title: PlayStation 4 system software

text: The augmented reality application, the Playroom comes pre-installed with the PlayStation 4 console. It was demonstrated at E3 2013 and utilizes the Sony PlayStation Camera technology. According to Sony, it is a "fantastically fresh augmented reality entertainment experience", which has been created by combining the light bar located on the front of DualShock 4 controller with the PlayStation Camera. Players are allowed to produce a small floating robot called Asobi, who interacts with the players, scans their faces and shoots fireballs. Once the PlayStation Camera identifies the player with the help of the light bar on the front, a flick on the touchpad of the DualShock 4 controller brings up the augmented reality Bots function of the PlayRoom, which creates the illusion that there are hundreds of little bots inside the controller, which can be released simply with a tap on the track pad that functions like the PlayStation Vita. PS4 owners can view their smartphone or PlayStation Vita for drawing the object and flick it anywhere for the augmented reality Bots to play with.


title: PlayStation 4 system software

text: Through Remote Play users can operate their PS4 through the uses of a PlayStation Vita handheld game console, allowing for the play of PS4 games and other media on the small device via streaming. All games that do not require the PlayStation Move or PlayStation Camera are compatible.


title: PlayStation 4 system software

text: The second screen can be used to display unique content when playing games that support this option, but it should not be confused with a split-screen. The second screen may be used to show extra content like maps, alternate camera angles, radar or even playbooks in sports games. Apart from PlayStation Vita, other mobile devices such as iPads or Android tablets can also be used as a second screen. That comes in the form of both the official PlayStation App and game companion apps such as Knack's Quest.


title: PlayStation 4 system software

text: A heavy emphasis on social features has been placed on the PlayStation 4 console, loading up the PS4 with a number of share-centric apps and features. The [What's New] feature, which allows users to check out their friends' latest activities via a landing page full of their pictures, trophies and other recent events, is an easy way to find out what friends have been up to. On the other hand, a cross-chat feature dubbed [Party Chat] is an interesting way to keep in touch. This gives gamers the ability to chat with other users whether or not they're playing the same title.


title: PlayStation 4 system software

text: The PS4's sharing capabilities adds another layer to console gaming. PS4 owners are able to capture or livestream the gameplay with a simple button touch. They can record up to 60 minutes of their latest gaming exploits with a quick press of the Share button on the controller. Footage can be shared on Facebook, Twitter and YouTube. They also have the ability to broadcast their gameplay in real-time to Twitch and Ustream in addition to recording videos.


title: PlayStation 4 system software

text: There are also other social features such as community creation. Some of them are introduced via system updates. Favorite Groups is a new section within the Friends app, and acts as a way to quickly access other people a user plays with the most. This feature is aimed at making it easier and faster to get into a game session with friends. On the other hand, communities are new hubs that can be formed around shared interests like games, activities, or play styles. There also exist other smaller social features on PS4, such as the ability to message a friend with a request to watch their gameplay live.


title: PlayStation 4 system software

text: While the PlayStation 4 console can function without an Internet connection, it provides more functionality when it is connected to the Internet. For example, updates to the system software may be downloaded from the Internet, and users may play online when the Internet is properly connected. Online play is the main pillar for the PlayStation 4, but a PlayStation Plus subscription is required to play the majority of PS4 titles online, unlike PlayStation 3 titles. According to Sony, they are developing many new ways to play and connect for PS4 which requires a large investment of resources. As a result, Sony claim they cannot keep such a service free and maintain its quality at the same time considering the cost, and they thus decided that it would be better to charge a fee in order to continue to offer a good service.


title: PlayStation 4 system software

text: The web browser included in the PlayStation 4 console is based on the open source WebKit layout engine, unlike the PlayStation 3 which uses the NetFront browser. Using the same modern Webkit core as Safari from Apple, the PS4 web browser receives a very high score in HTML5 compliance testing. However, just like other major browsers, it does not support the deprecated Adobe Flash, which means that websites which still require Flash might not display properly or function as intended. Also, the PDF format is not supported. However, one clear advantage for gamers is being able to cut between gaming and browsing and back again with no loss of gameplay due to the multitasking feature of the web browser. Additionally, while the PS4 web browser has limited support for USB keyboards, it does not seem to support USB mice at all.


title: PlayStation 4 system software

text: Furthermore, with Internet connection enabled the PlayStation 4 allows users to access a variety of PlayStation Network (PSN) services, including the PlayStation Store, PlayStation Plus subscription service, and more. Users may download or buy games and other content from these services. Also, gamers are able to play a selection of PS3 titles via the Internet-based PlayStation Now gaming service. PS Now is a cloud-based gaming subscription service from Sony Interactive.


title: PlayStation 4 system software

text: The PlayStation 4 supports playing standard 12-centimeter DVD-Video discs; DVD recordable and rewritable discs except those that have not been finalized; and standard Blu-ray discs with the exception of Blu-ray Recordable Erasable version 1.0 discs and Blu-ray XL format discs. Unlike all previous PlayStation consoles the system does not support the Compact Disc format at all, including Compact Disc Digital Audio and Video CD format discs. Blu-ray 3D support was added in system software version 1.75. In 2015, Sony partnered with Spotify to bring the music streaming service to the PlayStation 4, allowing music to be streamed in the background of any game or application for both free and premium members of Spotify.


title: PlayStation 4 system software

text: The Media Player application included with the system can be used to play media files on USB storage devices or media servers. According to the PlayStation 4's user guide, media formats supported include videos contained in the MP4, MKV and AVI formats and encoded in H.264 AVC High Profile 4.2, MPEG4 ASP, MPEG2 Visual, AVCHD, and XAVC S; audio encoded in MP3, FLAC, or AAC; or AC-3 (Dolby Digital) and photos encoded in JPEG, BMP, or PNG. The PlayStation 4 Pro also supports videos encoded in H.264 AVC High Profile 5.2. If users have a PlayStation VR headset connected, they can view 360-degree videos inside the headset.


title: PlayStation 4 system software

text: The PlayStation 4 was not backward compatible with any games from previous PlayStation consoles at launch. Though PlayStation 4 users cannot play PlayStation 3 games directly, in 2014, the PlayStation Now cloud-based streaming service allowed for the streaming of selected PS3 games. In December 2015, Sony added PlayStation 2 backward compatibility and republished some PS2 games such as "Dark Cloud" and "Grand Theft Auto III", "", and "" on the PS4 via the PlayStation Store in the Americas and Europe. Supported PS2 games run via software emulation (upscaled to high definition) on PS4 systems instead of having been remastered. Each one has been updated to access various PS4 features, including Trophies, Share Play, Broadcasting, Remote Play and second-screen features. However, the original PS2 game discs, and PS2 Classics re-released for the PS3 are not compatible with the PS4 system.


title: PlayStation 4 system software

text: The initial version of the system software for the PlayStation 4 is 1.01 as pre-installed on the original consoles. Support for the Remote Play and second screen experiences were added in version 1.50, which was launched on the same day the PlayStation 4 console itself was released in North America on November 15, 2013. Both features are accessible from the PlayStation Vita console by using its PS4 Link application, and the second screen functionality is also accessible from smartphones and tablets through the PlayStation Mobile app. It is also able to record or share video clips as well as broadcasting gameplay to Twitch or Ustream. It supports Blu-ray and DVD-Video playback, and version 1.60 was released on February 4, 2014, improving DVD playback. Version 1.60 also adds support for Pulse Elite wireless headsets. Version 1.70 was released on April 30, 2014, and adds a number of new features, such as the addition of a rich video editor called ShareFactory that offers users the tools to combine, edit and personalize captured video clips. This update also adds the abilities to share video clips and screenshots while streaming, and to copy video clips and screenshots to USB storage. Version 1.75 was released on July 29, 2014, further adding the support for playback of Blu-ray 3D. It also improves the sound quality during 1.5-speed playback with Blu-ray and DVD video.


title: PlayStation 4 system software

text: On September 2, 2014, Sony released update 1.76 which came with minor changes and was the last update until 2.0.


title: PlayStation 4 system software

text: On October 28, 2014, Sony released update 2.00 as a major upgrade to the PlayStation 4 system software. Among the features introduced is Share Play, which allows PlayStation Plus users to invite an online friend to join their play session via streaming, even if they do not own a copy of the game. Users can pass control of the game entirely to the remote user, or partake in cooperative multiplayer as if they were physically present. This version also adds a YouTube app and the ability to upload video clips to YouTube, and users can now play music stored on USB storage devices. Also, with the support for custom themes and the ability to change the background color, users can set themes for home screens and function screens for each user in this version.


title: PlayStation 4 system software

text: On March 26, 2015, Sony released update 2.50, adding a suspend/resume feature to allow players to jump in and out of games with the PS button, and games are suspended in the low-power Rest Mode instead of closing completely.


title: PlayStation 4 system software

text: On September 30, 2015, Sony released update 3.00. It introduced "entirely new features" and user-interface enhancements. Among the new features was the ability to share videos directly to Twitter, a dedicated PlayStation Plus section, tweaks to the interface for streaming on YouTube, improvements to social features such as messages and group creation, and the ability to save screenshots as PNGs. An increase in online storage capacity from 1 GB to 10 GB was also introduced for PlayStation Plus Members.


title: PlayStation 4 system software

text: Sony states that this update will create "new ways to connect with friends and players around the world, expanding the social capabilities of the system even further".


title: PlayStation 4 system software

text: On April 6, 2016, Sony released update 3.50, that would enable the PS4 to use Remote Play functionality on Windows and macOS (formerly named OS X). "VG247" reported that the update will allow Remote Play functionality on computers running Windows 8.1, Windows 10, OS X Yosemite, and OS X El Capitan. Furthermore, the article explains that Remote Play will support resolution options of 360p, 540p, and 720p, frame rate options of 30 FPS and 60 FPS, and that one DualShock 4 controller can be connected via the computer's USB port.


title: PlayStation 4 system software

text: On September 13, 2016, Sony released update 4.00, which added High Dynamic Range (HDR) and home screen folder support, 1080p streaming, tweaks to menus and game info screens for greater overview, and streamlined interfaces.


title: PlayStation 4 system software

text: On March 9, 2017, Sony released update 4.50 including support for installing applications on external hard drives, custom wallpapers, refined Quick Menu, simplified notifications list, custom status updates, 3D Blu-Ray support for the PlayStation VR


title: PlayStation 4 system software

text: and support for the preloading of game patches. However it is up to the developer to make use of it. The first game to take advantage of pre loading game patches is LittleBigPlanet 3.


title: PlayStation 4 system software

text: On October 3, 2017, Sony released update 5.00. Overhauling the master/sub-account system, the update allows for more customization of accounts for family members and roles, and applying parental controls to each account. The groups system is replaced with a new friends management system, along with support for 5.1 and 7.1 surround sound configurations for PlayStation VR. A new tournament bracket viewer has been made, along with tweaks to broadcasting (with 1080p streaming at 60 frames per second on Twitch now possible), and other changes to PS Message, notifications, and the quick menu. Lastly, it introduces localization for Czech, Greek, Hungarian, Indonesian, Romanian, Thai, and Vietnamese languages.


title: PlayStation 4 system software

text: 5.50 was released on March 8, 2018. It includes playtime restrictions for child accounts, the ability to hide applications from the library, custom wallpapers via USB, a supersampling mode on PS4 Pro and the ability to delete notifications.


title: PlayStation 4 system software

text: 5.53 was released on April 12, and 5.55 was released on May 17, 2018. Both only include updates to improve system performance.


title: PlayStation 4 system software

text: On March 7, 2019, Sony released Update 6.50 that allowed users to use Remote Play on iOS devices through the Remote Play app from the App Store, and other minor improvements.


title: PlayStation 4 system software

text: On May 10, 2019, Sony Interactive Entertainment added the ability to remove purchased games from the Download List for PlayStation Store and delete games from My Profile.


title: PlayStation 4 system software

text: On October 8, 2019, Sony released update 7.00. The major feature that was added was the ability to use Remote Play on select Android devices running the Android Lollipop version and above.


title: PlayStation 4 system software

text: In addition, other features include chat transcription and the expanded limit for party users from 8 to 16.


title: PlayStation 4 system software

text: On December 19, 2019, Sony released update 7.02 with the goal of improved system performance and stability.


title: PlayStation 4 system software

text: On October 14, 2020, Sony released update 8.00. It brought changes to existing Party and Message features. Other additions include new avatars, enhanced 2-step verification system and updated parental controls.


title: PlayStation 4 system software

text: On April 14, 2021, Sony released update 8.50, which enabled cross-play between the Playstation 4 and Playstation 5. They also added the feature to request to join game session leaders, and more.


title: PlayStation 4 system software

text: On September 15, 2021, Sony released update 9.00 allowing PlayStation 4 users to access PlayStation 5 trophies, improvements to parental controls and messages feature.


title: PlayStation 4 system software

text: This update also fixed the eventual cbomb issue discovered by Destruction Games that would cause PlayStation 4's to no longer be able to play physical or digital games. Controversially, it has caused serious issues for some.


title: PlayStation 4 system software

text: On February 19, 2022, Sony released update 9.04 which claimed to have "improved system performance." and fixed issues with the game Cyberpunk 2077.


title: PlayStation 4 system software

text: On March 23, 2022, Sony released update 9.50 with Party Feature updates and Ukrainian language support.


title: PlayStation 4 system software

text: On September 21, 2022, Sony released update 10.01 which claimed to have "improved system performance."


title: Ciclosporin

text: Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, and in organ transplants to prevent rejection. It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).


title: Ciclosporin

text: Common side effects include high blood pressure, headache, kidney problems, increased hair growth, and vomiting. Other severe side effects include an increased risk of infection, liver problems, and an increased risk of lymphoma. Blood levels of the medication should be checked to decrease the risk of side effects. Use during pregnancy may result in preterm birth; however, ciclosporin does not appear to cause birth defects.


title: Ciclosporin

text: Ciclosporin is believed to work by decreasing the function of lymphocytes. It does this by forming a complex with cyclophilin to block the phosphatase activity of calcineurin, which in turn decreases the production of inflammatory cytokines by T-lymphocytes.


title: Ciclosporin

text: Ciclosporin was isolated in 1971 from the fungus "Tolypocladium inflatum" and came into medical use in 1983. It is on the World Health Organization's List of Essential Medicines. In 2020, it was the 212th most commonly prescribed medication in the United States, with more than 2million prescriptions. It is available as a generic medication.


title: Ciclosporin

text: Ciclosporin is indicated to treat and prevent graft-versus-host disease in bone marrow transplantation and to prevent rejection of kidney, heart, and liver transplants. It is also approved in the US for treating of rheumatoid arthritis and psoriasis, persistent nummular keratitis following adenoviral keratoconjunctivitis, and as eye drops for treating dry eyes caused by Sjögren's syndrome and meibomian gland dysfunction.


title: Ciclosporin

text: In addition to these indications, ciclosporin is also used in severe atopic dermatitis, Kimura disease, pyoderma gangrenosum, chronic hives, acute systemic mastocytosis, and posterior or intermediate uveitis with noninfective cause. It is also used, albeit infrequently, in severe rheumatoid arthritis and related diseases.


title: Ciclosporin

text: Ciclosporin has also been used in people with acute severe ulcerative colitis and hives that do not respond to treatment with steroids.


title: Ciclosporin

text: Side effects of ciclosporin can include gum enlargement, increased hair growth, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, increased cholesterol, trouble breathing, numbness and tingling (particularly of the lips), itchiness, high blood pressure, potassium retention (possibly leading to hyperkalemia), kidney and liver dysfunction, burning sensations at finger tips, and an increased vulnerability to opportunistic fungal and viral infections. Ciclosporin causes hypertension by inducing vasoconstriction in the kidneys and increasing sodium reabsorption. The increase in blood pressure can cause cardiovascular events; it is thus recommended that the lowest effective dose for people requiring long-term treatment be used.


title: Ciclosporin

text: Ciclosporin use after a kidney transplantation is associated with increased levels of uric acid in the blood and, in some cases, gout. This is due to the decrease in glomerular filtration rate, which leads to uric acid retention. Use of azathioprine as an alternative has shown to reduce the incidence of gouty arthritis.


title: Ciclosporin

text: Ciclosporin is listed as an IARC Group 1 carcinogen (i.e. there is sufficient evidence of carcinogenicity in humans), specifically leading to squamous cell skin cancer and non-Hodgkin lymphoma.


title: Ciclosporin

text: Ciclosporin's main effect is to lower the activity of T-cells; it does so by inhibiting calcineurin in the calcineurin–phosphatase pathway and preventing the mitochondrial permeability transition pore from opening. Ciclosporin binds to the cytosolic protein cyclophilin (immunophilin) of lymphocytes, especially of T cells. This cyclosporin—cyclophilin complex inhibits calcineurin, which is normally responsible for activating the transcription of interleukin 2. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the T-cell nucleus and increases the transcription of genes for IL-2 and related cytokines. Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reduced effector T-cell function; it does not affect cytostatic activity.


title: Ciclosporin

text: Ciclosporin also binds to the cyclophilin D protein that constitutes part of the mitochondrial permeability transition pore (MPTP), thus preventing MPTP opening. The MPTP is found in the mitochondrial membrane of cardiac muscle cells. MPTP opening signifies a sudden change in the inner mitochondrial membrane permeability, allowing protons and other ions and solutes of a size up to ~1.5 kDa to go through the inner membrane. This change of permeability is considered a cellular catastrophe, leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.


title: Ciclosporin

text: Ciclosporin is a cyclic peptide of 11 amino acids; it contains a single -amino acid, which is rarely encountered in nature. Unlike most peptides, ciclosporin is not synthesized by ribosomes.


title: Ciclosporin

text: Ciclosporin is highly metabolized in humans and animals after ingestion. The metabolites, which include cyclosporin B, C, D, E, H, and L, have less than 10% of ciclosporin's immunosuppressant activity and are associated with higher kidney toxicity. Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.


title: Ciclosporin

text: Cyclosporin is synthesized by a nonribosomal peptide synthetase, cyclosporin synthetase. The enzyme contains an adenylation domain, a thiolation domain, a condensation domain, and an N-methyltransferase domain. The adenylation domain is responsible for substrate recognition and activation, whereas the thiolation domain covalently binds the adenylated amino acids to phosphopantetheine, and the condensation domain elongates the peptide chain. Cyclosporin synthetase substrates include L-valine, L-leucine, L-alanine, glycine, 2-aminobutyric acid, 4-methylthreonine, and D-alanine, which is the starting amino acid in the biosynthetic process. With the adenylation domain, cyclosporin synthetase generates the acyl-adenylated amino acids, then covalently binds the amino acid to phosphopantetheine through a thioester linkage. Some of the amino acid substrates become N-methylated by S-adenosyl methionine. The cyclization step releases cyclosporin from the enzyme. Amino acids such as D-Ala and butenyl-methyl-L-threonine (Bmt) indicate cyclosporin synthetase requires the action of other enzymes. The racemization of L-Ala to D-Ala by alanine racemase is pyridoxal phosphate-dependent. The formation of butenyl-methyl-L-threonine is performed by a Bmt polyketide synthase that uses acetate/malonate as its starting material.


title: Ciclosporin

text: "Tolypocladium inflatum", the species currently used for mass production of Cyclosporin, has the biosynthetic genes arranged into a 12-gene cluster. Of these 12 genes, SimA () is the cyclosporin synthetase, SimB () is the alanine racemase, and SimG (similar to ) is the polyketide synthase. These genes are associated with an active retrotransposon. Although these sequences are poorly-annotated on GenBank and other databases, 90% similar sequences can be found for the Cyclosporin-producing "Beauveria felina" (or "Amphichorda ~"). SimB has two paralogs in the same organism with different but overlapping functions thanks to their low speficity.


title: Ciclosporin

text: In 1970, new strains of fungi were isolated from soil samples taken from Norway and from Wisconsin in the US by employees of Sandoz (now Novartis) in Basel, Switzerland. Both strains produced a family of natural products called cyclosporins. Two related components that had antifungal activity were isolated from extracts from these fungi. The Norwegian strain, "Tolypocladium inflatum Gams", was later used for the large scale fermentation of ciclosporin.


title: Ciclosporin

text: The immunosuppressive effect of the natural product ciclosporin was discovered on January 31, 1972 in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin at Sandoz. The chemical structure of cyclosporin was determined in 1976, also at Sandoz. The success of the drug candidate ciclosporin in preventing organ rejection was shown in kidney transplants by R.Y. Calne and colleagues at the University of Cambridge, and in liver transplants performed by Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on 9 March 1980, was a 28-year-old woman. In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.


title: Ciclosporin

text: The natural product was named cyclosporin by the German-speaking scientists who first isolated it and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs, the "y" was replaced with "i" so that the INN for the medication is spelled ciclosporin.


title: Ciclosporin

text: Ciclosporin is the INN and the British Approved Name (BAN), while cyclosporine is the United States Adopted Name (USAN) and cyclosporin is a former BAN.


title: Ciclosporin

text: Ciclosporin exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms of the medication have been developed for oral administration and for injection. Ciclosporin was originally brought to market by Sandoz (now Novartis), under the brand name Sandimmune, which is available as soft gelatin capsules, an oral solution, and a formulation for intravenous administration. These are all nonaqueous compositions. A newer microemulsion, orally-administered formulation, Neoral, is available as a solution and as soft gelatin capsules. Compositions of Neoral are designed to form microemulsions in contact with water.


title: Ciclosporin

text: Generic ciclosporin preparations have been marketed under various trade names, including Cicloral (by Sandoz/Hexal), Gengraf (by Abbott) and Deximune (by Dexcel Pharma). Since 2002, a topical emulsion of ciclosporin for treating inflammation caused by keratoconjunctivitis sicca (dry eye syndrome) has been marketed under the trade name Restasis. Ikervis is a similar formulation with a concentration of 0.1%. Inhaled ciclosporin formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.


title: Ciclosporin

text: Ciclosporin is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage and reperfusion injury (phase III) in traumatic brain injury. This multi-center study is being organized by NeuroVive Pharma and the European Brain Injury Consortium using NeuroVive's formulation of ciclosporin called "NeuroSTAT" (also known by its cardioprotection trade name of "CicloMulsion"). This formulation uses a lipid emulsion base instead of cremophor and ethanol. NeuroSTAT was compared to Sandimmune in a phase I study and found to be bioequivalent. In this study, NeuroSTAT did not exhibit the anaphylactic and hypersensitivity reactions found in cremophor- and ethanol-based products.


title: Ciclosporin

text: Ciclosporin has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury, and has been shown in animal experiments to reduce brain damage associated with injury. Ciclosporin blocks the formation of the mitochondrial permeability transition pore, which has been found to cause much of the damage associated with head injury and neurodegenerative diseases. Ciclosporin's neuroprotective properties were first discovered in the early 1990s when two researchers (Eskil Elmér and Hiroyuki Uchino) were conducting experiments in cell transplantation. An unintended finding was that cyclosporin A was strongly neuroprotective when it crossed the blood–brain barrier. This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.


title: Ciclosporin

text: Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia (blood flow restriction to tissue) and reperfusion injury (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction (heart attack) and when mutations in mitochondrial DNA polymerase occur. The heart attempts to compensate for disease state by increasing the intracellular to increase the contractility cycling rates. Constitutively high levels of mitochondrial cause inappropriate MPTP opening leading to a decrease in the cardiac range of function, leading to cardiac hypertrophy as an attempt to compensate for the problem.


title: Ciclosporin

text: Cyclosporin A has been shown to decrease cardiac hypertrophy by affecting cardiac myocytes in many ways. Cyclosporin A binds to cyclophilin D to block the opening of MPTP, and thus decreases the release of protein cytochrome C, which can cause programmed cell death. CypD is a protein within the MPTP that acts as a gate; binding by cyclosporin A decreases the amount of inappropriate opening of MPTP, which decreases the intramitochondrial . Decreasing intramitochondrial allows for reversal of cardiac hypertrophy caused in the original cardiac response. Decreasing the release of cytochrome C caused decreased cell death during injury and disease. Cyclosporin A also inhibits the phosphatase calcineurin pathway (14). Inhibition of this pathway has been shown to decrease myocardial hypertrophy.


title: Ciclosporin

text: The medication is approved in the United States for the treatment of atopic dermatitis in dogs. Unlike the human form of the medication, the lower doses used in dogs mean the drug acts as an immunomodulator and has fewer side effects than in humans. The benefits of using this product include the reduced need for concurrent therapies to bring the condition under control. It is available as an ophthalmic ointment for dogs called Optimmune, manufactured by Intervet, which is part of Merck. It is also used to treat sebaceous adenitis (immune response against the sebaceous glands), pemphigus foliaceus (autoimmune blistering skin disease), Inflammatory bowel disease, anal furunculosis (anal inflammatory disease), and myasthenia gravis (a neuromuscular disease).


title: Tower of Silence

text: A dakhma (), also known as a Tower of Silence, is a circular, raised structure built by Zoroastrians for excarnation (that is, the exposure of human corpses to the elements for decomposition), in order to avert contamination of the soil and other natural elements by the dead bodies. Carrion birds, usually vultures and other scavengers, consume the flesh. Skeletal remains are gathered into a central pit where further weathering and continued breakdown occurs.


title: Tower of Silence

text: Zoroastrian ritual exposure of the dead is first known of from the writings of the Ancient Greek historian Herodotus (mid-5th century BCE), who observed the custom amongst Iranian expatriates in Asia Minor. In Herodotus' account ("Histories" i.140), the Zoroastrian funerary rites are said to have been "secret", but were first performed after the body had been dragged around by a bird or dog. The corpse was then embalmed with wax and laid in a trench.


title: Tower of Silence

text: The discovery of ossuaries in both Eastern and Western Iran dating to the 5th and 4th centuries BCE indicate that bones were sometimes isolated, but separation occurring through ritual exposure cannot be assumed: burial mounds, where the bodies were wrapped in wax, have also been discovered. The tombs of the Achaemenid emperors at Naqsh-e Rustam and Pasargadae likewise suggest non-exposure, at least until the bones could be collected. According to legend (incorporated by Ferdowsi into his ; ), Zoroaster himself is interred in a tomb at Balkh (in present-day Afghanistan).


title: Tower of Silence

text: Zoroastrian exposure of the dead is first attested in the mid-5th century BCE "Histories" of Herodotus, but the use of towers is first documented in the early 9th century CE. The doctrinal rationale for exposure is to avoid contact with earth, water, or fire, all three of which are considered sacred in the Zoroastrian religion.


title: Tower of Silence

text: One of the earliest literary descriptions of such a building appears in the late 9th-century Epistles of Manushchihr, where the technical term is , 'ossuary'. Another term that appears in the 9th- to 10th-century texts of Zoroastrian tradition (the so-called "Pahlavi books") is ; in its earliest usage, it referred to any place for the dead.


title: Tower of Silence

text: Writing on the culture of the Persians, Herodotus reports on the Persian burial customs performed by the magi, which are kept secret. However, he writes that he knows they expose the body of male dead to dogs and birds of prey, then they cover the corpse in wax, and then it is buried. The Achaemenid custom is recorded for the dead in the regions of Bactria, Sogdia, and Hyrcania, but not in Western Iran.


title: Tower of Silence

text: The Byzantine historian Agathias has described the Zoroastrian burial of the Sasanian general Mihr-Mihroe: "the attendants of Mermeroes took up his body and removed it to a place outside the city and laid it there as it was, alone and uncovered according to their traditional custom, as refuse for dogs and horrible carrion".


title: Tower of Silence

text: Towers are a much later invention and are first documented in the early 9th century CE. The funerary ritual customs surrounding that practice appear to date to the Sassanid ra (3rd–7th CE). They are known in detail from the supplement to the "Shayest ne Shayest", the two "Rivayat" collections, and the two "Saddar"s.


title: Tower of Silence

text: Zoroastrian tradition considers human cadavers and animal corpses (in addition to cut hair and nail parings) to be "nasu", i.e. unclean, polluting. Specifically, the corpse demon (), is believed to rush into the body and contaminate everything it comes into contact with. For this reason, the (an ecclesiastical code whose title means, 'given against the demons') has rules for disposing of the dead as safely as possible. Moreover, the requires that graves, and raised tombs as well, must be destroyed.


title: Tower of Silence

text: To preclude the pollution of the sacred elements: earth (), water (), and fire (), the bodies of the dead are placed at the top of towers and there exposed to the sun and to scavenging birds and necrophagous animals such as wild dogs. Thus, as an early-20th-century Secretary of the Bombay Parsi community explained: "putrefaction with all its concomitant evils... is most effectually prevented."


title: Tower of Silence

text: Modern-day towers, which are fairly uniform in their construction, have an almost flat roof, with the perimeter being slightly higher than the centre. The roof is divided into three concentric rings: the bodies of men are arranged around the outer ring, women in the second ring, and children in the innermost ring. The ritual precinct may be entered only by a special class of pallbearers, called , from the , consisting of the word elements, ('caretaker') and ('pollutants').


title: Tower of Silence

text: Once the bones have been bleached by the sun and wind, which can take as long as a year, they are collected in an ossuary pit at the centre of the tower, where—assisted by lime—they gradually disintegrate, and the remaining material, along with rainwater run-off, seeps through multiple coal and sand filters before being eventually washed out to sea.


title: Tower of Silence

text: In the Iranian Zoroastrian tradition, the towers were built atop hills or low mountains in locations distant from population centres. In the early 20th century, Iranian Zoroastrians gradually discontinued their use and began to favour burial or cremation.


title: Tower of Silence

text: The decision to change the system was accelerated by three considerations: the first problem arose with the establishment of the Dar ul-Funun medical school. Since Islam considers unnecessary dissection of corpses as a form of mutilation, thus forbidding it, there were no corpses for study available through official channels. The towers were repeatedly broken into, much to the dismay of the Zoroastrian community. Secondly, while the towers had been built away from population centres, the growth of the towns led to the towers now being within city limits. Finally, many of the Zoroastrians found the system outdated. Following long negotiations between the "anjuman" societies of Yazd, Kerman, and Tehran, the latter gained a majority and established a cemetery some 10 km from Tehran at Ghassr-e Firouzeh (Firouzeh's Palace). The graves were lined with rocks and plastered with cement to prevent direct contact with the earth. In Yazd and Kerman, in addition to cemeteries, orthodox Zoroastrians continued to maintain a tower until the 1970s when ritual exposure was prohibited by law.


title: Tower of Silence

text: Following the rapid expansion of the Indian cities, the squat buildings are today in or near population centres, but separated from the metropolitan bustle by gardens or forests. In Parsi Zoroastrian tradition, exposure of the dead is also considered to be an individual's final act of charity, providing the birds with what would otherwise be destroyed.


title: Tower of Silence

text: In the late 20th century and early 21st century the vulture population on the Indian subcontinent declined (see Indian vulture crisis) by over 97% as of 2008, primarily due to diclofenac poisoning of the birds following the introduction of that drug for livestock in the 1990s, until banned for cattle by the Government of India in 2006. The few surviving birds are often unable to fully consume the bodies. In 2001, Parsi communities in India were evaluating captive breeding of vultures and the use of "solar concentrators" (which are essentially large mirrors) to accelerate decomposition. Some have been forced to resort to burial, as the solar collectors work only in clear weather. Vultures used to dispose of a body in minutes, and no other method has proved fully effective.


title: Tower of Silence

text: The right to use the Towers of Silence is a much-debated issue among the Parsi community. The facilities are usually managed by the , the predominantly conservative local Zoroastrian associations. These usually having five priests on a nine-member board. In accordance with Indian statutes, these associations have domestic authority over trust properties and have the right to grant or restrict entry and use, with the result that the associations frequently prohibit the use by the offspring of a "mixed marriage", that is, where one parent is a Parsi and the other is not.


title: Tower of Silence

text: The towers remain in use as sacred locations for the Parsi community, though non-members may not enter them. In Mumbai visitors are shown a model of a tower. Organized tours can be taken to the site.


title: Lucas Jade Zumann

text: Lucas Jade Zumann (born December 12, 2000) is an American actor. He played Milo in the horror film "Sinister 2", Jamie Fields in the indie comedy-drama film "20th Century Women" and Gilbert Blythe in "Anne with an E".


title: Lucas Jade Zumann

text: Zumann was born in the Chicago, Illinois, neighborhood of Rogers Park, the oldest of four brothers. He is of Jewish heritage and attended Hebrew school. He attended Waters Elementary School, and then in fifth grade moved to the Chicago Waldorf School until eighth grade, and returned again for twelfth grade.


title: Lucas Jade Zumann

text: He was discovered by a talent agent when auditioning for a Disney talent search in Chicago at Paskal Rudnicke casting. His first foray into acting came as an ensemble member in a production of the musical "Oliver!" in his hometown at Music Theater Works (formerly Light Opera Works) . He then made a cameo in the Netflix series "Sense8".


title: Lucas Jade Zumann

text: Zumann's first big role was in the horror film "Sinister 2", playing Milo. He was also noticed by playing the character Jamie Fields, in the Oscar-nominated "20th Century Women", alongside Elle Fanning, Billy Crudup, Greta Gerwig and Annette Bening. He is known globally as Gilbert Blythe on the Canadian Netflix series "Anne with an E", and also portrayed Nathan Daldry/A in the teen rom-com movie "Every Day" (2018).


title: Gretl Braun

text: Margarete Berta "Gretl" Braun (; 31 August 1915 – 10 October 1987) was one of the two sisters of Eva Braun. She was a member of the inner social circle of Adolf Hitler at the Berghof. Gretl became the sister-in-law of Hitler following his marriage to Eva, less than 40 hours before the couple killed themselves together.


title: Gretl Braun

text: Braun married SS-Gruppenführer Hermann Fegelein, a liaison officer on Hitler's staff, on 3 June 1944. In the closing days of World War II, Fegelein was shot for desertion. Despite Gretl's ties to the Nazi regime, she managed to survive the war nearly completely unscathed. She changed her name, remarried, and lived a quiet life until her death in 1987.


title: Gretl Braun

text: Braun was the youngest of three daughters of school teacher Friedrich "Fritz" Braun and seamstress Franziska "Fanny" Kronberger. After dropping out of secondary school in Medingen at the age of 16, she worked as a clerk for the photography company of Heinrich Hoffmann, the official photographer for the Nazi Party, who also employed her sister Eva. Hitler provided the sisters with a three-bedroom apartment in Munich in August 1935, and the next year with a villa in Bogenhausen. Their father was not pleased with this arrangement and wrote to Hitler to protest about it. The sisters were keen photographers; in 1943 Gretl attended the Bavarian State School of Photography.


title: Gretl Braun

text: Gretl spent much time with Eva at Hitler's Berghof retreat in the Obersalzberg of the Bavarian Alps, where she enlivened the formal atmosphere by having fun, smoking, and flirting with the orderlies. According to Hitler's secretary, Traudl Junge, Hitler explained to her at length why he detested smoking, but she would not give up the habit. Gretl fell for Hitler's SS adjutant Fritz Darges, but he was suddenly dismissed by Hitler and posted to command a unit on the Eastern Front following an insubordinate comment at a meeting in 1944.


title: Gretl Braun

text: On 3 June 1944, she married SS-Gruppenführer Hermann Fegelein, who served as Reichsführer-SS Heinrich Himmler's liaison officer on Hitler's staff. Their wedding took place at the Mirabell Palace in Salzburg with Hitler, Himmler, and Martin Bormann as witnesses. Her sister Eva made all the wedding arrangements. A wedding reception at the Berghof and party at the Eagle's Nest at Obersalzberg lasted three days. The marriage provided Hitler with a formal link to Eva and a reason to include her at public functions. Fegelein was a known playboy and had many extramarital affairs.


title: Gretl Braun

text: Three days after Gretl's wedding, the Normandy Landings took place. The social scene at the Berghof effectively ended on 14 July 1944 when Hitler left for his military headquarters, never to return. On 19 January 1945, Gretl and Eva arrived at the Reich Chancellery in Berlin, but they left for Berchtesgaden on 9 February. Eva later returned alone. On 23 April she wrote her last letter to Gretl and included a request for her to destroy all her business papers, but to retain the personal correspondence or bury it. None of these documents have been found.


title: Gretl Braun

text: Gretl was pregnant and still at the Berghof when her husband was arrested for desertion on 28 April 1945 in an apartment in Berlin, having gone missing from the Führerbunker. Initially, out of consideration for Eva, Hitler considered ordering Fegelein assigned to the defence of Berlin. However, after learning of Himmler's offer to surrender to the western Allies, Hitler ordered Himmler arrested and Fegelein shot. Hitler married Eva Braun in the early morning hours of 29 April. On the afternoon of 30 April 1945 the couple committed suicide. On 5 May 1945 at Obersalzberg, Gretl gave birth to a daughter, whom she named Eva Barbara in memory of her sister. Eva Barbara committed suicide in 1971, after her boyfriend was killed in a car accident.


title: Gretl Braun

text: Braun married Kurt Berlinghoff on 6 February 1954 in Munich. She died on 10 October 1987 in Steingaden, Bavaria, aged 72.


title: Spaced repetition

text: Spaced repetition is an evidence-based learning technique that is usually performed with flashcards. Newly introduced and more difficult flashcards are shown more frequently, while older and less difficult flashcards are shown less frequently in order to exploit the psychological spacing effect. The use of spaced repetition has been proven to increase the rate of learning.


title: Spaced repetition

text: Although the principle is useful in many contexts, spaced repetition is commonly applied in contexts in which a learner must acquire many items and retain them indefinitely in memory. It is, therefore, well suited for the problem of vocabulary acquisition in the course of second-language learning. A number of spaced repetition software programs have been developed to aid the learning process. It is also possible to perform spaced repetition with flashcards using the Leitner system.


title: Spaced repetition

text: Alternative names for spaced repetition include spaced rehearsal, expanding rehearsal, graduated intervals, repetition spacing, repetition scheduling, spaced retrieval, and expanded retrieval.


title: Spaced repetition

text: Over the years, techniques and tests have been formed to better patients with memory difficulties. Spaced repetition is one of these solutions to help better the patients' minds. Spaced repetition is used in many different areas of memory from remembering facts to remembering how to ride a bike to remembering past events from childhood. Recovery practice is used to see if an individual is able to recall something immediately after they have seen or studied it. Increasing recovery practice is frequently used as a technique in improving long-term memory, essentially for young children trying to learn and older individuals with memory diseases.


title: Spaced repetition

text: The basis for spaced repetition research was laid by Hermann Ebbinghaus, who suggested that information loss over time follows a forgetting curve, but that forgetting could be reset with repetition based on active recall.


title: Spaced repetition

text: The spaced repetition training was first tested by Landauer and Bjork in 1978; they gathered a group of psychology students showing the students pictures of a certain individual followed by that individual's name. This is also known as a face-name association. With the repetition of seeing the person's name and face they were able to associate the name and face of that individual shown with the expansion of time due to the spaced repetition.


title: Spaced repetition

text: Schacter, Rich, and Stampp in 1985 furthered the research to include people who have amnesia and other memory disorders. The findings showed that using spaced repetition can not only help students with name face association but individuals dealing with memory impairments.


title: Spaced repetition

text: In 1989, C. J. Camp decided that using this technique with Alzheimer's patients may increase their duration of remembering particular things. These results show that the expansion of the time interval shows the strongest benefits for memory.


title: Spaced repetition

text: Spaced repetition is a method where the subject is asked to remember a certain fact with the time intervals increasing each time the fact is presented or said. If the subject is able to recall the information correctly the time is doubled to further help them keep the information fresh in their mind to recall in the future. With this method, the patient is able to place the information in their long-term memory. If they are unable to remember the information they go back to the previous step and continue to practice to help make the technique lasting (Vance & Farr, 2007).


title: Spaced repetition

text: The expansion is done to ensure a high success level of recalling the information on the first time and increasing the time interval to make the information long-lasting to help keep the information always accessible in their mind.


title: Spaced repetition

text: Throughout the development of spaced repetition, they have found that patients using this technique with dementia are able to recall the information weeks—even months—later. The technique has been successful in helping dementia patients remember particular objects' names, daily tasks, name face association, information about themselves, and many other facts and behaviors (Small, 2012). Sufficient test evidence shows that spaced repetition is valuable in learning new information and recalling information from the past.


title: Spaced repetition

text: Small combines the works and findings of quite a few scientists to come up with five reasons why spaced repetition works: it helps show the relationship of routine memories, it shows the benefits of learning things with an expansion of time, it helps the patient with Alzheimer's dementia keep their brain active, it has a high success level with little to no errors, and the technique is meaningful for the patient to do and remember more things (Small, 2012). Joltin et al. (2003), had a caregiver train a woman with Alzheimer's by giving her the name of her grandchild over the phone while asking her to associate with the picture of the grandchild posted on the refrigerator. After training, the woman was able to recall the name of her grandchild five days later.


title: Spaced repetition

text: The notion that spaced repetition could be used for improving learning was first proposed in the book "Psychology of Study" by Prof. C. A. Mace in 1932: "Perhaps the most important discoveries are those which relate to the appropriate distribution of the periods of study... Acts of revision should be spaced in gradually increasing intervals, roughly intervals of one day, two days, four days, eight days, and so on."


title: Spaced repetition

text: In 1939, H. F. Spitzer tested the effects of a type of spaced repetition on sixth-grade students in Iowa who were learning science facts. Spitzer tested over 3600 students in Iowa and showed that spaced repetition was effective. This early work went unnoticed, and the field was relatively quiet until the late 1960s when cognitive psychologists, including Melton and Landauer and Bjork, explored manipulation of repetition timing as a means to improve recall. Around the same time, Pimsleur language courses pioneered the practical application of spaced repetition theory to language learning, and in 1973 Sebastian Leitner devised his "Leitner system", an all-purpose spaced repetition learning system based on flashcards.


title: Spaced repetition

text: With the increase in access to personal computers in the 1980s, spaced repetition began to be implemented with computer-assisted language learning software-based solutions (see ), enabling automated scheduling and statistic gathering, scaling to thousands of cards scheduled individually. To enable the user to reach a target level of achievement (e.g. 90% of all material correctly recalled at any given time point), the software adjusts the repetition spacing interval. Material that is hard appears more often and material that is easy less often, with difficulty defined according to the ease with which the user is able to produce a correct response.


title: Spaced repetition

text: The data behind this initial research indicated that an increasing space between rehearsals (expanding) would yield a greater percentage of accuracy at test points. Spaced repetition with expanding intervals is believed to be so effective because with each expanded interval of repetition it becomes more difficult to retrieve the information because of the time elapsed between test periods; this creates a deeper level of processing of the learned information in long-term memory at each point. Another reason that the expanding repetition model is believed to work so effectively is that the first test happens early on in the rehearsal process. The purpose of this is to increase repetition success. By having a first test that followed initial learning with a successful repetition, people are more likely to remember this successful repetition on the following tests. Although expanding retrieval is commonly associated with spaced repetition, a uniform retrieval schedule is also a form of spaced repetition procedure.


title: Spaced repetition

text: Spaced repetition is typically studied through the use of memorizing facts. Traditionally speaking, it has not been applied to fields that required some manipulation or thought beyond simple factual/semantic information. A more recent study has shown that spaced repetition can benefit tasks such as solving math problems. In a study conducted by Pashler, Rohrer, Cepeda, and Carpenter, participants had to learn a simple math principle in either a spaced or massed retrieval schedule. The participants given the spaced repetition learning tasks showed higher scores on a final test distributed after their final practice session.


title: Spaced repetition

text: This is unique in the sense that it shows spaced repetition can be used to not only remember simple facts or contextual data but it can also be used in fields, such as math, where manipulation and the use of particular principles or formulas (e.g. y = mx + b) is necessary. These researchers also found that it is beneficial for feedback to be applied when administering the tests. When a participant gave a wrong response, they were likely to get it correct on the following tests if the researcher gave them the correct answer after a delayed period. Spaced repetition is a useful tool for learning that is relevant to many domains such as fact learning or mathematics, and many different tasks (expanding or uniform retrieval). Many studies over the years have contributed to the use and implementation of spaced repetition, and it still remains a subject of interest for many researchers.


title: Spaced repetition

text: Some have theorized that the precise length of intervals does not have a great impact on algorithm effectiveness, although it has been suggested by others that the interval (expanded interval vs. fixed interval, etc.) is quite important. The experimental results regarding this point are mixed.


title: Spaced repetition

text: Most spaced repetition software (SRS) is modeled after the manual style of learning with physical flashcards: items to memorize are entered into the program as question-answer pairs. When a pair is due to be reviewed, the question is displayed on a screen, and the user must attempt to answer. After answering, the user manually reveals the answer and then tells the program (subjectively) how difficult answering was. The program schedules pairs based on spaced repetition algorithms. Without a computer program, the user has to schedule physical flashcards; this is time-intensive and limits users to simple algorithms like the Leitner system.


title: Spaced repetition

text: The Leitner system is a widely used method of efficiently using flashcards that was proposed by the German science journalist Sebastian Leitner in the 1970s. It is a simple implementation of the principle of spaced repetition, where cards are reviewed at increasing intervals.


title: Spaced repetition

text: In this method, flashcards are sorted into groups according to how well the learner knows each one in Leitner's learning box. The learners try to recall the solution written on a flashcard. If they succeed, they send the card to the next group. If they fail, they send it back to the first group. Each succeeding group has a longer period of time before the learner is required to revisit the cards. In Leitner's original method, published in his book "" ("How To Learn To Learn"), the schedule of repetition was governed by the size of the partitions in the learning box. These were 1, 2, 5, 8 and 14 cm. Only when a partition became full was the learner to review some of the cards it contained, moving them forward or back, depending on whether they remembered them.


title: Spaced repetition

text: Graduated-interval recall is a type of spaced repetition published by Paul Pimsleur in 1967. It is used in the Pimsleur language learning system and is particularly suited to programmed audio instruction due to the very short times (measured in seconds or minutes) between the first few repetitions, as compared to other forms of spaced repetition which may not require such precise timings. The intervals published in Pimsleur's paper were: 5 seconds, 25 seconds, 2 minutes, 10 minutes, 1 hour, 5 hours, 1 day, 5 days, 25 days, 4 months, and 2 years.


title: Spaced repetition

text: Spaced repetition with expanding intervals has long been argued to be the most beneficial version of this learning procedure, but current research, which compared repetition procedures, has shown the difference between expanding repetition and uniform retrieval is either very little to nonexistent. Some researchers have found cases where uniform retrieval is better than expanding. The main speculation for this range of results is that prior research has not accounted for the possibility of their results being affected by either the spacing condition or the number of successful repetitions during study periods.


title: Spaced repetition

text: There are two forms of implementing spacing in spaced repetition. The first form is absolute spacing. Absolute spacing is the measurement of all the trials within the learning and testing periods. An example of this would be that participants would study for a total of thirty trial periods, but the spacing of these trials can either be expanding or uniform. The second form is called relative spacing. Relative spacing measures the spacing of trials between each test. An example of this would be if the absolute spacing was thirty, participants would either have expanding intervals (1–5–10–14) or uniform intervals (5–5–5–5–5–5). This is important in measuring whether or not one type of repetition schedule is more beneficial than the other.


title: Spaced repetition

text: A common criticism of repetition research has argued that many of the tests involved have simply measured retention on a short-term scale. A study conducted by Karpicke and Bauernschmidt used this principle to determine the major differences between the different types of repetition. The two focused on studying long-term retention by testing participants over the course of one week. The participants were either assigned to a uniform schedule or an expanding schedule. No matter what type of spacing was assigned to the ninety-six participants, each completed three repeated tests at the end of their rehearsal intervals. Once those tests were completed, participants came back one week later to complete a final retention test. The researchers concluded that it did not matter what kind of repetition schedule was used. The biggest contribution to effective long-term learning was the spacing between the repeated tests (absolute spacing).


title: Al Nassr FC

text: Al Nassr Football Club (; "Naṣr" meaning "Victory") is a Saudi Arabian football club based in Riyadh. Formed in 1955, the club plays its home games at the Mrsool Park. Their home colours are yellow and blue.


title: Al Nassr FC

text: Al Nassr is one of the most successful clubs in Saudi Arabia, Victory championships are estimated at 27 championships at the level of all competitions.


title: Al Nassr FC

text: At domestic level, the club has won nine Premier League titles, six King's Cups, three Crown Prince's Cups, three Federation Cups and two Saudi Super Cups. At international level, they have won two GCC Champions Leagues and held the impressive feat of pulling a historic Asian double in 1998, by claiming both the Asian Cup Winners' Cup and the Asian Super Cup.


title: Al Nassr FC

text: Al Nassr was established in 1955 by Zeid Bin Mutlaq Al-Ja'ba Al-Dewish Al-Mutairi. Training took place in an old playground at Gashlat Al-Shortah west of Al-Fotah Garden where there was a small football field and a small room to store balls and shirts. In addition to the Al-Ja'ba brothers, Ali and Issa Al-Owais were among the first to work at the club.


title: Al Nassr FC

text: The club operated as an amateur club until 1960 when it was registered officially with the General Presidency of Youth Welfare. It was at this time that Abdul Rahman bin Saud Al Saud became the head of Al Nassr. Al Nassr started in the second division of the league. They were promoted to the first division in 1963. During the 1970s and 1980s, the club won four Saudi Premier League titles, six King's Cups, three Crown Prince Cups and three Federation Cup. The team's success was built around the "Saudi Golden Trio" of Majed Abdullah, Fahd Al-Herafy and Mohaisn Al-Jam'aan.


title: Al Nassr FC

text: In the 1990s, Al Nassr won two further Saudi Premier League titles, a King's Cup and a Federation Cup. They also had success in several international tournaments, winning two GCC Champions Leagues, one Asian Cup Winners' Cup and one Asian Super Cup. As a champion of Asian Super Cup Al-Nasser FC represent the AFC region in the first FIFA Club World Cup in Brazil in 2000. In the competition Al Nassr played against Sport Club Corinthians Paulista, Real Madrid and Raja Casablanca, and finished 3rd in the group. Al Nassr won the competition's Fair Play award.


title: Al Nassr FC

text: After the Golden Trio's retirement, Al Nassr went into some major setbacks. In 2006–07, the club only avoided relegation on the last day of the season, which prompted honorary members of the club to begin an effective long-term plan, to revolutionize management and team members.


title: Al Nassr FC

text: After a major overhaul of playing staff, Al Nassr went on to win the Federation Cup 2008 against city rivals, Al Hilal. The club finished third in 2009–10 securing Asian Champions League football for the following season. In 2011–12, Al Nassr saw itself on the King Cup's final, only to finish as a runners-up, and in 2012–13, Al Nassr continued its steady steps into returning to the Saudi giant it once was, where it reached the Crown Prince Cup final, only to lose to Al Hilal on penalties.


title: Al Nassr FC

text: In 2013–14, Al Nassr finally achieved its long-term goal of returning to crowning stages, by earning an impressive double against city rivals Al Hilal on both league and Crown Prince cups. The team subsequently qualified for the 2015 AFC Champions League following the astonishing accomplishment.


title: Al Nassr FC

text: In the 2014–15 season, Al Nassr continued defending the title as holding champion, by winning the league, and reaching the King's Cup final, as well as qualifying for the Crown Prince's semi-final. The identity of a returning champion still persists within club halls.


title: Al Nassr FC

text: In the 2018–19 season, Al Nassr won the league. As well as making it to the King's Cup semi finals, and the Asian Champions league quarter finals.


title: Al Nassr FC

text: In both 2020 and 2021, Al Nassr saw themselves win the Saudi Super Cup In succession, beating Al Taawoun FC 1-1 (5-4p) in 2020, and beating their fierce city rivals, Al Hilal SFC, 3–0.


title: Al Nassr FC

text: Al Nassr is the Arabic word for "victory." Clubs with the same name are found in Oman, Kuwait, Bahrain, UAE and Libya but the Saudi Arabian club was the first to take the name.


title: Al Nassr FC

text: The club's logo represents the map of Arabia with yellow and blue colors. Yellow for the gorgeous sand of the Arabian deserts, and blue for the magnificent water in the Arabian Sea, the Arabian Gulf and the Red Sea surrounding the Arabian Peninsula. Recently the old logo has been replaced by a "more modern version", but still is heavily influenced by the old club logo. The new logo only represents the football team while the old logo represents the club as a whole.


title: The Venetian Las Vegas

text: The Venetian Las Vegas is a luxury hotel and casino resort located on the Las Vegas Strip in Paradise, Nevada, United States, on the site of the old Sands Hotel. Designed by KlingStubbins, the hotel tower contains 36 stories and rises . The Venetian is owned by Vici Properties and operated by Apollo Global Management.


title: The Venetian Las Vegas

text: The Venetian resort complex includes the adjacent Palazzo resort and The Venetian Convention and Expo Center center, as well as the upcoming MSG Sphere at The Venetian. The Venetian-Palazzo complex includes the world's second-largest hotel, with 4,049 rooms, 3,068 suites and a casino.;


title: The Venetian Las Vegas

text: In April 1996, Sheldon Adelson announced plans to create the largest resort on the Strip. This project would be situated on the former Sands property. On November 26, 1996, eight years after it was purchased by the owners of The Interface Group—Adelson, Richard Katzeff, Ted Cutler, Irwin Chafetz and Jordan Shapiro, the Sands Hotel was imploded to make way for The Venetian Resort Hotel Casino. Groundbreaking for the hotel began on April 14, 1997.


title: The Venetian Las Vegas

text: The resort opened on May 3, 1999, with flutter of white doves, sounding trumpets and singing gondoliers. Actress Sophia Loren joined Adelson, the chairman and owner, in dedicating the first motorized gondola. Built at a cost of $1.5 billion, it was one of the most expensive resorts of its kind when it opened.


title: The Venetian Las Vegas

text: On June 27, 2003, the 1,013-room Venezia Tower opened. It was built on top of the garage parking lot.


title: The Venetian Las Vegas

text: In 2004, the Venetian agreed to pay a $1 million penalty to settle a 12-count Gaming Control Board complaint. One of the 12 complaints alleged the hotel had held a drawing for a Mercedes-Benz that was rigged to be won by a high roller who had lost a large amount in the casino. The executives involved were fired.


title: The Venetian Las Vegas

text: 2007 saw the opening of the sister resort in Macau, The Venetian Macao, modeled after the original Las Vegas property.


title: The Venetian Las Vegas

text: In October 2011, the Cantor Race & Sportsbook opened, which was the only Las Vegas sportsbook that was open 24 hours a day. On June 11, 2012, the Venetian opened Carnevale, a summer-long festival that is anchored by a nightly 3-D projection show on the clock tower.


title: The Venetian Las Vegas

text: In 2013, the Venetian agreed to pay the U.S. Department of Justice $47.4 million to settle charges over "alleged money laundering activities".


title: The Venetian Las Vegas

text: Like other casinos in the state, the Venetian closed indefinitely in March 2020 in response to the COVID-19 pandemic and its effects on the state. In April 2020, the Venetian announced plans to incorporate emergency medical personnel and automatic camera-based body temperature scans into its eventual reopening, which occurred on June 4, 2020.


title: The Venetian Las Vegas

text: By the end of 2020, Las Vegas Sands wanted to focus on its operations in Macau, as Asia was expected to recover from the pandemic's impact at a faster rate. The company was in early discussions to sell the Venetian, the Palazzo, and the Sands Expo. Adelson died in January 2021, and Las Vegas Sands announced two months later that it would sell the three Las Vegas facilities for $6.25 billion. Through the deal, Vici Properties bought the land under the facilities for $4 billion, and Apollo Global Management acquired the operations for $2.25 billion as part of a triple net lease agreement with Vici. The sale was finalized in February 2022. The two hotel properties retained their names, but the Sands Expo was renamed the Venetian Expo.


title: The Venetian Las Vegas

text: The hotel uses Venice, Italy, as its design inspiration and features architectural replicas of various Venetian landmarks, including the Palazzo Ducale, Piazza San Marco, Piazzetta di San Marco, the Lion of Venice Column and the Column of Saint Theodore, St Mark's Campanile, and the Rialto Bridge. The logo was designed by Ross Patrick at Maddocks & Company. The design architects for this project were The Stubbins Associates and WAT&G. Interior design was provided by Wilson Associates and Dougall Associates for the casino.


title: The Venetian Las Vegas

text: The Venetian includes an indoor shopping mall known as the Grand Canal Shoppes. The Venetian Convention and Expo Center serves as the convention center for the Venetian and Palazzo. In October 2001, the Guggenheim Hermitage Museum opened within the resort, featuring its first collection.


title: The Venetian Las Vegas

text: In 2015, the resort's TAO Nightclub generated over $50 million in revenue, according to Nightclub & Bar Top 100. With an Asian-inspired theme, TAO features a 20 foot tall Buddha statue, an infinity edge pool stocked with koi, eight private "sky boxes" with mini-bars, a 40-foot-long terrace with views of the Strip, and two dance rooms. TAO Beach, located on top of TAO Nightclub, is the Venetian's day club and pool party. It offers seven cabanas, each with television, DVD player, Xbox 360, a stocked mini-fridge and a safe for valuables.


title: The Venetian Las Vegas

text: The adjacent MSG Sphere at The Venetian, which is being built in partnership with The Madison Square Garden Company, will open in 2023.


title: The Venetian Las Vegas

text: The Venetian is home to four theaters: The Opaline Theatre, The Palazzo Theatre, The Sands Showroom, and The Venetian Theatre. In October 2005, Blue Man Group opened at the Blue Man Theatre and continued performing there until September 2012, when the show relocated to the Monte Carlo resort. On June 24, 2006, the show, "," opened at a new Paris Opera House styled theatre at The Venetian. The show concluded on September 2, 2012. Tim McGraw and Faith Hill headlined their Soul2Soul concert series which began in December 2012 and ended in April 2014.


title: Association of American Universities

text: The Association of American Universities (AAU) is an organization of American research universities devoted to maintaining a strong system of academic research and education. Founded in 1900, it consists of 63 universities in the United States (both public and private) and two universities in Canada—the University of Toronto and McGill University. AAU membership is by invitation only and requires an affirmative vote of three-quarters of current members.


title: Association of American Universities

text: The AAU was founded on February 28, 1900, by a group of 14 Doctor of Philosophy degree-granting universities in the United States to strengthen and standardize American doctoral programs. American universities—starting with Johns Hopkins University in 1876—were adopting the research-intensive German model of higher education. Lack of standardization damaged European universities' opinions of their American counterparts and many American students attended graduate school in Europe instead of staying in the U.S. The presidents of Harvard University, Columbia University, Johns Hopkins University, the University of Chicago, and the University of California sent a letter of invitation to nine other universities—Clark University, Catholic University of America, Cornell University, the University of Michigan, Princeton University, the University of Pennsylvania, Stanford University, the University of Wisconsin, and Yale University—to meet in Chicago in February 1900 to promote and raise standards. The AAU's founding members elected Harvard's Charles William Eliot as the association's first president and Stanford's David Starr Jordan as its first chairman.


title: Association of American Universities

text: In 1914, the AAU began accrediting undergraduate education at its member and other schools. German universities used the "AAU Accepted List" to determine whether a college's graduates were qualified for graduate programs. Regional accreditation agencies existed in the U.S. by the 1920s, and the AAU ended accrediting schools in 1948.


title: Association of American Universities

text: For its first six decades, the AAU functioned as a club for the presidents and deans of elite research universities to informally discuss educational matters, and its day-to-day operations were managed by an executive secretary. In the 1970s, the AAU shifted to a role of active advocacy on behalf of its members' interests; dues were raised, more staff members were hired, and its chief executive was given the title of president and the duty of becoming far more publicly visible than his predecessors.


title: Association of American Universities

text: Today, the AAU consists of 65 U.S. and Canadian universities of varying sizes and missions that share a commitment to research. The organization's primary purpose is to provide a forum for the development and implementation of institutional and national policies in order to strengthen programs in academic research, scholarship, and education at the undergraduate, graduate, and professional levels.


title: Association of American Universities

text: The largest attraction of the AAU for many schools, especially nonmembers, is prestige. Since the AAU's founding, it has "been a grouping of the elite in the American university world," and "[n]ew presidents of nonmember universities often list gaining admission to the AAU as a goal of their administration." For example, in 2010 the chancellor of nonmember North Carolina State University described it as "the pre-eminent research-intensive membership group. To be a part of that organization is something N.C. State aspires to." A spokesman for nonmember University of Connecticut called it "perhaps the most elite organization in higher education. You'd probably be hard-pressed to find a major research university that didn't want to be a member of the AAU." In 2012, the newly elected chancellor of University of Massachusetts Amherst, a nonmember of AAU, reaffirmed the objective of elevating the campus to AAU standards and the hope of becoming a member in the near future, and called it a distinctive status. Because of the lengthy and difficult entrance process, boards of trustees, state legislators, and donors often see membership as evidence of the quality of a university.


title: Association of American Universities

text: The AAU acts as a lobbyist at its headquarters in Washington, DC, for research and higher education funding and for policy and regulatory issues affecting research universities. The association holds two meetings annually, both in Washington. Separate meetings are held for university presidents, provosts, and other officials. Because the meetings are private, they offer the opportunity for discussion without media coverage. Prominent government officials, businessmen, and others often speak to the groups.


title: Association of American Universities

text: , AAU members accounted for 58 percent of U.S. universities' research grants and contract income and 52 percent of all doctorates awarded in the United States. Since 1999, 43 percent of all Nobel Prize winners and 74 percent of winners at U.S. institutions have been affiliated with an AAU university. Approximately two-thirds of the American Academy of Arts and Sciences 2006 Class of Fellows are affiliated with an AAU university. The faculties at AAU universities include 2,993 members of the United States National Academies (82 percent of all members): the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine (2004).


title: Association of American Universities

text: AAU membership is by invitation only, which requires an affirmative vote of three-fourths of current members. Invitations are considered periodically, based in part on an assessment of the breadth and quality of university programs of research and graduate education, as well as undergraduate education. The association ranks its members using four criteria: research spending, the percentage of faculty who are members of the National Academies, faculty awards, and citations. Non-member universities whose research and education profile exceeds that of a number of current members may be invited to join the association; current members whose research and education profile falls significantly below that of other current members or below the criteria for admission of new members will be subject to further review and possible discontinuation of membership. A vote by two-thirds of the member institutions can revoke membership for poor rankings. annual dues are $80,500. All 63 U.S. members of the AAU are also classified as Highest Research Activity (R1) Universities by the Carnegie Classification of Institutions of Higher Education, as are three of the five former AAU members.


title: Association of American Universities

text: In 2014, the AAU supported the proposed Research and Development Efficiency Act arguing that the legislation "can lead to a long-needed reduction in the regulatory burden currently imposed on universities and their faculty members who conduct research on behalf of the federal government." According to the AAU, "too often federal requirements" for accounting for federal grant money "are ill-conceived, ineffective, and/or duplicative." This wastes the researchers' times and "reduces the time they can devote to discovery and innovation and increases institutional compliance costs."


title: Association of American Universities

text: Similar organizations around the world include the Russell Group (United Kingdom), U15 (Germany), League of European Research Universities (Europe), BRICS Universities League (BRICS), Association of East Asian Research Universities (mainland China, Japan, South Korea, Hong Kong, and Taiwan), C9 League (China), Group of Eight (Australia), RU11 (Japan), and the U15 Group of Canadian Research Universities (Canada).


title: Association of American Universities

text: All institutions of both the Ivy League and University Athletic Association are members of the AAU, while 13 of the 14 Big Ten institutions are as well. The next highest member percentage total is the Pac-12 Conference where 9 of the 12 institutions are members.


title: Runaway Jury

text: Runaway Jury is a 2003 American legal thriller film directed by Gary Fleder and starring John Cusack, Gene Hackman, Dustin Hoffman, and Rachel Weisz. An adaptation of John Grisham's 1996 novel "The Runaway Jury", the film pits lawyer Wendell Rohr (Hoffman) against shady jury consultant Rankin Fitch (Hackman), who uses unlawful means to stack the jury with people sympathetic to the defense. Meanwhile, a high-stakes cat-and-mouse game begins when juror Nicholas Easter (Cusack) and his girlfriend Marlee (Weisz) appear to be able to sway the jury into delivering any verdict they want in a trial against a gun manufacturer. The film was released October 17, 2003.


title: Runaway Jury

text: In New Orleans, an ex-employee perpetrates a mass shooting with a machine pistol at a stock brokerage firm. 11 people are killed and several others wounded in the incident. Among the dead is Jacob Wood. Two years later, with attorney Wendell Rohr, Jacob's widow Celeste takes Vicksburg Firearms to court on the grounds that the company's gross negligence led to her husband's death. During jury selection, jury consultant Rankin Fitch and his team communicate background information on each of the jurors through electronic surveillance to defense attorney Durwood Cable, who is in the courtroom.


title: Runaway Jury

text: In the jury pool, Nicholas (Nick) Easter attempts to get himself excused from jury duty. Judge Frederick Harkin refuses, claiming he's giving him a lesson in civic duty, and Fitch tells Cable that the judge has now given them no choice but to select Nick as a juror. Nick's congenial manner wins over his fellow jurors, but Frank Herrera, a Marine veteran, who takes an instant dislike to him.


title: Runaway Jury

text: A woman named Marlee makes an offer to Fitch and Rohr by phone: she will deliver the desired verdict to the first bidder. Rohr dismisses the offer, assuming it to be a tactic by Fitch to obtain a mistrial. Fitch asks for proof that she can deliver, though, which Nick provides by getting a juror expelled. By observing the jurors' behaviour through concealed cameras, Fitch identifies Nick as the influencer and orders his apartment to be searched, but finds nothing.


title: Runaway Jury

text: Marlee retaliates by getting one of Fitch's jurors bounced. Fitch then blackmails three jurors, leading Rikki Coleman, to attempt suicide. He also sends his men to find a concealed storage device in Nick's apartment with key information, after which they set fire to it. Nick shows the judge video footage of Fitch's men breaking into his apartment, and the judge orders the jury sequestered.


title: Runaway Jury

text: Rohr's key witness, a former Vicksburg employee, doesn't show up. After confronting Fitch, Rohr decides that he cannot win the case. He asks his firm's partners for $10 million to pay Marlee. Fitch sends an operative, Janovich, to kidnap Marlee, but she fights him off and raises the price to $15 million. On principle, Rohr changes his mind and refuses to pay. After the CEO of Vicksburg Firearms loses his temper under cross-examination as a witness and makes a bad impression on the jury, Fitch agrees to pay Marlee to be certain of the verdict.


title: Runaway Jury

text: Fitch's subordinate Doyle, who is investigating Nick, finds that Nick is, in fact, Jeff Kerr, a law school drop-out. He then travels to Gardner, Indiana, where Jeff and his law school girlfriend Gabby (ie. Marlee) both come from. Doyle gently quizzes Gabby's mother, who reveals that Gabby's sister died in a shooting years ago when she was in high school. At the time, the town of Gardner sued the manufacturer of the guns used and lost; Fitch had helped the defense win the case. Doyle concludes that Nick and Marlee's offer is a set-up, and he calls Fitch, but it is too late as the money has already been paid.


title: Runaway Jury

text: Nick receives confirmation of receipt of payment, and he makes a speech, asking them to review the facts. Saying they owe it to Celeste Wood to deliberate, much to the chagrin of Herrera. He launches into a rant against the plaintiff, which undermines his support. The gun manufacturer is found liable, with the jury awarding $110 million in general damages to Celeste Wood.


title: Runaway Jury

text: After the trial, Nick and Marlee confront Fitch with a receipt for the $15 million bribe which they will make public unless he retires. Fitch asks how they got the jury to vote for the plaintiff, to which Nick replies that he didn't; clarifying he stopped Fitch from stealing the trial by getting the jury to vote with their hearts. Nick and Marlee inform an indignant Fitch that the $15 million "fee" will benefit the shooting victims in Gardner.


title: Runaway Jury

text: In August 1996, Arnon Milchan and distribution partner Warner Bros. paid a record $8 million for the rights to the novel and first-look rights to Grisham's next novel. Directors slated to helm the picture included Joel Schumacher and Mike Newell, with the lead being offered to Edward Norton and Will Smith. The novel's focus on big tobacco was retained until the 1999 film "The Insider" was released, necessitating a plot change from tobacco to gun companies.


title: Runaway Jury

text: "Runaway Jury" received generally positive reviews from critics. The film has a 73% approval rating on Rotten Tomatoes, with the site calling the film "an implausible but entertaining legal thriller." On Metacritic, it has weighted average score of 61 out of 100, based on 38 reviews, indicating "generally favorable reviews". Audiences polled by CinemaScore gave the film an average grade of "A−" on an A+ to F scale.


title: Runaway Jury

text: Roger Ebert gave the film three out of four stars and stated that the plot to sell the jury to the highest-bidding party was the most ingenious device in the story because it avoided pitting the "evil" and the "good" protagonists directly against each other in a stereotypical manner, but it plunged both of them into a moral abyss.


title: The Man Who Knew Too Much (1956 film)

text: The Man Who Knew Too Much is a 1956 American suspense thriller film directed and produced by Alfred Hitchcock, starring James Stewart and Doris Day. The film is Hitchcock's second film using this title, following his own 1934 film of the same name but featuring a significantly different plot and script.


title: The Man Who Knew Too Much (1956 film)

text: In the book-length interview "Hitchcock/Truffaut" (1967), in response to fellow filmmaker François Truffaut's assertion that aspects of the remake were by far superior, Hitchcock replied, "Let's say the first version is the work of a talented amateur and the second was made by a professional."


title: The Man Who Knew Too Much (1956 film)

text: The film won an Academy Award for Best Original Song for "Que Sera, Sera (Whatever Will Be, Will Be)", sung by Doris Day. It premiered at the 1956 Cannes Film Festival on April 29.


title: The Man Who Knew Too Much (1956 film)

text: An American family – Dr. Benjamin "Ben" McKenna, his wife, popular singer Josephine “Jo” Conway McKenna, and their son Henry "Hank" McKenna – are vacationing in French Morocco. Traveling from Casablanca to Marrakesh, they meet Frenchman Louis Bernard. He seems friendly, but Jo is suspicious of his many questions and evasive answers.


title: The Man Who Knew Too Much (1956 film)

text: Bernard offers to take the McKennas to dinner, but cancels when a suspicious-looking man knocks at the McKennas' hotel-room door. At a restaurant, the McKennas meet friendly English couple Lucy and Edward Drayton. The McKennas are surprised to see Bernard arrive and sit elsewhere, apparently ignoring them.


title: The Man Who Knew Too Much (1956 film)

text: The next day, visiting a Moroccan market with the Draytons, the McKennas see a man chased by police. After being stabbed in the back, the man approaches Ben, who discovers he is Bernard in disguise. The dying Bernard whispers that a foreign statesman will be assassinated in London and that Ben must tell the authorities about "Ambrose Chappell". Lucy returns Hank to the hotel while Ben, Jo and Edward go to a police station for questioning about Bernard's death. An officer explains that Bernard was a French Intelligence agent.


title: The Man Who Knew Too Much (1956 film)

text: Ben receives a phone call at the police station; Hank was kidnapped but will not be harmed if the McKennas say nothing to the police about Bernard's warning. Knowing Hank was left in Lucy's care, Ben dispatches Edward to locate him. When Ben and Jo return to the hotel, they discover Edward checked out. Ben realizes the Draytons are the couple Bernard was looking for and are involved in Hank's abduction. When he learns the Draytons are from London, he decides he and Jo should go there and try to find them through Ambrose Chappell.


title: The Man Who Knew Too Much (1956 film)

text: In London, Scotland Yard's Inspector Buchanan tells Jo and Ben that Bernard was in Morocco to uncover an assassination plot; they should contact him if they hear from the kidnappers. Leaving friends in their hotel suite, the McKennas search for a person named Ambrose Chappell. Jo realizes that "Ambrose Chapel" is a place, and the McKennas arrive at the chapel to find Edward leading a service. Jo leaves the chapel to call the police. After Edward sends his parishioners home, Ben confronts him and is knocked out and locked inside. Jo arrives with police, but they cannot enter without a warrant.


title: The Man Who Knew Too Much (1956 film)

text: Jo learns that Buchanan has gone to a concert at Royal Albert Hall, and asks the police to take her there. Once the police and Jo leave, the Draytons take Hank to a foreign embassy. In the Royal Albert Hall lobby, Jo sees the man who came to her door in Morocco. When he threatens to harm Hank if she interferes, she realizes he is the assassin sent to kill the foreign prime minister.


title: The Man Who Knew Too Much (1956 film)

text: Ben escapes the chapel through its bell tower and reaches the Royal Albert Hall, where Jo points out the assassin. Ben searches the balcony boxes for the killer, who is waiting for a cymbal crash to mask his gunshot. Just before the cymbals crash, Jo screams and the assassin misses his mark, only wounding his target. Ben struggles with the would-be killer, who falls to his death.


title: The Man Who Knew Too Much (1956 film)

text: Concluding that Hank is likely to be at the embassy, but that it is sovereign and exempt from an investigation, the McKennas secure an invitation from the grateful prime minister. The ambassador organized the plot to kill the prime minister, and blames the failed attempt on the Draytons. Knowing that Hank can testify against them, he orders the Draytons to kill the boy.


title: The Man Who Knew Too Much (1956 film)

text: The prime minister asks Jo to sing. She loudly performs "Que Sera, Sera", so that Hank will hear her. Lucy, who is guarding Hank while Edward prepares to murder him, is distressed at the prospect of killing a child, so she encourages the boy to whistle along with the song. Ben finds Hank. Edward tries escaping with them at gunpoint, but when Ben hits him, he falls down the stairs to his death.


title: The Man Who Knew Too Much (1956 film)

text: The McKennas return to their hotel suite. Ben explains to their now-sleeping friends, "I'm sorry we were gone so long, but we had to go over and pick up Hank."


title: The Man Who Knew Too Much (1956 film)

text: Alfred Hitchcock's cameo is a signature occurrence in most of his films. In "The Man Who Knew Too Much" he can be seen 25:42 into the film, in the lower left corner, watching acrobats in the Moroccan market, with his back to the camera, wearing a light gray suit, and putting his hands into his pockets, just before the spy is killed. Bernard Herrmann, who wrote the film score, cameos as the conductor at Royal Albert Hall, the only time Herrmann appeared on-camera in a film.


title: The Man Who Knew Too Much (1956 film)

text: Alfred Hitchcock first considered an American remake of "The Man Who Knew Too Much" in 1941, but only brought back the idea in 1956 to make a film that would fulfill a contractual demand from Paramount Pictures. The studio agreed it was a picture that could be well-adapted to the new decade. The Royal Albert Hall sequence drew some inspiration from H.M. Bateman's comic "The One-Note Man", which followed the daily life of a musician who plays only one note in a symphony, similar to the cymbal player in the film.


title: The Man Who Knew Too Much (1956 film)

text: Screenwriter John Michael Hayes was hired on the condition that he would not watch the early version nor read its script, with all the plot details coming from a briefing with Hitchcock. Only the opening scenes of the script were ready when filming began, and Hayes had to send the subsequent script pages by airmail as he finished them.


title: The Man Who Knew Too Much (1956 film)

text: Hitchcock's frequent composer Bernard Herrmann wrote the "background" film score; however, the performance of Arthur Benjamin's "Storm Clouds Cantata", conducted by Herrmann, is used as source music for the climax of the film. Herrmann was given the option of composing a new cantata to be performed during the film's climax. However, he found Arthur Benjamin's cantata "Storm Clouds" from the original 1934 film to be so well suited to the film that he declined, although he did expand the orchestration, and inserted several repeats to make the sequence longer. Herrmann can be seen conducting the London Symphony Orchestra with mezzo-soprano Barbara Howitt and chorus during the Royal Albert Hall scenes. The sequence in the Royal Albert Hall runs for 12 minutes without any dialogue from the beginning of "Storm Clouds Cantata" until the climax when Doris Day's character screams.


title: The Man Who Knew Too Much (1956 film)

text: Doris Day's character in the film is a well-known, now retired, professional singer, and at two points in the film she sings the Livingston and Evans song "Que Sera, Sera (Whatever Will Be, Will Be)", a performance which won the 1956 Academy Award for Best Original Song. Day's recording of the song reached number two on the US pop charts. and number one in the UK.


title: The Man Who Knew Too Much (1956 film)

text: Reviews for the film were generally positive, although some critics expressed a preference for the 1934 original. Bosley Crowther of "The New York Times" wrote, "James Stewart tops his job in 'Rear Window' as the man who knows too much, and Doris Day is surprisingly effective as the mother who is frantic about her child ... Even in mammoth VistaVision, the old Hitchcock thriller-stuff has punch." "Variety" wrote that while Hitchcock draws "the footage out a bit long at 119 minutes, he still keeps suspense working at all times and gets strong performances from the two stars and other cast members." "Harrison's Reports" called the film a "highly exciting and entertaining suspense thriller" that "grips the audience from start to finish." Richard L. Coe of "The Washington Post" also liked the film, calling it "a dandy of its popular kind" if "a wee bit too leisurely." John McCarten of "The New Yorker" wrote in a negative review that while the remake was "unquestionably bigger and shinier than the original, it doesn't move along with anything like the agility of its predecessor. There can be no doubt, of course, that Mr. Hitchcock at one time was a master of celluloid suspense, but increasingly of late he has been turning out movies that are too overweight to indulge in the tricks of his salad days." "The Monthly Film Bulletin" wrote: "Although a quite entertaining thriller, with some characteristically shrewd and caustic Hitchcock touches, it is likely to disappoint devotees of the first film. It lacks the earlier pace and excitement; the peculiarly English charm of the original has been exchanged for a vague VistaVision and Technicolor cosmopolitanism; the dentist episode and the siege climax are unhappily missing." C. A. Lejeune of "The Observer" wrote that the plot had "a tendency to meander" with "jokes that may have looked more humorous in typescript," concluding that the film was "strong" as long as it stuck to the main plot, "But the first 'Man Who Knew Too Much' was stronger in every way."


title: The Man Who Knew Too Much (1956 film)

text: The film was a commercial success. Filmed on a budget of $1.2 million, it grossed $11,333,333 at the domestic box office, earning $4.1 million in US theatrical rentals.


title: The Man Who Knew Too Much (1956 film)

text: On the review aggregator Rotten Tomatoes, the film has an approval score of 87% based on 39 reviews, with an average rating of 7.80/10. The site's consensus reads, "Remaking his own 1934 film, Hitchcock imbues "The Man Who Knew Too Much" with picturesque locales and international intrigue, and is helped by a brilliantly befuddled performance from James Stewart."


title: The Man Who Knew Too Much (1956 film)

text: In 2004, American Film Institute included the song "Que Sera, Sera (Whatever Will Be, Will Be)" as No. 48 in AFI's 100 Years...100 Songs.


title: The Man Who Knew Too Much (1956 film)

text: "The Man Who Knew Too Much" was kept out of re-release by Hitchcock until 1983 when it was acquired by Universal Pictures. The film has been released on home video by Universal Pictures Home Entertainment in VHS, Betamax, Laserdisc, DVD and Blu-ray formats. The 2000 DVD has a documentary on the making of the film, including interviews with Hitchcock's daughter Patricia Hitchcock and members of the production crew.


title: Thyroid-stimulating hormone

text: Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T), and then triiodothyronine (T) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.


title: Thyroid-stimulating hormone

text: TSH (with a half-life of about an hour) stimulates the thyroid gland to secrete the hormone thyroxine (T), which has only a slight effect on metabolism. T is converted to triiodothyronine (T), which is the active hormone that stimulates metabolism. About 80% of this conversion is in the liver and other organs, and 20% in the thyroid itself.


title: Thyroid-stimulating hormone

text: TSH is secreted throughout life but particularly reaches high levels during the periods of rapid growth and development, as well as in response to stress.


title: Thyroid-stimulating hormone

text: The hypothalamus, in the base of the brain, produces thyrotropin-releasing hormone (TRH). TRH stimulates the anterior pituitary gland to produce TSH.