ubach) is the star of Bob's favorite play.
Baboo (voiced by Gary Anthony Williams) is Queen Kazoo's dog.

text: Episodes[edit]

text:
No.
Title [4]
Directed by
Written by
Storyboards by
Original air date
Prod.
code [5]
U.S. viewers
(millions)

1a
"Hawaii Pug-Oh"
Scott Bern
Harland Williams
Paul Cohen
April 14, 2017 (2017-04-14)
101
1.39[6]

When Bob says he'd love to feel the sand on his toes, pug puppy brothers Bingo and Rolly go on a mission to Hawaii.

1b
"A.R.F."
Trevor Wall
Bob Smiley
James Gibson
April 14, 2017 (2017-04-14)
101
1.39[6]

Bob introduces the pups to A.R.F., a robotic dog that is programmed to clean up their messes.

2a
"The French Toast Connection"
Stephanie Arnett
Brendan Duffy
Kris Wimberly
April 14, 2017 (2017-04-14)
TBA
1.36[6]

Bingo and Rolly travel to France to get Bob some french toast.

2b
"Take Me Out to the Pug Game"
Scott Bern
Sean Coyle
Doris Umschaden
April 14, 2017 (2017-04-14)
TBA
1.36[6]

The pugs chase Bob's prized baseball across the city.

3a
"The Go-Long Retriever"
Stephanie Arnett
Jessica Carleton
Kris Wimberly
April 21, 2017 (2017-04-21)
TBA
0.99[7]

Bingo and Rolly try to get away from a self-fetching stick that begins chasing them.

3b
"Pot O' Pugs"
Scott Bern
Bob Smiley
Doris Umschaden
April 21, 2017 (2017-04-21)
TBA
0.99[7]

After Bob says he needs a pot of gold, the pups search for one at the end of a rainbow.

4a
"A Pyramid Scheme"
Trevor Wall
Jeff Rothpan
Julia Briemle
April 21, 2017 (2017-04-21)
TBA
1.05[7]

Bingo and Rolly travel to Egypt to find the missing Great Pyramids.

4b
"Special Delivery"
Stephanie Arnett
Bob Smiley
Otis Brayboy
April 21, 2017 (2017-04-21)
TBA
1.05[7]

The pugs try to deliver a Mother's Day card for Bob.

5a
"Design-A-Dog"
Scott Bern
Jessica Carleton
Paul Cohen
April 28, 2017 (2017-04-28)
TBA
0.91[8]

Bingo and Rolly accidentally chew Bob's childhood toy.

5b
"Ice, Ice Puggy"
Trevor Wall
Darrin Rose
James Gibson
April 28, 2017 (2017-04-28)
TBA
0.91[8]

When Bob runs out of ice, the pugs go to Antarctica to get him some.

6a
"Free Whaley"
Trevor Wall
Sean Tweedley
Julia Briemle
May 5, 2017 (2017-05-05)
106
1.05[9]

Bingo and Rolly help a baby whale that has been separated from her family.

6b
"Putting It Together"
Stephanie Arnett
Brendan Duffy
Otis Brayboy
May 5, 2017 (2017-05-05)
106
1.05[9]

The pugs retrace their steps to remember where they buried Bob's unicycle.

7a
"Hissy's Big Day"
Trevor Wall
Bill Fuller
Julia Briemle
May 12, 2017 (2017-05-12)
107
1.05[10]

After Hissy has had a bad morning, Bingo and Rolly try to make her feel better by taking her to their favorite places.

7b
"Go, Dog. Go!"
Stephanie Arnett
Bob Smiley
Otis Brayboy
May 12, 2017 (2017-05-12)
107
1.05[10]

The reprogrammed A.R.F. takes the pugs where they want to go but the pugs learn that the robotic dog isn't programmed to bring them back.

8a
"Pigs and Pugs"
Trevor Wall
Jessica Carleton
Bill Breneisen & Alfred Gimeno
May 19, 2017 (2017-05-19)
108
1.04[11]

Bob mistakes a mud-covered pig for Rolly and accidentally leaves him behind on the farm.

8b
"Bob Loves Mona"
Scott Bern
Joe Ansolabehere (story)
Jessica Carleton
Rudi Bloss
May 19, 2017 (2017-05-19)
108
1.04[11]

The pugs travel to the Great Wall of China to search for the missing Mona Lisa.

9a
"Don't Rain on my Pug-rade"
Trevor Wall
Bob Smiley
Arthur Valencia
June 16, 2017 (2017-06-16)
109
1.59[12]

When Bob can't leave his house to watch a parade, the pups enlist a family of ducks to march past the house.

9b
"Their Royal Pug-ness"
Stephanie Arnett
Bob Smiley
Otis Brayboy
June 16, 2017 (2017-06-16)
109
1.59[12]

Bingo and Rolly head to England to learn how to treat a queen.

10a
"Scuba-Doggies"
Scott Bern
Jessica Carleton (story)
Bob Smiley
Rudi Bloss
June 23, 2017 (2017-06-23)
110
1.25[13]

The pups go to The Great Barrier Reef to find Bob’s package that was lost at sea.

10b
"Walking the Bob"
Trevor Wall
Bob Smiley
Bill Breneisen
June 23, 2017 (2017-06-23)
110
1.25 [13]

The pups lead a blurry-visioned Bob home.

11a
"Hissy's Kitty"
Stephanie Arnett
Jessica Carleton
Kris Wimberly
July 7, 2017 (2017-07-07)
111
1.21[14]

When Bob brings home a lost kitty, Bingo and Rolly try find her a home.

11b
"Polly Wants a Pug"
Scott Bern
Michael Olson & Bob Smiley
Julia Briemle & Doris Umschaden
July 7, 2017 (2017-07-07)
111
1.21[14]

While in Florida, Bingo and Rolly search for an old friend of Bob's.

12a
"Leave it to Beavers"
Trevor Wall
Jessica Carleton
Julia Briemle
July 14, 2017 (2017-07-14)
112
1.35[15]

Bingo and Rolly try to build a dam to protect their doghouse from a rainstorm.

12b
"Counting Sheep"
Stephanie Arnett
Jessica Carleton
Otis Brayboy
July 14, 2017 (2017-07-14)
112
1.35[15]

When Bob says he'll count sheep to sleep, the pugs herd a flock of sheep into the backyard to help.

13a
"Captain Rolly"
Scott Bern
Brian Hall
Rudi Bloss
July 28, 2017 (2017-07-28)
113
1.20[16]

The pugs attend the Captain Dog fan party.

13b
"The Coolest Dogs in Town"
Trevor Wall
Brian Hall
Bill Breneisen
July 28, 2017 (2017-07-28)
113
1.20[16]

A.R.F takes Bingo and Rolly places to get cool.

14a
"Puzzling Pugs"
Stephanie Arnett
Harland Williams(story)
Michael Olson and Harland Williams
Ashley Lenz
August 11, 2017 (2017-08-11)
TBA
1.25[17]

Bingo, Rolly, and Hissy find a leopard for Bob's puzzle after A.R.F tears it up.

14b
"Rhapsody in Pug"
Scott Bern
Amy Van Curen
Doris Umschaden
August 11, 2017 (2017-08-11)
TBA
1.25[17]

Bingo and Rolly go to a concert.

15a
"The Legend of Ol' Snapper"
Trevor Wall
Sean Coyle
Julia Briemle
August 25, 2017 (2017-08-25)
TBA
0.84[18]

Bob's fishing pole is stolen by a legendary creature.

15b
"Adventures in Puppy-Sitting"
Stephanie Arnett
Jessica Carleton
Otis Brayboy
August 25, 2017 (2017-08-25)
TBA
0.84[18]

The pugs are tasked to babysit a big dog that causes trouble around the town.

16a
"Bye Bye, Butterfly"
Trevor Wall
Jessica Carleton & Harland Williams
Ed Baker
September 22, 2017 (2017-09-22)
TBA
0.63[19]

Bingo and Rolly help a butterfly find a way back to her family.

16b
"A Seat at the Theatre"
Scott Bern
Jessica Carleton
Rudi Bloss
September 22, 2017 (2017-09-22)
TBA
0.63[19]

Bingo and Rolly try to take a seat to Bob's favorite play and try not to wake up Hissy at the same time.

17a
"Return to the Pumpkin Patch"
Scott Bern
Bob Smiley (story)
Amy Van Curen
Doris Umschaden
October 1, 2017 (2017-10-01)
TBA
0.97[20]

Bingo, Rolly and Hissy go to a pumpkin patch to find Bingo's collar after he loses it in the maze.

17b
"Haunted Howl-oween"
Stephanie Arnett
Amy Van Curen (story)
Jessica Carleton
Ashley Lenz
October 1, 2017 (2017-10-01)
TBA
0.97[20]

Bingo and Rolly go on a mission to find Chloe's Halloween Costume.

18a
"Close Encounters of a Pug Kind"
Trevor Wall
Brian Hall
Bill Breneisen
October 13, 2017 (2017-10-13)
TBA
0.84[21]

The pups go to a gathering of UFO enthusiasts to find someone from space and mistake a lost Chameleon for an alien.

18b
"History Mystery"
Stephanie Arnett
Amy Van Curen
Otis Brayboy
October 13, 2017 (2017-10-13)
TBA
0.84[21]

When the pups find a doggie toy that isn't theirs, they go on a mission to find its original owner.

19a
"Art for Pug's Sake"
Stephanie Arnett
Bob Smiley
Kris Wimberly
November 10, 2017 (2017-11-10)
TBA
0.94[22]

The pugs try to hang something of Bob's at a famous Italian art museum.

19b
"Winter Wonderpug"
Scott Bern
Bob Smiley
Doris Umschaden
November 10, 2017 (2017-11-10)
TBA
0.94[22]

Bingo and Rolly look for the first snowflake of the season while helping other animals prepare for winter.

20a
"A Very Pug Christmas"
Scott Bern
Jessica Carleton & Brian Hall (story)
Roger Dondis
December 1, 2017 (2017-12-01)
125
1.03[23]

On Christmas Eve, Bingo and Rolly help Santa search for Bob's Christmas present when it goes missing in the sleigh.

20b
"The Latke Kerfuffle"
Trevor Wall
Jessica Carleton
Bill Breneisen
December 1, 2017 (2017-12-01)
125
1.03[23]

Bingo and Rolly help Bob make latkes for their neighbor Chloe's Hanukkah party.

21a
"Puggy-ology"
Scott Bern
Jessica Carleton
Rudi Bloss
February 23, 2018 (2018-02-23)
TBA
0.72[24]

Bingo and Rolly help Bob's younger sister look for historical items.

21b
"Squirrels Just Wanna Have Fun"
Trevor Wall
Jean Ansolabehere
Bill Breneisen
February 23, 2018 (2018-02-23)
TBA
0.72[24]

Bingo and Rolly try to catch a squirrel who's been making noises in their house.

22a
"The Great Pug-scape"
Stephanie Arnett
Amy Van Curen
Kris Wimberly
March 9, 2018 (2018-03-09)
TBA
0.71[25]

After Hissy gets a time out, Bingo and Rolly try to break her out of her punishment.

22b
"Luck of the Pug-ish"
Scott Bern
Sean Coyle
Kelly James
March 16, 2018 (2018-03-16)
TBA
0.76[26]

The Pugs travel to Ireland in search of a four-leaf clover to bring Bob good luck.

23a
"The Great Shirt Rescue"
Scott Bern
Jean Ansolabehere
Rudi Bloss
March 23, 2018 (2018-03-23)
TBA
0.84[27]

When Bob loses his lucky shirt, the pugs stage a heist to get it back.

23b
"A Pugtastic Day with Grandma"
Trevor Wall
Bill Fuller (story)
Michael Olson
Carole Holliday
March 30, 2018 (2018-03-30)
TBA
0.89[28]

The pugs stay at Bob’s Mom’s house while he goes out of town.

tag: table

text: Home media[edit]

text:
Region
Title
Episode(s)
Season
Running time
Released
Ref.

1
Going on a Mission!
6
1
183 minutes
April 10, 2018 (2018-04-10)

text: Awards and nominations[edit]

text:
Year
Award
Category
Nominee
Result
Ref.

2018
Daytime Emmy Awards
Outstanding Individual in Animation
Steve C. Meyers
Won

Outstanding Casting for an Animated Series or Special
Allyson Bosch
Nominated


document_title: Renal protein reabsorption

question_text: where does most reabsorption in the kidney occur

text: Renal protein reabsorption

text: Renal protein reabsorption is the part of renal physiology that deals with the retrieval of filtered proteins, preventing them from disappearing from the body through the urine.

text: Almost all reabsorption takes place in the proximal tubule. Only ~1%[1] is left in the final urine.

text: The proteins cross the apical membrane by endocytosis. They are subsequently degraded in lysosomes. The remaining free amino acids are transported across the basolateral membrane by amino acid transporters.[1]

text: Overview table[edit]

text:
Characteristics of oligopeptide reabsorption

Characteristic
proximal tubule
loop of Henle
Distal convoluted tubule
Collecting duct system

S1
S2
S3

reabsorption (%)
99[1]

reabsorption (mmoles/day)

Concentration

apical transport

endocytosis[1]

basolateral transport proteins

amino acid transporter[1]

Other reabsorption features


document_title: International Development Association

question_text: which institute is known as soft loan window of world bank

text: International Development Association

text: History[edit]

text: During the 1940s and 1950s, developing countries with the poorest incomes began realizing that they could no longer afford to borrow capital and needed more-favorable lending terms than offered by the International Bank for Reconstruction and Development (IBRD).[10] At the onset of his inaugural term in 1949, then-President of the United States Harry S. Truman assembled an advisory group to suggest ways to accomplish his Point Four Program, of which a significant component was an effort to strengthen developing countries, especially those nearest to the Eastern Bloc, to dissuade them from aligning with other communist states. The advisory group recommended an international mechanism that would function somewhere in between providing strictly-loaned and strictly-granted funds.[11] The UN and United States government published reports expressing support for the creation of a multilateral, concessional lending program for the poorest developing countries.[10] However, the United States was largely unresponsive and ultimately distracted by its involvement in the Korean War and unconvinced that development needed greater financial stimulation.[11]

text: Developing countries grew increasingly frustrated with not being able to afford IBRD lending and perceived the Marshall Plan as a comparatively generous gift to European nations. In the late 1940s and early 1950s, developing countries began calling for the United Nations (UN) to create a development agency that would offer technical support and concessional financing, with a particular desire that the agency adhere to other UN bodies' convention of each country having one vote as opposed to a weighted vote. However, the United States ultimately opposed proposals of that nature. As the United States grew more concerned over the growth of the Cold War, it made a concession in 1954 at the behest of its Department of State by backing the conception of the International Finance Corporation (IFC). Despite the launch of the IFC in 1956, developing countries persisted in demanding the creation of a new concessional financing mechanism and the idea gained traction within the IBRD.[11] Then-President of the IBRD Eugene R. Black, Sr. began circulating the notion of an International Development Association, as opposed to an idea of a concessional named the Special United Nations Fund for Economic Development (SUNFED) governed by the United Nations.[12] Paul Hoffman, the Marshall Plan's former Administrator, proposed the idea of a soft-loan facility within the World Bank, where the US would have a preponderant voice in the allocation of such loans.Democratic Senator Mike Monroney of Oklahoma supported this idea.[12] As Chairman of the Senate Subcommittee on International Finance, Monroney proposed a resolution recommending a study of the potential establishment of an International Development Association to be affiliated with the IBRD.[10] Monroney's proposal was more preferred received within the United States than the SUNFED.[11] The resolution passed the senate in 1958, and then-U.S. Treasury Secretary Robert B. Anderson encouraged other countries to conduct similar studies. In 1959, the World Bank's Board of Governors approved a U.S.-born resolution calling for the drafting of the articles of agreement.[10] SUNFED later became the Special Fund and merged with the Expanded Programme of Technical Assistance to form the United Nations Development Programme.

text: By the end of January 1960, fifteen countries signed the articles of agreement which established the International Development Association. The association launched in September of that same year with an initial budget of $913 million ($7.1 billion in 2012 dollars[13]).[14][15] Over the next eight months following its launch, the IDA grew to 51 member states and loaned $101 million ($784.2 million in 2012 dollars[13]) to four developing countries.[10]

text: Governance and operations[edit]

text: The IDA is governed by the World Bank's Board of Governors which meets annually and consists of one governor per member country (most often the country's finance minister or treasury secretary). The Board of Governors delegates most of its authority over daily matters such as lending and operations to the Board of Directors. The Board of Directors consists of 25 executive directors and is chaired by the President of the World Bank Group. The executive directors collectively represent all 187 member states of the World Bank, although decisions regarding IDA matters concern only the IDA's 172 member states. The president oversees the IDA's overall direction and daily operations.[16] As of  July 2012[update], Jim Yong Kim serves as the President of the World Bank Group.[17] The association and IBRD operate with a staff of approximately 10,000 employees.[18]

text: The IDA is evaluated by the Bank's Independent Evaluation Group. In 2009, the group identified weaknesses in the set of controls used to protect against fraud and corruption in projects supported by IDA lending.[19] In 2011, the group recommended the Bank provide recognition and incentives to staff and management for implementing activities which implement the Paris Declaration on Aid Effectiveness principles of harmonization and alignment, promote greater use of sector-wide approaches to coordination, and explain the reasons why when a country's financial management system is not used so that the client country may address those shortcomings. It also recommended that the Bank collaborate with development partners to strengthen country-level leadership of development assistance coordination by offering greater financial and technical support.[20] Development economists, such as William Easterly, have conducted research which ranked the IDA as featuring the most transparency and best practices among donors of development aid.[21][22]

text: Researchers from the Center for Global Development expect that the IDA's collection of eligible borrowing countries will decrease by half by the year 2025 (marking the 65th anniversary of the association's establishment) due to graduations and that remaining borrowers will consist primarily of African countries and will face substantial population declines. These changes will imply a need for the association to carefully examine its financial models and business operations to determine an appropriate strategy going forward. The center recommended that the World Bank leadership begin discussing the long-term future of the IDA.[23]

text: Membership[edit]

text: The IDA has 173 member countries which pay contributions every three years as replenishments of its capital.[2] The IDA lends to 81 borrowing countries, nearly half of which are in Africa.[24] Membership in the IDA is available only to countries who are members of the World Bank, particularly the IBRD.[25] Throughout its lifetime, 36 borrowing countries have graduated from the association, although a number of these countries have relapsed as borrowers after not sustaining their graduate status.[2]

text: To be eligible for support from the IDA, countries are assessed by their poverty and their lack of creditworthiness for commercial and IBRD borrowing.[26] The association assesses countries based on their per capita income, lack of access to private capital markets, and policy performance in implementing pro-growth and anti-poverty economic or social reforms.[7][27] As of  2012[update], to borrow from the IDA's concessional lending programs, a country's gross national income (GNI) per capita must not exceed $1,175 (in 2010 dollars).[24]

text: Countries that graduated from IDA lending[edit]

text: The following countries have graduated from their eligibility for IDA lending.[28]

text:
Albania (2008)
 Azerbaijan (2011)
 Botswana (1974)
 Chile (1961)
 China (1999)
 Colombia (1962)
 Costa Rica (1962)
 Dominican Republic (1973)
 Ecuador (1974)
 Egypt (1999)
 El Salvador (1977)
 Equatorial Guinea (1999)
 India (1994)
 Indonesia (2008)
 Jordan (1978)
 Macedonia (2002)
 Mauritius (1975)
 Montenegro (2008)
 Morocco (1975)
 Paraguay (1977)
 Philippines (1993)
 Saint Kitts and Nevis (1994)
 Serbia (2007)
 South Korea (1973)
 Swaziland (1975)
 Syria (1974)
 Thailand (1979)
 Tunisia (1977)
 Turkey (1973)

text: Countries relapsed to IDA lending[edit]

text: The following countries have relapsed to their eligibility for IDA lending and have not yet re-graduated or have instead become partially eligible (also referred to as a blend country).[28]

text:
Cameroon (1994)
 Congo (1994)
 Cote d'Ivoire (1992)
 Honduras (1991)
 Nicaragua (1991)
 Nigeria (1989)
 Papua New Guinea (2003, partially eligible)
 Zimbabwe (1992)

text: Replenishment rounds[edit]

text: The IDA is a unique part of the World Bank as it requires continuous replenishment of its resources. Member countries replenish its funds through contributions in addition to supplementary funds provided by the International Bank for Reconstruction and Development and the International Finance Corporation (IFC).[29][30] Whereas the IBRD acquires most of its funds by raising capital on international financial markets, the IDA heavily depends on contributions from its member states.[5] The IDA received 2 billion in special drawing rights ($3 billion USD) from the IBRD and IFC.[31] Approximately half of the IDA's resources come from the 45 donating member countries.[2] In its early years, the IDA received most of its replenishments from the United Kingdom and United States but, because they were not always reliable sources of funding, other developed nations began to step in and fill the economic gaps not met by these two countries.[32] Every three years, member nations that provide funds to the IDA gather together to replenish the IDA's resources.[33] These funds come primarily from well-developed countries including the United States, Japan, France, Germany, and the United Kingdom[34] with 58% from the US, 22% from France, and 8% from the UK.[35] As of 2014, there have been 17 IDA replenishment rounds.[36] Fifty one member countries participated in the IDA's 16th replenishment of $49.3 billion USD.[2][37] The IDA's loans and grants are usually not paid in full to the borrower at the outset, but rather disbursed incrementally as needed by the project. Most of the donor countries such as the United States commit letters of credit to the IDA which bear no interest and are not able to be transferred or revoked, and which are exchanged for cash as needed for project disbursal. Other countries pay their contributions in full on the date of commitment to the IDA so that it may cover its operating expenses. Donors receive no return of funds and repayments from borrowers are again loaned to future projects such that donors won't need to commit those funds again in the future.[38]

text: Although the IDA's funds are now regularly replenished, this does not happen without some financial and political challenges for the donating countries. When donor countries convene to negotiate the replenishments, there is often intense discussion about redefining the association's goals and objectives or even about reforming the IDA.[39] Due to delays in the United States Congress impeding the approval of IDA funding, the association's members implemented a set of policy triggers outlining the commitment threshold necessary for replenishment to take effect. The threshold imposed a requirement that an aggregate share of 85% in voting stock is necessary for executing a replenishment. The threshold was implemented with the aim to compel the United States to participate in replenishment rounds. Though countries intended for the triggers to hold the United States to its commitments, the threshold ultimately provided the United States a de facto veto power over replenishment and capital increase negotiations due to its ability to bring replenishment negotiations to an impasse by threatening to withhold support. The U.S. has used this influence to further its long-term foreign policy objectives and short-term political and economic goals by imposing conditionality on replenishment negotiations.[11][dubious  – discuss]

text: Lending[edit]

text: The IDA lends to countries with the aim to finance projects that will develop infrastructure and improve education, healthcare, access to clean water and sanitation facilities, and environmental responsibility.[2][40] It is considered to be the soft lending window of the World Bank, while the IBRD is considered to be the hard lending window.[41][42] The association offers grants and loans with maturities ranging from 25 to 40 years, grace periods of 5 to 10 years, and interest rates of 2.8% or 1.25% depending on whether the borrower is a blend country and to which degree it is eligible. Regular IDA-eligible borrowers may take advantage of no-interest loans.[43] Financial resources are allocated to eligible countries based on their success at implementing pro-growth and a poverty-reducing domestic policies. The IDA uses the World Bank's Country Policy and Institutional Assessment (CPIA) development indicator to determine each country's place in a resource allocation index. It then prioritizes its lending to those countries which are indicated to be most promising in terms of favorable policies and aid effectiveness.[27][44][45] The IDA adopted the Crisis Response Window in 2007 to enable the rapid provision of emergency financing in response to crises. The association adopted the Immediate Response Mechanism in 2011 to provide IDA borrowers with immediate access to withdraw undisbursed portions of their loans, should a crisis arise that meets the mechanism's criteria.[46]

text: Africa[edit]

text: Because African countries face some of the most severe poverty and underdevelopment, and because 39 of those countries are the IDA's poorest member states, the association allocates approximately half of the IDA's resources toward financing projects in those countries. As a result of its efforts to improve the region, the IDA has helped bring electricity to an additional 66 million Africans since 1997, helped build or restore 240,000 kilometers of paved roads, and helped enroll an additional 15 million African children in school since 2002.[47] The IDA was approved in May 2012 to provide $50 million USD worth of credit to the Women Entrepreneur Development Project as part of an effort to help women in Ethiopia participate in business as skilled employees or leaders.[48] Although the positive outcomes of the IDA's efforts in Africa had been historically slow, the large allocation of funding to African countries led to positive outcomes particularly within agriculture and infrastructure development efforts.[32]

text: Asia[edit]

text: The IDA's efforts in Asia have been particularly successful. Numerous Asian countries have graduated from the IDA lending program, including the Philippines, China, South Korea, and Thailand.[49] Of the association's borrowing countries, approximately 20 are in Asia.[24] The association's efforts in South Asia have focused primarily on projects for education, healthcare, transportation, agriculture, and energy.[50] Due to rapid growth in Asian countries' populations, some pockets of poverty have emerged. To mitigate this effect, the IDA adopted an economic plan of action which established organizations to improve education and healthcare, with a focus on reducing poverty across Asian nations in ways that are compatible with local culture.[49]


question_text: drugs that are substrates of cytochrome p450 3a4 and cyp2d6

text: Function[edit]

text: CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids components.

text: The CYP3A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and some pharmacological agents. Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, CYP3A4 is responsible for about half of this metabolism,[5] substrates include acetaminophen, codeine, ciclosporin (cyclosporin), diazepam, and erythromycin. The enzyme also metabolizes some steroids and carcinogens.[6] Most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, and many protoxins being toxicated into their toxic forms (for examples – see table below).

text: CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), i.e. (±)-8,9-, (±)-11,12-, and (±)-14,15-epoxyeicosatrienoic acids.[7] The EETs have a wide range of activities including the promotion of certain types of cancers (see epoxyeicosatetraenoic acid#cancer). CYP3A4 promotes the growth of various types of human cancer cell lines in culture by producing (±)-14,15-epoxyeicosatrienoic acids which stimulate these cells to grow,[8] The cytochrome P450 is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE).[9] 20-HETE has a wide range of activities that also include growth stimulation in breast and other types of cancers (see 12-hydroxyeicosatetraenoic acid#cancer).

text: Evolution[edit]

text: The CYP3A4 gene exhibits a much more complicated upstream regulatory region in comparison with its paralogs.[10] This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands, instead of relying on gene variants for wider specificity.[10] Chimpanzee and human CYP3A4 are highly conserved in metabolism of many ligands, although four amino acids positively selected in humans led to a 5-fold benzylation of 7-BFC in the presence of the hepatotoxic secondary bile acid lithocholic acid.[11] This change in consequence contributes to an increased human defense against cholestasis.[11]

text: Tissue distribution[edit]

text: Fetuses do not really express CYP3A4 in their liver tissue,[clarification needed] but rather CYP3A7 (EC 1.14.14.1), which acts on a similar range of substrates. CYP3A4 is absent in fetal liver but increases to approximately 40% of adult levels in the fourth month of life and 72% at 12 months.[12][13]

text: Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body, where it may play an important role in metabolism. CYP3A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows prodrugs to be activated and absorbed – as in the case of the histamine H1-receptor antagonist terfenadine.

text: Recently CYP3A4 has also been identified in the brain, however its role in the central nervous system is still unknown.[14]

text: Mechanisms[edit]

text: Cytochrome P450 enzymes perform an assortment of modifications on a variety of ligands, utilizing its large active site and its ability to bind more than one substrate at a time to perform complicated chemical alterations in the metabolism of endogenous and exogenous compounds. These include hydroxylation, epoxidation of olefins, aromatic oxidation, heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, dehydrogenation reactions, and aromatase activity.[15][16]

text: Hydroxylation of an sp3 C-H bond is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand.[17] In fact, hydroxylation is sometimes followed by dehydrogenation, leading to more complex metabolites.[16] An example of a molecule that undergoes more than one reaction due to CYP3A4 includes tamoxifen, which is hydroxylated to 4-hydroxy-tamoxifen and then dehydrated to 4-hydroxy-tamoxifen quinone methide.[16] Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes.

text: The first pathway suggested is a cage-controlled radical method ("oxygen rebound"), and the second involves a concerted mechanism that does not utilize a radical intermediate but instead acts very quickly via a "radical clock".[17]

text: Inhibition through fruit ingestion[edit]

text: In 1998, various researchers showed that grapefruit juice, and grapefruit in general, is a potent inhibitor of CYP3A4, which can affect the metabolism of a variety of drugs, increasing their bioavailability.[18][19][20][21][22] In some cases, this can lead to a fatal interaction with drugs like astemizole or terfenadine.[19] The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the Lancet entitled "Interactions of Citrus Juices with Felodipine and Nifedipine" and was the first reported food-drug interaction clinically. The effects of grapefruit last from 3–7 days, with the greatest effects when juice is taken an hour previous to administration of the drug.[23]

text: In addition to grapefruit, other fruits have similar effects. Noni (M. citrifolia), for example, is a dietary supplement typically consumed as a juice and also inhibits CYP3A4;[24] pomegranate juice has this effect as well.[25]

text: Variability[edit]

text: While over 28 single nucleotide polymorphisms (SNPs) have been identified in the CYP3A4 gene, it has been found that this does not translate into significant interindividual variability in vivo. It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates.

text: CYP3A4 alleles which have been reported to have minimal function compared to wild-type include CYP3A4*6 (an A17776 insertion) and CYP3A4*17 (F189S). Both of these SNPs led to decreased catalytic activity with certain ligands, including testosterone and nifedipine in comparison to wild-type metabolism.[26]

text: Variability in CYP3A4 function can be determined noninvasively by the erythromycin breath test (ERMBT). The ERMBT estimates in vivo CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (14C-N-methyl)-erythromycin.[27]

text: Induction[edit]

text: CYP3A4 is induced by a wide variety of ligands. These ligands bind to the pregnane X receptor (PXR). The activated PXR complex forms a heterodimer with the retinoid X receptor (RXR), which binds to the XREM region of the CYP3A4 gene. XREM is a regulatory region of the CYP3A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4. Activation of the PXR/RXR heterodimer initiates transcription of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in the presence of aflatoxin B1, M1, and G1. Indeed, due to the enzyme's large and malleable active site, it is possible for the enzyme to bind multiple ligands at once, leading to potentially detrimental side effects.[28]

text: Induction of CYP3A4 has been shown to vary in humans depending on sex. Evidence shows an increased drug clearance by CYP3A4 in women, even when accounting for differences in body weight. A study by Wolbold et al. (2003) found that the median CYP3A4 levels measured from surgically removed liver samples of a random sample of women exceeded CYP3A4 levels in the livers of men by 129%. CYP3A4 mRNA transcripts were found in similar proportions, suggesting a pre-translational mechanism for the up-regulation of CYP3A4 in women. The exact cause of this elevated level of enzyme in women is still under speculation, however studies have elucidated other mechanisms (such as CYP3A5 or CYP3A7 compensation for lowered levels of CYP3A4) that affect drug clearance in both men and women.[29]

text: CYP3A4 substrate activation varies amongst different animal species. Certain ligands activate human PXR, which promotes CYP3A4 transcription, while showing no activation in other species. For instance, mouse PXR is not activated by rifampicin and human PXR is not activated by pregnenalone 16α-carbonitrile[30] In order to facilitate study of CYP3A4 functional pathways in vivo, mouse strains have been developed using transgenes in order to produce null/human CYP3A4 and PXR crosses. Although humanized hCYP3A4 mice successfully expressed the enzyme in their intestinal tract, low levels of hCYP3A4 were found in the liver.[30] This effect has been attributed to CYP3A4 regulation by the growth hormone signal transduction pathway.[30] In addition to providing an in vivo model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity.[30]

text: CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.[31] Due to the enzyme's extensive presence in the intestinal mucosa, the enzyme has shown sensitivity to starvation symptoms and is upregulated in defense of adverse effects. Indeed, in fatheaded minnows, unfed female fish were shown to have increased PXR and CYP3A4 expression, and displayed a more pronounced response to xenobiotic factors after exposure after several days of starvation.[31] By studying animal models and keeping in mind the innate differences in CYP3A4 activation, investigators can better predict drug metabolism and side effects in human CYP3A4 pathways.

text: Turnover[edit]

text: Estimates of the turnover rate of human CYP3A4 vary widely. For hepatic CYP3A4, in vivo methods yield estimates of enzyme half-life mainly in the range of 70 to 140 hours, whereas in vitro methods give estimates from 26 to 79 hours.[32] Turnover of gut CYP3A4 is likely to be a function of the rate of enterocyte renewal; an indirect approach based on recovery of activity following exposure to grapefruit juice yields measurements in the 12- to 33-hour range.[32]

text: Technology[edit]

text: Due to membrane-bound CYP3A4's natural propensity to conglomerate, it has historically been difficult to study drug binding in both solution and on surfaces. Co-crystallization is difficult since the substrates tend to have a low Kd (between 5-150 μM) and low solubility in aqueous solutions.[33] A successful strategy in isolating the bound enzyme is the functional stabilization of monomeric CYP3A4 on Ag nanoparticles produced from nanosphere lithography and analyzed via localized surface plasmon resonance spectroscopy (LSPR).[34] These analyses can be used as a high-sensitivity assay of drug binding, and may become integral in further high-throughput assays utilized in initial drug discovery testing. In addition to LSPR, CYP3A4-Nanodisc complexes have been found helpful in other applications including solid-state NMR, redox potentiometry, and steady-state enzyme kinetics.[34]

text: CYP3A4 ligands[edit]

text: Following is a table of selected substrates, inducers and inhibitors of CYP3A4. Where classes of agents are listed, there may be exceptions within the class.

text: Inhibitors of CYP3A4 can be classified by their potency, such as:

text:
Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.[35]
Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.[35]
Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.[35]

text:
Selected inducers, inhibitors and substrates of CYP3A4[36]

Substrates
Inhibitors
Inducers

some immunosuppressants

ciclosporin (cyclosporin)[35][37]
tacrolimus[35][37]
sirolimus[35][37]

many chemotherapeutics

docetaxel[35][37]
tamoxifen[35][37]
paclitaxel[35][37]
cyclophosphamide[37]
doxorubicin[37]
erlotinib[38]
etoposide[37]
ifosfamide[37]
teniposide[37]
vinblastine[37]
vincristine[35]
vindesine[37]
imatinib[35]
irinotecan[35]
sorafenib[35]
sunitinib[35]
vemurafenib[35]
temsirolimus[35]
anastrozole
gefitinib

azole antifungals

ketoconazole[37]
itraconazole[37]

macrolides

clarithromycin[35][37]
erythromycin[35]
telithromycin[35]

(not azithromycin)[35]

dapsone[35] (in leprosy)
tricyclic antidepressants

amitriptyline[37]
clomipramine[37]
imipramine[37]
cyclobenzaprine[39]

SSRIs

citalopram[37]
norfluoxetine[37]
sertraline[37]

some other antidepressants

mirtazapine[37] (NaSSA)
nefazodone[37]
reboxetine[37]
venlafaxine[37] (SNRI)
trazodone[35] (SARI)

buspirone[35][37] (anxiolytic)
antipsychotics

haloperidol[35][37]
aripiprazole[35]
risperidone[35]
ziprasidone[35]
pimozide[37]
quetiapine[35]

opioids (mainly analgesics)

alfentanil[35][37]
buprenorphine[40] (analgesic, addiction maintenance treatment)
codeine[35] (analgesic, antitussive, antidiarrheal)
fentanyl[35]
hydrocodone (partial involvement, not the bioactivation factor)[41]
methadone[35] (analgesic, addiction maintenance treatment)
levacetylmethadol[35]
tramadol (to inactive metabolites, do not confuse with metabolism via CYP2D6)

benzodiazepines

alprazolam[35][37]
midazolam[35][37]
triazolam[35][37]
diazepam[35] (bioactivation to desmethyldiazepam)

some hypnotics

zopiclone[37]
zaleplon[35]
zolpidem[35]

donepezil[37] (acetylcholinesterase inhibitor)
statins

atorvastatin[35][37]
lovastatin[35][37]
simvastatin[37]
cerivastatin[35]

(not pravastatin)[35]
(not rosuvastatin)[35]

calcium channel blockers

diltiazem[35][37]
felodipine[35][37]
nifedipine[35][37]
verapamil[35][37]
amlodipine[35]
lercanidipine[35]
nitrendipine[35]
nisoldipine[35]

amiodarone[37] (class III antiarrhythmic)
dronedarone[37] (class III antiarrhythmic)
quinidine[35] (class I antiarrhythmic)
PDE5 inhibitors

sildenafil[35][37]
tadalafil[42]

kinins[37] (vasodilators, smooth muscle contractors)
sex hormones agonists and antagonists

finasteride[35][37] (antiandrogen)
estradiol[35] (estrogen)
progesterone[35]
ethinylestradiol[37] (hormonal contraceptive)
testosterone[35] (androgen)
toremifene[37] (SERM)
bicalutamide[43]

H1-receptor antagonists

terfenadine[35][37]
astemizole[35][44]
chlorphenamine[35]

Protease inhibitors

indinavir[35][37]
ritonavir[35][37]
saquinavir[35][37]
nelfinavir[35][37]

non-nucleoside reverse transcriptase inhibitors

nevirapine[37]

some glucocorticoids

budesonide[37]
hydrocortisone[35]
dexamethasone[35]

albendazole[45][46] (antihelminthic)
cisapride[35][37] (5-HT4 receptor agonist)
aprepitant[35] (antiemetic)
caffeine[35] (stimulant)
cocaine[35] (stimulant)
cilostazol[35] (phosphodiesterase inhibitor)
dextromethorphan[35] (antitussive)
domperidone[35] (antidopaminergic)
eplerenone[35] (aldosterone antagonist)
lidocaine[35] (local anesthetic, antiarrhythmic)
ondansetron[35] (5-HT3 antagonist)
propranolol[35] (beta blocker)
salmeterol[35] (beta agonist)
warfarin[47] (anticoagulant)
clopidogrel, becoming bioactivated[48] (antiplatelet)
omeprazole[37] (proton pump inhibitor)
nateglinide[35] (antidiabetic)
methoxetamine[49]
montelukast (leukotriene receptor antagonist)

Strong

protease inhibitors

ritonavir[35][37][50]
indinavir[35]
nelfinavir[35]
saquinavir[35]

some macrolide antibiotics[50]

clarithromycin[35][37]
telithromycin[35]

chloramphenicol (antibiotic)[51]
some azole antifungals

ketoconazole[35][37]
itraconazole[35][37]

nefazodone[35][37] (antidepressant)
cobicistat

Moderate

aprepitant[35] (antiemetic)
some calcium channel blockers

verapamil[35]
diltiazem[35]

some macrolide antibiotics

erythromycin[35]

some azole antifungals[50]

fluconazole[35]

bergamottin (constituent of grapefruit juice)[35]
Valerian[52]

Weak

cimetidine[35] (H2-receptor antagonist)
buprenorphine (analgesic)[53]
cafestol (in unfiltered coffee)[54]
orphenadrine
gabapentin
valproic acid[55]

Unspecified potency

amiodarone[35] (antiarrhythmic)
ciprofloxacin[35] (antibiotic)
dithiocarbamate[35] (functional group)
voriconazole[35] (antifungal)
imatinib[35] (anticancer)
mifepristone[35] (abortifacient)
norfloxacin[35] (antibiotic)
some non-nucleoside reverse transcriptase inhibitors[56]

delavirdine[35]

gestodene[35] (hormonal contraceptive)
mibefradil[35] (in angina pectoris)
fluvoxamine[35]
star fruit[35][57]
milk thistle[58]
niacinamide[59]
ginkgo biloba[60]
piperine[61]
isoniazid[62]
quercetin[63]

Strong potency

antiandrogens

Enzalutamide[64]

Unspecified potency

anticonvulsants, mood stabilizers

carbamazepine[35][37][50]
phenytoin[35][37] (anticonvulsant)
oxcarbazepine[35]
topiramate[65]

barbiturates[50]

phenobarbital[35][37]
Butalbital

St. John's wort[35][37]
some bactericidals

rifampicin[35][50]
rifabutin[35][37]

some non-nucleoside reverse transcriptase inhibitors[56]

efavirenz[35]
nevirapine[35]

some hypoglycemics

pioglitazone[35]
troglitazone[35]

glucocorticoids[35] (blood glucose increase, immunosuppressive)
modafinil[35] (stimulant)
quercetin[66]
capsaicin[67]

text: Interactive pathway map[edit]

text: Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

text: Jump up ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP46359".

tag: ol