Binding to AT 1R results in vasoconstriction and aldosterone secretion, leading to salt and water retention and ultimately increasing arterial blood pressure. Ang II, the main vasoactive peptide of angiotensin metabolites in the systemic RAS, elicits its downstream physiologic and pathophysiological effects predominantly via the angiotensin II type 1 receptor (AT 1R), which is ubiquitously expressed in the cardiovascular system. Ang I is then converted to the potent vasoconstrictor, angiotensin II (Ang II Ang 1-8), by the zinc metalloprotease, ACE, which is highly expressed by endothelial and epithelial cells in the vasculature, kidneys, and lungs ( Skeggs et al., 1956) and shed into the circulation by unknown proteases ( Ehlers et al., 1996 Woodman et al., 2000). Renin, an aspartyl protease, is responsible for hydrolyzing the serum globulin, angiotensinogen, releasing the peptide angiotensin I (Ang I Ang 1-10) ( Page and Helmer, 1940). A reduction in renal blood flow or blood sodium levels leads to the release of renin into the circulation, mostly from renal juxtaglomerular cells in the walls of the afferent arterioles of the kidney ( Davis and Freeman, 1976). The systemic renin-angiotensin system (RAS) plays a central role in regulating extracellular fluid volume and arterial vasoconstriction ( Fig. Peptidases and receptors within these systems are important drug targets for the treatment of various cardiovascular diseases, including hypertension, heart failure, and coronary artery syndrome. Hence, there is a growing need for novel antihypertensive and cardiovascular drugs that are effective, affordable, and safe with no adverse side effects and that reduce the need for the administration of multiple drugs.īlood pressure and cardiovascular function are regulated by multiple interacting systems, including in large part the enzyme-catalyzed formation and degradation of vasoactive peptides and hormones in overlapping regulatory systems ( Fig. Suboptimal control of hypertension is associated with target organ damage leading to heart failure, ischemic heart disease, stroke, kidney dysfunction, retinopathy, and vascular dementia, all of which are major causes of disability and premature death. In addition, patients receiving treatment may suffer from significant side effects such as angiotensin-converting enzyme (ACE) inhibitor–induced persistent cough and, more rarely, life-threatening angioedema ( Simon et al., 1992 Agah et al., 1997 Bas, 2017 Stone and Brown, 2017). This contributes to the growing global burden of cardiovascular disease ( Oparil et al., 2018). Hypertension is the main risk factor for cardiovascular disease despite the availability of more than 100 commercial drugs and drug combinations for treating hypertension, a substantial proportion of the hypertensive population has uncontrolled or suboptimally controlled hypertension ( Oparil and Schmieder, 2015). Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.Ĭardiovascular disease is responsible for more than 30% of all deaths worldwide, most of which occur in developing countries ( Benjamin et al., 2017). These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT 1R axis. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure–regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT 1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate.
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I love that BenQ threw in an Android TV adapter instead of opting for a built-in OS that may potentially get sluggish with age plus the adapter can be replaced with newer versions in future models. It’s a teeny hassle, but you only need to do it once, and it only takes a few seconds. You will need to undo two screws and remove the top of the projector before you can plug in the pocket-knife-sized adapter, though, as there’s a dedicated slot for it in there. The projector ships with an Android TV wireless adapter. Ports are all on the back for easy access, while controls for settings and navigation-as well as the manual zoom and focus dials- are on the side. It’s shaped like a cube and has a black front with a white case on the other sides, with stylish vents wrapping around the sides of the projector, adding to its simple yet playful style. It measures 10.7 x 7.8 x 10.2 inches (excluding the adjustable feet) and weighs 14.1 pounds, so you’ll need to ensure you have either enough space on the surface you want to set it on or enough clearance for your screen if you plan on mounting it to your ceiling (which I’ll talk about more later on). But make no mistake-the X3000i is by no means small. The x3000i has a stylish modern design, and it looks incredibly similar to the company’s previous X1300i model for those familiar with that. Connectivity: Bluetooth 4.2, 802.11 a/b/g/n/ac (2.4G/5G), Google Chromecast (via included Android adapter).Inputs/Outputs: 2x HDMI 2.0b, USB Type A-1, 3.5mm Mini Jack, RS-232 in (DB-9 pin), DC 12V Trigger (3.5mm Jack), Optical Audio out.Sound: 2x 5W speakers, with support for eARC, Dolby Atmos, virtual 3D surround.Keystone Adjustment: 2D, Auto +/- 30 degrees Vertical/Horizontal. Lamp Life: 20,000 hours Normal/SmartEco mode, 30,000 Eco.Brightness: 3,000 ANSI lumens (about 900 nits).Color Coverage: 100% DCI-P3 Cinematic Color.Native Resolution: 4K UHD (3840 x 2160) with HDR-PRO/HDR10 support.It’s the one to beat anywhere near this price point. The projector is fun to use, and it can easily handle game night just as well as movie night. Plus, with an included Android TV wireless adapter, built-in speakers, and multiple mounting options, the X3000i effortlessly pulls double duty as a home theater projector. The company advertises the X3000i as an immersive open-world gaming projector, saying it “overwhelms you with the most cinematic visual and auditory impact.” And with three dedicated gaming modes, virtual 3D surround sound, support for eARC and Dolby Atmos, low latency (16ms 4K at 60Hz), a bright 4LED light source, and 100% DCI-P3 color gamut coverage, that statement is hard to argue with. Blacks are solid but could be a little richerīenQ first announced the X3000i at CES 2022, which was exciting, and after going hands-on with it for a few weeks, I can say it’s truly impressive.110% vertical offset not ideal for ceiling mounting. Outstanding color accuracy and image quality. Who could ask for more? Here’s What We Like With bright color-accurate images, low latency, and multiple gaming modes. We tend to only think about projectors when it comes to TV alternatives, but not often enough for gaming when, actually, projectors like the BenQ X3000i are perfectly tailored for the task. So to many this means Black Deert will forever languish in mediocrity, perhaps as the 'most wasted potential' MMO to date. To be fair to Pearl Abyss though, this point has been raised so many times over the last years, and they have made it clear that they do not want such a social game. The effect it would have on the community as a whole, and as a consequence their profits, would be outstanding. I sincerely hope they come to realise the immense power of creating many and varied meaningful positive social interactions in-game. After all, humans are fundamentally social creatures. I've been disheartened that Pearl Abyss doesn't seem to understand this. The power of social bonding (and all the directly, and indirectly, related positives that come with it) simply cannot be overstated. From this perspective is grinding a spot one of the few thing that can have meaningful social interactions. Even if I have many other activities that are equivalent to the grinding in terms of profit, then it stays soulless as long as there is no meaningful social interactions - at least for me. The skins of the AI may change (but don't worry, whatever skin it wears it will still stand still, waiting for you to slaughter it), the scenery may change, a seemingly different manner of applying damages with different visual effects may be used (aka "class") but you will do the exact same thing from lvl 1 to late game with almost no variation. Whatever you do, be it PvE, Lifeskills or even PVP (because in proportion you will need a huge amount of time spent in PvE or Lofeskills to get gear), you will repeat the same basic actions for thousands of hour. The game feels souless because what it offers at its core despite its apparent large panel of activities, places and such is actually very thin : grinding. “Caramel connoisseurs, this is your beverage. And speaking of sexual, just read the description of the Caramel Ribbon Crunch: The two flavors I speak of are Mocha Cookie Crumble (not photographed in this article) and Caramel Ribbon Crunch. But it is May, and that means frappucino happy hour between three and five pm, early enough that I’m not at work yet but late enough that I still get that pissy “are you going to be hungry for dinner” look from someone who constantly forgets that I have the appetite of a butcher’s disposal unit and about as discriminating of a diet.Īs with any year, Starbucks has crazy two crazy new flavors, and as with any year they are limited with just enough time that you will fall in love with them before they get yanked off the menu in what is probably a combination of reminding you who wears the daddy pants in this relationship, and also because they find the sighs of disappointment strangely gratifying in a sexual way. When ready to make, blend the coffee cubes with protein powder, some milk, and a little of the homemade caramel.Happy Hour is just about the only time you can get me into a Starbucks, owing to the fact that I’m generally too cheap to spend an entire combo meal’s worth on a single drink when the gods of McDonald’s have graced this earth with something I like to call the value menu sweet tea.Make the caramel sauce and store until ready to use.Brew the coffee and freeze in an ice cube tray.You can also use it on pancakes, in dessert recipes, etc! How to make the caramel ribbon crunch frappuccino: You can leave it in an air-tight mason jar in the fridge and warm it up a few seconds before using. This recipe will make enough caramel to have a few fraps, which is great because then you don’t have to worry about making it every time you want one! I love prepping a batch for the week. Monk fruit or coconut sugar: Either works! Coconut sugar will create a normal colored caramel, whereas the monk fruit caramel will be lighter in color. Macro Mike makes a really good caramelized white chocolate protein that is INSANE in this! You can use code “amb-dani” for a discount!Ĭoconut milk: Use full-fat canned coconut milk or the consistency of the caramel won’t be as authentic as normal caramel. Protein Powder: Use a really yummy tasting protein powder to add to the flavor of the recipe even more! I love using a vanilla or salted caramel protein powder. I love Bulletproof coffee because it not only tastes amazing but is also tested for toxins/pesticides, which is so important as coffee is heavily sprayed! You can use code “dani20” for 20% off on any purchase on their website. Again, equally as delish, just not the exact same flavor – if that makes sense! What you’ll need to make a caramel ribbon crunch frappuccinoĬoffee: You can use your favorite ground coffee. The second, is a nut butter based caramel that you can quickly whisk together in a bowl. The first is made on the stove top and takes about 20 minutes to make, BUT it’s so worth it! It tastes most like the real deal as it is actual caramel. I tested two different caramel recipes for this recipe. And I’m not kidding when I say it seriously tastes like the real deal! This Starbucks copycat Caramel Ribbon Crunch Frappuccino is SO close to the real deal, but made vegan, high protein, and refined sugar-free! I am all for enjoying the real deal, but when you want one on a regular basis, it’s great to have an option without all of the added sugar and crazy ingredients. It was a comedy-action short film about a poker game that turns Arthur Ford is the main villain protagonist of the 2019 video game Boneworks. Check the Configuration below for details. Fandom Cortex RPG Muthead Futhead Fanatical Follow Us. In Boneworks, players take the role of Arthur Ford, a rogue Strong is one of the six main Avatars of BONELAB. MythOS City is built upon the advanced framework engine. Boneworks teaches the adept craftsman to Please link to the wiki here: Use discovered physics weapons, instruments, and objects to struggle throughout harmful playscapes and mysterious structure. Use any weapon, tool, or found objects to battle through dangerous playscapes, mysterious architecture, and. You must have an account to contribute to this project. A wise man once told me, "He who dwell on the past have eyeballs glued to his bum As natural a medium as wood or clay, bone has been used by mankind for millennia for instruments of craft, are and war. At first this mod started as a project to restore the old Clone Wars mod, but since the mod is currently not. BONEWORKS is an Experimental Physics VR Adventure. Boneworks (stylized as BONEWORKS) is a 2019 first person shooter VR game developed and published by Stress Level Zero. Boneworks starts in an introductory tour designed as a history of VR interaction. Step 4: Opening STEAM VR And Playing Boneworks VR (ONLY For STEAM VR Users) I f you love Boneworks then you'll love these gmes for. He originates from the Street Puncher II simulation. Just lost my only armadyl chestplate due to a bug in ToB, kept this instead (Reddit). “With the issue that affected Deadman we set a precedent of attempting to restore accounts to the best of our ability if any sort of loss was caused by an action within our control.” * Jagex has recommended that players who discover glitches in RuneScape should report it to Jagex immediately either in-game or via the "Submit a Bug Report" option on the RuneScape website. Minor graphical glitches generally go unpunished while major abuse may result in a permanent ban. The punishment for guilty parties varies depending on the particular glitch and the degree to which it was abused. Rules on bug abuseĪbuse of glitches is a direct breach of the "bug abuse" rule as stated under Rule 4 of the rules of RuneScape. On 7 June 2018, Jagex stated that they previously set a precedent with the handling of the World 347 Glitch and aimed to restore players' accounts when losing items or experience to glitches if Jagex were completely to blame. Although they understood what the long-term effects of the economy in RuneScape would be, Jagex refused to rollback the game.Prior to 24 April 2018, Jagex upheld a strict policy of no items returned that were lost from glitches however, after the World 347 Glitch, they "restored" items lost from the glitch with the form of bonds (as well as restoring experience). Only the first player to reveal how the glitch worked was rewarded. This allowed for Jagex to disable the glitch. Eventually, Jagex offered a lifetime RuneScape membership for whoever could tell them how the bug worked, with multiple players coming forward and explaining it to them. Several days of item duplication made a massive change to the RuneScape economy as players started to duplicate other, less valuable items such as ores. Because of the glitch, the purple partyhat remains the cheapest of them all, despite originally being the rarest and most expensive partyhat.Īlthough Jagex soon found out about the glitch, they could not immediately do anything to fix it, as they themselves did not understand the process behind the "duplication". Many people do wonder what the price and abundance of the rare items would be like if the glitch was never found, as the glitch brought in hundreds of illegitimately acquired rare items. This led to a crash in the price of many rare items and the effect this has had is still visible to today in certain items. Within days, hundreds of players knew how to execute the glitch. These players then created several items, the most expensive at the time: specifically partyhats. In his excitement, the experimenter revealed to a few people how to execute the glitch. The quantity of the item is shown as 0 on the trade screen of the player creating the item but it would show up as a quantity of 1 on the trade screen of the player receiving the item. For example, the number for the Rune 2-handed sword was 81, so that value would be entered into AutoRune and the player who was trading with the one using AutoRune would be able to receive that item. The glitch was performed by trading with a player, and then using AutoRune to enter the numerical value that corresponded with a certain non-stackable item to have an item pop up and be traded to the other person. Therefore, the glitch did essentially duplicate the item, creating a new one although you didn't even need to own the item to "duplicate" it, so it's more appropriately called "item spawning". Although the player never managed to trade the scythe, he did discover how to create any non-stackable item. A player named " Sixfeetunder" had been experimenting with RuneScape by using a third-party program called AutoRune in an attempt to simply trade the scythe. The glitch was not originally an attempt to duplicate items. Following the glitch and continuing today, they are the least expensive.Ī large number of partyhats created using the glitch Before the glitch, Pink Partyhats (Now called Purple Partyhats) were the most expensive partyhat. Its effects continue to have an impact on the economy of RuneScape today. The Duplication glitch was the most famous glitch of RuneScape Classic, exploited on 7 November 2003. Have you read The Clan of the Cave Bear? What did you think? Do you agree with what I’ve said about it? Let me know in the comments. It made me wonder how modern society would treat Neanderthals if they were still alive today. The Clan have strict gender roles and are incredibly resistant to change. The Clan of the Cave Bear intelligently explored some serious issues that are still present in society today. I think the problem was his motivation he didn’t like Ayla because she was different and because people paid attention to her but not him. His evildoing felt cartoonish and grotesque. I thought that Broud was an unconvincing villain. It was unthinkable that a child, a girl child at that, could reason her way to that conclusion so easily. “I will be old enough to have a baby in this many years,” she gestured with assurance, positive of her deduction. She put down the first hand and held up only three fingers. Her next action caught him completely by surprise, it was a concept he had spent years mastering himself. “When I am this many?” she asked, holding out her eight fingers again. Ayla looked at her other hand, and immediately held up three fingers, folding down her thumb and forefinger. With only one hand, it had been especially difficult for him when he was learning. Creb made three more slash marks, and put three fingers over them. It had taken many repetitions before Goov had understood. How had the girl been able to grasp the idea so quickly? She hadn’t even asked what slash marks had to do with fingers, or what either had to do with years. I don’t know how much of it was true (especially the cultural stuff), but it was realistic.Ĭreb was thunderstruck. My favourite thing about this book is looking at the differences and similarities between humans and Neanderthals. I could really sympathise with Ayla’s struggles to fit in so much of the book felt familiar and relatable to modern experiences. It was a gripping story about people and their relationships, many of which appear unchanged for thousands of years. However, the son of the leader’s mate, Broud, hates her and does everything he can to make Ayla’s life miserable. The medicine woman, Iza, adopts her as her daughter as teaches her about herbs and healing. ‘The Clan,’ as they call themselves, come to love Ayla, despite her strange actions and ugly (they think) appearance. Ayla is a young cro-magnon human taken in by a group of Neanderthals after her people are killed in an earthquake. Set in prehistoric Europe, this is the first book in the Earth’s Children series. Please see our full disclosure for further information. This post may contain affiliate links, which means I may receive a commission, at no extra cost to you, if you make a purchase through a link. Retain the quality of the design into the variable data print stream, as if you were printing each document manually straight from the Adobe application XMPie harnesses Adobe’s technology as part of the composition process.Benefit from InDesign’s feature-rich interface to provide support for brand compliance and strict color management.Create your templates, with fewer steps in the design workflow – instead of supplying various designs of the same document. Create variable content or designs for different document versions.Drive variability into every aspect of your InDesign document.UCreate Print, aka uDirect, is our desktop VDP solution that harnesses the Adobe InDesign workflow: Please accept statistiques, marketing cookies to watch this video. Go beyond Data Merge: Let’s take a look at the different XMPie plug-ins and what you can do with them: By allowing you to turn your documents or artwork into templates, you can streamline the entire workflow. When the document or artwork is ready to be created, XMPie software merges the data, and logic with the design in real-time to generate highly relevant, personalized pieces with no pre-processing steps that would inevitably cause inconsistencies. This is one of XMPie’s sweet spots, as it natively supports the Adobe workflow via its variable data plug-ins. This way you can demonstrate that you understand each of your customers, who they are, what they want, and most importantly, that you value their business.īy using XMPie, you’ll have more control in the way that you connect to the data, more control over what you can creatively do with the data (without have to touch the actual data file) and you ultimately have more control over how you create the output. You can personalize or customize any element of a print-based InDesign layout or control changes within still or moving artwork to reach one or millions of recipients. With XMPie you can do everything that is possible with the in-built Adobe tools, and take it to a much higher level. But what if you need more options and flexibility, and you want to spend more time focusing on the actual design, instead of getting swamped by the data merge process? Impression orientée par les données et VDPĭata Merge is an effective tactic to make your communications stand out from the competition, and Adobe InDesign and Illustrator include a built-in feature to help with this task. Redesigned New Tab page - now you have quick access to the sites you visit most often, and you can also reopen closed tabs or your last browsing session, or start an InPrivate Browsing session. One-click access to your favorite sites - with Pinned Sites, you can get to your favorite sites directly from the Windows taskbar without having to open your browser first.Ī combined search and Address bar - one place to either navigate to a website or start a search. Streamlined and simplified design - gives you the basic controls you need and puts the focus on your websites. It's all-around fast - hardware-accelerated text, video, and graphics speed up performance and make websites perform like programs that are installed on your computer. * Windows Vista 32-bit * Windows Vista 64-bit * Windows 7 32-bit Internet Explorer 9 RC is also available for the following versions of Windows: With Internet Explorer 9, websites perform and feel more like the programs you use every day on your PC. Other features, like hardware acceleration, deliver an all-around faster browsing experience. Internet Explorer 9 has a streamlined design, fewer dialog boxes to click through, more intuitive navigation, and many new features that speed up your web browsing experience.įeatures like Pinned Sites let you pin your favorite website directly to the taskbar for one-click access. The improvements to Internet Explorer are as much about what you don't see as what you do see. 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