The mobile apps have great security but are pretty bare-bones. What you won't get are the consumer-friendly features that made CrashPlan for Home so appealing, such as drive shipping and mobile-device backups. And you get unlimited backup space for unlimited devices as long as you're willing to pay $10 per month per computer. CrashPlan supports full-drive-image backups to local drives and backs up Linux/macOS-formatted networked drives. Its plan for small businesses retains that service's very fast upload and download speeds, and adds business-friendly features such as support for Red Hat and Ubuntu Linux and unlimited (if you want) retention of old versions of files.Īlmost everything is customizable, including frequency of backups, retention of deleted files, account security and where to download restored files. Top 3 best cloud backup solutionsĬrashPlan had the best cloud backup service for consumers until it quit the market in 2017. Each of the cloud backup services we’ve thoroughly tested and reviewed uses industry-standard encryption on their servers to protect your data but you can also use your own private key instead. Cloud backup services provide the same peace of mind for consumers. This is why many small businesses utilize “off-site” backups to minimize the threat of physical disasters. Even with one of the best external hard drives hooked up to your computer or as a stand-alone backup device on your home network, it could still be stolen or damaged in a flood or fire, leaving you with nothing. Each of these services constantly copies data back and forth from your computer to cloud servers elsewhere in the world which can easily be reached from anywhere with internet access.Ĭloud backup is a necessary thing to have as you can’t always rely on local backup drives to protect your data. The best cloud backup solutions can help protect you from dealing with data loss since you always have an extra copy of your most important files stored securely in the cloud.
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AT&T: The ACP benefit can be used toward any AT&T internet plan.Some ISPs that are participating in the ACP If it does, it should be able to assist you and walk you through whatever steps are needed to complete the process. The third option is to contact your ISP directly and ask if it participates in the ACP. You must print out an application, complete it and send your copies of the required documents to ACP Support Center, PO Box 9100, Wilkes-Barre, PA 18773. You can create a new account at ACP's online application portal. You have three different ways to apply for the Affordable Connectivity Program. You can refer to the ACP site's Show You Qualify page for a full list of acceptable documents. (Note: If you plan to mail the application, do not send your original documents, only copies.) Among the paperwork you'll need is proof of income, including either a tax return, pay stub or Social Security statement of benefits, or proof of program participation, including approval letters, benefit verification letters or statement of benefits. If you can't skip that step, prepare to pull together several documents. You must follow up with your ISP and ensure that the FCC approves it for this step. Similarly, if you are currently enrolled in your ISP's low-income program but are not participating in Lifeline, you may also be able to avoid using the ACP site. You're not required to use the Apply Now button on the ACP site. Remember how I talked about skipping a step when I mentioned the Lifeline program? If you're already a part of Lifeline, you can contact your ISP directly to enroll in the ACP. If any of the above is met, you may also be eligible for a one-time discount of up to $100 for a desktop computer, tablet or laptop. Meeting the eligibility requirements of a participating ISP's existing low-income program. Approval for free or reduced-price school lunch programs or school breakfast programs.Received a federal Pell Grant during the current award year.Participation in specific Tribal programs, including Bureau of Indian Affairs General Assistance, Tribal TANF and Food Distribution Program on Indian Reservations.Here's how that breaks down: ACP qualification: Total incomeįinally, other things that would make you eligible include: Regardless of participation in the above programs, your household will be eligible if your income is less than or equal to 200% of the federal poverty guidelines. You can also qualify for the ACP based on your income. If you or anyone in your household currently participates in particular government assistance plans - including Federal Public Housing Assistance, Medicaid, Supplemental Nutrition Assistance Program, Supplemental Security Income and Special Supplemental Nutrition Program for Women, Infants, and Children special supplemental nutrition program - you will also be eligible to opt into the ACP. Other programs can qualify you for the ACP if you're not taking advantage of Lifeline. It also helps you skip a step, which I'll describe shortly. Any funds from the ACP will be an additional discount to what you receive via Lifeline. Through the Lifeline program, you can receive a discount of just over $9 monthly on your internet service (and just over $34 per month for those on Tribal lands). Thus, at least one home member must meet the criteria for the household to participate.įirst, if you or anyone in the household participates in the federal Lifeline program, you'll also be eligible to participate in the ACP. It's intended to help low-income households afford broadband connections for school, work, health care, utilities and other services. Help Me Write created an email from scratch using information gleaned from the airline's emailed offer of a voucher.Not everyone is eligible for the Affordable Connectivity Program. In his demo at Google I/O, Pichai used Help Me Write to draft an email asking for a full refund from an airline for a canceled flight. You can then further edit the email manually or send it as is. A "refine" button can shorten the text, elaborate or make the email more formal. Whereas Smart Reply offers basic automated replies, and Smart Compose provides suggestions as you type, Help Me Write goes well beyond, creating a full email from a basic prompt. The new Help Me Write feature for generative AI email creation in Gmail expands on the "Smart Compose" feature that Google introduced in 2018, as well as the "Smart Reply" feature added in 2017. Android 14: The Biggest Features Announced at Google I/O 2023.Google Reveals Its AI-Powered Search Engine to Keep Up With Competition.Google Pixel Fold Hands-On: Samsung Has New Competition.Google I/O's Big Reveals: Pixel Fold, 7A, Android 14, AI and More. Please contact our friendly customer Customer Service representative for further details ( or 0401 031 455). We also provide a free personal delivery service for Melbourne Metro customers only. We dispatch orders from Monday to Friday and signature required upon receipt.Īustralia Wide and International. Beating at 28,800vhp, the power reserve is just 38 hours. Available on a metal bracelet or blue rubber strap, both options come with Oris’s patented and extendable security folding clasp and Quick Strap Change system.All of our packages are shipped by the following courier services: Australia Post, DHL, Fedex. The applied indices, the dot in the inverted triangle on the bezel and the hour and minute hands are treated with Super-LumiNova.Īn automatic Sellita SW220-1-base movement – Oris calibre743 – powers the watch. Like all Aquis divers, the unidirectional and notched rotating bezel has a (teal blue) ceramic insert, and robust crown guards flank the screw-down crown. Balancing the display, the date window is at 3 o’clock.Ī chunky diver with a 45.5mm diameter and a thickness of 15.9mm, the 500m water-resistant case of the Aquis Small Second Date surpasses that of standard Aquis Date models. Here the running seconds are displayed on a snailed sub-dial at 9 o’clock and highlighted with a luminous hand. Although there has been a blue gradient dial version of the Small Second Date, this 2023 model also flaunts a blue gradient dial but closer in tone to teal blue.Īs our readers know, the indication of the seconds is a mandatory feature on a professional ISO 6425 dive watch. The small seconds version of the Oris Aquis Date debuted in 2017 and, as its name indicates, combined a date window and a small seconds counter on the dial. Quick facts: 43.5mm diameter – stainless steel – green ceramic insert in bezel – screw-down crown with guards – 300m water-resistant – gradient green dial – indices and hands with SLN – date at 6 o’clock – proprietary Oris calibre 400 automatic – 5-day power reserve – anti-magnetic components – h,m,s, date and stop-seconds – stainless steel bracelet (ref. Produced by a network of suppliers with state-of-the-art industrial techniques, calibre 400 is a robust automatic anti-magnetic movement with a five-day power reserve and a 10-year warranty. Developed entirely in-house by COO Beat Fischli and his team, the mandates were for a high-performance and anti-magnetic movement to keep pace with consumers’ lifestyles for longer periods of time. Like the powerful 10-day, hand-wound calibre 110, conceived in-house by Oris in 2014 and used in its high-end models, the Oris Calibre 400 is a proprietary manufacture movement. The Aquis Date 43.5mm was the first model to be equipped with the brand’s proprietary calibre 400 in 2020. Revamped in 2017, the family also has more hardcore divers, like the 1,000m water-resistant AquisPro Date Calibre 400 and the Aquis Depth Gauge. Available in a host of case sizes, shared features of all Aquis Date models include a 300m water-resistant case, a screw-down crown, a unidirectional dive bezel (save the diamond-set versions) and, as the name indicates, a date window on the dial at 6 o’clock. Unlike Oris’s vintage-inspired Sixty Five collection, the Aquis has a far more contemporary vibe making it an attractive option for those in search of a resilient, all-terrain yet stylish watch. The Oris Aquis collection surfaced in 2011 as an evolution of the brand’s underwater timepieces that first surfaced in 1965. For 2023, Oris welcomes attractive new gradient dial colours for its Aquis Small Second Date and Aquis Date Calibre 400. The Aquis family of sporty, high-performance dive watches is one of the most popular, and its 43.5mm Aquis Date was the first to be powered by the brand’s powerful manufacture automatic movement in 2020. Oris has consolidated a solid reputation for its resilient, purpose-built dive, pilot and sports watches that do the job in style without breaking the bank. This has always been such a great reminder to me of how much I need Jesus, and how he freely offers to strengthen and help us when we abide in Him.Īnd of course, the melody and chords make the lyrics even more powerful. Child of weakness, watch and pray find in me thine all in all.’ “ It doesn’t get much better than the first verse, “I hear the Savior say ‘Thy strength indeed is small. I like a lot of hymns, but Jesus Paid it All has some of the best lyrics. Whether you’re planning an Easter service with Jesus Paid it All or you just want to play it with personal worship, these chord charts are just what you need. Get ready to worship with these chord charts in 5 different keys, perfect for different vocal ranges. We will sing and praise the One who paid our debt and raised our lives up from the dead.Jesus Paid it All chords are easy to play on a variety of instruments. We will turn from our sin, we will trust him, and we will sing. We will relinquish the shame we’ve harbored for so long and we will abandon our self-absorbed efforts to make ourselves worthy. We will stop condemning ourselves for past sins. Yes, we will trust him, and we will forsake the foolish pursuits that used to consume our lives. We look forward to that day when we will stand before his throne, repeating the wonder that he died to save our souls. The stain of sin that marred your life has now been washed white as snow. It was a slaughter you deserved - a punishment reserved for you - that he took upon himself, in your place, so that you get peace. He was crushed, viciously slaughtered, for your iniquities. Your transgressions - all your sins - were the ones that pierced him and ones for which he paid. Can you feel the weight of these words? The wonder? Which means, to bring it home a little more, Isaiah 53 is for you. Instead, we are beckoned to draw near, to hear the Savior say to us, through the description of his ancient pains, Child of weakness, watch and pray. We should beware of distancing ourselves from these words, of assuming that we are so removed from their relevance in our twenty-first-century world. It’s that he has borne our griefs and carried our sorrows, that he was pierced for our transgressions, crushed for our iniquities upon him was the chastisement that brought us peace, and by his wounds we are healed. He was absolutely afflicted.īut it’s not just that Jesus bore grief, or that he was pierced or crushed or wounded. A lot of terrible things - a true curse - is targeting the Messiah. To be sure, there is a lot happening here. He was pierced for transgressions, even crushed. Isaiah tells us he has borne grief and carried sorrow.
Meanwhile, you can use bright yellows such as lemon zest, bumblebee and Tuscany yellow in small quantities to add a bright fun accent, or use subtler shades such as daffodil, cream and French vanilla if you want to apply it in larger areas. Zen interiors – these types of designs are often boxy, angular and very symmetrical, using high contrast combination of finishes such as white and dark wengue. Because most of the warm tones would already be found on its wood elements, it is best to use cooler-toned grays such as arctic ice, slate gray, silver and other similar colors, to add more contrast to the colors. You can use gold on small items such as picture frames, tassels, sculptures, pillow embroider and other subtle accessories. Gold in the form of metals, trims, satin and silk fabrics would also produce great results for contemporary spaces. Mustard is a great shade of yellow you can use for such purposes, as it has a more subdued feel while retaining a somehow playful vibe. The yellows would need to be more subdued and less loud if you want a more elegant feel. You can play around with different materials and textures to use it on, to give your design more depth and tactile aesthetic. For grays, dove gray and charcoal gray would work well with the style. For these types of spaces, it is best to avoid loud colors and keep it toned down. There are many popular design styles nowadays, and although they tend to be a more playful and experimental with their approach, certain shades of yellow and gray match better with certain styles and work hand-in-hand with the other colors and finishes to achieve a specific ambiance.Ĭontemporary / Transitional Styles – these styles are usually used to describe contemporary spaces which uses a few classic furniture pieces or draws inspiration from traditional styles and recreates them to give a more updated look. You must always keep in mind the style and look you are trying to achieve before deciding among the many different shades of gray and yellow. Gray and Yellow have many different shades, and depending on your combination, it produces different looks and ambiance. The calm & cool gray, combined with the loud & bright yellow, tend to neutralize the negative qualities of each color, and produce results which has the best of both worlds - the calm & elegant quality of gray, and the fun & refreshing vibe of yellow. Yellow, on the other hand, has a bright, positive and youthful energy to it, but tends to be a bit overwhelming when used in large surfaces or large quantities. However, gray can be a little sombre or boring, especially when you don’t use an accent color. It is well-lauded for its flexibility, making it a safe color of choice, no matter what style you are trying to achieve. This color combination has even gained further popularity in the past few years as recent design styles and trends has a penchant for using grays. Gray is one of the most popular and well-used neutral color. This gallery offers stylish gray & yellow bedroom designs in a variety of styles and decor. SpeedTour includes SVRA and Trans Am and SCCA Pro's FRA and Formula 4 open-wheel series and IGT contemporary sports car racing. The agreement enables WeatherTech to showcase its brand in the context of SpeedTour weekends. but also worldwide as products are exported overseas. Car interior products are sold under the WeatherTech brand and provided to many automobile manufacturers as an Original Equipment Supplier, enabling WeatherTech to garner not just appeal in the U.S. WeatherTech's corporate headquarters is in Bolingbrook, Ill., where all the manufacturing happens and is home to R&D, engineering, product design, tool manufacture, marketing, order fulfillment, and shipping. Not to mention the communities, and supporting the small businesses of where those workers live every day.” Every manufacturing job creates up to five other jobs, including the delivery of products, packaging, designing, engineering and so on. When something is made in America, it means more than just a good-paying job for someone. "As a business owner, I want to create high-quality products designed, engineered, and manufactured right here in America, built by American workers. “SVRA and Trans Am are great American racing organizations and have been throughout their histories," said David MacNeil, Founder, and CEO of WeatherTech. “I appreciate the pride they take in being an American manufacturer. "We take a special pleasure in relationships with partners who come to us with a full understanding of the power of motorsports as a marketing and branding platform," said Tony Parella, Owner and CEO of both Trans Am and SVRA. For decades, WeatherTech has been committed to manufacturing in the United States and is well-known in motorsports circles. Southlake, TX (April 14, 2021) – SVRA and The Trans Am Series Presented by Pirelli announced today an agreement that makes WeatherTech the “Official Interior Vehicle Protection Company” for both premier road racing organizations. It will be interesting to see the dynamic of father versus son next week.WEATHERTECH JOINS TRANS AM AND SVRA FAMILY OF PARTNERS April 14, 2021Īll-American Manufacturer Expands Motorsport Footprint “He and Gunnar ran some laps to get comfortable with the car and we came away from the test encouraged. “When he mentioned he wanted to run at Road America in another car it was a natural for us to get a second car ready. “David is a competitor in business and on the track,” team owner Alex Job said. The entry expands the Alex Job Racing operation to three cars for the race. I’m pretty sure that we are going to have a very large support crew for the weekend.” Jeannette added: “It’s WeatherTech’s home track and David has thousands of laps around there. I will see if I can keep things close with my son Cooper.” Gunnar is a great teammate and coach and I am looking forward to next weekend. “Alex Job and the team have reams of data on the track, so my learning curve with the Porsche was pretty short. “Gunnar and I were able to get a few laps in the car a few weeks ago and I felt comfortable, turned some pretty fast laps and feel good about our effort. “I had so much fun running with my son and the team at Daytona that I thought the Road America race a perfect track to get out there and run again. “I have driven a lot of different cars there and I am looking forward to racing the new Porsche on the IMSA weekend. “Road America is a track that I have a lot of miles around,” David MacNeil said. The duo had an opportunity to test the Alex Job Racing-prepared car at Road America during the WeatherTech International Challenge Weekend three weeks ago. MacNeil, founder and CEO of WeatherTech, and Jeannette were a part of the driver line-up for the Rolex 24 Hour At Daytona in January with Cooper MacNeil, Leh Keen and Shane van Gisbergen.Īfter leading much of the latter part of the race, the team finished 13th. WeatherTech Racing will add a second car for drivers David MacNeil and Gunnar Jeannette for next weekend’s IMSA WeatherTech SportsCar Championship Continental Tire Road Race Showcase to run at Road America August 5-7. However, if you play beyond a certain point, the game will warn you that further saves may not be suitable for the finals. Sledujte Wands and Witches Witchisode 2 A Harry Potter I Would Bang v Czech na, nejlep hardcore pornostrnce. Some "tough" characters now have reduced skills and abilities requirements during their quests.Īlso, according to your numerous requests, we have removed the restrictions on playing time in this version. In addition, we have made some changes to the game balance. Both are achieved through new events with old characters. And also several new events with special art for them.Īlso, we introduced the way to influence relationships between NPCs, as well as the way to know about these relationships. New scene with Ron for the male character. New scenes with Harry for the female character. New scenes with Luna (for both male and female characters). The new content includes new scenes with Hermione (for the male and female characters, but more for the females). The eight previously started quests were expanded and completed. 2.00 Magical Wands for witches and wizards (80) 11.07 Small Amethyst Wand, Handmade Wand, Baby Witch Wand, Amethyst Wand, Witch Wand, Wiccan Wand, Witch Gift, Fantasy Wand (1k) 16.06 Handcrafted Magic Wand with Crystal, Various Quartz Witch Wand, Fairy Wand, Cosplay Costume Props, Gift for Witcher Fan (7) 1.17 1. English localization has been greatly improved. Android version should work normally now. Instead, we focused on completing previously started quests. Ten of Wands - Tarot of the Witch's Garden A card of burdens and responsabilities, but with the light of strength leading the way. Wands and Witches Devlog Like 9 1 year ago by GreatChikenStudio Version updated to 0.95a. However, you probably want to know what's new in this update?Īs we already wrote, there are no new quests in this version. We are always happy to receive your feedback, and we are glad that you are interested in playing our game. The final size of the game has grown several times compared to the originally planned one. During the development of the game, we even changed its concept several times. We have always listened to the wishes of our Patrons and players. The next public version will contain the story endings. As an excuse, we can say that the game is really close to completion. It took a very long time, and again we apologize to those players who are waiting for our game to continue every time. The great part is that it can automatically detect multiple languages, including English, Chinese, French, Spanish, Japanese, Korean, Arabic, Italian, German, Portuguese, Vietnamese, Malay, Russian, Dutch, Thai, Swedish, Finnish, Danish, Norwegian, Hungarian, and more. Moreover, the top-notch image processing engine gets rid of any distortions and shadows for a flawless look. On top of it all, it is a completely free-to-use app, no hidden subscriptions you can, however, support the app with donations.Ĭheck out this super simple and feature-rich document scanner app that quickly scans documents without watermarks and edits them the way you need.įP Scanner effortlessly recognizes and extracts text to digitize, whether it’s business documents, shopping receipts, photos, ID cards, or something else. On top of it all, it is a completely free-to-use app, no hidden subscriptions you can, however, support the app with QuickScan is privacy-focused and does not collect any data. It even allows you to edit the PDF’s dimension to a print-friendly size. QuickScan is a well-designed app and caters to almost every need of a document scanner. The app also supports super flexible exports so that you can save the file to Files, iCloud, Google Drive, Dropbox, or send it as a message, mail, or AirDrop to neighboring devices. It even shows you an estimated output file size, and you can adjust the quality settings as per your need. You can then perform the search, select text, copy/paste inside the PDF. The created PDF has the text integrated, such that it becomes searchable. What’s great is that you can save just this recognized text or the complete scanned document as PDF. i.e., use real-time OCR and recognize the text in the PDF or images.Īnd alongside English, the QuickScan also supports other languages like German, French, Italian, Chinese, Spanish, etc. Furthermore, you can employ a feature like Live Text. You can scan documents with an iPhone camera or import existing PDFs or images into the app. QuickScan is an all-in-one app for scanning documents. Price: Free (In-app purchases start at $1.99)ĭownload 4. Not just that, it also comes with a handy PDF converter and allows you to send a scanned doc as fax as well.Īs for pricing, it’s available for 3 days free to let you get started without paying anything. In terms of OCR, I have found Scanner Unlimited quite efficient as it excels in extracting any photo text. And with the quick sharing feature, you can share your scanned docs with anyone via several mediums including WhatsApp, Gmail, Facebook Messenger, Slack, and more. Moreover, you can easily sign your documents and even be able to add multiple signatures to the same document. The app supports any kind of document to keep the incompatibility at bay. It meets all your scanner needs in one application. It not only scans documents but also barcodes, QR codes, and business cards. What puts Scanner Unlimited: Scan & Sign is the ability to make document scanning pretty straightforward while ensuring there are no compromises with the quality. And that too without cutting down on the essential features. While there is no shortage of document scanners in the iOS App Store, there are very few apps that can offer a simplified document scanning experience. Price: Free (In-app purchases start at $2.99) Due to its top-notch PDF conversion features for text and photographs, Scanner App – PDF Editor tops our list. Any iPhone photo may be converted to PDF, as well as screenshots. Last but not least, the Scanner App has the easiest-to-use PDF editor, enabling you to edit your document before sharing it. Moreover, the scans can be saved as PDF or JPG files also. So, use the camera on your iPhone to scan anything with a signature on it, including books, paper notes, invoices, and contracts. One of this app’s most salient features is the ability to scan your signature. This, combined with other features, makes this program one of the best document scanners available. Additionally, it allows you to merge multiple PDFs in quick succession. This PDF Editor app can boost your productivity at work and everyday life by converting your device into a quick, portable scanner with automatic text recognition (OCR). Students and people who work in small offices need this simple but useful scanner app to quickly scan, store, and share any document in PDF, JPG, or Word format. It is suitable for those who require a quick alteration of their papers into PDFs. We bring you the Scanner App – PDF Editor, one of the most effective portable document scanners for iPhone users. How To Tell If A Rental Might Be A SCAM.What are some good rental agencies in South Maui?.What are some good rental agencies in West Maui?.What are the different ways to Book a Maui vacation?.Where do I find some good, inexpensive restaurants on Maui?.What are some of the best restaurants on Maui?.Underwater Photography Tips and Equipment Ideas.Whale and Snorkel Trip Reports with Pictures.Can I Still Snorkel Ahihi-Kinau Area Reserve?.NEW Ahihi-Kina'u Map and Snorkel Info, October 2018.What are rules and info on Haleakala Sunrise Reservations 2020.Where do I find information about ocean safety?. Information about VOG (Volcanic Fog) Events on Maui.What are some good things to know about traveling to Maui?.Your also less likely to be screwed with by car rental companies or hotels because of Costco being their number one wholesaler. You also have the power of Costco behind you just like you do at their stores. Obviously some are better than others simply because everyone has different tastes. I've never had a bad unit in all my trips with them. As for condo resorts, yes, you don't get to pick your individual unit but at the same time any unit they sell has to meet certain Costco requirements before it can be sold. At least from the Bay Area, I never find Costco having better airfare than what I can get on my own.Īs for the original question, yes, Costco is a great way to go plus during non-Covid times, the packages include a rental car which makes the package that much better of a deal. You can easily book a Costco trip without airfare, simply unblock the "Flying From" box during the search. Costco, like anyone else is required to follow the airline's rules on canceling. The Costco non-refundable issue is generally the airfare portion of your trip, not the land or rental car portion. It also describes the correspondence between invariant and non-invariant ensembles and concludes by introducing a simple field theory in 1+1 dimensions which reproduces level statistics of both of the two random matrix models and the classical Wigner-Dyson spectral statistics in the framework of the unified formalism of Luttinger liquid. It then considers a non-trivial unfolding and how it changes the form of the spectral correlations, along with the appearance of a ghost correlation dip in RMT and Hawking radiation. It first provides an overview of non-invariant Gaussian random matrix theory (RMT) with multifractal eigenvectors and invariant random matrix theory (RMT) with log-square confinement before discussing self-unfolding and not self-unfolding in invariant RMT. This article examines two random matrix ensembles that are useful for describing critical spectral statistics in systems with multifractal eigenfunction statistics: the Gaussian non-invariant ensemble and the invariant random matrix ensemble. Leur stabilité et leur géométrie sont comparées à celles des motifs voisins dans les peptides Des modes de repliements particuliers aux n-hydroxypeptides ont été reconnus et caractérisés. Les résultats sont exposés dans le troisième chapitre, et le quatrième chapitre est une discussion de ces résultats en relation avec les observations conduites sur des composés pseudopeptidiques voisins. Le second chapitre décrit la synthèse des n-hydroxypeptides examinés et les méthodes d'étude structurale utilisées. Le premier chapitre est un rappel des connaissances nécessaires à la compréhension de la suite. Pour cela, les homologues n-hydroxyles de dipeptides protégés à leurs extrémités par une fonction amide ont été préparés et étudiés en solution par RMN et spectroscopie ir, à l'état solide par diffraction des rayons X, et soumis à une analyse théorique par dynamique moléculaire. Le but de cette thèse est de reconnaitre l'influence structurale de la n-hydroxylation d'une séquence peptidique. Nous avons pu isoler plusieurs motifs se fixant dans le site actif de l'enzyme constituant des pistes intéressantes dans la conception d'inhibiteurs de l'activité enzymatique. En parallèle, nous avons réalisé un criblage de ligands de cette enzyme par RMN à flux continu robotisé. Ces structures nous ont permis d'apporter une explication possible sur l'adaptation de cette enzyme aux différents antibiotiques. Nous avons également modélisé la structure du deuxième variant. Nous avons résolu la structure de l'enzyme sauvage et du premier variant par cristallographie aux rayons X. Deux variants de cette enzyme se sont répandus dans les souches cliniques résistantes : le premier confère une résistance élargie à tous les aminoglycosides, le second confère une résistance élargie à une autre classe d'antibiotiques, les fluoroquinolones. Nous avons étudié une de ces enzymes de résistance, l'AAC(6')-Ib conférant la résistance aux aminoglycosides, antibiotiques à large spectre utilisés principalement en milieu hospitalier pour lutter contre des infections sévères. La résistance aux antibiotiques apparaît aujourd'hui comme un problème majeur de santé publique, en particulier à cause de l'apparition de souches de bactéries multirésistantes par production d'enzymes de modification de ces antibiotiques. |
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