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Movies Like John Tucker Must Die
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Do you have a void in your life after finishing your favorite movie of all time? Relax and get back on your couch because we have just the perfect films for you! These rom-com movies like John Tucker Must Die will make you giggle and cry with their hilarious scenes and lovely moments. It's no surprise that you've come seeking more. JTMD is just the kind of film that makes you want to see more. For teen girls, the film is amusing and highly relatable. It accurately represents how most teenage girls feel for a guy at one point in their lives, yet do nothing about it. This film, on the other hand, fulfills every girl's fantasy of having a crush.
John Tucker Must Die, a teen rom-com directed by Betty Thomas, was released in 2006. The plot revolves around a man named John (Jesse Metcalfe) who is dating three different girls at the same time. Kate Spencer (Britanny Snow), a waitress at a cafe where he brings every girl he dates, discovers his scheme. After learning the truth, the three girls pledge to exact vengeance. They urge Kate to seduce him first with her cutesy charms, then destroy his heart in the same way he broke theirs. The movie keeps you on edge the entire time and never gets boring. A great movie to watch with friends with the never-getting old cliches.
10 Best Movies Like John Tucker Must Die
The Other Woman
What's Your Number?
After thorough research and binge-watching of rom-com movies, we have gathered just the perfect movies like John Tucker Must Die for you. This list is based on how similar the plot, genre, vibes, overall setting, and etc. is to JTMD. Hopefully one of these will be able to feed your craving!
Released in April 2014, The Other Woman is a classic romantic comedy movie. If you want a similar plot to movies like John Tucker Must Die, this should be your first choice. Critics also call the Other Woman the grown-ups JTMD. From character types to narrative specifics, The Other Woman shares a lot with the 2006 teen film. Both flicks revolve around an extremely similar storyline. Both John Tucker and Mark King from The Other Woman have three different relationships. When the three ladies discover that he is cheating on them all, they band together to exact vengeance.
Moreover, in both films, the plot entails convincing him that nothing is wrong and surreptitiously injecting him with hormones to make him more feminine. Not to forget how both films have a brother as a love interest. Mark's girlfriend, Carly, is taken aback when she hears about his marriage with another woman. Kate, his wife, is introduced to her and the two become fast friends. Kate, on the other hand, learns of Mark's affair with Amber. The three women then decide to teach Mark a lesson by teaming up. If you are looking for a good laugh and relatable movie with a similar plot to John Tucker Must Die, this one is definitely for you.
The film, Mean Girls, is a classic teen movie to which almost every girl can relate at some point. It is probably the chickiest of all chick flicks. This film is completely believable and relatable. Every single one of those characters may be a genuine person. The film depicts today's youth and describes what high school is really like. It explains everything but in a more entertaining and watchable manner. It's extremely quotable, with quotes that will never go out of style. It's amusing, quotable, realistic, and non-dramatic. If you like watching the high-school cliches in movies like JTMD, this is the one for you!
Mean Girls was released in 2004 and received a lot of great feedback. With a rating of 84% on Rotten Tomatoes and 89% on Google, it is safe to say that the movie is quite a big hit. Cady, an adolescent, begins a new school and quickly finds herself in trouble. It all begins when she falls in love with Regina's ex-boyfriend, the harsh and popular girls' leader at the school. The group of mean girls bully Cady and makes her life a living hell. Cady tries to make high school bearable with the help of her two friends, Janis and Damian. Learn how they deal with the school's mean females by watching the film.
Just Friends Movie
Looking for movies like JTMD to help you make the most of your vacation? If that's the case, you should watch Just Friends. It's not only funny, but it also has an excellent plot that will keep you engaged throughout. Just Friends is a romantic comedy directed by Roger Kumble and released in 2005. Young Ryan Reynolds plays Chris Brander, while Amy Smart plays Jamie Palamino in the film. The movie plot revolves around an obese and unpopular high school guy and his hardships in getting the one he loves.
As Chris faces the struggle of being obese, he develops a secret crush on his best friend, Amy. After mustering up all the courage he had, Chris finally decides to confess to her by writing his feelings in her yearbook. However, Amy's ex-boyfriend, Tim, reads Chris's feelings out loud to which Amy rejects breaking Chris's heart. After getting hurt badly, he vows to become so successful and prove himself to the world.
Just Friends is the ideal film for everyone who can't take themselves seriously and has been injured by a romantic interest. Even if you watch it over and over, you will never grow bored. This film contains a lot more heart than you'd anticipate from actors who had previously appeared in American Pie, Waiting, and Scary Movie. It isn't obscene in any way. It's also hilarious from beginning to end.
If you want to watch some high school romance with some beautiful friendships in movies like John Tucker is Bad, LOL is the one for you. Lol is a 2012 movie having the setting of an era where social media is at its peak. The movie greatly depicts a life of a spoiled teen girl who fights with her adolescent problems with the help of her best friends.
The acting in the film is excellent. Miley looks incredibly stunning in it. Furthermore, the connections are so lovely and genuine that they will give you butterflies. It accurately reflects many of the feelings that teenagers and adults experience. Also, It's not like any other cliché teen or girl film. Definitely not for action junkies, but a nice romantic film for adults and mature teenagers. The movie has a great plot and some extremely beautiful special moments. Lastly, It's a great movie to watch when you're feeling down in the dumps. If you're feeling down, turn on the television and start watching LOL. I promise you'll feel better.
The film, Picture This, a Metro-Goldwyn-Mayer production, was released on July 13, 2008. It's a family film with a romantic comedy plot that falls into the same category as movies like John Tucker Must Die. Even though critics have trashed the film, it boasts an above-average rating on Rotten Tomatoes and Google reviews. Stephen Herek, who directed numerous hit vintage 90s films, is the director of this film.
The plot follows Mandy (Ashley Tisdale), an average high school student who falls in love with Drew Patterson, the hottest man in her school (Robbie Amell). She gets a date to the school's biggest party of the year. However, the film takes a turn for the better when her father, Mr. Tom (Kevin Pollak), orders her to be grounded on the day of the event. Mandy decides to sneak out of her house with the help of her best friends, Alexa and Cayenne, who are frustrated by the change of circumstances. Join Mandy on her exciting day by watching the film.
Tisdale from High School Musical is adorable and brilliant, and she shines in this part as the lovably irrepressible Mandy, who always seems to rise above adversity. Though portraying Tisdale throws her heart and her into the part and manages to make the story convincing. Teens will like the amusing take on high school social structure and will root for Mandy and her friends as she defies the popularity scale and distinguishes herself from the bossy popular kids simply by being loyal to her heart.
Released in 2011, What's Your Number makes into the list of movies like John Tucker Must Die by giving the same fuzzy feeling to the audience. The movie is directed by Mark Mylod who is known for directing the popular series Game of Thrones and the hit movie Succession (2018). Moreover, the film is adapted from a book called 20 Times a Lady. It has a very decent rating of 6.1/10 on IMDB and 4.2/5 on Google Reviews.
Ally Darling (Anna Faris), the female character in the film, is suffering from heartbreak after her 19th lover dumps her. When Ally comes across a strange magazine called "What's Your Number?" that claims that women who have had more than 20 boyfriends are less likely to find a husband, she becomes concerned that this could be her final chance to find a loving partner. In order to discover true love, Ally begins calling her ex-boyfriends in the hopes that one of them will become her husband.
This movie is absolutely hilarious just like John Tucker Must Die, this will make you cry from laughter. Furthermore, the chemistry between Evans and Faris is obvious from the start. Their humorous timing complements one another, and they appear to be a fantastic match on television. Anna Faris has a terrific sense of humor, and I guarantee you'll be rolling on the floor laughing at her fake British accent in the film. Overall, it's precisely what you'd expect from a Romantic Comedy. On a day when you don't have much to do, the movie will be a great source of entertainment.
10 Things I Hate About You Movie
The movie, 10 Things I Hate About You is a cult classic movie that had its release in 1999. Ever since its airing, the movie 10 Things I Hate About You keeps on gaining more fans similar to other movies like John Tucker is Bad. These cult classics, romantic comedy movies are the best way to have fun at weekends and sleepovers. The best thing about such movies is how relatable they are to teenagers of every generation.
The story follows Cameron James (Joseph Gordon Levitt), a high school boy who falls in love with Bianca Stratford right away (Larisa Oreynik). Bianca, on the other hand, is unable to date until her older sister, Kat Stratford (Julia Stiles), does. Kat is an antisocial individual who despises males as a result of her horrific experiences with her ex. Hence, Cameron devises a plan to seduce Kat into falling in love with a strange man named Patrick Verona (Heath Ledger).
This film is one of the most well-known and genre-defining Rom Coms of all time. 10 Things I Hate About You, which came released during the height of the Rom-Com movie era in the late 1990s and early 2000s, encapsulates everything such films tried (and frequently failed) to achieve. It's humorous, touching, and intelligent, with references that are both highbrow and approachable. It finds moments of passionate longing, true connection, and even meaningful social commentary in a genre that is often considered meaningless. It juxtaposes the cheesiness and cliches of Rom Coms with the snobbery and elitism so frequently associated with Shakespeare, mocking and celebrating them both at the same time.
The movie Clueless is another one of cult classic rom-com teen movies like John Tucker Must Die that will keep you on edge the entire time. The movie had its release in 1995, however, it is still relatable to teens nowadays. It is without a doubt one of the greatest girls flick ever filmed. The film is difficult to forget and leaves a pleasant aftertaste that makes you desire more. It's a narrative that every adolescent going through their senior year can relate to.
The movie is written and directed by Amy Heckerling known for writing commercially successful movies. Immediately after its release, Clueless became one of the most successful teen films of its time. The movie has an amazing rating on many movie critic sites such as rotten tomatoes and IMDB. If you are looking for some teen movies with good female friendships, you have to watch this film.
The story revolves around Cher, an affluent adolescent, and her high school experiences. Cher's status as a rich youngster immediately draws everyone's attention. Cher, on the other side, resolves to help a new student who is nearly unnoticeable become popular, in contrast to other high school girls. While dealing with her high school issues, Cher meets the love of her life. Check out the movie to see how Cher fights for her love.
Looking for incredibly hilarious movies like John Tucker Must Die? Then, here you go! Whatever It Takes has everything it takes to be a perfect teen comedy movie. Notice the pun? Hope it was not so bad haha! Anyways, Whatever it takes is an amazing movie to watch on weekend with your friends or lover. If you are a teen, you may find yourself relating to a lot of things. And, if you are an adult, Whatever it takes is the best movie to watch to remind yourself of your teen days.
Because the film was released in 2000, you may find it a little dated and tacky. Nonetheless, you can not deny how hilarious and intriguing the movie is. The plot involves Ryan (Shane West), who falls in love with Ashley (Jodi Lyn O'Keefe), a hot girl from his school. However, he is unaware that Maggie (Marla Sokoloff), his female best friend for life, has a crush on him. Things become much more complex when Chris (James Franco), a prominent jock, develops feelings for Maggie. There isn't even a love triangle in this film; it's a complete square!
It's an outrageously hilarious film that will make you laugh so hard you'll cry. Not to mention how the gripping plot will keep you on the edge the entire time! Furthermore, James Franco's outstanding performance in this film was the icing on the cake. You must see this film at least once in your life!
Movies like John Tucker Must Die are so refreshing that they will cheer you up no matter how sad you are. One of such movies is Sleepover. Released in 2004, Sleepover is a family romantic comedy movie directed by Joe Nussbaum. It's about a bunch of young teenage females coming of age as freshmen in high school having the "ideal" rebellious night. This film will portray friendship, love, and frenemies in the best possible light. It may appear cheesy due to the time gap as it was released in 2004, but it is an incredibly sincere film. This is the one for you if you enjoy seeing girls team up together to exact vengeance on others. Moreover, the cast is very attractive so trust you will not be disappointed.
The plot follows a group of four rebellious best friends, Julie (Alexa Pena Vega), Hannah (Mika Boorem), Yancy (Kallie Flynn Childress), and Farrah (Scout Taylor Compton). It all starts when they are challenged to a scavenger expedition by a bunch of prominent cruel girls led by Stacy Blake (Sara Paxton). The four BFFs decide to spend the night at Julie's house, from which they sneak out for the hunt and unwittingly go on the most incredible trip of their lives.
These ten films are your best bet if you're looking for something to fill the JTMD-shaped hole in your heart. These will make you get tears from laughter and give you butterflies both at the same time.
In summary, the top ten mind-blowing movies like John Tucker is Bad to watch are as follows:
What's Your Number
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Features, Opinion
A Look Back at the Romanian Revolution: Could the Same Thing Happen in Russia?
Marta R., 8 months ago 3 8 min read
Russian woman waves her handkerchief, as a sign of peace, to the police, during the Russian protests; Sefa Karacan / Anadolu Agency / Getty
https://thebite.aisb.ro/author/marta-r/
Bucharest's run-down buildings: the silent testimony of decades of neglect
In January, an estimated 40,000 people gathered in the streets of central Moscow, protesting against the jailing of Russian opposition leader, Alexei Navalny. In the months since, thousands of demonstrators have been arrested by riot police, and Navalny went on a 24-day hunger strike—only fueling tensions and outrage.
A little over thirty years ago, a similar situation unfolded in Romania. After 21 years of living under a tyrannical dictator, Nicolae Ceaușescu, citizens were impoverished and oppressed. Protests demanding an end to communist rule spread throughout the country, and eventually ended with the execution of Ceaușescu and his wife on national television.
With Russian protests demanding an end to a similarly autocratic government, can we predict a similar outcome to Romania's revolution?
The Russian protests, explained
Russian protestors clash with police; Sergey Ponomarev for The New York Times.
As we begin to unravel the timeline of the protests in Russia, it is essential to identify Alexei Navalny as one of the key characters involved in the events. The 44-year-old Russian lawyer has been an opposition leader for over 20 years, protesting against the governing party and its ways. In 2018, he refounded "Russia of the Future," the main Russian political opposition party, and has run for public positions such as the mayor of Moscow.
"Gandhi did it in his day, as did Martin Luther King…Humanity has this historical experience of fighting injustice and tyranny." —Navalny on his activism.
Navalny became known on an international level when he was left in a coma in August of 2020, poisoned. Shortly after, he was transferred to a hospital in Berlin, where he received treatment and recovered. The reason for his hospitalization was attributed to a Novichok agent poisoning (a lethal poison developed by the Soviet Union and Russia between the 1970s and 90s). Navalny's battle with Putin, the current Russian president, became deeply personal when he accused the leader of ordering the attack.
Although heavy and serious, many have supported Navalny's accusation, pressing countries and organizations to take the necessary sanctions against Russian officials. Therefore, when NATO (North Atlantic Treaty Organization) urged Russia to offer a transparent and just investigation into Navalny's poisoning, even greater importance was brought to the issue. It was considered a threat to global security, as it breached international laws regarding the use of any chemical weapons.
Yet, after regaining his health in Germany and planning his next moves, Navalny returned to Moscow on the 17th of January. He was immediately detained by the police and taken into custody, triggering protests all over Russia. Then, when he was sentenced to two-and-a-half years in jail on February 2nd, even more people gathered on the streets. The sentence was due to the violation of his parole from a 2014 case, which was deemed, at the time, as "arbitrary and unreasonable" by the ECHR (European Court of Human Rights).
The protests took a violent turn when the police acted with force on the crowds. A few thousands were then arrested and detained for participating in the gatherings, as the violence spread. This, in combination with the lack of immediate results that could be obtained, meant that protests died down. However, the fight didn't end there, with Navalny now recovering from an almost month-long hunger strike. Even though he is still jailed, his team has continued to fight for his release, even organizing large rallies last month, in an active call to the government.
A look at the Romanian Revolution: Why did it succeed?
In Romania, after more than 40 years of the communist rule, in mid December of 1989, people began gathering on the streets of the city of Timișoara. They expressed their dissatisfaction with the government and its actions and were fighting for the fall of the communist regime. The similar shifts of power in neighboring countries set the stage for the Romanians, bringing hope of real progress.
A man holds up the Romanian flag with its communist symbol torn out, on the balcony of the Ministry of Internal Affairs, where Ceaușescu held his last speech, photo courtesy of protv.ro.
After the protests began in Timișoara, they quickly spread throughout the country in cities like București, Sibiu, Cluj-Napoca and Brașov. And on December 21st, when Nicolae Ceaușescu, the former communist leader of Romania, attempted to deliver a speech to a crowd in Bucharest, it was clear a revolution was in the works.
What followed was a violent fight between protestors and Romanian officials, as they began using military force on the crowds.
AISB Romanian Teacher Ioana Nanu recalls that night, when her father got home from work. "He came in, crying, I remember clearly," she says. "He was so impressed [by] what he had seen on the streets."
The next day, on December 22nd, more than 100,000 angry protestors gathered outside the Communist Party Headquarters and forced their way inside. It's suspected that the army refused to hold back the mob and that Stănculescu, the Minister of Defense, took the protestors' side, but he's since refuted this fact. Regardless, Romanians found power in numbers and Ceaușescu fled the city by helicopter.
Could the same thing happen in Russia?
Although there are considerable differences between the Russian protests and the Romanian Revolution, understanding the "successes" Romanian protestors experienced 30 years ago gives us an idea of what could happen in Russia if opposition activists continue to mobilize.
It becomes clear, as we begin to think about the parts of an uprising, that there are two distinct stages that need to be achieved in order for it to result in change: outrage among a large group of people, and a calculated opposition. Real change begins when people refuse to be silenced any longer.
Amplifying the voice of the people into real change is the step that naturally follows. In the case of the Romanian Revolution, the army's refusal to follow Ceaușescu's orders ultimately overthrew the government. Yet, apart from that possibility, how else can change be materialized?
Navalny meets with some of his supporters, during his 2018 presidential campaign; James Hill for the New York Times.
Although not the case in most movements, the Russian protests have a very clear face: Navalny. As mentioned before, the opposition leader has a strong team of people backing the movement, along with a political party. So, if there was a moment where the Russian government were to collapse, the opposition would be ready to step in. This is one of the things that could ensure success, as it would offer an alternative to the current government, dodging the chaos which would otherwise unfold due to a lack of structure.
Additionally, Navalny plays the role of a public inspiration, something that most protests, including the Romanian Revolution, lacked. As he has proved time and time again, his courage seems limitless and he is willing to risk everything for what he believes in.
Many have asked themselves why he came back to Russia when he knew he would be arrested. AISB Humanities Teacher Joshua Giddens puts it simply: "If you want to change things, you have to be willing to take a blow."
For Giddens, Navalny appears like a revolutionary, a modern-day Gandhi. And, for Russian people, having such a clear leader may bring hope and, consequently, a more calculated fight.
Media: A blessing or a curse?
Although we may be inclined to believe that the media didn't have a big role to play during the Romanian Revolution, historians argue that it was one of the determining factors in triggering change. However, the defining element of a totalitarian regime is that it monopolizes the economy and, therefore, all of the media. So, how did the Romanians of 1989 stay in touch with what was going on?
Apart from the controlled television shows prepared by the government, it is estimated that 70% of citizens over 15 listened to "Radio Europa Liberă" (Radio Free Europe). A foreign radio station, it streamed shows in Eastern Europe and was supported by Voice of America, BBC and DW/DLF.
They began covering the events in Timișoara, gathering valuable testimonies that slowly revealed the bigger picture. Seeing the brave acts people were beginning to take, Romanians all over the country gathered their courage and joined the movement.
So, if the media was so powerful 30 years ago, its effects now, in an era of digital communication, could be even greater.
Campaign workers and staff during Navalny's mayoral campaign in 2013; Sergey Ponomarev for The New York Times.
Therefore, it comes as no surprise that once Navalny posted the "Putin's Palace" documentary, about the Russian President's alleged $1 billion Black Sea Coast residence, the millions of people that watched it were even more determined to continue the protests and turn up in larger numbers. This proved that one of the greatest powers of social media remains the ease with which information is spread, reaching millions.
Ultimately, social media manages to trigger the first part of the change, where people begin to speak up. However, what draws people in, the feelings of involvement and purpose, are, paradoxically, what stunts a movement's growth.
Yes, social media ensures that information reaches many, but it produces an army of individuals. Everyone becomes their own small leader, involved in the movement, but not truly invested in fighting for the change. As an initiative loses its momentum, people disperse, leaving back the few who had always been there. So, in reality, although social media is a double-edged sword, its value should not be disregarded.
As the movement in Russia evolves, seemingly without measurable results, we have to remember that not all forms of success look the same and that progress is built gradually. Only when we acknowledge that the doorway towards change is in front of us, can we begin the fight.
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Jennifer Stevens
Wow, what a sophisticated article, Marta! It's really interesting to compare protests around the world to understand how change is acquired. It's amazing how quickly people around Romania mobilized and how quickly it became a revolution. It was also interesting to consider how this might have been different today, with the addition of social media.
8 months ago	Reply
I love this perspective. It's crazy to think how differently things spread in the past and now with the addition of social media. Extremely well-written, amazing job Marta.
I found this article very well-written and quite thought-provoking, Marta. I wonder if some Russians are also looking at the parallels (and differences) you mention between the protests going on now in their country and the ones in Romania in 1989 (as well as, perhaps, some of the more recent ones after the "Collectiv" tragedy). I do wonder, though, as to your point about possible support for protestors within Ceausescu's government, whether Putin has the same "weakness." I suppose time will tell. In any case, kudos for your work on this.

redpajama_set_name: RedPajamaCommonCrawl


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Structure, function and pharmacology of human itch GPCRs
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Chengwei Zhang3,
Wenlei Ye ORCID: orcid.org/0000-0002-4694-14934,
Byron W. Hayes5,
Jing Liu ORCID: orcid.org/0000-0003-4740-243X3,
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Brian J. Bender2,
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Jian Jin ORCID: orcid.org/0000-0002-2387-38623,
Brian K. Shoichet ORCID: orcid.org/0000-0002-6098-73672,
Jonathan F. Fay ORCID: orcid.org/0000-0003-1822-23848 &
Bryan L. Roth ORCID: orcid.org/0000-0002-0561-65201
Nature volume 600, pages 170–175 (2021)Cite this article
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The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2,3,4,5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.
Fig. 1: Cryo-EM structures of MRGPRX2 complexes.
Fig. 2: G-protein coupling of MRGPRX2.
Fig. 3: Discovery of MRGPRX2-selective inverse agonists.
Fig. 4: Agonist discovery and the cryo-EM structure of MRGPRX4.
The coordinate and cryo-EM map of MRGPRX2–Gq–cortistatin-14, MRGPRX2–Gi1–cortistatin-14, MRGPRX2–Gq–(R)-ZINC-3573, MRGPRX2–Gi1–(R)-ZINC-3573 and MRGPRX4–Gq–MS47134 have been deposited to PDB (EMDB) with accession codes 7S8L (EMD-24896), 7S8M (EMD-24897), 7S8N (EMD-24898), 7S8O (EMD-24899) and 7S8P (EMD-24900), respectively. The cryoEM micrographs of MRGPRX4–Gq–MS47134, MRGPRX2–Gq–cortistatin-14, MRGPRX2–Gq–(R)-ZINC-3573, MRGPRX2–Gi1–cortistatin-14 and MRGPRX2–Gi1–(R)-ZINC-3573 have been deposited in the EMPIAR database (https://www.ebi.ac.uk/empiar/) with accession numbers EMPIAR-10852, EMPIAR-10853, EMPIAR-10854, EMPIAR-10855 and EMPIAR-10856, respectively. The MRGPRX2 antagonist C9 and C9-6 and negative control C7, and the MRGPRX4 agonist MS47134 and negative control X2-2 will be made available via Sigma-Millipore.
Zylka, M. J., Dong, X., Southwell, A. L. & Anderson, D. J. Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family. Proc. Natl Acad. Sci. USA 100, 10043–10048 (2003).
CAS PubMed PubMed Central ADS Google Scholar
McNeil, B. D. et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519, 237–241 (2015).
CAS PubMed ADS Google Scholar
Green, D. P., Limjunyawong, N., Gour, N., Pundir, P. & Dong, X. A mast-cell-specific receptor mediates neurogenic inflammation and pain. Neuron 101, 412–420.e413 (2019).
Yu, H. et al. MRGPRX4 is a bile acid receptor for human cholestatic itch. eLife 8, e48431 (2019).
Meixiong, J., Vasavda, C., Snyder, S. H. & Dong, X. MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus. Proc. Natl Acad. Sci. USA 116, 10525–10530 (2019).
Chompunud Na Ayudhya, C., Roy, S., Alkanfari, I., Ganguly, A. & Ali, H. Identification of gain and loss of function missense variants in MRGPRX2's transmembrane and intracellular domains for mast cell activation by substance P. Int. J. Mol. Sci. 20, 5247 (2019).
PubMed Central Google Scholar
Ikoma, A., Steinhoff, M., Stander, S., Yosipovitch, G. & Schmelz, M. The neurobiology of itch. Nat. Rev. Neurosci. 7, 535–547 (2006).
Greaves, M. W. & Wall, P. D. Pathophysiology of itching. Lancet 348, 938–940 (1996).
Liu, Q. et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139, 1353–1365 (2009).
Lembo, P. M. et al. Proenkephalin A gene products activate a new family of sensory neuron–specific GPCRs. Nat. Neurosci. 5, 201–209 (2002).
Azimi, E. et al. Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight 1, e89362 (2016).
Kroeze, W. K. et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22, 362–369 (2015).
Lansu, K. et al. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat. Chem. Biol. 13, 529–536 (2017).
Subramanian, H. et al. β-Defensins activate human mast cells via Mas-related gene X2. J. Immunol. 191, 345–352 (2013).
Olsen, R. H. J. et al. TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat. Chem. Biol. 16, 841–849 (2020).
English, J. G. et al. VEGAS as a platform for facile directed evolution in mammalian cells. Cell 178, 748–761.e717 (2019).
Wacker, D. et al. Structural features for functional selectivity at serotonin receptors. Science 340, 615–619 (2013).
Lu, L., Kulka, M. & Unsworth, L. D. Peptide-mediated mast cell activation: ligand similarities for receptor recognition and protease-induced regulation. J. Leukoc. Biol. 102, 237–251 (2017).
Che, T. et al. Structure of the nanobody-stabilized active state of the kappa opioid receptor. Cell 172, 55–67.e15 (2018).
Che, T. et al. Nanobody-enabled monitoring of kappa opioid receptor states. Nat. Commun. 11, 1145 (2020).
Rasmussen, S. G. F. et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477, 549–555 (2011).
Rosenbaum, D. M. et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318, 1266–1273 (2007).
Ogasawara, H., Furuno, M., Edamura, K. & Noguchi, M. Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells. J. Leukoc. Biol. 106, 1069–1077 (2019).
Shinkai, H. et al. N-(cyclohexylcarbonyl)-d-phenylalanines and related compounds. A new class of oral hypoglycemic agents. 2. J. Med. Chem. 32, 1436–1441 (1989).
Irwin, J. J. & Shoichet, B. K. ZINC–a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model. 45, 177–182 (2005).
Meixiong, J. et al. Identification of a bilirubin receptor that may mediate a component of cholestatic itch. eLife 8, e44116 (2019).
Azimi, E., Reddy, V. B. & Lerner, E. A. Brief communication: MRGPRX2, atopic dermatitis and red man syndrome. Itch (Phila) 2, e5 (2017).
Chen, E. et al. Inflamed ulcerative colitis regions associated to MRGPRX2-mediated mast cell degranulation and cell activation modules, defining a new therapeutic target. Gastroenterology 160, 1709–1724 (2021).
Kozlitina, J. et al. An African-specific haplotype in MRGPRX4 is associated with menthol cigarette smoking. PLoS Genet. 15, e1007916 (2019).
Li, Z. et al. Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain. Proc. Natl Acad. Sci. U.S.A. 114, E1996–E2005 (2017).
Thapaliya, M., Chompunud Na Ayudhya, C., Amponnawarat, A., Roy, S. & Ali, H. Mast cell-specific MRGPRX2: a key modulator of neuro-immune interaction in allergic diseases. Curr. Allergy Asthma Rep. 21, 3 (2021).
Kim, K. et al. Structure of a hallucinogen activated Gq-coupled 5-HT2a serotonin receptor. Cell 182, 1574–1588.e1519 (2020).
Draper-Joyce, C. J. et al. Structure of the adenosine-bound human adenosine A1 receptor-Gi complex. Nature 558, 559–563 (2018).
Koehl, A. et al. Structure of the µ-opioid receptor–Gi protein complex. Nature 558, 547–552 (2018).
Mastronarde, D. N. Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 152, 36–51 (2005).
Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).
Punjani, A., Zhang, H. & Fleet, D. J. Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction. Nat. Methods 17, 1214–1221 (2020).
Bepler, T., Kelley, K., Noble, A. J. & Berger, B. Topaz-Denoise: general deep denoising models for cryoEM and cryoET. Nat. Commun. 11, 5208 (2020).
Rosenthal, P. B. & Henderson, R. Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy. J. Mol. Biol. 333, 721–745 (2003).
Heymann, J. B. & Belnap, D. M. Bsoft: image processing and molecular modelling for electron microscopy. J. Struct. Biol. 157, 3–18 (2007).
Sanchez-Garcia, R. et al. DeepEMhacer: a deep learning solution for cryo-EM volume post-processing. Commun. Biol. 4, 874 (2021).
Grant, T., Rohou, A. & Grigorieff, N. cisTEM, user-friendly software for single-particle image processing. eLife 7, e35383 (2018).
Xing, C. et al. Cryo-EM structure of the human cannabinoid receptor CB2–Gi signaling complex. Cell 180, 645–654.e613 (2020).
Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004).
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).
Robertson, M. J., van Zundert, G. C. P., Borrelli, K. & Skiniotis, G. GemSpot: a pipeline for robust modeling of ligands into cryo-EM maps. Structure 28, 707–716.e703 (2020).
Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010).
Besnard, J. et al. Automated design of ligands to polypharmacological profiles. Nature 492, 215–220 (2012).
Longo, P. A., Kavran, J. M., Kim, M. S. & Leahy, D. J. Transient mammalian cell transfection with polyethylenimine (PEI). Methods Enzymol. 529, 227–240 (2013).
This work was supported by NIH grants U24DA116195 (to B.L.R., B.K.S. and J.J.) and R35GM122481 (to B.K.S.), and by the Michael Hooker Distinguished Professorship to B.L.R. and NIH grant R01-DK121969, R01-DK121032 and R56-AI139620 to S.N.A. We thank J. Peck and J. Strauss of the UNC Cryo-EM Core Facility for technical assistance in this project. W.Y. is partly supported by Program for Breakthrough Biomedical Research funded by the Sandler Foundation, University of California, San Francisco. L.Y.J. is a Howard Hughes Medical Institute investigator. We thank S.-L. Shyng for the plasmids encoding human Kir6.2 and SUR1. The Titan X Pascal used for this research was kindly donated to J.F.F. by the NVIDIA Corporation.
John D. McCorvy
Present address: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
Justin G. English
Present address: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
These authors contributed equally: Can Cao, Hye Jin Kang
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
Can Cao, Hye Jin Kang, Ryan H. Gumpper, Samuel T. Slocum, Brian E. Krumm, Katherine Lansu, John D. McCorvy, Wesley K. Kroeze, Justin G. English, Jeffrey F. DiBerto, Reid H. J. Olsen, Xi-Ping Huang, Shicheng Zhang, Yongfeng Liu, Kuglae Kim & Bryan L. Roth
Department of Pharmaceutical Sciences, University of California San Francisco, School of Medicine, San Francisco, CA, USA
Isha Singh, Brian J. Bender, Joel Karpiak & Brian K. Shoichet
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
He Chen, Chengwei Zhang, Jing Liu & Jian Jin
Department of Physiology, University of California, San Francisco, San Francisco, CA, USA
Wenlei Ye & Lily Y. Jan
Department of Pathology, Duke University Medical Center, Durham, NC, USA
Byron W. Hayes & Soman N. Abraham
Howard Hughes Medical Institute, San Francisco, CA, USA
Lily Y. Jan
Program in Emerging Infectious Diseases, Duke–National University of Singapore, Singapore, Singapore
Soman N. Abraham
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
Jonathan F. Fay
Can Cao
Hye Jin Kang
Isha Singh
He Chen
Chengwei Zhang
Wenlei Ye
Byron W. Hayes
Jing Liu
Ryan H. Gumpper
Brian J. Bender
Samuel T. Slocum
Brian E. Krumm
Katherine Lansu
Wesley K. Kroeze
Jeffrey F. DiBerto
Reid H. J. Olsen
Xi-Ping Huang
Shicheng Zhang
Yongfeng Liu
Kuglae Kim
Joel Karpiak
Jian Jin
Bryan L. Roth
C.C. designed the experiments, performed the cloning, expression and purification of all the signalling complexes for cryo-EM study, built the models, refined the structures, performed BRET assays, participated in MRGPRX4 drug screening, analysed the data, and prepared the figures, tables and manuscript. H.J.K. designed experiments, performed drug screening and functional assays, analysed the data and assisted in preparing the manuscript, and reviewed and edited the manuscript. J.F.F. made the grids, and collected and processed the cryo-EM data. I.S. performed the SAR study for MRGPRX2. H.C., C.Z. and J.L. performed the SAR study for MRGPRX4, and designed, synthesized and characterized the MRGPRX4 agonists. W.Y. performed electrophysiology for Kir6.2/SUR1. R.H.G. assisted in the modelling and validation of structures. B.W.H. performed the LAD2 mast cell degranulation assay. B.J.B. assisted in the structure modelling. J.K. supported agonist discovery and optimization for MRGPRX4. S.T.S. performed the GPCRome assay. B.E.K. designed the Gq protein construct and assisted in the reviewing and editing of the manuscript. K.L., J.D.M., W.K.K., J.F.D. and R.H.J.O. performed the initial screening for MRGPRX4 compounds. J.G.E., X.-P.H. and Y.L. helped with the initial functional assays. S.Z. and K.K. assisted in the protein expression. S.N.A. guided the LAD2 mast cell degranulation assay. J.J. supervised the medicinal chemistry experiments. B.K.S. supervised the docking and compound design and edited the manuscript. L.Y.J. contributed to funding application. B.L.R. supervised the entire project, guided the structural and functional work and prepared the manuscript.
Correspondence to Brian K. Shoichet, Jonathan F. Fay or Bryan L. Roth.
A patent describing the MRGPRX2 antagonists has been filed by UCSF listing B.L.R., B.K.S., C.C., I.S. and H.J.K. as inventors.
Peer review information Nature thanks the anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
Extended Data Fig. 1 MRGPRX2 transducerome screening using TRUPATH.
a, MRGPRX2 effectively couples to 14 distinct G proteins upon stimulation of agonists (R)-ZINC-3573 and cortistatin-14 (C-14) in HEK 293T cells. Net BRET values of MRGPRX2 together with positive controls of either neurotensin receptor 1 (NTSR1, agonist NT1-13) or β2AR (agonist isoproterenol) are shown in each panel. Data represent mean ± s.e.m. of n = 3 biological replicates. b, Heatmap of the relative log potency (logEC50) of (R)-ZINC-3573 and cortistatin-14 for 14 distinct G proteins. c, Heatmap of the relative efficacy (Emax) of (R)-ZINC-3573 and cortistatin-14 for 14 distinct G proteins.
Extended Data Fig. 2 CryoEM images and data-processing of MRGPRX2-Gq-(R)-ZINC-3573, MRGPRX2-Gi1-(R)-ZINC-3573 and MRGPRX4-Gq-MS47134 complex.
a–c, Representative motion corrected cryo-EM micrographs (scale bar, 100 nm) of respective ligand bound GPCR heterotrimeric complex particles imaged at a nominal 45k x magnification and representative two-dimensional class averages. The experiment was repeated three times with similar result. The exact number of movies and particles used for each complex are shown in the flow chart. d–f, Flow chart of cryo-EM data processing, GSFSC plot of auto-masked final map (black) and map-to-model real-space cross correlation (red) as calculated form phenix.mtriage. g–i, Respective polar plots of particle angular distributions and local resolution estimations heat maps. j–l, Local cryo-EM density maps of TM1-7, respective ligands, and α5 and αN helix of respective G-protein.
Extended Data Fig. 3 CryoEM images and data-processing of MRGPRX2-Gq-Cortistatin-14 and MRGPRX2-Gi1-Cortistatin-14 complex.
a, b, Representative motion corrected cryo-EM micrograph (scale bar, 100 nm) of MRGPRX2 G-protein cortistatin-14 (C14) particles imaged at a nominal 45k x magnification and representative two-dimensional class averages. The experiment was repeated three times with similar result. The exact number of movies and particles used for each complex are shown in the flow chart. c, d, Flow chart of cryo-EM data processing. GSFSC plot of auto-masked final map (black) and map-to-model real-space cross correlation (red) as calculated form phenix.mtriage. e, f, Viewing direction distribution and local resolution estimation heat maps. g, h, Local cryo-EM density maps of TM1-7, Cortistatin-14 ligand, α5 and α N helix of respective G-protein. Also shown inset are residues W151 and F82 of the b-subunit (blue).
Extended Data Fig. 4 Structural comparison of Gq- and Gi1-coupled MRGPRX2 complex.
a, b, Structural comparison of the MRGPRX2-Gi1-cortistatin-14 complex (blue) with MRGPRX2-Gq-cortistatin-14 complex (cyan). Top view for the key interactions in sub-pocket 1 (a). Side view to show the overall conformational of cortistatin-14 (b). c–e, structural comparison of MRGPRX2-Gi1-(R)-ZINC-3573 complex with MRGPRX2-Gq-(R)-ZINC-3573 complex. Gi1 and Gq are shown in green and salmon, respectively. Gi1-coupled MRGPRX2 and Gq-coupled MRGPRX2 are shown in blue and cyan, respectively. Side view of the whole complex (c), top view (d) and bottom view (e) of MRGPRX2. f, ICL3 of Gq is not clearly resolved in the Gq-coupled MRGPRX2 complex. g, Close-up view of the ICL3 in the Gi1-coupled MRGPRX2 structure with surrounding EM map at a threshold of 0.14. h, i, MRGPRX2 ICL3 mutations R214ICL3A and L216ICL3A impair cortistatin-14 (h) and (R)-ZINC-3573 (i) stimulated Gi1 activation. Data represent mean ± s.e.m. of n = 3 biological replicates. j, k, BRET2 Gi1 assays reveal that I135ICL2A mutation of MRGPRX2 attenuates cortistatin-14 (j) and (R)-ZINC-3573 (k) stimulated Gi1 activation. Data represent mean ± s.e.m. of n = 3 biological replicates. l–m, BRET2 Gq assays reveal that I135ICL2A mutation of MRGPRX2 greatly reduced cortistatin-14 (l) and (R)-ZINC-3573 (m) stimulated Gq activation. Data represent mean ± s.e.m. of n = 3 biological replicates.
Extended Data Fig. 5 Non-conserved motifs in Mas-related GPCRs and the critical role of acidic residues E1644.60 and D1845.38 in MRGPRX2 activation.
a, Sequence alignment of the key residues in sodium site, DRY motif, PIF motif and CWxP motif, as well as residues involved in disulfide bond formation in Mas-related GPCRs. Class A conserved residues are highlighted in green. b, cryoEM map of the TM4-TM5 disulfide bond in MRGPRX2-Gq-(R)-ZINC-3573 complex. c, d, Break of the TM4-TM5 disulfide bond by C1684.64A and C1805.34A mutations abolishes the cortistatin-14 stimulated Gq activation (c) and reduces the Emax of (R)-ZINC-3573 stimulated Gq activation by 60% (d). Data represent mean ± s.e.m. of n = 3 biological replicates. e–g, Compared with WT (e), E1644.60A (f) and D1845.38A (g) totally abolish the peptide stimulated Gq activation of MRGPRX2. Data represent mean ± s.e.m. of n = 3 biological replicates.
Extended Data Fig. 6 Unique structural features of MRGPRX2 and MRGPRX4.
a, MRGPRX2 and MRGPRX4 have a unique structural arrangement at the PIF motif compared with the G protein coupled active structures of 5-HT2AR (PDB ID 6WHA), A2AR (PDB ID 5G53) and β2AR (PDB ID 3SN6). Residue 5.50 shifts away from the TM3-TM6 interface and does not engage L3.40 and F6.44 in MRGPRX2 and MRGPRX4. b, With G6.48, TM6 of both MRGPRX2 and MRGPRX4 packs closer to TM3 compared with the G protein coupled active structures of 5-HT2AR (PDB ID 6WHA), A2AR (PDB ID 5G53) and β2AR (PDB ID 3SN6), leading to an occluded canonical agonist binding pocket. c, (R)-ZINC-3573, cortistatin-14 and MS47134 bind to MRGPRX2 and MRGPRX4 at a position that is far away from residue 6.48, respectively. Cortistatin-14 is shown as cartoon. Small molecule compounds of receptors are shown as spheres.
Extended Data Fig. 7 Analog screening and functional characterization of MRGPRX2 antagonists.
a, b, Dose-response curves of initial 14 analogs of '1592 (a) and 8 analogs of C9 (b) in the presence of EC80 concentration of (R)-ZINC-3573 using MRGPRX2 FLIPR Ca2+ assay. Data represent mean ± s.e.m. of n = 3 biological replicates. c, Dose-response curves of two potent MRGPRX2 antagonists C9 and C9-6 and an inactive compound C7 in the presence of EC80 of each MRGPRX2 peptide using MRGPRX2 FLIPR Ca2+ assay. Data represent mean ± s.e.m. of n = 3 biological replicates.
Extended Data Fig. 8 Functional characterization of optimized MRGPRX4 agonists.
a, Dose-response curves of Kir6.2/SUR1 current inhibition by indicated chemicals. Data represent mean ± s.e.m. from n=4 biological replicates. b, d, f, h. Current-voltage relationships of whole-cell traces recorded in 150 mM KCl with the supplements of indicated chemicals of the labeled concentrations. c, e, g, Time courses showing the whole-cell-current responses to the indicated chemicals of the labeled concentrations. i, MRGPRX4 agonists X4-4 and MS47134 have a higher selectivity over Kir6.2/SUR1 channel compared with nateglinide. EC50 (nM) of each tested compound is shown. j, Screening of MS47134 across the GPCRome (at 320 receptors) using the PRESTO-Tango platform with 3 µM MS47134. Red dashed line indicated threefold of basal levels. Data represent mean ± s.e.m. of fold over basal for each receptor (n=4 technical replicates).
Extended Data Fig. 9 Structural comparison of Gq-coupled MRGPRX2 and MRGPRX4.
a–d, Structural comparison of the MRGPRX4-Gq-MS47134 complex with the MRGPRX2-Gq-(R)-ZINC-3573 complex. The receptor and Gq protein of MRGPRX4-Gq complex are colored by green and blue, respectively. The receptor and Gq protein of MRGPRX2-Gq complex are colored by cyan and salmon, respectively. Side view (a), Close-up view of αN-ICL2 interaction region (b), α5 helix region (c), and the cytoplasmic side of receptors (d). e, The acidic residues E1574.60 and D1775.38 of MRGPRX4 are shielded by the inserted ECL2. Side chain of D177 is not resolved but modeled here for a better visual interpretation. f, Residues E1644.60 and D1845.38 of MRGPRX2 extend to the cationic agonists accessible pocket. g, Due to the variance in residue 2.39, Y243H5.23 of Gq adopts different side-chain conformations to interact with Y130ICL2 of MRGPRX4 and Y137ICL2 of MRGPRX2. h, i, BRET2 Gq assays for Y130ICL2A of MRGPRX4 (h) and Y137ICL2A of MRGPRX2 (i). Data represent mean ± s.e.m. of n = 3 biological replicates.
Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics
See Supplementary Information page 1 for contents
Reporting Summary
Supplementary Tables
Cao, C., Kang, H.J., Singh, I. et al. Structure, function and pharmacology of human itch GPCRs. Nature 600, 170–175 (2021). https://doi.org/10.1038/s41586-021-04126-6
Issue Date: 02 December 2021
Scratching the itch with cryo-EM
Jagannath Maharana
Parishmita Sarma
Arun K. Shukla
News & Views 19 Jan 2022
History of Nature
Nature (Nature) ISSN 1476-4687 (online) ISSN 0028-0836 (print)


text:
by Alexandre Goncalves on August 28, 2014
Conflicting Frames: The Dispute Over the Meaning of Rolezinhos in Brazilian Media
This research analyzes the battle of frames in the controversy surrounding rolezinhos–flashmobs organized by low-income youth in Brazilian shopping malls. To analyze the framing of these events, a corpus of 4,523 online articles was compiled. These articles, published between December 7th, 2013, and February 23 rd, 2014, were investigated using Media Cloud-the system for large scale content analysis developed by the Berkman Center at Harvard and the MIT Center for Civic Media. Data from Facebook indicated which articles received more attention on the social network. A framing analysis was performed to describe the conflicting frames in the debate. The 60 most popular texts–those that attracted 55% of the social media attention in the corpus-were content analyzed. They served as an input for a hierarchical cluster analysis algorithm that grouped articles with similar frame elements.
The result of the cluster analysis led to the identification of three frames: one that criminalized rolezinhos or at least tried to discourage them (arrastdo frame), another that acquitted the youth and blamed police, government, State, or society for discriminating poor citizens (apartheid frame), and a third frame that criticized both conservatives and progressives for using the controversy to push their particular agendas (middle ground frame).
After finding the keywords that singled out each frame, natural language processing methods helped to describe the genesis and evolution of those frames in the overall corpus as well as the framing strategies of the main actors.
Filed Under: theses Tagged With: Brazil, flashmobs, Media Cloud, rolezinhos
About Alexandre Goncalves
During his master's program, Alexandre Gonçalves investigated recent controversies in Brazil across both traditional and independent media that have led to social and legal changes. He is interested in issues such as agenda-setting, framing analysis, and public opinion. These interests are fueled by his experience in the media and his knowledge of information technology – especially databases and natural language processing.
He also worked as a reporter at the Brazilian daily newspaper O Estado de S. Paulo, where he covered biotechnology and science policy.
Before becoming a journalist, he had worked as an information architect at many software companies.
Thesis: Conflicting Frames: The Dispute Over the Meaning of Rolezinhos in Brazilian Media


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From Russia, With Accents
by Max Kenneth on April 24, 2008 March 17, 2013
If anyone can pull off the role of satirical, socio-political prophet and shnooky belletrist, it's Gary Shteyngart. The author of The Russian Debutante's Handbook and Absurdistan, Shteyngart is one of the punchiest and funniest young novelists out there. His writing, colored and coarsened by the blunt cynicism of his 1970s upbringing in the Soviet Union, draws on intricate tessellations of classic Russian literature, self-deprecating Semitic humor, and current global politics. Being a Jew born in 1972 in the anti-Semitic Soviet Union and having immigrated to Queens in 1979, he has achieved status as a perpetual outsider, who can observe from remove and criticize with greater perspicacity.
With Shteyngart teaching a creative writing class at Princeton this semester, I decided to catch him for a lunchtime interview in his 185 Nassau office. When I walk in, I am confronted with a short man with thick-framed glasses, a dark beard, and a kiwi-green Penguin shirt from which an open button allows bristly chest hair to emerge. Through bites of his Zorba's sandwich, he discusses the trajectory of his literary career, his predictions about the rise and fall of the United States, and his third novel in the works.
To comprehend Shteyngart's political and social criticism, it is important to understand from where his literary shtick derives. Yet the exact origin of the influence on Shteyngart's fiction is difficult to pinpoint as a duality exists therein. He is simultaneously connected to the classic Russian literary tradition and the American Jewish tradition: his novels are intertextually buffed-up with allusions to Goncharov's Oblomov and Dostoevsky's The Idiot while he injects his work with the Yiddish invective and the verklempt mishegos of Philip Roth or Saul Bellow fiction. In his work, he can at once consider Pushkin and an abortive bris.
This juxtaposition of American and Russian influences finds its root in his early reading habits.
"One of the first things I remember reading as a kid was a Russian translation of Tom Sawyer with an introduction by Stalin," he explains, "and I think that set the mood for the sort of clash of civilizations that I would undergo."
The folk satire of Twain's writing made him a hit in the Soviet Union, and Shteyngart does not divorce this social satire from his own work.
Shteyngart points to the satirical Don Quixote as the first monumental work of fiction, and in this clarification, it seems fitting to place Shteyngart within the picaresque tradition continued by Mark Twain.
Whether a Castilian spoof of the chivalric romance as with Don Quixote, a critique of racism in the ante-bellum South as with Huckleberry Finn, or a derisive glance at twenty-first century oil politics as with Absurdistan, the peripatetic picaresque structure of these novels presents a certain unfulfilled quest, a striving for something greater.
The hidalgo ingenioso, Huck, and Misha Vainburg of Absurdistan are all quixotic wanderers, all delightfully pitiable and invoking a disposition to mockery. Whether mockery for mere humor or for political commentary, the meandering protagonists and narratives invoke a widely cast net of observation and scrutiny—whether across the Mississippi or the Volga.
But using the juxtaposition of Stalin and Tom Sawyer as a microcosm, the satisfying flavor of entertainment in Shteyngart's fiction is always marinated in political satire. His first novel intrepidly derides Arthur Anderson LLP and his second Halliburton. Politics for him are part and parcel of the satire, and he wears his political satire on his rolled-up sleeve. Let's face it: he began writing his first book while a politics major at Oberlin.
"I grew up with Brezhnev jokes…I grew up with satire," he says. "And writing during the time of the Bush administration is the perfect time to be a satirist, because it's where evil and stupidity collide."
His voice, a cadent tenor, has a stark New York verve to it, and when politics are the topic, it deepens, pops more at the lips in incensed modulation.
Shteyngart sees himself immersed in a tradition of this political fiction, following, for example, the Gogolian works that spoof Russian governmental bureaucracy and serfdom during the second half of the nineteenth century. He cites the Canadian satirist Mordecai Richler as another major influence in this realm.
Though Shteyngart has had his works treated with the utmost seriousness in reviews and criticism in major literary journals and newspapers, he realizes the danger of humorous writing for those producing works of serious literary merit.
"Comic-fiction is sort of a dirty word in literary circles," he says. "It's like writing science fiction or something. My next book, a comic science fiction book, will surely raise the heckles of some people."
Shteyngart has been called the Jewish Nabokov, and his next work's surfeit of self-referencing reinforces the connection.
Jerry Shteynfarb (to Shteyngart what Vivan Darkbloom is to Nabokov), the writer character who steals Misha Vainburg's Latina girlfriend in Absurdistan, may make a brief appearance in the new novel. In the work, a son of Russian immigrants in dating a daughter of Korean immigrants and placed before a complicated kaleidoscope of global modernity with the rise of the East.
"It's a comedy about the collapse of the United States," Shteyngart explains. "It's set in the very near future. Things fall apart economically mostly, but also politically. It's about the decline of literature. It's about the hyper-connectivity that people now have. And it's a love story. It's about trying to find a form of love in a society that is just completely divorced from real intimacy."
The two main characters each take a turn at narrating the novel, and this collision of old and new, East and West, is the precipitate found in his polyphonic novelistic concoction. The symbiosis of the two worlds finds its route in the versatility of language.
"I love the English language," he says. "English can tackle anything. It's so far ranging. And it's so able, because it's so universal, to bring in so many other parts of other languages. It's like a smorgasbord. I have Korean friends who banter on with Yiddish all the time: 'Oh, I bought some schmatas from this yenta.'"
Shteyngart is known for writing with definite, calculating plot points that all change throughout the course of the novel. With this novel, though, he explains that he has a particularly rich selection of options.
"There are so many ways to blow this country up," he says.
Foreseeing, with prescient eschatology, the demise of the U.S. in this new novel, Shteyngart also claims to see the atrophy of this country firsthand during his Wednesday trips from New York to Princeton.
"I've been taking New Jersey Transit over here," he says reflectively. "You feel like you're entering a kind of Rothian America coming over here. You know, passing Newark. What's interesting about it is that this country really had its peak, and a lot of that peak you can see in the industry—those big iron bridges you pass, the container ports. All this stuff, it rings of a past, a really mighty past. But the world is moving at a hyper-speed and it's not happening here….You look at the decline of the Spanish Empire, the British Empire, the Dutch Mercantile Empire; it's never pretty."
Shteyngart scorns nationalism and feelings of religious or political superiority in favor of viewing the downfall of great nations as inevitable.
"And there's no question that this century will belong to the Asian economic renaissance," he says. "What happens in those societies is not just that they go down the road of hyper-modernity, but that they stumble head first into it. And it's interesting as a writer. I want to read more fiction from that part of the world."
In fact, Shteyngart is intricately involved with immigrant writers; Chang-Rae Lee played an instrumental role in editing Shteyngart's first book and placing it with his publisher.
For Shteyngart, the cardinal sin in the modern world, and symptom most indicative of its maladies, is the culture of consumption. This consumption—with cultural and economic colonialism—will cause of the fall of the U.S. The perfect distillation of this situation can be found in Misha Vainburg, the 300-pound protagonist of Absurdistan, who achieves the moniker Snack Daddy during his own continued consumption of foodstuffs and Americana. He's part massive Russian from Sergei Dovlatov's Ours and part burger-munching juggernaut.
Shteyngart finds this culture of consumption in Russia today when he visits his native Petersburg.
"It's pretty depressing," he laments. "Everyday I see the worst aspects of Western culture being brought over there and being consumed with great fanfare."
In order to connect with the bacchanal debauchery of this consumption, Shteyngart actually wrote much of Absurdistan in Rome.
"Rome was so important," he says, "because I was writing about a very decadent fellow [Misha Vainburg]. And it was very helpful also to be surrounded by people who indulged in drink and sex in copious amounts and who, at the same time, had very few responsibilities. There was a certain scene I fell into there."
Obsessed with chronicling and critiquing this consumption and Saturnalia, Shteyngart has his new book actually starts out in Rome.
What emerges from this social-ontological residue is the reemergence of a world inhabited by the superfluous man—an idealistic hero who is too aloof or omphaloskeptic to be bothered with global social problems. The term "superfluous man," coined by Turgenev, appeared as a nineteenth-century Russian literary archetype beginning with Pushkin's Eugene Onegin that, quite Byronically, emerged from Childe Harold's Pilgrimage.
"We are living in a world where a certain kind of man is superfluous," Shteyngart says. "You could say man has always been superfluous. We live in a time where anyone who wants to contemplate the world instead of just contemplate oneself is the odd-man out. We live in a world of hyper self-expression."
He cites a culture of self-involved literary workshops across the country and world and the navel-gazing blogosphere to indicate how people have reseized the pen. With the emergence of this self-consumption in graffomania, Shteyngart sees an uncertain present in literature.
"I think literature is in a huge state of flux right now," he says. "And it's very difficult to say what's going to happen to it as reading declines exponentially and writing expands exponentially. Everybody wants to write, no one wants to read, and I think that's part of the culture of self-expression in which we live."
Some, he admits, speculate on a grim outcome to this trend.
"Philip Roth always said the novel's going to die in fifteen years, but then again, he may also die in fifteen years," Shteyngart says with a smile.
The decayed state of literature is not endemic to the U.S. alone.
"Russia has also seen a crisis in literature," he says. "After the collapse of the Soviet Union when the most important thing was passing around samizdat, now it's a commercial activity like anything else."
With the unimpressive efforts of Victor Pelevin or the limp prose of Victor Erofeyev, Andrei Bitov, and Vasily Aksyonov, the living old guard of Russian literature has taken a self-contented and impotent move in literary realms. Hell, even Vladimir Sorokin's Blue Salo, in which the clones of Stalin and Khruschchev engage in sodomitical acts of homosexuality, is one of the only daring displays of literary insurrection to emerge in post-Soviet Russia.
But Shteyngart has found himself on the right side of the world for his literary emergence. In the States, Shteyngart's genre of Jewish-rooted fiction is thriving. Take Jonathan Safran Foer's 2002 Everything is Illuminated and Michael Chabon's 2007 The Yiddish Policemen's Union; two of the most celebrated books of this decade fall into this category. And, indeed, it is this genre of Semitic cynicism that resonates still further now with Shteyngart's prediction of the undoing of America and the slow but sure unraveling of the American dream.
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Home›Music News›Film/TV News›"And the Writer Is..." Songwriting Podcast Features Hitmakers Tranter and Evigan
"And the Writer Is..." Songwriting Podcast Features Hitmakers Tranter and Evigan
Film/TV News, Latest, More Industry News
Big Deal Music and Mega House Music's new podcast series And the Writer Is... explores the creative process, inspirations and pitfalls of songwriters. Each week, Multiplatinum songwriter Ross Golan (Selena Gomez, Keith Urban, Flo Rida) sits down with the emerging writers in the music business to discuss personal experiences and behind-the-scenes anecdotes. Since launching in late January, the podcast has received over 42,7000 downloads, and reached No. 30 on Apple Music's Top Music podcast chart.
Out now, Episode 6 focuses on Jason Evigan, the Grammy-nominated co-writer behind Jason DeRulo's "Talk Dirty," Nick Jonas' "Chains" and David Guetta's "Lovers In The Sun." Topics include the rise and fall of his Top 40-charting punk band After Midnight Project, spirituality, the power of handclaps and the "Jason Evigan-isms" that other writers now reference in sessions.
Episode 5 features a wide-ranging conversation with Justin Tranter, the Semi Precious Weapons frontman who helped pen Justin Bieber's song "Sorry." "He's probably the hottest writer in the music business," says Golan in his intro. "We did this interview less than two months ago, and since then he's released the Imagine Dragons single 'Believer,' Julia Michaels' debut single 'Issues,' Maroon 5's single 'Cold' and Linkin Park's single 'Heavy.'" Tranter, who recently joined GLAAD's National Board of Directors, discusses misogyny and homophobia in the music business, actors vs. musicians, commercial radio's downward spiral and collecting royalties in the age of Trump.
Guests for the first season include Evan Bogart, Benny Blanco, J. Kash and Bonnie McKee. The show is produced by Grammy-nominated songwriter/producer Joe London (Pitbull, Thomas Rhett, Fifth Harmony).
New episodes of And the Writer Is… are posted each Monday, and are available on major podcast directories including iTunes, GooglePlay, TuneIn, Stitcher, Blurbrry and others, as well as their website. Each episode is accompanied by a Spotify playlist of the guest's hits at open.spotify.com/user/andthewriteris.
For episodes and more information, visit andthewriteris.com.
TagsAnd The Writer Is...big deal musicJason EviganJustin TranterMega House Musicpodcastsongwriting
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The Real Time host doesn't know Hardwick well, but he says he read Chloe Dykstra's account of his alleged emotional and sexual abuse. "There's a show on — I shouldn't plug it because it's my network rival — but there's a show on Showtime called The Affair," he says when asked about Hardwick. "Have you ever seen it? It's a Rashomon-type show where the first half hour is his story, then the second half hour is her story. So, they're showing basically the same sequence of events through the eyes of two different people. And, of course, what you see is how differently people remember the exact same situation. They didn't invent that, but it's an interesting way to look at a relationship. So I have no idea. What I do know is this: It's got to be different when you have 30 accusers than when you have one. When it's a Bill Cosby, when it's a Harvey Weinstein, when it's any of these situations where dozens and dozens of people come forward, then it's almost preposterous to say, 'Well, there's nothing to see here.' But when it's one person, I have no idea. And of course, it's probably wrong to condemn someone based on one person, because relationships touch our rawest nerves, and people then sometimes do remember things wrong, or sometimes have personal revenge motivations. We just don't know. Should we believe the woman? Yes, of course. But also every case is an individual case. I don't think anyone should be arguing that women, ethereal creatures though they are, are infallible."


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NWR reflects over the past year
Windhoek, 22 November 2018 – As the year comes to an end, it is worth reflecting on some of the progress Namibia Wildlife Resorts (NWR) made. The economic challenges that the country faces played a role in how the company fared. However, it was these trying times that showed how resilient the company is.
From a business perspective, NWR generated N$ 361 million in revenue for the 2017/18 financial year. This was fuelled by the aggressive marketing drive that the company undertook in addition to the introduction of the Kavango Zambezi (KAZA) tour package. This package alone attracted a lot of interest at ITB Berlin and the Africa Showcase: North America roadshow that NWR attended. The company also went on a cost-cutting drive that yielded very positive results. For instance, in 2013 the company's cost of sales was standing at 72% and was brought down to 43% this year with next year's target being 35% which is the industry standard.
To reach these targets, NWR has been hard at work at finalising its Khorixas training institution. "The key focus of the institution will be equipping our staff members and other interested individuals on the best practices within the hospitality industry. The lodging will still be open to the general public and will be catered to by the students. We anticipate opening it at the beginning of 2019 officially", says Mrs Zelna Hengari, NWR managing director.
Equally, NWR introduced its revised NamLeisure cards which for the first time started offering a 25% discount on meals and activities along with a student card. "Looking at the current interest on the cards,it is safe to say that they have tremendously assisted our domestic travellers to enjoy all that NWR has to offer at discounted rates. Over the past few months, we have seen a huge uptake from first-time buyers due to the additional discounts now on offer", says Mrs Anna Onen, NWR sales and reservations manager.
It is a common fact the world over that, for any company to grow, it requires partners to help it expand its share of the market. NWR is fortunate enough to have good working relations with its tour operators who supply the business with a great deal of its clientele. It was for this reason that it held a function specifically to reward its top performing tour operators. "This event was a testament to the value that we place on our partners in addition to our appreciation of them," says Mr Mufaro Njabulo Nesongano, NWR corporate communications and online media manager.
In solidifying its ability to host big tour groups, NWR undertook over 50 bikers through the KAZA countries (Angola, Botswana, Namibia, Zambia and Zimbabwe) in less than ten days. The tour aimed to showcase the most significant conservation area in the world as well as expose the bikers to the various communities within these areas. "To date, each time I speak with the bikers that were on this tour, all of them cannot stop talking about the Namibian part, which to them was the best of all. From our side, this tour showed us that we have what it takes to host big tour groups. Therefore, as we go ahead, this is going to be one of our key focus areas. It was just unfortunate that the man that spearheaded the realisation of the Tshwane Legend Bikers Club tour, Mr Ernest Mokganedi passed on in July. This was a big blow to the plans that we had. However, we made a promise to ourselves to ensure that we continue where he left off" says Mrs Hengari.
In giving back, NWR hosted some primary school learners from across the capital city at its Hardap resort under its Enviro-Kidz programme. The programme aims at educating learners on the importance of looking after their environment. "Due to the huge interest that we received, we will take in more learners and also include learners from around the country next year. We aim to afford them an equal opportunity to experience Namibia's national parks and to learn about how important they are to us as a country", says Mr Nesongano.


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Militants take over two LGAs in Cross River; ...displaces civil and traditional authorities
Armed militias have taken control of two local government areas in Cross River State and displaced virtually every civil authority in the area.
The militia, generally believed to be members of Bakassi Strike Force, had been operating in the area for some time. But they recently seized control of Bakassi and Akpabuyo local government areas, displacing both civil and traditional authorities in the councils.
It was reliably gathered that the elected chairmen of the two local governments had fled the area for several month now, while the councillors hold their legislative sittings in Calabar. The secretariats of both local councils have also been deserted by civil servants for fear of being kidnapped or attacked by the militants.
To try to stem the slide into anarchy, the state governor, Professor Ben Ayade, has appealed to President Muhammadu Buhari to extend the activities of "Operation Delta Safe", a security taskforce protecting oil installations in the Niger Delta, to Cross River State. Ayade said his state should not to be isolated in the battle to keep the Niger Delta safe. He also promised to increase the firepower of the state's security taskforce, "Operation Skolombo."
Militancy has gripped Cross River State for the past few months. And militants are being blamed for an increasing wave of kidnapping, armed robbery, and other criminal activities, especially, in Calabar, the state capital.
But Bakassi and Akpabuyo local government areas, which share maritime boundary with Cameroon, recently became a lawless, anarchic zone in which militants rule. It was discovered that the militants collected rents and levies from people doing business in the council areas, which they termed "protection money", a situation that has made many people to flee.
The militants are said to have also rendered the state judicial organs and the traditional institutions in Akpabuyo and Bakassi local governments impotent, as the militias now handle matters that should otherwise be handled by the conventional courts, village heads, clan chiefs, and paramount rulers.
A source conversant with the situation, but pleaded not to be named, said, "There is total anarchy there now, and people are actually running to Cameroon now for help. First of all, the local government chairmen in both places don't go to office, and they have not gone to office over the past one and a half years. They have written, complained, begged, and appealed, to no avail.
"The legislatures in those places don't meet at the local government headquarters. They hold their meetings in Calabar so as to fulfil the statutory requirements that they hold a certain number of meetings in a session.
"So, effectively, there is no governance in those areas."
The source said the locals had made a failed bid to contain the armed men.
"The traditional institutions have tried to fight, but they can no longer sustain the fight. They don't have guns, they don't have money," the source stated. "What we have now is that militants have set up a parallel government. They are the ones that resolve land disputes, they are the ones that resolve family disputes, and if husband and wife quarrel they go to militants. Of course, their methods are crude but effective.
"They rely on jungle justice, they cane people. Culprits pay fines of goats, drinks, and money."
Though, as gathered, there are police posts and soldiers stationed in the areas, the security agents appear to be overwhelmed by the militants.
When contacted, the chairman of Akpabuyo Local Government Area, Mr. Patrick Ene Okon, refused to speak on the issue. But the chairman of Bakassi Local Government Area, Mrs. Edisua Usang Iso, admitted that militants were operating in her council area. She, however, denied that the activities of the militants were affecting the administration of the council. Iso said, though, the council had lost substantial revenue to their activities, the federal government should grant amnesty to them and incorporate them into the federal government's amnesty programme for Niger Delta militants.
The Bakassi local government chairman denied abdicating her duties and deserting the council secretariat, saying she goes to Bakassi whenever it is necessary.
However, confirming the occupation of the Bakassi area on Friday, when he addressed the press on the security situation in the state, Ayade vowed that the militants will be dislodged from the area.
The governor said, "The three kingpins, we have identified their homes, we have the coordinates of their armoury, we have a clear picture of their modus operandi and we are working on a massive attack. I speak as the United States would do. They let you know that they are coming for you and they will come after you.
"We are coming after them. We know all the militants who are now parading and taking full occupation of Bakassi. We would free the people of Bakassi. The people of Bakassi have seen enough pain. Lands taken, oil wells taken, reduced to want in spirit, body and economy, we cannot afford also to create a perilous nightmare for the same people."
Addressing newsmen yesterday at the Peace Park, Calabar, shortly after a five-hour security council meeting, the governor, accompanied by service commanders in the state, as well as his security adviser, unveiled a new security agenda aimed at containing the emerging threat in the state.
Credit: ThisDay


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High Voltage Indoor Karting files for brewing permit
Rick Armon Beacon Journal/Ohio.com @ArmonRickABJ
High Voltage Indoor Karting in Medina has filed for a state brewing permit.
But Tim Obert, one of the managers, said there are no definite plans or timetable for launching a brewery.
"It's just something we want to have in our back pocket," he said Monday. (Feb. 11)
High Voltage offers indoor electric karting in a 40,000-square-foot building at 333 Foundry St. — with the track winding outside during better weather. The karts can go as fast as 50 mph, but don't hit that top speed at High Voltage because of the track.
"As we look at future plans, our building is quite large. Just trying to figure out what else to do with the building," Obert said.
The business, which has been open since March 2015, started serving beer in November. Obert said High Voltage keeps watch to make sure that people aren't drinking and driving karts.
For more details about High Voltage, click here.


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Q: Rarely used function that is unused affecting the performance There is an essential function in the program that is rarely used. However, I found out that even when this function is not used in a particular execution, this function causes an increase in runtime overhead.
For detailed explanation...
Below code is my very best attempt at writing a minimal example to show what I mean, but I apologize in advance if it doesn't make sense. I'm working in a minimal space of C language, so if the code looks pretty unoptimized, that is because I have no choice :( (I am very open to any suggestions, of course)
// extra_function.c
int extra_array[6] = {0, 1, 2, 3, 4, 5}
void copy_array(int *array, int num) {
  switch (num) {
  case (0):
    for(int i = 0; i < 6; ++i)
            array[i] = extra_array[i];
            break;
  }
}

// main.c
#include "extra_function.c"
int main(int argc, char *argv[]) {
  int target_array[10] = {0};
  int copy_check = 0;
  if (argc == 2) {
    copy_check = 1;
  }

  // high runtime overhead
  if (copy_check == 1) {
    copy_array (target_array, 0);
  }

  // never used
  if (false) {
    copy_array (target_array, 0);
  }
}

To summarize, basically, I need to use a function copy_array instantiated outside of main.c to copy a statically allocated array from extra_function.c into main.c.
From looking at main.c, a condition argc == 2 must happen for copy_check variable to become 1, otherwise copy_array function will never be called.
In my scenario, argc == 2 condition will never happen.
However, it seems that because there is a possibility that argc == 2 condition can happen, runtime overhead increases even though this condition never occurs.
Why is this happening? Is it because even though a function may never be called in this execution, there is some sort of initialization done underneath that causes the runtime overhead?
I was able to find this out because by making the function not used (as shown in // never used), I was able to save a runtime overhead.
Please let me know if my question is unclear, I understand that this question may sound ridiculous, but I have been trying to figure out why this is happening, but to no avail.
Here is a similar question: Unused function changes performances, but this seems like it is regarding solely unused function while my question is regarding rarely used function unused.
I appreciate any help you can provide.

A:
Is it because even though a function may never be called in this
execution, there is some sort of initialization done underneath that
causes the runtime overhead?

Runtime overhead is caused by initialization of target_array. If target_array is not used you can skip its initialization e.i use int target_array[10]; instead of int target_array[10] = {0};
If target_array is allocated on the heap in your "real" program, you can define a pointer only and do the memory allocation in copy_array if needed. Defining a pointer only int* target_array=nullptr; definitely will not cause overhead.

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text:
Der Healthy-Worker-Effekt (HWE) bezeichnet einen statistischen Effekt in epidemiologischen Kohortenstudien, der einen besseren Gesundheitsstatus von Beschäftigten als dem der Gesamtbevölkerung aufzeigt. Daher wird die arbeitende Bevölkerung statistisch oft als gesünder ausgewiesen.

Dies ist dadurch zu erklären, dass innerhalb einer Kohorte Berufstätige einen gewissen Gesundheitszustand aufweisen müssen, um ihre Arbeit ausführen zu können, während in der Gesamtbevölkerung unter anderem auch diejenigen Personen enthalten sind, die krankheitsbedingt arbeitsunfähig sind. Dieser verzerrende Effekt bedingt, dass Vergleiche zur Gesamtbevölkerung in der Regel problematisch sind. Der "Healthy-Worker-Effekt" kann also zu einer Unterschätzung der arbeitsbedingten Morbidität führen, wofür langjährige Nachtarbeiter im Drei-Schichten-Betrieb ein klassisches Beispiel sind.

Der Healthy-Worker-Effekt ist eine spezielle Form der Stichprobenverzerrung ().

Einzelnachweise
  J. Baillargeon: Characteristics of the healthy worker effect. Occup Med. 16(2):359-66. 2001. Review. PMID 11319057.

Arbeitsmedizin
Medizinstatistik

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Can we get a round of applause for the writer, director, actress, and producer Issa Rae? Plus, she's natural! This week, she appeared on the cover of Complex magazine. The "Insecure" creator rocked a red form-fitting outfit and big Afro. On Instagram, Rae said she was channeling her favorite heroine, Pam Grier. You can always count on the 32-year-old to rock a new natural hairstyle!
Issa Rae's natural hairstyles include twists, puff, updos, cornrows, and a lot more! Her hairstylist, Felicia Leatherwood who is also Skai Jackson's stylist, keeps her hair on point! Earlier this month, Issa Rae appeared in an issue of the Hollywood Reporter for their Comedy Actress Roundtable. The producer rocked a pink suit and big cornrows going back into a puff. She came through with the classic 70's look!
In 2011, Issa Rae's web series "Misadventures of an Awkward Black Girl" came out on YouTube. The series focused on the character "J" and her "awkward" love and work life. The series ended in 2013 after two seasons.
The MisAdventures of Awkward Black Girl book was published in 2015 and appeared on the New York Times best seller's list! Unlike the web series, the book contained Issa Rae's memoirs. Her show Insecure on HBO first aired in 2016. Last night, episode 1 of Season 2 aired.
What do you think of Issa Rae and her natural hairstyles?
Black History Month: Diahann Carroll as "Julia"