Later on, during the ten years of French reoccupation (1806 to 1815), the art collection was transferred to the Naples National Archaeological Museum. What remained was looted by the French troops of General Championnet who were billeted there during the short life of the Republic in 1799. When the Parthenopaean Republic was declared in 1799, King Ferdinand IV fled to Palermo on board Nelson's Vanguard, taking the most valuable items from the museum with him. In 1787, on the advice of Jacob Philipp Hackert, a laboratory for the restoration of paintings was created. Over the years, the palace was enlarged and filled with more art. During that year King Charles VII of Naples and Sicily (later Charles III, king of Spain) decided to build a hunting lodge on the Capodimonte hill, but then decided that he would instead build a grand palace, partly because his existing residence, the Palace of Portici, was too small to accommodate his court, and partly because he needed somewhere to house the fabulous Farnese art collection which he had inherited from his mother, Elisabetta Farnese, last descendant of the sovereign ducal family of Parma. 160 and get off at Milano stop.įrom the Capodimonte Royal Palace or from Piazza Dante take a bus of No.24 and get off at Capodimonte stop.The vast collection at the museum traces its origins back to 1738. The National Museum of Capodimonte (Museo di Capodimonte)įrom Naples Central Station take a metro of line 2 and get off at Cavour stop. To visit the museum satisfyingly, it would take a half-day. Enjoy a peaceful day forgetting the hustle and bustle of Naples here. There is a spacious park in front of the palace and many local children play soccer. The museum of Capodimonte is located on the hill overlooking the city of Naples. Catherine (Nozze mistiche di Santa Caterina)
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![]() I felt Ava's pain while she was waiting for news of John, and I felt John's pain when learning of Ava's impending marriage. When I read Five Years Gone last December, I was floored. So, in One Year Home, readers get to see how John and Julianne begin to grow together, all while hoping for Ava and Eric to be able to work through the kinks in their brand-new marriage. Meanwhile, Ava and Eric begin to experience difficulties. Another reason Julianne thinks of walking away is the very fact that she is drawn to John, and that is wrong on so many levels. However, should she be successful, she will get a coveted promotion at her job. John just might be the biggest challenge she's ever faced. Julianne wants to walk away more than once. How in the world will John work with Julianne? He is certain that every time he looks at her he will be reminded of Ava, and the fact that she married Julianne's brother Eric. That person is Julianne Tilden, Ava's sister-in-law of all people. John is more than reluctant to participate, so he is assigned someone that will prepare him. The world wants to meet the biggest hero this country has ever had. Before the Navy will let him go, however, John must cooperate and complete a media blitz. ![]() Now on the road to recovery, John wants to retire. Not only did John lose his leg, but he suffered an infection that almost took his life. He lost his two best friends during the coup. Losing Ava was not the only loss John had to endure. Just before her wedding, John was discovered to be alive, but by then, Ava's heart belonged to Eric. Believing John to be dead, Ava eventually found love. Ava never stopped loving John and he never stopped loving her. So John could never tell Ava anything, including the fact that he might be gone for years.įive years have passed, and Ava finally moved on with her life, even falling in love with and getting married to Eric. When hand-picked for this special assignment, John could not have any personal ties, especially a significant other. In so doing, John was forced to leave the love of his life, Ava, behind. For starters, he was deployed for years with a team of dedicated soldiers who worked feverishly to bring down the world's most wanted terrorist. John West is a Navy Captain who has been through hell and back - and on more than one level. PURCHASE IT NOW Kindle | Apple Books | Nook | Kobo | Google The hotly anticipated follow up to Five Years Gone releases on Aug. There’s no way I can want this man, or so I tell myself, and when Eric finds out I’ve developed feelings for the man causing trouble in his new marriage, well… The more time we spend together, the more our mutual disdain morphs into something that feels an awful lot like desire. So much so that my brothers worry about me being exploited by those who would take advantage of my unwavering love for others.īut John… He’s in a class by himself, and his bitterness is a festering wound that I begin to wish I could somehow fix for him. I’m determined to do the job, even if I dislike John from the moment I meet him. It takes five seconds to realize Ava’s ex is going to be the most complicated and difficult client I’ve ever had, but the opportunity to represent the most celebrated man in the world could make my career. I need help handling the relentless requests, and when Ava sends her new sister-in-law to manage the media circus for me, I’m prepared to hate her on principle. I’d prefer to wallow in my depression and heartbreak, but the whole damned world wants a piece of the SEAL Team leader who helped capture the world’s most-wanted terrorist. She had no choice but to move on with her life during my six-year deployment and has now married Eric. I have no idea how to survive without my beloved Ava. He came home a hero and lost the only woman he’s ever loved… ![]() Remember how Intel were dominated and AMD was just lagging behind despite their efforts, then Ryzen came in which is a huge departure from their previous architecture, and due to Intel's complacency, AMD quickly catched up. M1 does have a huge head start doesn't mean it will remained for next few years. That is remained to be seen and that is entirely up to Qualcomm at this point. I want to see Microsoft embrace competition in the CPU space and offer AMD and Intel flavors of more devices, as other OEMs have in the past. It throws out the 2-in-1 appeal of the Surface family, so it's a product I never find myself recommending to anyone. I'd buy a Surface Pro with Ryzen, and would have done the same for a Surface Book, but I really don't care for the Surface Laptop line. Limiting Ryzen to Surface Laptop is super lame. I do wish Microsoft would stop playing coy with AMD hardware. The Duo mostly needs to be addressed on a software level and having 2022's Duo resources focused on that might make future releases smoother and more appealing to people. I would like them to skip the Duo in the fall and move it to a spring launch with the majority of Android flagships (while using the 2023 Qualcomm SoC, not a 2022 one a year late). This all seems pretty safe and expected, though no mention of accessory refreshes seems like something they should address on a few fronts as well. So we'll have to see about seeing it launch in 2023. Microsoft's head of Mixed Reality experiences, Alex Kipman, has already said that a HoloLens 3 is in development and will focus on three key areas, those being improved immersion, comfort, and acceptability. ![]() ![]() Given that HoloLens 1 was released in 2016, and HoloLens 2 in 2019, a HoloLens 3 in 2022 would make sense. That brings us to HoloLens, which I'm torn about whether or not we'll see a third generation in 2022. Not much else is known about the hardware, but sources say Microsoft is serious about Windows on ARM and is excited about the platform going into 2023. In the spring, I'm told that Microsoft is planning to ship its own ARM devkit with a flagship processor based on Qualcomm's Snapdragon 8cx Gen3. I've heard Windows on ARM will be a focal point for Microsoft in 2022. I'm told the client is still on track to ship in 2022, so perhaps we'll hear more about this new client in the coming months. ![]() Microsoft had originally planned to ship previews of the Monarch client this year, but wasn't able to do so for unknown reasons. I'm also expecting the Mail & Calendar apps to be replaced with Microsoft's "Project Monarch" Outlook client in 2022. A number of in-box apps are also expected to get updates, including Notepad and Groove Music, both of which are already in preview. Version 22H2 is codenamed "Sun Valley 2" internally, which lends further credence to the 1511 comparison, as that was codenamed Threshold 2 after the initial release. Android app support is also set to ship with version 22H2. Users will be able to download new Widgets from the Microsoft Store, though unpackaged apps from outside the Store will be able to provide their own widgets as well. I'm told some developers have already been briefed on how third-party widgets will work. Microsoft is also expected to expand the Widgets panel with new features and support for third-party widgets. This will include features such as a true system wide dark mode that touches legacy UI in addition to modern interfaces, and the return of missing functionality, especially around the Taskbar. Version 22H2 is said to serve a similar purpose to that of Windows 10's version 1511, which focused on "finishing off" the OS with features and changes that simply didn't make it in time for the initial release. I'm told the current engineering schedule has mainline development on version 22H2 scheduled for completion in May 2022, with a final build expected sometime in the summer and general availability in the fall. Regarding Windows, Microsoft has already said that the next version of Windows 11 will begin shipping in the second half of 2022, which lines up with Microsoft's new release cadence for Windows in general. Perhaps this will give Microsoft a chance to use 2022 to focus on fixing up the software and OS issues that have plagued the Duo line so far. My sources tell me this plan could still change, but as it currently stands Microsoft does not intend to ship Surface Duo 3 next year and is targeting a 2023 release instead. That brings us to Surface Duo, which may also miss out on a hardware release in 2022. Source: Windows Central (Image credit: Source: Windows Central) I enjoyed most of it, and thought the acting was phenomenal. As each of them is pushed to the edge, the truth about their pasts. ![]() ![]() There are multiple plots, which mean it is best seen as a binge stream over a few days. Thriller revolving around a trio of mysterious characters, each with a troubling past. Music drowns out voices, and the dark sets made it hard for me to watch in a well lit room. The production values are generally good, but the sound is at time uneven. Sadly, the pacing is uneven, with more happening in the first episode than in the next three. They all have something to hide, and the series gives us the slow, plodding revelation of their secrets. Baker might reprise the role of Theresa, in both flashbacks with. The show is helmed by Harriet Warner of "Call the Midwife," but its Louisiana setting, subject matter, and pacing seem more rooted in the gloomy "True Detective." Fear and depression follow each of the three lead characters through the steamy swamps and grimy buildings. As for its cast, it's pretty safe to say that both Lily Rabe as Emma and Amy Brenneman as Mary would return in a second chapter. Top cast Lily Rabe Emma Hall Amy Brenneman Mary Barlow Hamish Linklater John Tyler Enrique Murciano Pete Guillory Marque Richardson Tom Johnston. Cast and charactersEdit Starring Lily Rabe as Emma Hall Amy Brenneman as Mary Barlow Main Chiara Aurelia as Rose Lord Ashley Madekwe as Lisa Guillory. ![]() Meanwhile, someone is killing young girls, and a local foster home is full of potential victims. Linklater is a serial predator who hopes to stop looking for prey. Rabe is the woman who was there when her serial killer boyfriend snatched Theresa, and cannot forgive herself for not stopping him. In this series, Brenneman plays a grieving mother who will (quite literally) do anything to find out what happened to Theresa, her missing daughter. Tell Me Your Secrets is an American thriller television series.The series was written and created by Harriet Warner and directed by John Polson. Watch the full trailer for Tell Me Your Secrets below, then hit the comments and let us know if you’ll be trying the show.Amy Brenneman Lily Rabe and Hamish Linklater all started on the stage before graduating to "character actors" on film and television. TNT ultimately scrapped Tell Me Your Secrets in June 2020, after all episodes had been filmed, but it was picked up by Amazon just four months later. Cast & Crew Lily Rabe Emma Hall Actor Amy Brenneman Mary Barlow Actor Hamish Linklater John Tyler Actor Enrique Murciano Pete Guillory Actor Chiara Aurelia Rose Lord Actor Harriet Warner Creator. The project was initially ordered to pilot at TNT in 2017, then snagged a series order at that network the following year. Tell Me Your Secrets‘ cast also includes Enrique Murciano ( Without a Trace) as Peter Guillory, a therapist with seemingly good intentions, along with Charles Esten ( Nashville) in a recurring role. Maisel: Production Officially Underway on Season 4īut as each character is pushed to the edge, “the truth about their pasts and motives grows ever murkier, blurring the lines between victim and perpetrator,” per the drama’s logline. The Underground Railroad: Watch the Hypnotic, Reverse-Motion Trailer for Barry Jenkins' Amazon Adaptation Rabe’s Emma is a young woman who once looked into the eyes of a dangerous killer Brenneman’s Mary is a grieving mother obsessed with finding her missing daughter and Linklater’s John is a former serial predator desperate to find redemption. 19 with all 10 episodes, Amazon announced Wednesday.ĭescribed as an “intense, morally complex” drama, Tell Me Your Secrets follows Rabe ( American Horror Story), Brenneman ( The Leftovers) and Hamish Linklater ( Legion) as a trio of characters that have mysterious and troubling pasts. ![]() Lily Rabe (Emma Hall) and Hamish Linklater (John Tyler) are a couple in real life and have two children. Four years after its pilot was initially ordered, Tell Me Your Secrets at last has a premiere date: The psychological thriller, starring Lily Rabe and Amy Brenneman, will drop Friday, Feb. Follows a trio of characters, each with a mysterious and troubling past: a young woman who once looked into. ![]() ![]() Uses Reed Solomon error correction, which means it can withstand some damage without loss of data. Barcodes have a fixed size with offset rows of hexagonal modules arranged around a unique finder pattern.Īrea-efficient symbology capable of encoding and reading approximately 850 characters. Encoded data encoded may include text letters, numbers, and actual bytes of data such as extended characters, Unicode characters, and images.Īn international barcode that's used on UPS shipping labels for world-wide addressing and package sorting. Data Matrix can be more efficient and compact than other 2D symbologies like PDF417 and QR-Code. Encoded data can include alphabetic characters, numbers, text, and bytes of data, including extended types, Unicode characters, and small pictures.Ĭapable of encoding much larger quantities of data than standard linear barcodes. FontĪrea-efficient symbology capable of encoding large amounts of data. Two-dimensional (2D) barcode fonts and encoders are only included in version 19.1 and later. Superset of UPC-A, with an extra digit added to every UPC-A number.6-digit variation of UPC-A that suppresses trailing zeros.The fonts can be printed in sizes from 12 points up to 32 points. UPC and EAN barcode font characters are contained in a single font represented in several different heights. ZIP code encoded in half and full height bars.Postal Numeric Encoding Technique used by the United States Postal Service to assist direct mail.Primarily for inventory control, marking storage containers and shelves in warehouse environments.Two out of five bars or spaces are wide.The second digit is encoded in the five interleaved spaces (or white lines). ![]() The first digit is encoded in the five bars (black lines). Continuous two-width barcode symbology encoding digits.Compact barcodes compared to other fonts like Code 39, especially when text is mostly digits.High-density linear barcode symbology for alphanumeric or numeric-only barcodes.Parentheses ( ) can be used as the start and stop code so letters don't appear readable version of the fonts.Uppercase letters A, B, C, and D are used for start and stop codes.Self-checking, no checksum characters requirement.Characters 0-9, letters A to D and the following symbols: - $ / +.Each bar and space is from 1 to 4 modules wide.Each character is nine modules wide, with three bars and three spaces.Every symbol includes two check characters.Primarily by Canada Post to encode delivery information.Nine elements per character (five bars and four spaces).* is used for both start and stop delimiters.43 characters, uppercase letters (A through Z), numeric digits (0 through 9), and special characters (.It defines how to encode the data, including computation of a checksum and required start and stop marker symbol.įor information and examples about adding barcodes to reports, see Adding Barcodes to Reports. Barcode symbology is the mapping between data and the barcode image. Knowing the specifications is useful for calibrating fonts used on report layouts. The fonts have different specifications for characteristics like encode numbers, symbols, uppercase, and lowercase text. APPLIES TO: Business Central 2021 release wave 1 (v18.0) and laterīusiness Central online includes the following one-dimensional (1D) and two-dimensional (2D) barcode fonts and symbologies from IDAutomation. Players can also join clans and organizations, by contacting other players in the forum. Players who join the site's official forum can buy and equip items of their choice,by trading or receiving them in various tourneys and events. The online multiplayer also has a ranking system for each colored belt, which ranges from the lowest belt (White Belt) to the highest belt (Elite Belt). Players can also use their own custom textures on the body parts. The game also includes character customization (the appearance of heads, joints, and limbs may be changed), online multiplayer, a ghost showing a preview of what the current joint settings will do to the ragdoll, and the saving and sharing of replays. These mods can change the appearance or affect the motion of the ragdolls, and can add objects to the environment which players can interact with. There are also many different mods, both official and user-created. There are a number of different play modes, based on the amount of frames per turn, lengths of matches, distances between opponents, gravity, and ease of dismemberment or fracture. This occurs when a disallowed body part (normally any part beside the hands, feet and wrists) touches the ground, or when any body part touches the ground outside the boundaries of a square or circular dojo. In most modes of play, another means of winning is causing the opponent's disqualification. The goal of the game is to score as many points as possible during a fight by landing blows on the opponent's ragdoll, with points being awarded based on the amount of damage inflicted. Through careful manipulation of the ragdoll's joints, arbitrarily complex attacks can be performed. File:toribash hand texturestoribash communitytoribash texture set freetorishoptoribash skins downloadfree toribash texturestoribash skin makertoribash head textures 128x128 i saw a guy on toribash today and he had a head texture that had a guys half face and the A torso colour doesnt count as a body texture, no. ![]() When properly manipulated, one ragdoll will strike the other, and if enough damage is inflicted with a single blow, a limb or body part may be dismembered, or fractured. The game is played by relaxing, holding, extending or contracting the various joints on the player's character and hitting the spacebar to advance time by a user-specified amount, the default being ten frames. ![]() ![]() We’ve talked before about what you need to get started with animation from a software perspective, well this week we’ll let you know what sort of hardware system requirements you need to be meeting before you buy your very first animating computer. What does a good animating computer need? This is the most important part for your machine. Rendering your finished project is always going to be the task that makes your computer sweat the most. You want a powerful and efficient CPU to cope with the intensive rendering in a reasonable amount of time.ĭuring this task, it’s your processor that’ll be doing the legwork. A decent CPU will turn your renders from day-long slogs into a matter of hours. Ideally a quad core that operates at 2Ghz at the very least. One that is capable of running a 64-bit operating system too.Ī capable GPU is vital, especially if you have your heart set on 3D. A good GPU will enable your machine to perform modeling, mapping, and animation work in 3D spaces smoothly and with more stability. Make sure to check which brand your chosen software prefers, often incompatibilities will lead to crashes and disabled features. #Toon boom studio cannot perform action insufficient memory software Go dedicated rather than integrated (this basically means you’ll have enough power). You want your GPU to have at least 2GB of RAM, too. Having more RAM in your system allows the computer to store information on what is currently being worked on. Essentially, it allows you to perform multiple tasks at once and assist with processor performance, speeding up your workflow. There are plenty of brands to choose from, but for a for a reliable and affordable option, Kingston is a safe bet. This is where you’ll be storing your projects and other files. As with most of the items I’ve listed here, more is definitely better.Īt least 1TB of storage is a must. If you have any less storage you’ll find yourself running out of space quicker than you think! So what do I need for my chosen software? That sounds like a lot if you’ve never animated before, but high quality projects complete with audio are pretty chunky files. If you want to know what the system requirements are for your animation tool of choice – look no further. Here are some of the industry-standard and most widely-used animation programs alongside the recommended specs straight from the developers themselves. ![]() Microsoft Windows 7 (SP1), 10 ProfessionalĦ4-bit Intel or AMD multi-core processor with SSE4.2 instruction setĪ detailed list of recommended systems and graphics cards can be found here.Įor a full list of System Requirements for Autodesk Maya and it’s various versions, check out their jumbo list of them here. ![]() OpenGL 3.2 compatible graphics with 2GB RAM #Toon boom studio cannot perform action insufficient memory full
In Tekken 2, as in the first tournament, the 20-year-old Nina was once again hired to assassinate the sponsor of the current tournament, Kazuya Mishima. Her story was further expanded in later games. After this, both sisters went their separate ways with Nina using her skills to become an assassin, and Anna joining the paramilitary and becoming an officer in the Tekken Force.Īnna plays only a very minor role in the story of the first game, appearing as a sub-boss character for Nina. When Richard died under mysterious circumstances the sisters blamed each other, leading to a long-standing rivalry between them. Anna was also personally trained by her mother. She and Nina were taught various martial arts by their father, a former assassin Richard Williams since young age. The character was met with positive critical reception.Īppearances In video games Īnna Williams was the youngest daughter of an Irish father, Richard and British mother, Heather and was raised in Ireland together with her elder sister Nina. In the other Tekken media, including films, Anna usually appears in role of a minor villainess. She is defined by her rivalry with her older sister Nina, a trait that has been around since the original Tekken game.Īnna originally shared most of her moves with her older sister Nina, but has since gained a more idiosyncratic moveset. She is also, although unbeknownst to her, the maternal aunt of boxing competitor Steve Fox. Anna is the narcissistic and arrogant younger sister of the quiet and serious Nina Williams, the personal bodyguard of Kazuya Mishima and second-in-command at G Corporation. ![]() Paramilitary ( Death by Degrees, Blood Vengeance)Īssassin ( The Motion Picture, live-action film)Īssassination arts (fusion of Koppo-jutsu, Submission Wrestling and Hapkido)Īnna Williams ( Japanese: アンナ・ウィリアムズ, Hepburn: Anna Wiriamuzu) is a fictional character in the Tekken fighting game series, first appearing in Tekken in 1994. Tamako Nohama (Japanese dub of the Tekken film). ![]() Kaori Yamagata ( The Motion Picture, Drama CD).Yumi Tōma ( Tekken 1 - Tekken Tag Tournament). ![]() If you click on this then we may receive a small amount of money from the retailer when you purchase the item. Read MBY’s Raymarine Axiom review With each product is a ‘Buy it now’ link. Raymarine’s Axiom MFDs are compatible with their own proprietary Lighthouse charts and Navionics, C-MAP Essentials, and C-MAP 4D MAX+. A smartphone or tablet can also be connected as a second screen. Once mounted and connected, this camera sends its imagery to the MFD and overlays useful information such as AIS targets’ speed, heading and collision warning data, course to steer visuals and lay lines to name a few. In 2019 alongside the launch of Lighthouse 3 Raymarine unveiled and an augmented reality system, which will work on Axiom MFDs – though it will require the purchase and mounting of a FLIR camera. This will mean that if your boat is one of those already in the library you will automatically get a set of performance polars (which can take significant time to develop from scratch) which will make auto routing and layline functions even more accurate and boat specific. Currently Raymarine are in the process of building a library of yachts into Lighthouse 3. Lighthouse 3 was launched in 2019 and is an impressive bit of kit, and certainly upgrades a great many of the company’s sailing features. The Axiom series comes with Raymarine’s proprietary Lighthouse 3 operating system. Beyond the screen size there is practically no difference between the models, so it will simply be a case of selecting the right size for your boat and your budget. Raymarine’s Axiom MFDs come in three sizes, 7, 9 or 12in screens and feature a touchscreen surrounded by a border and a few basic buttons on the bottom edge of the screen. Best chartplotters available right now Raymarine Axiom MFD Happily in the last decade or so improvements have worked to both make units more user friendly and have seen something of a levelling process across the market, which means you would be hard pushed to pick the wrong unit, though some will inevitably work better for your needs than others. A chartplotter by itself might be something you are after if you are very limited in terms of space and/or budget, or have (and intend to remain with) very few other electronics onboard. The terms are broadly used interchangeably, typically an MFD works as a chartplotter but also functions as a whole system hub too, connecting a variety of information sources.įor the most part, MFDs are what you would look to put on most cruising yachts and racing yachts of the modern era. ![]() Before we get into which are the best chartplotters or MFDs, it is worth briefly noting the difference between the terms ‘chartplotter’ and ‘MFD’. ![]() A hydrogen bond surrogate approach for stabilization of short peptide sequences in α-helical conformation. All-hydrocarbon stapled peptides as synthetic cell-accessible mini-proteins. Aromatic oligoamide foldamers with a ‘wet edge’ as inhibitors of the helix mediated p53-hDM2 protein–protein interaction. 8 Prabhakaran P, Barnard A, Murphy NS, Kilner CA, Edwards TA, Wilson AJ.Synthesis of biphenyl proteomimetics as estrogen receptor-α coactivator binding inhibitors. 7 Williams AB, Weiser PT, Hanson RN, Gunther JR, Katzenellenbogen JA.Solid-phase methodology for synthesis of O-alkylated aromatic oligoamide inhibitors of α-helix-mediated protein-protein interactions. 6 Murphy NS, Prabhakaran P, Azzarito V, Plante JP, Hardie MJ et al.Chem.5,161–173 ( 2013).▪▪ Excellent review covering the different molecular approaches to inhibiting α-helix mediated protein–protein interactions using the α-helical secondary structure as a design principle. Inhibition of α-helix-mediated protein–protein interactions using designed molecules. 5 Azzarito V, Long K, Murphy NS, Wilson AJ.Oligobenzamide proteomimetic inhibitors of the p53-hDM2 protein–protein interaction. 4 Plante JP, Burnley T, Malkova B et al.Terphenyl-based helical mimetics that disrupt the p53/HDM2 interaction. Assessment of helical interfaces in protein–protein interactions. Chem.1,65–93 ( 2009).▪ Critical and in-depth review of the different strategies for targeting protein–protein interactions using small molecules. Targeting protein–protein interactions for therapeutic intervention: a challenge for the future. Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest References A current update on the therapeutic status of the different approaches is provided, as well as indications as to their long-term potential. This article will highlight the emerging importance of helix length control in the context of helix-mediated PPIs through a discussion of the contemporary chemical approaches to identifying novel helix mimetic inhibitors, including all-hydrocarbon stapling, hydrogen bond surrogates and optimized peptides emerging from in vitro screening methods. ![]() By extension, precise control over the length of α-helix mimetics is necessary to ensure optimal disruption of α-helix-mediated PPIs. Nature’s ability to precisely control the length of α-helices, especially in the context of helix-mediated PPIs, is key to ensuring the optimal interaction of protein partners. We aim to show their utility to further understand FOXP3 transcriptional dynamics and explore their potential use in altering the immune landscape in combination with other immune-focused therapies.The most abundant protein secondary structure in nature – the α-helix – is frequently found at protein interfaces, making it an important lead structure for the design of small-molecule modulators of protein–protein interactions (PPIs). Our overall goal is to use these SAHs as investigatory drugs to demonstrate proof-of concept of the druggability of FOXP3. SAHs overcome three major protein-protein interaction (PPI) therapeutic hurdles, namely: cellular penetrance, target specificity, and secondary structure stability. We developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain, in an effort to impede FOXP3 transcriptional function. To overcome dosing limitations and off-target effects from antibody-based Treg deletional strategies, we investigated the ability to target FOXP3, the master regulator of Treg development, maintenance, and suppressive function using hydrocarbon stapled alpha-helical peptides (SAHs). Despite continuing advances in the development of novel cellular-, antibody- and chemotherapeutic-based strategies to increase anti-tumor immunity, Treg presence and activity within the tumor microenvironment remains a complicating factor to their clinical efficacy. Background Regulatory T cells (Tregs) have been a therapeutic target of interest since early pre-clinical work revealed that their depletion led to enhanced tumor control. |
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