**Author details**

Nor'Aishah Hasan1,2\*, Mohd Rafii Yusoff1,3, Abdul Rahim Harun4 and Faiz Ahmad4

1 Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

2 Faculty of Applied Science, Universiti Teknologi MARA, Cawangan Negeri Sembilan, Kampus Kuala Pilah, Negeri Sembilan, Malaysia

3 Department of Crop Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

4 Agrotechnology and Bioscience Division, Malaysian Nuclear Agency, Kajang, Selangor, Malaysia

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**115**

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[9] Hasan N, Rafii MY, Abdul Rahim H, Nusaibah SA, Mazlan N, Abdullah S. Genetic analysis and identification of SSR markers associated with rice blast disease in a BC2 F1 backcross population. Genetics and Molecular Research.

[10] Miah G, Rafii MY, Ismail MR, Puteh AB, Rahim HA, Asfaliza R, et al. Blast resistance in rice: A review of conventional breeding to molecular approaches. Molecular Reproduction and Development. 2013;**40**:2369-2388

[11] Nadeem MA, Nawaz MA, Shahid MQ, Doğan Y, Comertpay G, Yıldız M, et al. DNA molecular markers in plant breeding: Current status and recent advancements in genomic selection and genome editing. Biotechnology & Biotechnological Equipment.

[12] Shabir G, Aslam K, Khan AR, Shahid M, Manzoor H, Noreen S, et al. Rice molecular markers and genetic mapping: Current status and prospects. Journal of Integrative Agriculture.

[13] Jiang GL. Plant marker-assisted breeding and conventional breeding: Challenges and perspectives. Advances in Crop Science and Technology. 2013;**1**:105

[14] Thottappilly G, Magonouna HD, Omitogun OG. The use of DNA markers for rapid improvement of crops in Africa. African Crop Science Journal.

[15] Collard BCY, Jahufer MZZ,

Brouwer JB, Pang ECK. An introduction to markers, quantitative trait loci (QTL) mapping and marker-assisted selection for crop improvement: The basic concepts. Euphytica. 2005;**142**:169-196

[16] Xu Y. Molecular Plant Breeding. Wallington, UK: CABI International; 2010. p. 734. ISBN 978-184593-392-0

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[1] Shahbandeh M. World rice acreage 2010-2018. 2020. Available from: https://www. statista.com/statistics/271969/ world-rice-acreage-since-2008/

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[2] Bandumula N. Rice production in Asia: Key to global food security. Proceedings of the National Academy of Sciences, India Section B: Biological Sciences. 2017;**88**:1323-1328. DOI: 10.1007/s40011-017-0867-7

[3] Rejesus RM, Mohanty S, Balagtas JV. Forecasting Global Rice Consumption. Working Paper. North Carolina State

[4] Singh PK, Nag A, Arya P, Kapoor R, Singh A, Jaswal R, et al. Prospects of understanding the molecular biology of disease resistance in Rice. International

Journal of Molecular Sciences.

[5] Oladosu Y, Rafii MY, Samuel C, Fatai A, Magaji U, Kareem I, et al. Drought resistance in Rice from conventional to molecular breeding: A review. International Journal of Molecular Sciences. 2019;**20**:3519

[6] Khan MH, Dar ZA, Dar SA. Breeding strategies for improving Rice yield—A review. Agricultural Sciences. 2015;**6**:467-478. DOI: 10.4236/

[7] Collard BCY, Mackill DJ. Markerassisted selection: An approach for precision plant breeding in the twentyfirst century. Philosophical Transactions of the Royal Society B. 2007;**363**:557-572

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jury from obtaining knowledge about the case outside the courtroom. Actress Sarah Paulson repeats original statements and the physical gestures of the real Marcia Clark, but her tone of voice and pleading with Lance Ito appear more aggressive and desperate on television, whereas in 1995, Clark seemed centered as she tried to plead reason into the judge. Likewise, the series includes, and rightly so, Johnnie Cochran's response to Clark's objection, as it once again illustrates how the attorney elevated certain issues pertaining to the Simpson case to social issues in the US in general. In this particular instance, Cochran argued that the prosecution's protests constituted violations against his defendant's right of free speech. Originally, he debated: "There seems to be this great fear of the truth about anybody speaking in this case. This is still America and we can talk, we can speak. Nobody can stop us" (Court Transcript, 22 September 1995). It is noteworthy that his use of the personal pronouns 'we' and 'us' remains vague and open to interpretation. It is unclear whether Cochran refers to the defense team or the entire African American community in general, whereby the court becomes an enabler of injustice in that it silences free speech. *ACS* preserved Cochran's ambiguous statement and his purposeful use of personal pronouns to add emotive impact to his arguments: "My goodness. There's a great deal of fear of the truth in this case. Your Honor, this is still America. Can we still talk?" (*ACS*, disc 4, episode 10, 01:40-48).

Likewise, the television series depicts the public pressure and consequent inner struggle Judge Ito was subjected to considering many of his motions were taken out of the context of the criminal trial and applied to social issues and debates in the entire United States. In the aforementioned case, if he ruled against the defense who argued for free speech, Ito would appear complicit in the attempt to silence "the truth in this case." In this regard, historian Walter L. Hixson asserts:

The actors in the criminal justice system—police, prosecutors, defense attorneys, judges, and juries—succumbed in varying degrees to the external pressures that roiled the administration of justice. […] Popular trials such as the [the Simpson case] contain all the features that captivate the public: drama, narrative, rhetoric, and advocacy. Such cases tend to obscure the criminal or legal issues in question, as they provide an opportunity to advance other causes before, during, and after the courtroom proceedings. (Hixson 2)

While adhering to the original court transcripts in some instances, there is a perceptible exaggeration of emotions for dramatic purposes in the series in other cases, in particular with regard to Cuba Gooding Jr. and his impersonation of O.J. Simpson. An analysis of the original footage reveals differences that give ground to criticizing his performance. During the original trial, there is no truly tangible moment during which Simpson broke character and showed any facet of his role other than the self-confident and innocent man and father. During his speech on September 22, he expressively underlined this image by speaking clearly and distinctly to all

present. This becomes observable with regard to his emphasis of certain words as, for instance, in "I am mindful of the mood and the stamina of this jury. I have *confidence*, a lot more it seems than Miss Clark has, of their integrity" (Court Transcript, 22 September 1995, emphasis added).The fictional character appears exhausted and weak as the actor inserts prolonged pauses in his monologue that were absent in Simpson's 1995 plea for acquittal (e.g.,*ACS*, disc 4, episode 10, 02:23). As Emily Nussbaum writes in *The New Yorker*, although "Cuba Gooding, Jr., captures the football star's gasbag egotism [he] falls short of the regal charisma that drew people to [O.J. Simpson]" (Nussbaum, *New Yorker*, 31 January 2016).

One can also observe the series' repeated and more prominent focus on other participants in the case. During Simpson's short speech, the camera cuts to a medium shot of Robert Kardashian to capture his reaction to the defendant's argument (*ACS*, disc 4, episode 10, 02:15). This seemingly trivial shot is, on the contrary, quite suggestive. As was demonstrated in the chapter "The Bronco Chase," Kardashian was significant to the structure of the series. Oftentimes, his conflicting views, doubts, and insecurities pertaining to O.J. Simpson dominated and shaped the narrative of an episode. Initially, he was certain of his friend's innocence and even agreed to renew his practice license to be able to join the defense team. However, with new information surfacing on almost a daily basis (e.g., the polygraph test Simpson failed), Kardashian began questioning his friend's innocence. Thus, capturing the attorney's reaction when Simpson speaks of the "misrepresentations made about myself and *my* Nicole" (02:12, emphasis added) becomes a powerful visual tool to externalize the attorney's inner struggles. This assumption is further supported by the fact that Kardashian lowers his glance upon hearing the seemingly innocent words "my Nicole" (02:13), which, in accordance with the prosecution's argument, could be interpreted as an indication that Simpson considered his ex-wife a possession, and if he could not have her, nobody else could.

Similarly, quick cuts between Simpson, his family, and the Goldmans serve as a reminder of how differently his speech was perceived by all parties, thereby offering a perspective of the situation the courtroom camera did not originally provide in 1995.When Simpson speaks of his children, the camera cuts to Fred and Kim Goldman who wince at the painful irony of his statement: "I have four kids. Two kids I haven't seen in a year" (02:42). While Simpson's children are alive and well, the Goldmans have lost an important part of their family, one they can never bring back. Simpson's pain of not having seen his children for a year is thereby relativized against the background of the murders. Hence, the series temporarily succeeds in placing emphasis on the victims who were so often neglected during the 1995 trial. When Simpson's speech continues with, "And every week, they ask me, 'Dad, when are you coming home? –Howmuch longer?'"(02:46), thereis another quick cutin the sequence, this time to Simpson's mother and oldest son, Jason, who look tense and

worried. In contrast to the Goldmans, they hope for their son's and father's acquittal and release.

As indicated above, Marcia Clark's performance during this particular part of the trial is more exaggerated, aggressive, and accusing than the prosecutor's original interaction with Judge Ito and O.J. Simpson in 1995. In the television series,Clark challenges the celebrity defendant directly to take a seat in the witness chair if he really wishes to rectify wrong assumptions about him and the female murder victim: "You want to address misrepresentations about you and Nicole? Take a seat in the blue chair, and we can have a discussion" (2:58-3:02). A medium close-up shot has the prosecutor face the camera as she dares Simpson to testify (03:00). The latter, likewise captured in the shot, is filmed laterally in contrast, with his gaze directed toward the ground, thus presenting Simpson in a subordinate position to the prosecutor who seems much more dominating and present through the frontal perspective. Clark's original request, however, diverges notably from the filmic adaptation. First, she never spoke to Simpson directly, since all motions are to be passed through the judge and are then redirected to the defendant's attorney(s). Second, due to the ritualized nature of motions, Marcia Clark's original inquiry sounds formal and even respectful: "May I also ask, your Honor, for the court to inquire of Mr. Simpson, perhaps he would allow me then the opportunity, since he would like to make these statements to the court, I would like the opportunity to examine him about them. May he take a seat in the blue chair and we will have a discussion?" (Court Transcript, 22 September 1995). This alludes to the fact that, as was observable with the series' characterization of Al Cowlings (see chapter 1.3, "From Chase to Arrest"), many protagonists on *American Crime Story* display a more aggressive and angry tone to their actions than their real-life counterparts. While exaggeration is an important part of dramatic television, it misrepresents people for the sake of entertainment and tension, similar to the way the main players in the case were sold as epitomes of specific social roles in the media in the 1990s.

*ACS* also parts with its literary source, Jeffrey Toobin's *The Run of His Life*, to continue the dramatic arc of the show, noticeable in the way the main players are shown receiving notice and reacting to the information that the jury had reached a verdict. Toobin, for instance, shared in his account that he heard the news during a conversation with Scott Gordon, a policeman from Santa Monica. Upon ascertaining that jury deliberations were over, he exclaimed: "You're shitting me….  I know you're shitting me…" (Toobin 428). In the TV adaptation, however, it is none other than Judge Lance Ito who utters a surprised "Are you shitting me?" (*ACS*, disc 4, episode 10, 21:18) when he learns that the verdict is in. Having Ito curse constitutes a stark contrast to the personality the viewers experienced in 1995 during the original trial and his image as a weak judge. This verbal contrast, in combination with a zoom-in shot to create surprise, is effective in demonstrating that even an experienced judge such as Lance Ito did not expect the jury to come to a decision within four hours. Johnnie Cochran reacts in a similar way (21:33), while Robert Shapiro exclaims: "My God, they've discussed this case less than anybodyin America" (21:51).

The scenes leading up to the announcement of the verdict are a combination of cinematic and stock shots. In particular with regard to the tense situation in Los Angeles, the archival footage of the measures taken by the police took in preparation for the adjudication as well as the partly tumultuous demonstrations of both white and African American citizens in the city (23:05) was used to enhance the authenticity and the emotional appeal of the newly filmed television scenes. One particular choice of stock images stands out in the series, namely the inclusion of short clips from Oprah Winfrey's talk show, considering her proliferation in American popular culture. According to Kimberly Springer, "Oprah Winfrey's embodiment, her cultural productions, her actions, and her ideology constitute *The Oprah Culture Industry* (TOCI). The sheer number of productions and enterprises indicates TOCI's extensive reach into American lives, media, and culture" (Springer xii). Similar to O.J. Simpson, Winfrey was able to seemingly transcend race, which allows her to attract a highly diverse audience. In 1994,media scholar Janice Peck described Winfrey "as a comforting, nonthreatening bridge between black and white cultures" (Peck 91), and her influence continues undisputed. Therefore, Winfrey's comments on the Simpson case from 1995 transition smoothly into the modern filmic adaptation of 2016.

In the clip in question, the TV personality is standing in front of her audience as she proclaims that "history is in the making" (*ACS*, disc 4, episode 10, 23:18), referring to the pending announcement of the verdict in the Simpson murder case. She then turns around and asks her viewers, "Who's nervous? Is anybody nervous here?" (23:24). A panning medium shot of the panel reveals an equal number of African American and white audience members raising their hands, as they shyly smile at their hostess. Later, after the announcement of the verdict on *ACS*, another clip is inserted from the talk show to demonstrate Winfrey's reaction to the acquittal in her studio. While two female African American audience members jump up from their seats in joy and start cheering, Winfrey remains emotionless, even stoic, with her arms folded in front of her chest, looking away from the exhilarated women. At a closer look, one can also observe a white woman in the background staring at the two audience members in disapproval (30:29). An initially collective group was visibly divided into two opposing parties while the hostess attempted to remain impartial. The reactions of both Winfrey and her audience thus allude to the fact that

participating in rituals and the emotional energy emanating from them builds into greater social integration and a "society," as partaking in interaction rituals "chains" people to the larger social body. The inverse also occurs in that interaction ritual chains "gone wrong" can produce negative energy and damage the social body. (Shulman 65)

In order to further enhance the authentic factor of the fictional series, cinematographer Nelson Cragg also simulated the grainy images of the 1995 courtroom camera by means of different color palettes and camera angles. Each location or set required specific color grading adjustments to convey the atmosphere of the era and the site of filming. For the sequences in the District Attorney's Office, for instance, the creative team used blues, greens, and grays to relay the industrial nature of the building, and "[t]he Kardashian house was driven by a skin-tone peach color that was popular in the mid 1990s" (Hogg, *Sound & Picture*, 28 September 2016). Similarly, the color scheme of the courtroom sequences encompasses warm-toned browns, beiges, and mustard yellows to accentuate the wooden interior of the place. In contrast, the camera used to record the proceedings in 1995 did not allow the deliberate adjustment of color palettes due to the limited technological possibilities of the era and was therefore depended on the bright lighting of the courtroom lamps that did not serve any artistic purpose.Thus, to recreate the impressions of the Court TV footage, the *ACS* shots in question are brighter and far less rich in color (e.g., *ACS*, disc 4, episode 10, 28:07). In addition, the images appear pixelated and only transfer the same fixed angle shots the 1995 courtroom camera displayed, although the television series was recorded on a professional 2K resolution ALEXA camera. In an interview, Cragg stated that producer

Ryan [Murphy] originally wanted to shoot on 35mm film. It's a period piece, from 1994, so we both liked the idea of a little bit of grain in capturing the look of that era. But the reality of how I wanted to shoot the show—to run many, many cameras and shoot lots of footage—it just wasn't feasible to shoot film with 20- to 30 minute takes and four to five cameras. So we ended up shooting digitally. (Kaufman, *Creative Planet Network*, 25 February 2016)

The immediate events surrounding the verdict announcement are very closely based on Jeffrey Toobin's *The Run of His Life*.This observation becomes particularly apparent with regard to the portrayal of jury deliberations. Due to the secret nature of those conversations, the show's creators had no original material to base their adaptation on and therefore relied more closely on the narrative and the dialogues the author provided. For instance, Toobin presents a detailed account of what happened on the morning of the first and ultimately last day of jury deliberations: "At 9:16 A.M. on Monday, October 2, the twelve members of the jury settled into chairs in the deliberation room just across the back hallway from Ito's courtroom" (Toobin 425). In the television series, the scene in question opens with a close-up shot of a clock that shows 9:16 a.m. with the next tick (*ACS*, disc 4, episode 10, 17:28). Once everyone settled down in the deliberation room, the foreperson, Armanda Cooley, "asked her colleagues for advice about how to proceed. She had never before served on a jury" (Toobin 425). In the filmic adaptation, Clooney's insecurity is expressed as well and almost word-for-word, as she exclaims: "Okay. I've never been a foreperson before. I've never even been on a jury before, so if any of you have suggestions, I'm open to hearing them" (*ACS*, disc 4, episode 10, 17:29). Toobin continued with: "After a little more discussion,it was agreed that Cooley would conduct a vote by secret ballot, just to get a sense of what everyone was thinking" (Toobin 425). Subsequently, in the TV series, one juror suggests: "Why not take a vote? […] I mean, just to get a sense of the room" (*ACS*, disc 4, episode 10, 17:40).

In other instances, the close relying on Toobin's material worked to the series' disadvantage, when certain words were taken out of their literary context. For instance,in the true crime account, Toobin writes: "Goldman had bruises on his knuckles. If they were from fighting back, why didn't O.J. have any bruises on his body?" (Toobin 426). The author uses the male victim's last name and the defendant's first name for reference. In *ACS*, it is an African American juror who raises the very same question: "Goldman had injuries on his hands, like he was defending himself. Why didn't O.J. have any marks on him?" (*ACS*, disc 4, episode 10, 20:08). In this instance, the TV director decided to let a juror ask the question Toobin had posed from his first-person authorial perspective, which subsequently changes the connotation of the question on television. Having a black juror refer to the white murder victim by his last name and the African American defendant by his nickname creates different parameters of distance between the juror, Ronald Goldman, and O.J. Simpson. The last name suggests that the juror aims to establish more figurative space between herself and the victim, or that there is no emotional connection to Ronald Goldman at all. By referring to the suspect as "O.J.," however, she indicates sympathy towards Simpson and a personal connection to some degree. Hence, the sentence, as written in *The Run of His Life*, communicates far less antagonism than in the series.

There are also numerousillustrative examples of how events on *ACS* are rendered incorrectly for greater dramatic effect. In the TV series, for instance, the process of jury deliberation is told from a perspective that favors the assumption that the only two white jurors in the room were forced to render an acquittal.The show's director creates strong racial tension, whereby the black jurors assume the roles of the oppressors and the white jurors are portrayed as the oppressed. According to Toobin,it was "Carrie Bess [...], a single black woman with grown children and a civil-service job–[who] volunteered to tabulate the responses on a blackboard" (Toobin 425–426). On *ACS*, however, it is "Anise Aschenbach (the defense's white 'demon'" (426), i.e., one of the two white jurors) who tallies the votes (*ACS*, disc 4, episode 10, 18:29) and later advocates to convictO.J. Simpson. Furthermore,althoughitis not revealed who wanted to acquit or adjudge the defendant, the second vote for conviction is immediately attributed to the only other white juror in the group. All eleven heads turn towards the end of the table, where the woman is seated. Visually, the TV audience is placed in the seat of said juror through a Point of View shot. This technique, also known as a first-person shot, allows the viewers to see and experience the emotions of the character in question as they happen.With regard to the deliberate creation of racial tension in the show, it is a particularly notable shot because it places an overwhelmingly white TV audience in the figurative shoes of another white person who was a minority inside the deliberation room in 1995.

#### The Verdict Announcement

The main verdict announcement commences almost thirty minutes into the last episode of *American Crime Story*.There is a loud bang of the gavel, and a close-up shot of Simpson's face fills the TV screen for several seconds (25:54), giving the audience the opportunity to look the defendant in the eyes and analyze his facial expressions. With such detailed camera perspectives, the conveyed messages depend on the talent and the demeanor of the actor, since the viewers receive their cues only from a professional playing a character and not the real person. In this regard, the TV adaptation allows for a much more intimate observation of the athlete through the close-up, as the courtroom camera usually halted at a medium shot, in which Simpson was only shown from a lateral perspective. According to Béla Balázs, the close-up perspective establishes an intimacy between the actor and his audience that lets the latter decipher the actor's subtle shades of meaning through the face:

Facial expression is the most subjective manifestation of man, more subjective than speech, for vocabulary and grammar are subject to more or less universally valid rules and conventions, while the play of features […] is a manifestation not governed by objective canons, even though it is largely a matter of imitation. This most subjective and individual of human manifestations is rendered objective in the close-up. (Balázs 316)

Although *ACS* uses the close-up to its advantage to display emotion, the quality of the shot, however, always depends on the quality of the acting.

Following the establishing shot, the layout of the courtroom and the seating of the participants and spectators are established through several successive flash cuts (*ACS*, disc 4, episode 10, 26:17), i.e., quick shots that help set the stage for the following longer scenes and record the presence of certain characters, such as the prosecution, the defense, or the victims' families. The director placed importance on authentic gestures, and the sequences prior to the official reading of the verdict, such as the anxious folding of their hands by Cochran and Shapiro (26:01) or the way Marcia Clark folded her arms in front of her as a means to protect herself (26:03), coincide with the original footage. The information about the initiation process provided in the series, however,is partly inaccurate even though most of the scenes take place in judicial environments and buildings. While *American Crime Story* is not a documentary, but a dramatization of the Simpson trial, omissions or alterations in such a complicated and highly polarizing case are potentially problematic, particularly from the perspective of an uninformed viewer who bases their judgment of the events on the television show. For instance, as a result of the limited time available

per episode, the foreperson responsible for checking the accuracy of the signed jury forms finishes her task in a mere twenty seconds (27:50), whereas the actual procedure lasted for two minutes, allowing the tension in the courtroom to constantly rise.

Nevertheless, similar to the courtroom camera operator, *ACS*'s director did recognize the potential of Deputy Trower's walk from the clerk to the jury foreperson to mirror the agitation in the courtroom. In consistence with Court TV's footage, the focus of the camera is a close-up shot of O.J. Simpson who closely follows the Deputy's steps with his eyes (27:25). In *American Crime Story*, however, the already existing tension is further intensified as all background noises fade away, and the Deputy's footsteps become the only perceptible sound in the courtroom, with every step echoing like a heartbeat. Additionally, this particular scene was slowed down in post-production, with the effect that Trower's walk assumes a dooming quality; comparable to the march of an executioner before the final judgment as observed by the condemned. Analogous to the way the position of the courtroom camera transformed the television audience into a second jury panel in 1995 by establishing feelings of belonging and recognition (if only illusionary), in the series, the director used Point of View shots to directly place the audience in the proverbial shoes of a jury member. E.g., as the jury walks along the hallway towards the entrance of the courtroom, viewers essentially become one with the panel as the cameraman strides among the actors (26:33). Thereby, the audience can experience the feeling of being a part of the process of decision-making in the Simpson case and the excitement of entering a room where all eyes are, at least for the moment, set on them.

With regard to style and cinematic realization, the adjudication and immediate reactions to the acquittal offer the richest material for analysis. The show reaches the peak of tension in the seconds preceding the reading of the verdict. There is complete silence in the courtroom apart from the minimalist sound of a heartbeat, symbolizing universal dread and anxiety (29:13), and it slows down to almost a stop in the seconds before Deirdre Robinson utters the words "not guilty." Stock footage of citizens holding hands, praying, or covering their mouths in anticipation while staring at their TV sets are intertwined with fictional scenes from inside the courtroom (29:34). Then, resulting from the possibilities of post-production, the television screen is "cut in half " by means of the split screen technique, which allowed the creative team behind *ACS* to demonstrate emotionally charged juxtapositions simultaneously.The split screen first captures the reactions of Marcia Clark and O.J. Simpson to the acquittal. Both close their eyes at the announcement; one in defeat, the other with relief (29:41). Next, the show juxtaposes the Goldmans and Simpson's close family as they break down in tears; once again, one family sobbing in defeat while the other cries tears of joy (29:44). The subsequent split screen shots contrast other spectators' reactions in a rapid sequence to display as many emotions as possible: e.g., Christopher Darden vs. Robert Shapiro (30:07) and Judge Ito vs. Denise

Brown (30:09). These fictional reactions are combined with stock footage of public responses. The split screen illustrates America's division among racial lines as African American citizens erupt in joyous celebrations while white Americans freeze in disbelief at the outcome of the trial (30:16). The shots replace each other in quick succession, which increases the pace of the sequences in question, simulating the turmoil that took over the country shortly after the acquittal.The display of different public sentiments alsoillustrates how a verdict announcement,if televised, becomes a social event on a large scale:

Elocution [has always been] a social event. The audience gathered to witness the speaker through a collective that brought friends and strangers together to meet and greet. This event was a moment of communal experience, listening together to what they heard–from reserved claps of appreciation to uproarious laugher to the insulting taunts of hecklers–they listened and responded together. The event was also a ritual with its customary beginnings and endings; it was a ritual of information gathering, persuasion, affirmation, and change. (Madison and Hamera xiii)

According to Richard Schechner, public gatherings and demonstrations, as seen during the Simpson trial and particularly on October 3, constitute evidence for the long social history of "unofficial performances" (Schechner, "Future of Ritual" 49) that characteristically take place "in […] locales not architecturally imagined as theatres" (49). The streets of Los Angeles became a stage for social expression as critics and supporters of O.J. Simpson prayed, sang, and screamed for the conviction or release of the accused. Meanwhile, in the crowd, other citizens captured the gatherings on their camcorders and,in turn, became spectators of the spectators. In his 1962 *Introduction to Modernity*, French philosopher and sociologist Henri Lefebvre wrote: "[A] town is a place with a way of living which demands participation and encompasses spectacle […]. A town creates situations; and it is within the context of the urban milieu that the creative activity of situations, and thus of a style and a way of living, is best undertaken" (Lefebvre 345–346). Around a decade later, in 1977, Yi-Fu Tuan alluded to the relationship between the urban space and performativity, when he wrote that "the city was and is an elaborate conglomeration of innumerable stages for the performance of private and semi-public dramas" (Tuan, *Space and Place* 173–174).

According to anthropologistMilton Singer, all these elements made the Simpson trial a "cultural performance" (Singer, *Traditional India* xiii) which is characterized by a "definitely limited time span[,] at least a beginning and an end, an organized program of activity, a set of performers, an audience, and a place and occasion of performance" (Singer,*Great Tradition* 27). Herein lies the "paradoxology of performance" (Davis 27). Scholars, such as Schechner, point to the cultural and historical limitlessness of performance, "yet it is always embodied or embedded at particular places

in specific times" (26). O.J. Simpson's criminal trial is forever bound to one particular courtroom and the proceedings to a specific time period (1994 to 1995). Taking those thoughts further, I argue that it was the courtroom camera which levered out the ephemerality of this performance event and captured its liveness through a gavel-to-gavel coverage. And it is this very liveness that creates "the notion that the live performance seems to have a self-evident realness and value that the purportedly secondary 'mediated' ones do not" (Madison and Hermera xxi). The last day of O.J. Simpson's criminal trial, as captured in both the original footage and on *ACS*, demonstrated not only the spectacle and performances happening inside the courtroom, but also how the entire city of Los Angeles became a significant part of this reality show on a broader level.

### **Conclusion**

It has been over twenty-five years since O.J. Simpson stood trial for murder. His widely televised criminal case, dubbed the Trial of the Century, involved far more than the death of two people; it proved the victory of the sensational on American television, oftentimes at the cost of mutual respect and morality. Simpson's *cause célèbre* was framed and argued around television and reflected the changing media landscape in the US in the 1990s. By incessantly (re)interpreting events and narrativizing people, reality TV successfully conflated legal proceedings into entertainment programming. As has become apparent in the discussion of the Bronco Chase in the first chapter of this study, the genre capitalized on its hybridity to provide viewers with a multiplicity of frameworks and narratives through which knowledge was negotiated and constructed. The findings of this study point to the dangers of unrestrained media access to legal proceedings and demonstrate the distortive practices that dominate the reality TV realm. Due to the continuous and steady transmission of hypermediated images, the Simpson case was transmuted into a national media spectacle, creating a sense of proximity and immediacy to the events which, in the process, transformed audiences into witnesses and co-producers of the unfolding events. By taking advantage of the social and political conflicts in the country, the Simpson megaspectacle was artificially produced and maintained to increase the media's influence and create opportunities for financial and personal investment. In the process, the city of Los Angeles was reconceptualized as a marketplace, where "the ebb and flow of its energies [was] continuously organized by the objective of doing business" (Blum 181–82). Street vendors in front of the courthouse sold merchandize and other trial memorabilia and were among the most insatiable businessmen to take advantage of the proceedings in their desire to maximize profits.

The performative staging process can also be extended to the confines of an entire city, forming what Richard Schechner called the "direct theatre" (Schechner, *Future of Ritual* 86). The O.J. Simpson trial accentuated the significance of Los Angeles and specific places in the city as tourist attractions, sought out by locals and foreigners as the pivot of the proceedings. In this context, the city can be understood as a "system of desire organized around the search for experience" (Blum 262). Fans and connoisseurs of the Simpson case, for instance, visited and inspected the former crime scene or the athlete's Rockingham estate and travelled to the victims' burial sites. Drawing on Kirshenblatt-Gimblett's findings in *Destination Culture* (1998), "tourism stages the world as a museum of itself " (Kirshenblatt-Gimblett 7), infusing it with symbolic meaning and identity in a "constant spectacle of an ethical collision between the old and the new" (262). The direct theatre also involves "revolutionary street action" (86) such as the protests that erupted in the wake of Simpson's acquittal on the streets of Los Angeles, unearthing divisions and conflicts, which can be understood as "ritually necessary, temporary disruptions of an underlying unity" (86). Equally, reality-themed programs, through their position in a "social and media matrix" (Hill, Reality TV 6), transfer larger social and political issues onto smaller and more compact public scales, whereby the city is transformed into "a scene of collectivization" (Blum 3). In the academic field, it is indeed widely recognized that "the realms of city and theater have become intermixed" (Sennett 109).

When describing the process by which the urban city is converted into an object for consumption the way Los Angeles was in 1995, Saskia Sassen and Frank Roost speak of "place marketing" (Sassen and Roost 143), and Susan Fainstein and Dennis Judd assert that "[c]ities are sold just like any other consumer product […], where an unceasing flow of events constantly unfolds" (Fainstein and Judd 4). It is a reality that holds truth for the city of Los Angeles, then and now. L.A. became symbolic of "the city as a locus of the destabilized common situation" (Blum 88), opened up to what Judd and Fainstein call the "tourist gaze" (Fainstein and Judd 7). However, "[i]t is rarely evident that a location must be visited […], some significance must be assigned toit thatinvestsit withimportance"(4).The aforementioned pre-verdict CNN news report, for instance, put emphasis on the "swelling" of crowds, highlighting the supposed newsworthiness of the adjudication on the one hand and the communal gathering it represented on the other hand.The cultural and political importance of the O.J. Simpson trial was further stressed by the information that precautionary measures had even been taken on a federal level, and the President of the United States was aware of a murder trial which was, in reality, simply one of many others happening at the time. Fundamentally, there was nothing particular about the Criminal Courts Building (renamed Clara Shortridge Foltz Criminal Justice Center in 2002) or the immediate area surrounding the building. Many trials had been held at the site prior to the Simpson case, but rarely did they spark major national interest. Before turning into a symbolic place for social debate, 210 West Temple Street was "a piece of available open space" (Tuan 240). However, it is in the very nature of space that it can be transformed into "a stage for the life movie" (Gabler 211), either provided to the public conventionally (e.g., through the planned and commercialized concept of Disneyland) or by allowing people to provide it for themselves (212). Theimpact of the Simpson trial attracted people who sought to "immerse themselves

*in life*—that is, a confusion of sounds, colors, and movements that nevertheless are undergirded by a sense of order and common purpose" (Tuan 240, emphasis original). From this perspective, it is not surprising that historian Thomas Bender wrote in 1996: "It seems as if our best middle-class vision of the city today is that of an entertainment zone—a place to visit, a place to shop; it is no more than a live-in theme park. Such a city is a tourist site, even for its residents" (Bender, *LA Times*, 22 December 1996). In this sense, the Los Angeles County Superior Court gained notoriety as the main stage for the "site-specific theatre" (Tompkins 225) of the Trial of the Century, collecting \$400 million in hotel taxes, as people came to the city to watch the show live on site (Reed 174).

In similar fashion, the crime scene at Bundy and Simpson's Rockingham estate were staged as tourist attractions, where people travelled to in order to experience the places where Nicole Brown Simpson and Ronald Goldman had been killed, or the Bronco Chase found its dramatic end.The understanding of those areas as public attractions forced city officials and new tenants to actively and aggressively destroy those symbols of the Simpson case. 875 South Bundy Drive in Los Angeles, California, no longer exists. After being sold in 1997, the new owner of Nicole's condominium immediately began remodeling the exterior to detract tourists. Subsequently, the front gate, walkway, and the entrance to the building were significantly altered,and the address was changed to 879 South Bundy Drive. Similarly, Simpson's house in Brentwood at 360 North Rockingham no longer stands. After losing the civil suit in 1997, his property was foreclosed, and the mansion's new owner demolished the historic building to turn a tourist attraction back into a residence. According to Alan Blum, the city is shaped by continuous movement and stasis and coming and going. Motion, sedentariness, and "[s]paces, just as persons, persist and decline, are put to various uses, replenished, or left to rot, to abandonment and deteriorations" (Blum 236), or ultimately, destruction. These measures in the Simpson case forced *American Crime Story*'s production design team to build their own sets for the events they wanted to film.The murder scene, for instance, was in fact completely artificial and recreated on an empty lot in Brentwood one block from the actual site.

According to Blum, the distribution of scenes throughout the city also "enduce[s] people to explore territorial boundaries" (182), and he asserts that "the culture of the city is located as much in its topography of scenes as in its formal institutions" (183). The burial ground, as Joseph Roach elaborates, is one of a city's locations "where the gravitational pull of social necessity brings audiences together and produces performers […] from their midst" (Roach 28). Led by the desire to see and being seen—quite similarly to the cheering fans that filled the streets during the Bronco Chase—people understood the cemetery as a site for self-exhibitionism and participation. Likewise, Rojek establishes a connection between religious practice and celebrity when he argues that "[i]n secular society fans build their own reliquaries of celebrity culture. Always, the organizing principle behind the reliquary, from the standpoint of the fan, is to diminish the distance between the fan and the celebrity" (Rojek 58). This is the reason why cemeteries, where celebrities are buried, become popular tourist attractions. For instance, upon googling "Nicole Brown Simpson grave," the search engine lists numerous short videos, which have been uploaded to the video-sharing website YouTube by amateur filmmakers, showing their audience around the famous graveside. One channel, named *Steve's Trips Down Memory Lane*, entices potential viewers with the title "FAMOUS GRAVE TOUR: Remembering Nicole Brown Simpson At Ascension Cemetery in Lake Forest, CA." Another, only 47-second-long video, uploaded by the user Richard Yates, explains "How to find Nicole Brown Simpson Grave."The existence of public interest in finding the female victim's resting place indicates the changing understanding of the modern city. The filmmakers often narrate their trip and by doing so, become active performers in their own videos: "The great city is a theater. […] All city men become artists of a particular kind: actors" (Sennett 119). Steve, for instance, opens his video with a direct greeting of his audience: "Hey, good morning, everyone. I'm here this morning in Orange County […] at the Ascension Cemetery, where Nicole Brown Simpson is buried" ("Famous Grave Tour"). He first points out what a beautiful and warm Los Angeles day it is, forcing him to find protection in the shade of a tree, before casually transitioning into an explanation of the 1994 murders. In the next shot, Steve displays Nicole's grave, but actively aims to stay in the frame as well (01:03), even wondering "I don't know if you can see her grave behind me there" before deciding to "turn around so you can actually get a better view of it" (01:06). Similar to Walter Benjamin's notion of the *flâneur*, Steve "takes the city as his stage and promotes his own peregrinations as the necessary action that enlivens the landscape for his consumption" (Bennett 78) by intertwining information concerning the case and the Ascension cemetery with background information about himself. The viewer learns that in 1994, he "actually lived just a number of miles away" ("Famous Grave Tour," 03:44) from the cemetery, but at the time, he was not interested in visiting famous graves, yet. Now, however, being "semi-retired," Steve finally finds the time "to go do things, […] [he] didn't have time to do when [he] was busy working" (04:01), and he is "glad to be here today" (04:15). In the background, soft wind chimes hanging from a nearby tree provide the musical accompaniment to his narration. Steve also lets his audience know that the Ascension cemetery is indeed "a pretty small cemetery and the grave is easy to find if you want to visit" (01:37).The location's full address, phone number, and website link are conveniently provided in the information box under the video. After four minutes, his tour ends with a final close-up shot of Nicole's grave. In the upper left corner of the video, a smaller window pops up, offering to take the audience to another one of Steve's videos, titled "FAMOUS GRAVE TOUR: Remembering Ron Goldman At the Valley Oaks Cemetery in Westlake, CA."

The website *www.death2ur.com* is another source of information pertaining to famous burial sites. Arranged in alphabetical order, the user can choose from a great number of celebrity names. Upon clicking on the desired title, the visitor is taken to a new page, which contains numerous photographs of the grave as well as short explanations of any headstone inscriptions. Ronald Goldman's family, for instance, engraved the ankh, an ancient Egyptian hieroglyphic symbol, on his stone. The respective short text on *death2ur* next to Ronald's photograph explains that

[i]t was a symbol that Ronald Goldman took to represent his own life. After a rocky period, he had gotten things going in the right direction again. He had taken a job as a waiter and began working toward his dream of owning his own restaurant which he would call "The Ankh." It was a dream that would never be. (http://www .death2ur.com/ronald.htm)

A Google search leads the interested party to the *death2ur* YouTube channel, where the website's still pictures are enriched with amateur videos.There, too, one can find a grave tour around Nicole Brown Simpson's resting place. The unknown cameraman begins his video by filming his two companions, a man and a woman, casually dressed in denim wear and t-shirts, standing and staring at Nicole's grave.The man sips a hot beverage from a white disposable cup while the woman fixates her camcorder on the headstone ("Nicole Brown Simpson's Grave," 00:10). A sea of flowers lines the grave, and the cameraman and his friends notice that some are arranged in a cross formation (00:53). As they walk away from the site, the audience is able to listen in on their interaction. One of the interlocuters gets excited at the thought of potentially encountering members of the victim's family at the gravesite, to which one of the other speakers interjects that they might even see O.J. Simpson. Picking up on the cue, the filmmaker shares a story with his friends and audience about the day of Nicole's funeral, where Simpson was also present: "He actually looked into the casket and gave her a kiss and said 'Sorry, Nikki.'

The three chapters of this study explicate how, facilitated by the episodic nature of legal proceedings and driven by commercial interests, celebrification and storytelling played key roles in the social performances and the sensationalization and mediatization of the Simpson case. The findings presented here indicate that the media deliberately focused on the personalities the public desired to see, thereby explaining why prosecutor Marcia Clark's hair and clothes moved to the foreground while the life and death of the murder victims disappeared into obscurity. The danger herein lies in the reductionist principles of social typing and celebrification processes. As was discussed in the analysis of the glove demonstration in the third chapter of this study, complex characters and circumstances are trivialized, yet identified to be of major significance. Consequently, even though research indicates that television viewers are not the once believed passive consumers of mass media, the latter has power over what the audience thinks *about*. Had the focus of attention not been so stoically placed on the O.J. Simpson case, the public could have noticed the significance of other events that were happening in the country, e.g., the Oklahoma City Bombing in April of 1995.These findings accentuate the media's agenda-setting power and stress that the television medium does not denominate a pre-existing meaning but rather produces interpretations as an active "signifying agent" (Hall 64). Hence, the multiple narrative strings introduced over the course of the Simpson trial highly differed from each other, but were always advantageous to the presenter's desired point of view. It was left to the jury (TV audience, spectators…) to denominate the most credible account. Prosecutor Christopher Darden, e.g., described the murders in Brentwood as "rage killings"(Court Transcript, 27 September 1995) and O.J. Simpson's premeditated decision to inflict violence on his ex-wife as a "homicidal fit" in the wake of being left by both Nicole and his then-girlfriend Paula Barbieri. Indeed, Gerbner et al. assert that violent rhetoric "plays a key role in television's portrayal of the social order" (Gerbner et al. 180). As the following court transcript from Darden's closing argument illustrates, acts of physical aggression are readily recited to produce emotive impact, describe unequal power relationships, and reinforce conventional concepts of morality:

He [O.J. Simpson] made a choice that day. He chose Nicole over Paula and he lost them both. […] This is a rage killing and it is up front, and it is personal and that is why you see all the brutality that you see. […] And he is using a knife because he is there to settle a personal score, a personal vendetta that he has. […] And the rage that he has, the anger, the hate that he has for her that night at that time, […] it flows out of him and into the knife and from the knife into her, into her. […] With each thrust of that knife into her body and into Ron's body, there is a […] gradual release of that anger and that rage and he stabs, and he cuts, and he slices until that rage is gone and until these people are dead. And after that rage is gone, he is better. […] He just walked away. […] He is a murderer. He was also one hell of a great football player, but he is still a murderer. (Court Transcript, 27 September 1995)

O.J. Simpson's defense team presented numerous counter-narratives to the State's theory and relied on their client's professional achievements to imply that Simpson's service in the National Football League ultimately left him incapable of murder:

O.J. Simpson by all accounts has trouble with lateral movement from moving side to side because you saw […] those knee operations that basically spell NFL, National Football League […]. That is the price that a running back pays. And while I'm talking about running backs, wasn't it interesting yesterday that Ms. Clark in her argument says O. J. Simpson was a football player. He used to run through the line, and he has the killer instinct. […] O. J. Simpson hasn't played football for 15

years. The man is 46 years old now. He's not going to run with anything anymore. But she doesn't know much about sports, does she, because a running back avoids trying to be hit. It's what he does. […] Played football 15 years ago and he was the best at what he did. He won the Heisman Trophy, according to his daughter, the day she was born. Emblematic of the best football player in America. (Court Transcript, 27 September 1995)

Admittedly, it is the nature of trials to present different narratives in prosecution and defense of the defendant. However, I suggest that it is this very characteristic that opens legal proceedings up to public entertainment and exploitation, as there are seemingly no limitations or moral boundaries to the narrative propositions made in court and the media. In this context, narratives of shame and humiliation take center stage and are emblematic for the tabloidization of legal proceedings.

Notably, the O.J. Simpson case was not a 'megaspectacle' that was exclusively consumed by a local and national audience. Rather, the 1990s marked a time when the popularity of factual genres and the success of the Courtroom Television Network allowed for the globalization of legal performances. The Irish newspaper *Sunday Tribune*, e.g., reported on O.J. Simpson's 47th birthday on July 10, 1994, which he spent in jail while standing trial for the murders. Reporter Michael Miller wrote:

As Simpson languished behind bars, his attorney prepared for what could become the trial of the century, if the massive live television coverage and media exposure thus far is any indication. Even the preliminary hearing has received gavel-to-gavel nationwide coverage, with each of the three networks broadcasting live from the courtroom. (Miller, *Sunday Tribune*, 10 July 1994)

Even international news media outlets were thus aware of the impact the extensive coverage could and would have on the murder trial. In October of 1994, the German newspaper *Die Zeit* published Michael Schwelien's almost novelistic article on the case, titled "Die letzte große Rolle des O.J. Simpson" ("O.J. Simpson's Last Great Role"):

Angetan mit tadellosem Anzug, Zuversicht im Blick, entbietet O.J. den Kandidaten für die Jury ein höfliches *good afternoon*.  Respekt. […]

O.J. macht es sich bequem.  Er macht sich sorgfältig Notizen. Harte Arbeit steht bevor, gemeinsam stehen wir sie durch. Entspannung. […]

O.J. ist nicht wiederzuerkennen. Dies ist nicht der O.J., der am 20. Juni im Vorverfahren düster dreinblickend "unschuldig" hervorpreßte, als er Stellung nehmen mußte, ist nicht der O.J., der ohne Krawatte—Selbstmordgefahr—und mit gesenktem Haupt schon die Tür zur Todeszelle geöffnet zu haben schien. […] Dies ist der O.J., der alle Footballrekorde brach, der in Werbespots für den Hertz-Autoverleih durch Flughafenhallen raste, der O.J., der in den Filmkomödien "Die nackte Kanone" mitalberte, dies ist der richtige O.J., zuversichtlich, aus vollen Lippen und mit wissenden Augen lächelnd. (Schwelien, *Die Zeit*, 14 October 1994, emphasis original)

The excessive national and international interest in the Simpson story can be attributed to the fact that the case provided all the necessary and beloved elements that characterize traditional crime shows such as *Cops*, *America's MostWanted*, or *Undercover Stings*: the enigmatic murders, the car chase and arrest, the unpredictability and suspense, the violence and danger, the drama and tragedy, the revelation of dark secrets, and most importantly, the unequivocal and reassuring definition of what and who was good and bad.

Certainly, one might argue that the 1990s are over, and the popularity of televised trial proceedings has receded. At first glance, this seems to be the case, indeed. After the O.J. Simpson trial, Court TV faced declining numbers in viewers and revenue. Ownership of the channel changed numerous times. In 1997, Time Warner bought out Steven Brill's stake and in 2008, Court TV was replaced by truTV, which ironically implemented comedy series into its programming. There is little left of the crime network Steven Brill had once envisioned and brought to life. Similarly, the influence of celebrity seems to be in decline if judged by viewer ratings of award shows in the US. In an online article for *TIME Magazine*, Judy Berman cites the sinking audience numbers for the Academy Awards (Oscars), with an unprecedented low of only 23.6 million viewers in 2020 from a previous average of 40 million, as an indicator of the end of celebrity culture as we have known it (Berman, *TIME*, 16 January 2020). Likewise, in his article for the online publication *IndieWire*, journalist Tyler Hersko claims that "[t]he 71st Emmys Was a Catastrophic Failure for Awards Show Viewership" (Hersko, *IndieWire*, 23 September 2019). One of the reasons for this development seems to be TV producers' refusal to concur with contemporary viewing habits:

As for the prominence of streaming, it's the elephant in the room that the Emmys, regardless of which network is hosting it, needs to begin addressing. No, network and cable TV isn't going anywhere […] but streamers such as Netflix and Amazon Prime Video are steadily producing a larger chunk of the television shows that define the cultural zeitgeist. Streaming is the new norm for the distribution of television shows, yet viewers need access to the Fox channel to tune in to the Emmys. (Hersko, *IndieWire*, 23 September 2019).

One is left wondering if celebrity culture is slowly going extinct in a time and age where the public seems fed up with the larger-than-life status of actors and refuses to worship them for being better-than. In his fiery article, Freddy Gray describes this very sentiment:

Another year, another dreadful Oscars, another round of moral lectures from the beautiful people. It's all so tiresome. The only reason most people pay attention to these irritating award ceremonies is precisely so that they can be irritated. […] All these people [celebrities] are ridiculous. Nothing they say makes any difference to anything. Actors are increasingly aware […] that nobody cares what they think. At some unconscious level, these actors must know that they don't really know anything about politics or the real world. They can't admit this to themselves, of course, human nature being what it is, so they double down. They convince themselves that any angry reaction to their moralizing is an indication that they have dared to speak truth. How brave they are! And so the infuriating cycle continues. Actors end up almost trolling the public, and the public trolls them back on social media. (Gray, *Spectator USA*, 10 February 2020)

Considering these circumstances, one is initially inclined to assert that the popularity of a celebrity's public prosecution is now a monument of the past. At second glance, however, a different truth is revealed. Since the Simpson trial, numerous other cases have been extensively covered on television and sparked passionate public debates. Consider, for instance, the trials of Casey Anthony (2011), Dr. Conrad Murray (2011), George Zimmermann (2012), or Jodi Arias (2013), to name a few. As the analysis of the verdict coverage in the third chapter of this study has shown, even the Simpson trial continues to spark public interest, documentaries, and filmic adaptations due to lack of a general sense of closure. *American Crime Story* (2016) has introduced the case to a new audience and recaptured older viewers in its attempt to bring back the events onto the television screen. The juxtaposition of the original media coverage with its filmic pendants revealed that although the series thrives on dramatizations, exaggerations, additions, and omissions, the line between reality television and fictional formats is fine and oftentimes hard to pinpoint. Instead of representing two opposing ends of the spectrum, reality formats and TV adaptations share production processes and narrative discourses as well as elements of fact and fiction, unveiling a relationship of reciprocal influence.

Additionally, Court TV has also returned in new form: updated and fully digital, it offers livestreams, clips, and complete hearings of popular cases (https://www.co urttv.com). In the "About Us" section on the website, the reader learns:

For nearly two decades, Court TV brought high-profile courtroom dramas into American living rooms. Continuing that legacy, Katz Networks is rebooting one of the most iconic brands in television history. The new Court TV is devoted to live gavel-to-gavel coverage, in-depth legal reporting and expert analysis of the nation's most important and compelling trials. The network will run 24 hours a day, seven days a week and will air on cable, satellite, over-the-air and over-the-top. (https://www.courttv.com/about-us/)

Furthermore, the network's connection to O.J. Simpson, its most popular defendant, remains unbroken. The complete 2008 trial of *Nevada v. O.J Simpson and C.J. Stewart* is available in the "Trials on Demand" section of the website. Conclusively, as long as television exists, crime and celebrity will dominate its programming, in particular on reality formats. Fact and fiction will continue to coalesce, and audiences will be transformed into co-producers of media spectacles in the attempt to create collective national experiences.

### **Works Cited**

<sup>1</sup> All *ACS* episode references and quotations were extracted from this particular DVD source/collection. To avoid redundancy, I have refrained from listing each episode title individually in the Works Cited register of this study.

Andrejevic, Mark. "When Everyone Has Their Own Reality Show." *A Companion to Reality Television*. Ed. Laurie Ouellette. Chichester: Wiley, 2014. 40–56. Print.

Associated Press. "Washington Newseum Acquires O.J. Simpson's Acquittal Wardrobe for 'Trial of the Century' Display." 7 April 2010. Web. 29 July 2019. <htt ps://www.nydailynews.com/entertainment/gossip/washington-newseum-acq uires-o-simpson-acquittal-wardrobe-trial-century-display-article-1.168465>.

Austin, J.L. *How to Do Things with Words*. Oxford: Oxford UP, 1962. Print.

Balász, Béla. "The Close-Up." *Film Theory and Criticism: Introductory Readings*. 8th ed. Ed. Leo Braudy and Marshall Cohen. New York: Oxford UP, 2016. 198–200. Print.

Cartmell, Deborah, and Imelda Whelehan, eds. "Introduction." *The Cambridge Companion to Literature on Screen*. New York: Cambridge U P, 2007. 1–12. Print.

Cotterill, Janet. *Language and Power in Court: A Linguistic Analysis of the O.J. Simpson Trial*. New York: Palgrave Macmillan, 2003. Print.

Court Transcripts. Uploaded by Jack Walraven, http://simpson.walraven.org/.<sup>2</sup>

<sup>2</sup> All court transcripts quoted in this study have been taken from the website http://simpson. walraven.org/. As they have been arranged reader-friendly by year, month, and date by the site's owner, Jack Walraven, I have decided not to list each court transcript individually in this study's Works Cited.

Douglas, Susan J., and AndreaMcDonnell.*Celebrity: AHistory ofFame*.New York: New York UP, 2019. Print.

Grzesik, Jürgen.*Operative Lerntheorie: Neurobiologie und Psychologie der Entwicklung des Menschen durch Selbstveränderung*. Bad Heilbronn: Julius Klinkhardt, 2002. Print.

Hickethier,Knut.*Film-undFernsehanalyse*. 5th ed. Stuttgart: J.B.Metzler, 2012. Print. Hill, Annette. *Reality TV*. Abingdon: Routledge, 2015. Print.

Simpson-detailed-night-lesbian-sex-satisfied-black-men-like-OJ-Marcus-Alle n.html>.

Kellner, Douglas. *Media Spectacle*. London: Routledge, 2003. Print.

Kraszewski, Jon. *Reality TV*. New York: Routledge, 2017. Print.

Kurtz, Howard. "Up in the Air All Day Long." *Washington Post*. 21 June 1994. Web. 29 July 2019. <https://www.washingtonpost.com/archive/lifestyle/1994/06/21/up-i

n-the-air-all-day-long/bf15680a-1d53-4845-b410-3703edb23ace/?utm\_term=.88 73622e0f12>.

Mirzoeff, Nicholas. *An Introduction to Visual Culture*. London: Routledge, 1999. Print.

Brodsky Lacour. New York: Pantheon Books, 1997. vii-xxviii. Print.

*Theatre and Ritual*. Ed. Richard Schechner and Willa Appel. Cambridge: Cambridge UP, 1991. 245–249. Print.

tenfilmmaterial/75798967?adppopup=true. Accessed 8 March 2021.

2 Jul. 2012. Web. 16 November 2020. <https://edge.sagepub.com/system/files/7 7593\_13.1ref.pdf>.

Rapping, Elayne. *Law and Justice as Seen on TV*. New York: New York UP, 2003. Print.

Steven Chermak and Frankie Y. Bailey. Westport: Greenwood P, 2007. 153–167. Print.

**Tatjana Neubauer** (Dr. phil.), born in 1989, has been teaching and researching as a doctoral student at Johannes Gutenberg-Universität Mainz, Germersheim campus, since 2016 and until the successful completion of her PhD in September 2021. Her main research interests lie in (North) American Studies, Media Studies, and Native American Studies.

# Cultural Studies

Gabriele Klein Pina Bausch's Dance Theater Company, Artistic Practices and Reception

2020, 440 p., pb., col. ill. 29,99 € (DE), 978-3-8376-5055-6 E-Book: PDF: 29,99 € (DE), ISBN 978-3-8394-5055-0

 Markus Gabriel, Christoph Horn, Anna Katsman, Wilhelm Krull, Anna Luisa Lippold, Corine Pelluchon, Ingo Venzke Towards a New Enlightenment – The Case for Future-Oriented Humanities

October 2022, 80 p., pb. 18,00 € (DE), 978-3-8376-6570-3 E-Book: available as free open access publication PDF: ISBN 978-3-8394-6570-7 ISBN 978-3-7328-6570-3

 Sven Quadflieg, Klaus Neuburg, Simon Nestler (eds.) (Dis)Obedience in Digital Societies Perspectives on the Power of Algorithms and Data

March 2022, 380 p., pb., ill. 29,00 € (DE), 978-3-8376-5763-0 E-Book: available as free open access publication PDF: ISBN 978-3-8394-5763-4 ISBN 978-3-7328-5763-0


**3.4 31P NMR spectroscopy**

In the **Figure 6** are represented the 31P NMR-MAS spectra. A single isotropic signal was observed for all the spectra. It indicated also that a unique crystallographic site for the PO4 tetrahedron in the apatite structure was present. However a slight chemical shift towards the lower values was observed as well as a broadening of the peaks was attributed to the Nd substitution. This fact was related to a disorder induced in the apatite network caused by the substitution of La by Nd. This was previously seen with doped with rare earth apatite's [46–48].

### **3.5 Materials sintering**

Materials densification optimization has been performed by sintering the synthesized samples in the temperatures range 1250–1500°C with a fixed holding time of 6 h. Relative density *dre* was calculated using the equation:

**Figure 6.**

*31P NMR-MAS spectra of fluorbritholites Sr8La2*�*xNdx(PO4)4(SiO4)2F2 with (0* ≤ *x* ≤ *2).*

$$d\_{r\epsilon} = \frac{\rho\_{\text{the}}}{\rho\_{\text{exp}}} \times 100\tag{5}$$

where the theoretical density ρthe was calculated using the equation:

$$
\rho\_{\text{the}} = \frac{\text{ZM}}{\text{NAV}} \tag{6}
$$

(Z: number of molecules/unit cell, M: molecular weight Na: Avogadro number and V: volume of the unit cell) and experimental density determined from the mass and the dimension of sintered pellets by means of the equation

$$
\rho\_{\text{the}} = \frac{m}{\pi hr^2} \tag{7}
$$

**Figure 7** shows that relative density of the sintered samples strictly depends on sintering temperatures as well as on Nd content. An irregular trend was noted and the highest relative density 89% was obtained with x = 2 Nd content when sintered only at 1250°C. The remaining samples presents lower than densifications ratios obtained at

*Ionic Conductivity of Strontium Fluoroapatites Co-doped with Lanthanides DOI: http://dx.doi.org/10.5772/intechopen.102410*

**Figure 7.** *Relative density versus sintering temperature of Sr8La2*�*xNdx(PO4)4(SiO4)2F2 with (0* ≤ *x* ≤ *2).*

higher temperatures. From these data, it can be deduced that the grains morphology and size modification strongly depends on Nd content and sintering temperature. The Nd doping should improve the materials densification by reducing the porosity. This was confirmed by the percentage porosity of the higher densified samples calculated by the following equation:

$$p = (1 - dr) \times 100\tag{8}$$

As plotted on **Figure 8**, the porosity of the samples decreased as Nd content increased. This result muched the evolution of the relative density suggested to

**Figure 8.** *Porosity versus Nd content of maximum densified samples.*

increase when crystallite size is reduced (i.e. grain size). This should promotes the materials densifications by eliminating the intergranular porosity.

The microstructure of the samples given on **Figure 9** is closely coherent with the densification rates as well as porosity. Indeed, the micrographs show a progressive removal of the porosity when the Nd rate rises. Thus with x = 0 the microstructure is of intergranular aspect revealing the presence of abundant porosity. With x = 0.5, although some pores persist on the surface the porosity was reduced,. When x = 1 the open porosity has almost disappeared and only the closed porosity remains, reflecting the 89% densification.

$$\text{Sr}\_8\text{La}\_{2-x}\text{Nd}\_x(\text{PO}\_4)\_4(\text{SiO}\_4)\_2\text{F}\_2 \text{ with } (\mathbf{0} \le \mathbf{x} \le \mathbf{2}). \tag{9}$$

### **3.6 Impedance spectroscopy**

The ionic conductivity of the samples was determined between 400 and 800°C with a step of 20°C by complex impedance plots. Thus, for each sample, 20 complex impedance plots (plane, Z″ vs Z0 ) were plotted. The intercept of the semicircular arcs with the real axis allow obtaining the bulk resistance R. The ionic conductivity of the sintered samples was calculated from the equation:

$$
\sigma = \frac{\mathbf{e}}{\mathbf{S} \mathbf{R}} \tag{10}
$$

The thickness and the area of the sample were e and S, respectively. **Figure 10** reprinted the ionic conductivity σ versus the neodymium substitution. The first deduction is that σ depends on this substitution and particularly at higher temperatures. The curves obtained at 604 (877 K) and 482°C (755 K) indcated that the measured conductivity was about 4.4 � 10�7 S cm�1 . By contrary with the increase of Nd content, σ rose up to 1.73 � 10�6 S cm�1 at 779°C (1052 K). Hence, the electric conductivity of the samples depend onthe Nd substituted level.

The total activation energy of the samples was obtained from the Arrhenius equation:

$$
\sigma \mathbf{T} = \mathbf{A} \mathbf{e}^{-\frac{\mathbf{E}}{\mathbf{K} \mathbf{T}}} \tag{11}
$$

The parameters to define are the pre-exponential factor A, activation energy Ea, Boltzmann constant k and absolute temperature T, respectively. **Figure 11** shows an Arrhenius-type plot indicating that the electrical conduction of the materials is activated by heating. The σ values were slightly different from those found in the

**Figure 9.**

*Micrographs of sintered samples Sr8La2*�*xNdx(PO4)4(SiO4)2F2 (a) x = 0.0; (b) x = 0.5; (c) x = 1.0.*

*Ionic Conductivity of Strontium Fluoroapatites Co-doped with Lanthanides DOI: http://dx.doi.org/10.5772/intechopen.102410*

**Figure 10.** *Ionic conductivity versus neodymium content.*

**Figure 11.** *Plots of LnσT versus 1000/T of fluorbritholites Sr8La2xNdx(PO4)4(SiO4)2F2 with (0* ≤ *x* ≤ *2).*

literature [49, 50]. The difference might have resulted from the preparation and sintering methods reflected by the difference in densification ratios (range 72–83%). The slope in the Arrhenius plots versus temperatures gives the activation energy. This later parameter increased when Nd level rose reaching a maximum of 1.1 eV when x = 1 then decreased to 0.91 eV (**Table 4**). Moreover a slight break in slope for x ≥ 1 was detected in the Arrhenius plots. This was related to the Sr/NddF bond likely to the work of Njema and al [49]. In fact, in Sr8La2xNdx(PO4)4(SiO4)2F2 with (0 ≤ x ≤ 2) samples, the mobility of F along the *c* axis ensure the charge motion. Thus as the Nd-doping increased the F mobility was enhanced and the conductivity was improved. The fluoride ions motion along the structure should be related to the

*Mineralogy*

**Table 4.**

*Activation energy of Sr8La2*�*xNdx(PO4)4(SiO4)2F2 with (0* ≤ *x* ≤ *2).*

neodymium polarizability slightly higher than its of lanthanium. Herein, the polarizabilities of lanthanum and neodymium were 4.82, 5.01 Å3 , respectively [51, 52]. Laghzizil and *al* emphasized the improved fluoride mobility in the presence of polarizable cations localized in Me(2) site [53, 54].


**6. BACE-1 inhibitors in the treatment of Alzheimer's disease**

subsequently formed in the neurons. BACE-1 and the homologous BACE-2 are regulated differently and also control different processes. A disrupted intracellular calcium homeostasis may stimulate the genetic expression of BACE-1 *via* triggering the nuclear factor of activated T-cells of type 1 (NFAT1), which leads to over-production of Aβ. Expression of the BACE-1 can also be controlled by the level of Aβ1–42 (but not by the Aβ1–40) through some transcription factors. In addition, some plaques containing Aβ1–42 even increase the levels of BACE-1 in the adjacent neurons just before their death [10]. The homologous enzyme BACE-2 shares 64% of the sequence identity with BACE-1. The action of BACE-2 is in many aspects similar to the activity of α-secretase. BACE-2 triggers a cascade of cleavage of APP by the non-amyloido-

4 Alzheimer's Disease - The 21st Century Challenge

genic way. Its physiological function is associated with the organ pigmentation [11].

In order to clearly demonstrate the involvement of BACE-1 in the pathogenesis of AD, many prominent scientific groups worldwide dealt with developing a mouse model that had deactivated the gene for the production of BACE-1 (i.e., BACE-1 knockout (−/−) mice). At first, these strains of mice were viable, capable of reproduction, with the normal morphology of the body, without any obvious signs of damage of the tissues and normal blood picture [12]. This finding supported the idea that inhibition of BACE-1 can bring about the desired therapeutic effect without adverse effects. The results of this study also point to the fact that the related BACE-2 fails to offset the activity of BACE-1 in the formation of Aβ. It is interesting that hybridization of these BACE-1 knockout (−/−) mice with transgenic mice having the APP gene, which increasingly produce amyloid plaques, provided a generation, the newly born individuals of which did not exhibit the formation of Aβ, Aβ deposits or signs of memory impairment caused by production/accumulation of Aβ. As already mentioned, BACE-1 is located mostly in the presynaptic endings of neurons, where its physiological effects is assumed to occur. Over time, however, it was found that BACE-1 knockout (−/−) mice had impaired axonal conduction, experiencing hypomyelinization (i.e., disrupted formation of myelin, the substance that surrounds the axons and nerve fibers), memory disorders, disturbed neurochemical balance, pathological neurogenesis, astrogenesis, degeneration of neurons with increasing age, pathological changes in the retina and schizophrenic symptoms. All these discoveries observed in BACE-1 knockout (−/−) mice can serve as a model that reflects the potential adverse effects associated with the administration of BACE-1 inhibitors for normal animals or people [13].

The substrates subject to proteolysis by BACE-1 are in particular the membrane-bound proteins like APP. Many of these BACE-1 substrates undergo a process called ectodomain shedding (ectodomain is a part of a membrane protein which protrudes to the extracellular space), while at the same time, these substrates can be cleaved by proteases, called also disintegrins, and ADAM-related metaloproteases. The extent of cleavage of the substrate by ADAM related proteases or BACE-1 depends on the nature of the particular substrate. All the possible side effects caused by inhibition of BACE-1 thus may not be always exhibited, assuming that

The homology between BACE-1 and BACE-2 gave rise to arguments that BACE-1 inhibitors may simultaneously inhibit non-selectively also BACE-2. For this reason, transgenic BACE-2 knockout (−/−) mice were developed to clarify the physiological role of BACE-2 and to explore the benefits offered by inhibition of this enzyme. Similar to the BACE-1 knockout (−/−) mice, the

some substrates are hydrolyzed by another protease [14].

Currently, BACE-1 inhibitors have an exclusive position regarding the therapeutic options for introduction into clinical practice to treat AD [16]. Their mechanism of action is based on reducing the levels of Aβ in the brain. Although several of these inhibitors had already reached clinical testing, there are still important questions to answer, for instance, about their safety, the optimum degree of inhibition of BACE-1 needed to achieve the desired therapeutic effect without the presence of side effects, and the stage of the disease when these compounds are to be indicated in order to achieve the greatest assets [17].

Aβ is produced by neurons in the brain, partly also by astrocytes and other glial cells, which are involved in the formation of this protein in particular during the stress conditions accompanying the AD development. For the production of Aβ, the activity of both enzymes, BACE-1 and γ-secretase, is necessary [10]. The biochemical processes involving the activity of these enzymes are often referred in the literature as the amyloid pathway. Importantly, modulation or inhibition of these enzymes can reduce the formation of Aβ in the brain of patients with AD. On the other hand, activation of the non-amyloidogenic pathway by supporting the α-secretase activity may also reduce the formation of Aβ and currently it is alternatively considered as a promising approach for therapy of AD. An important role for the accumulation of Aβ is also played by the genetic aspects of AD. Nowadays, more than 200 autosomal-dominant mutations in APP and presenilin (PS) have been identified which contribute to the occurrence of familial forms of AD [18]. Without any exception, all these mutations increase the production of all Aβ isoforms, in particular the toxic Aβ containing 42 amino acids (Aβ1–42). An example might be seen in Swedish mutation of APP in the amino acids Lys670 and Met671, that is, the places where BACE-1 enzyme cleaves APP. This mutation results in higher proteolytic efficacy of BACE-1, which promotes an increased rate of the C99 fragment formation and thereby the total production of Aβ [19]. The *APOE-ε4* allele represents a major genetic risk factor for the development of AD with the late onset and it is also associated with an increased production and accumulation of Aβ. Similarly, mutation of ADAM10 metaloprotein, which is endowed with physiologically similar activity to that of α-secretase in neurons, causes the late onset of the AD by suppressing this enzyme activity, while the amyloidogenic cleavage of APP by BACE-1 prevails [20]. Recently, at least five different genes whose mutation contributes significantly to the increased formation of Aβ have been identified. Based on all these mutations and their effects, we can conclude that Aβ is responsible for the pathogenesis leading to the breakout and development of AD. Accordingly, some mutations in APP can represent a protecting mean to suppress the progression of AD. For example, a mutation in the Ala673 region (so-called Ala673Thr mutation) causes a lower affinity of APP to BACE-1, bringing the production of Aβ reduced by up to 40% [21].

Extensive research is dedicated to the development of small molecule inhibitors of BACE-1, capable to act centrally. The first experimental inhibitors were derived from short fragments of APP, being therefore peptide derivatives. These differed from APP by modified amino acid sequence and increased metabolic resistance against cleaving by BACE-1. In *in vitro* conditions these bulky peptide derivatives showed high affinity for BACE-1, especially due to the fact that the active site of BACE-1 is so large that it is able to cleave very large substrates. The disadvantage of these derivatives is that they do not possess true drug-like properties, exerting low oral availability and short half-life in the plasma. Such drug candidates are quickly metabolized and have low permeability through the blood-brain barrier. For these reasons, the researchers have focused on the development of small BACE-1 inhibitors that have high affinity for this enzyme, but are small enough to penetrate through the blood-brain barrier and, at the same time, to exhibit suitable pharmacokinetic properties. In addition, these compounds must be lipophilic enough to permeate through the cytoplasmic and endosome membrane to block the active site of BACE-1 located inside of the lumen. A large number of these compounds, however, reached only a limited concentration in the brain because in most cases, they reached high efflux mediated by P-glycoprotein (P-glycoprotein is an ATP-dependent pump, which removes xenobiotics and protects the brain from the effects of these compounds) [22].

The latest generations of BACE-1 inhibitors are characterized by a good capacity to permeate through the blood-brain barrier, by a suitable pharmacokinetic profile, and the ability to induce reduction of the cerebral levels of Aβ. The result of the research is a panel of several inhibitors of BACE-1, which have entered various stages of clinical testing [23].

MK-8931 was applied in three different doses (12, 40 or 60 mg) and the effect was compared with the placebo over a period of 7 days. The markers of Aβ1–40, Aβ1–42 and sAPP-β were also monitored. As in the previous phase, decrease in the levels of Aβ, depending on the dose of the drug (for the Aβ1–40 57% (12 mg), 79% (40 mg), 84% (60 mg)) was observed and, in addition, without the presence of the more serious side effects. The results of this phase of clinical trials are especially important because the pharmacokinetic and pharmacodynamic properties of this BACE-1 inhibitor are not affected by the quantity of Aβ present in the brain of patients with AD. At the end of 2012, MK-8931 advanced to the clinical phase (II/III) with patients suffering from mild to moderate dementia of AD type. This substance was administered in dosages of 12, 40 and 60 mg and controlled with placebo in the total sample of 200 patients. According to the initial promising results, extension of the third phase of clinical trials by another 1960 patients with AD is expected. Further evaluation of MK-8931 is simultaneously monitored within the III phase of clinical testing on 1500 patients with AD. The

Amyloid Beta Hypothesis: Attention to β- and γ-Secretase Modulators

http://dx.doi.org/10.5772/intechopen.75629

7

A non-peptidic BACE-1 inhibitor LY2811376 (**Figure 2**), which was analyzed in a study with oral administration, demonstrated satisfactory pharmacokinetic and pharmacodynamic properties in animal models, which promoted the compound to the first phase of clinical trials. These clinical studies, however, were soon discontinued due to adverse reactions, in particular in the area of inflammation of the retina and the occurrence of stroke. Although all other studies

results of both studies are to be expected in 2017–2018 [24].

**Figure 2.** Chemical structures of BACE-1 inhibitors in clinical testing.

**6.2. LY2886721**

#### **6.1. MK-8931**

In 2012, the results of the first phase of clinical trials with inhibitor MK-8931 were presented (**Figure 2**), which had been performed in 88 healthy individuals aged between 18 and 45 years. The safety, tolerability, pharmacokinetic and pharmacodynamic parameters after single or repeated administration were experimentally determined. MK-8931 was generally well tolerated, and no severe side effects were observed. The main goal in this first phase was to determine whether MK-8931 was capable of penetration into the brain to inhibit the activity of BACE-1. Biomarkers monitoring the levels of Aβ1–40, Aβ1–42 and soluble fragment of APP (sAPP-β), which is formed by BACE-1, were intensively studied. MK-8931 significantly decreased the concentrations of cerebrospinal Aβ, depending on the dose administered, and even in repeated oral administration a reduction of Aβ in the CSF of up to about 90% has been observed. The plasma half-life of MK-8931 after a single administration was around 20 h, which assumes the dosing schedule within the range of a single daily dose. This was followed by a clinical study 1b, where the safety, tolerability, pharmacokinetics and pharmacodynamics in 32 patients with mild to moderate dementia of the AD type were determined. Amyloid Beta Hypothesis: Attention to β- and γ-Secretase Modulators http://dx.doi.org/10.5772/intechopen.75629 7

**Figure 2.** Chemical structures of BACE-1 inhibitors in clinical testing.

MK-8931 was applied in three different doses (12, 40 or 60 mg) and the effect was compared with the placebo over a period of 7 days. The markers of Aβ1–40, Aβ1–42 and sAPP-β were also monitored. As in the previous phase, decrease in the levels of Aβ, depending on the dose of the drug (for the Aβ1–40 57% (12 mg), 79% (40 mg), 84% (60 mg)) was observed and, in addition, without the presence of the more serious side effects. The results of this phase of clinical trials are especially important because the pharmacokinetic and pharmacodynamic properties of this BACE-1 inhibitor are not affected by the quantity of Aβ present in the brain of patients with AD. At the end of 2012, MK-8931 advanced to the clinical phase (II/III) with patients suffering from mild to moderate dementia of AD type. This substance was administered in dosages of 12, 40 and 60 mg and controlled with placebo in the total sample of 200 patients. According to the initial promising results, extension of the third phase of clinical trials by another 1960 patients with AD is expected. Further evaluation of MK-8931 is simultaneously monitored within the III phase of clinical testing on 1500 patients with AD. The results of both studies are to be expected in 2017–2018 [24].

#### **6.2. LY2886721**

these mutations and their effects, we can conclude that Aβ is responsible for the pathogenesis leading to the breakout and development of AD. Accordingly, some mutations in APP can represent a protecting mean to suppress the progression of AD. For example, a mutation in the Ala673 region (so-called Ala673Thr mutation) causes a lower affinity of APP to BACE-1,

Extensive research is dedicated to the development of small molecule inhibitors of BACE-1, capable to act centrally. The first experimental inhibitors were derived from short fragments of APP, being therefore peptide derivatives. These differed from APP by modified amino acid sequence and increased metabolic resistance against cleaving by BACE-1. In *in vitro* conditions these bulky peptide derivatives showed high affinity for BACE-1, especially due to the fact that the active site of BACE-1 is so large that it is able to cleave very large substrates. The disadvantage of these derivatives is that they do not possess true drug-like properties, exerting low oral availability and short half-life in the plasma. Such drug candidates are quickly metabolized and have low permeability through the blood-brain barrier. For these reasons, the researchers have focused on the development of small BACE-1 inhibitors that have high affinity for this enzyme, but are small enough to penetrate through the blood-brain barrier and, at the same time, to exhibit suitable pharmacokinetic properties. In addition, these compounds must be lipophilic enough to permeate through the cytoplasmic and endosome membrane to block the active site of BACE-1 located inside of the lumen. A large number of these compounds, however, reached only a limited concentration in the brain because in most cases, they reached high efflux mediated by P-glycoprotein (P-glycoprotein is an ATP-dependent pump, which

removes xenobiotics and protects the brain from the effects of these compounds) [22].

inhibitors of BACE-1, which have entered various stages of clinical testing [23].

**6.1. MK-8931**

The latest generations of BACE-1 inhibitors are characterized by a good capacity to permeate through the blood-brain barrier, by a suitable pharmacokinetic profile, and the ability to induce reduction of the cerebral levels of Aβ. The result of the research is a panel of several

In 2012, the results of the first phase of clinical trials with inhibitor MK-8931 were presented (**Figure 2**), which had been performed in 88 healthy individuals aged between 18 and 45 years. The safety, tolerability, pharmacokinetic and pharmacodynamic parameters after single or repeated administration were experimentally determined. MK-8931 was generally well tolerated, and no severe side effects were observed. The main goal in this first phase was to determine whether MK-8931 was capable of penetration into the brain to inhibit the activity of BACE-1. Biomarkers monitoring the levels of Aβ1–40, Aβ1–42 and soluble fragment of APP (sAPP-β), which is formed by BACE-1, were intensively studied. MK-8931 significantly decreased the concentrations of cerebrospinal Aβ, depending on the dose administered, and even in repeated oral administration a reduction of Aβ in the CSF of up to about 90% has been observed. The plasma half-life of MK-8931 after a single administration was around 20 h, which assumes the dosing schedule within the range of a single daily dose. This was followed by a clinical study 1b, where the safety, tolerability, pharmacokinetics and pharmacodynamics in 32 patients with mild to moderate dementia of the AD type were determined.

bringing the production of Aβ reduced by up to 40% [21].

6 Alzheimer's Disease - The 21st Century Challenge

A non-peptidic BACE-1 inhibitor LY2811376 (**Figure 2**), which was analyzed in a study with oral administration, demonstrated satisfactory pharmacokinetic and pharmacodynamic properties in animal models, which promoted the compound to the first phase of clinical trials. These clinical studies, however, were soon discontinued due to adverse reactions, in particular in the area of inflammation of the retina and the occurrence of stroke. Although all other studies with the substance faded away, at present, LY2811376 has become a lead structure, which could be administered orally and reach its biological target behind the blood-brain barrier.

Over the last few years, it has turned out that four main factors are responsible for the enzymatic activity of γ-secretase complex: presenilin, anterior pharynx-defective, presenilin enhancer 2

Amyloid Beta Hypothesis: Attention to β- and γ-Secretase Modulators

http://dx.doi.org/10.5772/intechopen.75629

9

In recent years, a series of potential inhibitors of γ-secretase has been designed and synthesized. Unfortunately, most of them are not specific to cleaving APP with γ-secretase, and, like in the case of BACE-1, they prevent processing of other γ-secretase substrates that do not have any or at least no obvious role in the pathogenesis of AD. For these reasons, the inhibition of γ-secretase has been associated with serious side effects, which adumbrated the end for most

Historically, the first inhibitor of γ-secretase that underwent clinical studies was BMS-299897 (**Figure 3**) compound prepared by Bristol-Myers Squibb. In 2001, clinical trials of this molecule

and nicastrin, which are described further in this chapter [27].

drug candidates in clinical testing.

**Figure 3.** Inhibitors of γ-secretase in various stages of clinical testing.

**8. Inhibitors of γ-secretase in the clinical development**

The molecule marked with LY2886721 (**Figure 2**) represents the next evolutionary generation of orally acting BACE-1 inhibitors, which has entered into the second phase of clinical trials. Compared to its predecessor LY2811376, the novel drug LY2886721 did not exhibit any side effects in the area of the retina and any stroke. During the first phase of clinical trials on 47 healthy volunteers, no adverse effects were observed in 14 days (different dosing schemes repeated administration of 5, 15 and 35 or 70 mg single administration). The biological half-life fluctuated around 12 h, allowing the dosing once per day, when the drug holds the necessary biological effect even after substantial elimination from the body. Treatment with LY2886721 resulted in the reduction of the plasma and cerebrospinal levels of Aβ1–40 by up to 74% (i.e., after the highest dose of 70 mg). Similar decreasing changes were detected in the cerebrospinal levels of Aβ1–42 and sAPP-β, while the blood level of sAPP-*α* was increased, which is logically explainable by relative excess of α-secretase in comparison with BACE-1.

The second phase of clinical trials with LY2886721 was carried out in 130 patients with moderate to severe AD dementia type. This testing, however, was terminated because of liver abnormalities, but, presumably, this is not associated with inhibition of BACE-1 [25].

#### **6.3. E2609**

E2609 (**Figure 2**) is an orally available, nonpeptidic spirocyclic inhibitor of BACE-1, which induced a significant decline of brain levels of Aβ in preclinical studies. Based on this success, E2609 entered the first phase of clinical testing in which 73 volunteers, administered uniformly with increasing dose from 5 to 800 mg of the drug, and 50 volunteers, administered with different doses in the range of 25–400 mg, participated. The plasma half-life of E2609 is around 12–16 h, which again allows one-day dosing schedule. At the maximal single dose (400 mg), decrease of the cerebrospinal Aβ levels by up to 85% has been observed. The concentration of sAPP-β has been similarly reduced, while sAPP-*α* has been increased. Currently, the drug is in the third phase of clinical determinations [26].

## **7. γ-Secretase**

γ-Secretase is a member of aspartic protease family that cleaves glycoproteins of type I including APP. Unlike β-secretase, γ-secretase has a regulated intramembrane proteolytic activity (RIP), thus, it breaks down domains inside of the cytoplasmic membrane. It is known that it breaks down multiple substrates, and to this day more than 50 such substrates, including APP, have been identified. Among these substrates are Notch, Jagged and Nectin-1α. The signal transmission by RIP is implemented so that the released intracellular domain is moved into the nucleus, as it is in the case of Notch, which regulates specific gene expression. Notch is therefore cleaved to Notch intracellular domain, NICD, which causes in the nucleus the mentioned regulation. In relation to AD, this signal pathway is interesting from the perspective of development and function of the nervous tissue.

Over the last few years, it has turned out that four main factors are responsible for the enzymatic activity of γ-secretase complex: presenilin, anterior pharynx-defective, presenilin enhancer 2 and nicastrin, which are described further in this chapter [27].


*Edited by Marcelo L. Larramendy and Sonia Soloneski*

This edited book, Invertebrates-Experimental Models in Toxicity Screening, is intended to provide an overview of the use of conventional and nonconventional invertebrate species as experimental models for the study of different toxicological aspects induced by environmental pollutants in both aquatic and terrestrial ecosystems. Furthermore, it is hoped that the information in the present book will be of value to those directly engaged in the handling and use of environmental pollutants and that this book will continue to meet the expectations and needs of all interested in the different aspects of toxicity screening.

Photo by Jens Domschky / iStock

Invertebrates - Experimental Models in Toxicity Screening

Invertebrates

Experimental Models in Toxicity Screening

*Edited by Marcelo L. Larramendy*

*and Sonia Soloneski*


*Edited by Jasneth Mullings, Sage Arbor and Medhane Cumbay*

The concept of health-related quality of life (HRQoL) has evolved since the 1980s, with broad-based applications for clinical care, research, and health policy, as well as for individual and patient use. This book, *Health-Related Quality of Life - Measurement Tools, Predictors and Modifiers*, highlights measurement tools for HRQoL, as well as predictors and modifiers, examining HRQoL in various disease states, including psychological health. It also discusses ethical issues in the use of HRQoL measurements. The book is a compendium of original research, sharing perspectives from across developing and developed world settings. It is a useful text for researchers and students of academic disciplines in public health and clinical studies, extending to healthcare administrators and policymakers.

Published in London, UK © 2022 IntechOpen © filmfoto / iStock

Health-Related Quality of Life - Measurement Tools, Predictors and Modifiers

Health-Related Quality of Life

Measurement Tools, Predictors and Modifiers

*Edited by Jasneth Mullings, Sage Arbor*

*and Medhane Cumbay*


**2. Design for solar environmental catalysts**

The requirements for the highly active TiO2-based "solar environmental catalyst" are described below. As shown in Figure 1, the excitation from the VB electrons to the CB needs UV-light irradiation, occupying only 3% of the incident sunlight. From a viewpoint of the effective use of the sunlight, the response to the visible-light occupying 45% of the solar energy (Figure 1) should be particularly imparted to anatase TiO2 and anatase–rutile-mixed TiO2 (Requirement 1). However, even if TiO2 can be endowed with the visible-light activity, it is usually much smaller than the UV-light activity. Therefore, the inherent excellent UV-light activity of TiO2 should be compatible with the visible-light activity (Requirement 2). For high levels of visible and UV-light activities to be achieved, the enhancement of the ORR is crucial because it is usually the rate-determining step in the TiO2-photocatalyzed reactions [21] (Requirement 3).